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==Overview==
==Overview==


DM1 is considered an immuno-mediated disease that develops as a result of gradual destruction of insulin-producing pancreatic beta cells that eventually results in their total
Diabetes mellitus (DM) is the metabolic homeostasis disorder regulated by insulin which causes abnormalities in the carbohydrate and lipid metabolism. Type 1 diabetes (also called juvenile-onset diabetes mellitus, DM1, T1DM, and insulin-dependent diabetes mellitus) is considered an immuno-mediated disease that results in a gradual destruction of insulin-producing pancreatic beta cells, and subsequently leads to their complete loss and total dependence on exogenous insulin. The etiology and natural history of T1DM are not yet completely known; however, the genetic and environmental factors are likely responsible for the underlying damage. The genetic effect probably contributes 70 to 75% in the susceptibility to T1DM; while, environmental factors possibly initiates or stimulates the process resulting in the destruction of the beta cells and the disease onset. The disease process begins months to years before the onset of clinical signs such as polyuria, polydipsia, weight loss, and diabetic ketoacidosis. Clinical presentation usually begins at any age; however, most patients will be diagnosed before the age of 30 years. Type 2 diabetes mellitus (T2DM) is characterized by two underlying defects. The earliest abnormality being an insulin resistance which initially compensated with an increase in insulin secretion. Thereafter, T2DM develops due to a defect in insulin secretion that prevents such secretion from matching the increased requirements imposed by an initial insulin-resistant state. Therefore, T1DM results from an absolute insulin deficiency, and relative deficiency in T2DM. Although, the percentage of DM cases in children and adolescents caused by T2DM has risen in the past 1 to 2 decades; however, T1DM remains the most common form of DM in children. Acute and chronic complications including renal failure, retinopathy, neuropathy, and cardiovascular disease are related to and likely caused by the hyperglycemic state. Recombinant insulin analogs, insulin pumps, and newer devices for home monitoring have drastically improved the ability to control glucose concentrations in patients with DM. However, the feedback control in the healthy state that allows minute-to-minute regulation of insulin secretion cannot be recapitulated with current diabetes therapies; thereby achieving the full metabolic normalization not yet possible and making some degree of hyperglycemia persists in virtually all patients with diabetes.
loss and complete dependence on exogenous insulin. Clinical presentation can occur at any age, but most patients will be diagnosed before the age of 30 years. The disease process begins months to years before the onset of clinical signs such as polyuria, polydipsia, weight loss, and diabetic ketoacidosis. However, the etiology and natural history of DM1 are not yet completely known, with genetic and environmental factors believed to participate. The genetic effect probably contributes 70 to 75% in the susceptibility to DM1, with environmental factors possibly initiating or stimulating the process that will lead to the destruction of the beta cells and the onset of the disease.
 
Diabetes mellitus is a disorder of the metabolic homeostasis controlled by insulin, resulting in abnormalities of carbohydrate and lipid metabolism. Type 1 diabetes (also called juvenile-onset diabetes mellitus and insulin-dependent diabetes mellitus) is caused by an absolute insulin deficiency, the result of a loss of the insulin-producing beta cells of the pancreas. Type 2 diabetes mellitus is characterized by two underlying defects. The earliest abnormality in an individual who develops type 2 diabetes mellitus is insulin resistance, which initially is compensated for with an increase in insulin secretion. Type 2 diabetes mellitus then develops due to a defect in insulin secretion that prevents such secretion from matching the increased requirements imposed by the insulin-resistant state. Thus, diabetes mellitus always is caused by insulin deficiency: in type 1 diabetes mellitus, the deficiency is absolute; in type 2 diabetes mellitus, the deficiency is relative. Although the percentage of cases of diabetes in children and adolescents caused by type 2 diabetes has risen in the past 1 to 2 decades, type 1 diabetes remains the most common form of diabetes mellitus in children. Recombinant insulin analogs, insulin pumps, and newer devices for home monitoring have drastically improved the ability to control glucose concentrations in patients who have diabetes. However, the feedback control in the healthy state that allows minute-to-minute regulation of insulin secretion cannot be recapitulated with current diabetes therapies, making full metabolic normalization not yet possible. Thus, some degree of hyperglycemia persists in virtually all patients who have diabetes. Long-term complications, including renal failure, retinopathy, neuropathy, and cardiovascular disease, are related to and likely caused by the hyperglycemia.


==Historical Perspective==
==Historical Perspective==
*400–500 A.D.: Indian physicians called it madhumeha (‘honey urine’) because it attracted ants. The ancient Indian physician, Sushruta, and the surgeon Charaka were able to identify the two types, later to be named Type I and Type II diabetes.
*'''400–500 A.D.:''' Indian physicians named it madhumeha (‘honey urine’) as ants are attracted by urine sweetness. The ancient Indian physician, Sushruta, and the surgeon Charaka discovered the two forms of DM which are later classified as Type I and Type 2 diabetes. <ref name="Tipton2008">{{cite journal|last1=Tipton|first1=Charles M.|title=Susruta of India, an unrecognized contributor to the history of exercise physiology|journal=Journal of Applied Physiology|volume=104|issue=6|year=2008|pages=1553–1556|issn=8750-7587|doi=10.1152/japplphysiol.00925.2007}}</ref> <ref name="pmid13381732">{{cite journal| author=FRANK LL| title=Diabetes mellitus in the texts of old Hindu medicine (Charaka, Susruta, Vagbhata). | journal=Am J Gastroenterol | year= 1957 | volume= 27 | issue= 1 | pages= 76-95 | pmid=13381732 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13381732  }} </ref>
*1889: Von Mering and Minkowski, when experimenting on dogs, found that removal of the pancreas led to diabetes.
*'''1889:''' Von Mering and Minkowski while experimenting on dogs found that removal of the pancreas led to diabetes. <ref name="MeringMinkowski1890">{{cite journal|last1=Mering|first1=J.|last2=Minkowski|first2=O.|title=Diabetes mellitus nach Pankreasexstirpation|journal=Archiv für Experimentelle Pathologie und Pharmakologie|volume=26|issue=5-6|year=1890|pages=371–387|issn=0028-1298|doi=10.1007/BF01831214}}</ref>
*1921: Banting, Best and Collip, working in Macleod’s laboratory, ligated the pancreatic duct, causing the destruction of the exocrine pancreas while leaving the islets intact. In their elegant animal experiments, by using canine insulin extracts to reverse induced diabetes, they conclusively established that the deficiency of insulin was the cause of diabetes.
*'''1921:''' Banting, Best and Collip while working in Macleod’s laboratory ligated the pancreatic duct which resulted in the destruction of the exocrine pancreas while leaving the islets intact. They used canine insulin extracts in their animal experiment to reverse induced diabetes; and thereby, conclusively established that the deficiency of insulin was the cause of diabetes. <ref name="pmid20314060">{{cite journal| author=Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA| title=Pancreatic Extracts in the Treatment of Diabetes Mellitus. | journal=Can Med Assoc J | year= 1922 | volume= 12 | issue= 3 | pages= 141-6 | pmid=20314060 | doi= | pmc=1524425 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20314060  }} </ref>
*1922: One of the miracles of the last century was the discovery of insulin by Canadian surgeon Banting and his assistant Best. Following experimentation on dogs, their life-saving infusion of a bovine extract of insulin (made by their biochemist colleague, Collip) to a 14-year-old boy, Leonard Thompson, in 1922 at the Toronto General Hospital, proved to be a sensation in the world of diabetic therapy.
*'''1922:''' The discovery of insulin by Canadian surgeon Banting and his assistant Best was made. Following experimentation on dogs, their life-saving infusion of a bovine extract of insulin developed by their biochemist colleague, Collip to a 14-year-old boy, Leonard Thompson, in 1922 at the Toronto General Hospital emerged as a sensation in the world of diabetic therapy. <ref name="pmid20314060">{{cite journal| author=Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA| title=Pancreatic Extracts in the Treatment of Diabetes Mellitus. | journal=Can Med Assoc J | year= 1922 | volume= 12 | issue= 3 | pages= 141-6 | pmid=20314060 | doi= | pmc=1524425 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20314060  }} </ref>
*1960-1969: Urine strips in the 1960s and the automated ‘doit-yourself’ measurement of blood glucose through glucometers, produced by Ames Diagnostics in 1969, brought glucose control from the emergency room to the patient’s living room.
*'''1960-1969:''' Urine strips in the 1960s and the automated ‘doit-yourself’ measurement of blood glucose through glucometers produced by Ames Diagnostics in 1969 brought glucose control from the emergency room to the patient’s living room. <ref name="pmid6723038">{{cite journal| author=Free AH, Free HM| title=Self testing, an emerging component of clinical chemistry. | journal=Clin Chem | year= 1984 | volume= 30 | issue= 6 | pages= 829-38 | pmid=6723038 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6723038  }} </ref>
*1980: The first human insulin was manufactured by Graham Bell.
*'''1980:''' Graham Bell manufactured the first human insulin. <ref name="BellPictet1980">{{cite journal|last1=Bell|first1=Graeme I.|last2=Pictet|first2=Raymond L.|last3=Rutter|first3=William J.|last4=Cordell|first4=Barbara|last5=Tischer|first5=Edmund|last6=Goodman|first6=Howard M.|title=Sequence of the human insulin gene|journal=Nature|volume=284|issue=5751|year=1980|pages=26–32|issn=0028-0836|doi=10.1038/284026a0}}</ref>
*1982: the first biosynthetic insulin (humulin) was developed.
*'''1982:''' The first biosynthetic insulin (humulin) was developed by Eli Lilly. <ref name="pmid12446492">{{cite journal| author=Rosenfeld L| title=Insulin: discovery and controversy. | journal=Clin Chem | year= 2002 | volume= 48 | issue= 12 | pages= 2270-88 | pmid=12446492 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12446492  }} </ref>
*1986: Eisenbarth proposed the pathophysiological model of DM1 as a gradual deficiency of insulin production resulting from the destruction of pancreatic beta cells due to an autoimmune process mediated by T cells in individuals genetically susceptible to the disease, who were born with a normal number of beta cells but undergo a process of cell destruction, most likely after exposure to precipitating environmental factors.
*'''1986:''' Eisenbarth proposed the pathophysiological model of T1DM as a gradual deficiency of insulin production resulting from the autoimmune T cells mediated destruction of pancreatic beta cells in individuals genetically susceptible to the disease who were born with a normal number of beta cells; but undergo a process of cell destruction after being exposed to the precipitating environmental factors. <ref name="FlierUnderhill1986">{{cite journal|last1=Flier|first1=Jeffrey S.|last2=Underhill|first2=Lisa H.|last3=Eisenbarth|first3=George S.|title=Type I Diabetes Mellitus|journal=New England Journal of Medicine|volume=314|issue=21|year=1986|pages=1360–1368|issn=0028-4793|doi=10.1056/NEJM198605223142106}}</ref>
*November 14: Banting’s colossal contribution has been globally recognised by the declaration, since 2007, of his birthday (14th November) as World Diabetes Day.
*'''November 14:''' Since 2007, Banting’s colossal contribution has been globally recognized by the declaration of his birthday on November 14 as the World Diabetes Day. <ref>https://worlddiabetesday.org/about/</ref>


==Classification==
==Classification==
*Type 1 Diabetes mellitus
Diabetes mellitus in children has been classified into the following forms:
*Type 2 Diabetes mellitus
*Type 1 Diabetes mellitus (T1DM)
*Monogenic diabetes: Neonatal diabetes, MODY-maturity onset diabetes of the young, mitochondrial diabetes, and lipoatrophic diabetes
*Type 2 Diabetes mellitus (T2DM)
*Diabetes secondary to other pancreatic diseases, endocrinopathies, infections and cytotoxic drugs
*Monogenic diabetes: Neonatal diabetes, MODY-maturity onset diabetes of the young, mitochondrial diabetes, and lipoatrophic diabetes<ref name="Manna2007">{{cite journal|last1=Manna|first1=Thais Della|title=Not every diabetic child has type 1 diabetes mellitus|journal=Jornal de Pediatria|volume=0|issue=0|year=2007|issn=0021-7557|doi=10.2223/JPED.1714}}</ref>
*Diabetes related to certain genetic syndromes
*Diabetes secondary to other pancreatic diseases, endocrinopathies, infections and cytotoxic drugs<ref name="Manna2007">{{cite journal|last1=Manna|first1=Thais Della|title=Not every diabetic child has type 1 diabetes mellitus|journal=Jornal de Pediatria|volume=0|issue=0|year=2007|issn=0021-7557|doi=10.2223/JPED.1714}}</ref>
*Diabetes related to certain genetic syndromes<ref name="Manna2007">{{cite journal|last1=Manna|first1=Thais Della|title=Not every diabetic child has type 1 diabetes mellitus|journal=Jornal de Pediatria|volume=0|issue=0|year=2007|issn=0021-7557|doi=10.2223/JPED.1714}}</ref>


{| class="wikitable"
{| class="wikitable"
|+Characteristics of prevalent forms of primary diabetes in children and adolescents
|+Table 1: Characteristics of prevalent forms of primary diabetes in children and adolescents<ref name="PihokerGilliam2013">{{cite journal|last1=Pihoker|first1=Catherine|last2=Gilliam|first2=Lisa K.|last3=Ellard|first3=Sian|last4=Dabelea|first4=Dana|last5=Davis|first5=Cralen|last6=Dolan|first6=Lawrence M.|last7=Greenbaum|first7=Carla J.|last8=Imperatore|first8=Giuseppina|last9=Lawrence|first9=Jean M.|last10=Marcovina|first10=Santica M.|last11=Mayer-Davis|first11=Elizabeth|last12=Rodriguez|first12=Beatriz L.|last13=Steck|first13=Andrea K.|last14=Williams|first14=Desmond E.|last15=Hattersley|first15=Andrew T.|title=Prevalence, Characteristics and Clinical Diagnosis of Maturity Onset Diabetes of the Young Due to Mutations in HNF1A, HNF4A, and Glucokinase: Results From the SEARCH for Diabetes in Youth|journal=The Journal of Clinical Endocrinology & Metabolism|volume=98|issue=10|year=2013|pages=4055–4062|issn=0021-972X|doi=10.1210/jc.2013-1279}}</ref> <ref name="Rubio-CabezasHattersley2014">{{cite journal|last1=Rubio-Cabezas|first1=Oscar|last2=Hattersley|first2=Andrew T|last3=Njølstad|first3=Pål R|last4=Mlynarski|first4=Wojciech|last5=Ellard|first5=Sian|last6=White|first6=Neil|last7=Chi|first7=Dung Vu|last8=Craig|first8=Maria E|title=The diagnosis and management of monogenic diabetes in children and adolescents|journal=Pediatric Diabetes|volume=15|issue=S20|year=2014|pages=47–64|issn=1399543X|doi=10.1111/pedi.12192}}</ref><ref name="ChiangMaahs2018">{{cite journal|last1=Chiang|first1=Jane L.|last2=Maahs|first2=David M.|last3=Garvey|first3=Katharine C.|last4=Hood|first4=Korey K.|last5=Laffel|first5=Lori M.|last6=Weinzimer|first6=Stuart A.|last7=Wolfsdorf|first7=Joseph I.|last8=Schatz|first8=Desmond|title=Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association|journal=Diabetes Care|volume=41|issue=9|year=2018|pages=2026–2044|issn=0149-5992|doi=10.2337/dci18-0023}}</ref>
|-
|-
! Features !! Type 1 diabetes !! Type 2 diabetes !! MODY* !! Atypical diabetes**
! Features !! Type 1 diabetes !! Type 2 diabetes !! MODY* !! Atypical diabetes**
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*MODY is maturity-onset diabetes in the young or monogenic diabetes. **Atypical diabetes is also referred to as Flatbush diabetes, type 1.5 diabetes, ketosis-prone diabetes, and idiopathic type 1 diabetes. ¶In North America, type 2 diabetespredominates in African American, Hispanic,Native American, and Canadian First Nations children and adolescents and is also more common in Asian and South Asian than in Caucasian individuals. †Mirrors rate in general population. §Diabetes-associated (islet) autoantibodies to insulin, islet cell cytoplasmic, glutamic acid decarboxylase, or tyrosine phosphatase (insulinoma-associated) antibody (IA-2, ICA512, ZnT8 antibodies in 85–95%) at diagnosis.
* *MODY is maturity-onset diabetes in the young or monogenic diabetes.  
* **Atypical diabetes is also referred to as Flatbush diabetes, type 1.5 diabetes, ketosis-prone diabetes, and idiopathic T1DM.
* ¶In North America, T2DM predominates in African American, Hispanic, Native American, and Canadian First Nations children and adolescents; and is also more common in Asian and South Asian than in Caucasian individuals.
* †Mirrors rate in general population.
* §Diabetes-associated (islet) autoantibodies to insulin, islet cell cytoplasmic, glutamic acid decarboxylase, or tyrosine phosphatase (insulinoma-associated) antibody (IA-2, ICA512, ZnT8 antibodies in 85–95%) at diagnosis.


==Pathophysiology==
==Pathophysiology==


===Type 1 Diabetes Mellitus===
===Type 1 Diabetes Mellitus===
*Insufficient endogenous insulin leads to hyperglycemia, hyperglucagonemia, glucosuria, and without treatment, eventually ketosis, acidosis, dehydration, and death. About one-third of patients with newly-diagnosed type 1 diabetes present with diabetic ketoacidosis (DKA) which has a mortality rate of around 0.3-0.5%, despite aggressive treatment.
*'''Immune-mediated process:'''<ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref>
*The Diabetes Control and Complications Trial was the pivotal study published in 1993 documenting the clear association of chronic hyperglycemia with long-term microvascular complications such retinopathy, neuropathy, and microalbuminuria (as a surrogate for nephropathy). Follow-up studies have documented the association of chronic hyperglycemia with macrovascular complications as well as all-cause mortality. Iatrogenic hypoglycemia, however, was identified as the major limiting factor to intensive glucose control.
**The autoimmune destruction of beta cells probably occurs over the course of months to years before diabetes develops.  
*For the last several decades, therapies have focused on normalizing glucose while minimizing the risk of hypoglycemia while at the same time monitoring for chronic complications and acknowledging the important psychosocial factors that affect a growing and developing children with a chronic disease.
**›80% of beta cells must be lost before significant glycemic control gets impaired.
*The autoimmune destruction of beta cells probably occurs over the course of months to years before diabetes develops. It is believed that more than 80% of beta cells must be lost before glycemic control is impaired significantly. As beta-cell loss progresses beyond that point, insulin is insufficiently present to maintain glucose and lipid homeostasis. When glucose concentrations in the blood rise above approximately 180 mg/dL (10.0 mmol/L), glucosuria occurs, leading to an osmotic diuresis that causes polyuria. The polyuria stimulates polydipsia to maintain euvolemia. With further insulin deficiency, there is an increase in lipolysis from fat cells as well as protein breakdown, an exaggeration of the normal fasting state designed to provide alternative sources of fuel. These mechanisms, along with the caloric loss from glucosuria, result in the hyperphagia and weight loss typical of the undiagnosed diabetic state. With profound insulin deficiency, the process devolves into ketoacidosis, with marked hyperglycemia, dehydration driven by the glucosuric osmotic diuresis, and accumulation of ketoacids from the hepatic metabolism of the liberated fatty acids.
**As beta-cell loss progresses beyond that point, insulin is insufficiently secreted to maintain glucose and lipid homeostasis.  
**When glucose concentrations in the blood rise above ~180 mg/dL (10.0 mmol/L), glucosuria occurs leading to an osmotic diuresis that causes polyuria which further stimulates polydipsia to maintain euvolemia.  
**With further progression of insulin deficiency, there is an increase in lipolysis from fat cells as well as protein breakdown; thereby exaggerating the normal fasting state designed to provide alternative sources of fuel.  
**These complex mechanisms along with the caloric loss from glucosuria result in the hyperphagia and weight loss typical of the underlying undiagnosed diabetic state.  
**With profound insulin deficiency, the process devolves into ketoacidosis with marked hyperglycemia, dehydration driven by the glucosuric osmotic diuresis, and accumulation of ketoacids from the hepatic metabolism of the liberated fatty acids.
**Hence, insufficient endogenous insulin leads to hyperglycemia, hyperglucagonemia, glucosuria, and without treatment, eventually ketosis, acidosis, dehydration, and death.
*The Diabetes Control and Complications Trial (DCCT) was the pivotal study published in 1993 documenting the clear association of chronic hyperglycemia with long-term microvascular complications such retinopathy, neuropathy, and microalbuminuria (as a surrogate for nephropathy). Follow-up studies have documented the association of chronic hyperglycemia with macrovascular complications as well as all-cause mortality. Iatrogenic hypoglycemia, however, was identified as the major limiting factor to intensive glucose control. <ref>{{cite journal|title=The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus|journal=New England Journal of Medicine|volume=329|issue=14|year=1993|pages=977–986|issn=0028-4793|doi=10.1056/NEJM199309303291401}}</ref> <ref>{{cite journal|title=Intensive Diabetes Treatment and Cardiovascular Outcomes in Type 1 Diabetes: The DCCT/EDIC Study 30-Year Follow-up|journal=Diabetes Care|volume=39|issue=5|year=2016|pages=686–693|issn=0149-5992|doi=10.2337/dc15-1990}}</ref> <ref name="pmid9000705">{{cite journal| author=| title=Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. | journal=Diabetes | year= 1997 | volume= 46 | issue= 2 | pages= 271-86 | pmid=9000705 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9000705  }} </ref>


===Type 2 Diabetes Mellitus===
===Type 2 Diabetes Mellitus===
*Obesity leads to peripheral insulin resistance, which in turn leads to hyperglycemia as discussed. Independent of obesity, certain ethnicities have higher risks of insulin resistance and beta cell dysfunction. Hyperglycemia leads to an osmotic diuresis (polyuria), which increases thirst (polydipsia). This diuresis causes moderate to severe dehydration. Prolonged hyperglycemia can produce two distinct emergent states in type 2 diabetes mellitus in children.  
*'''Obesity''' leads to peripheral insulin resistance and subsequently hyperglycemia. Apart from obesity, certain ethnicities carries higher risks of insulin resistance and beta cell dysfunction. Thereby, hyperglycemia leads to an osmotic diuresis (polyuria) which increases thirst (polydipsia); and this subsequent diuresis causes moderate to severe dehydration. Hence, prolonged hyperglycemia can produce two distinct emergent states in children with T2DM.<ref name="CaprioPierpont2018">{{cite journal|last1=Caprio|first1=Sonia|last2=Pierpont|first2=Bridget|last3=Kursawe|first3=Romy|title=The “adipose tissue expandability” hypothesis: a potential mechanism for insulin resistance in obese youth|journal=Hormone Molecular Biology and Clinical Investigation|volume=33|issue=2|year=2018|issn=1868-1891|doi=10.1515/hmbci-2018-0005}}</ref>
*Diabetic ketoacidosis: much more common in children with type 2 diabetes mellitus compared to adults. Lack of insulin inhibits the body's ability to use glucose for energy and reverts to breaking down fat for energy. This leads to ketosis, acidosis, and electrolyte abnormalities and may lead to coma and death.  
*'''Diabetic ketoacidosis:''' It is much more common in children with T2DM than adults. Lack of insulin inhibits the body's ability to use glucose for energy and reverts to breaking down fat for energy. This leads to ketosis, acidosis, and electrolyte abnormalities and may lead to coma and death. <ref name= "ped 2 ch">Tillotson CV, Bowden SA, Boktor SW. Pediatric Type 2 Diabetes Mellitus. [Updated 2020 Nov 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431046/</ref>
*Hyperglycemic Hyperosmolar State (HHS): characterized by hypertonicity, extreme hyperglycemia (> 600 mg/dl), and severe dehydration. The profound hyperglycemia results in continued osmotic diuresis and intravascular depletion.
*'''Hyperglycemic Hyperosmolar State (HHS):''' It is characterized by hypertonicity, extreme hyperglycemia (> 600 mg/dl), and severe dehydration resulting from continued osmotic diuresis and intravascular depletion. <ref name= "ped 2 ch">Tillotson CV, Bowden SA, Boktor SW. Pediatric Type 2 Diabetes Mellitus. [Updated 2020 Nov 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431046/</ref>


==Etiology==
==Etiology==


===Type 1 Diabetes Mellitus===
===Type 1 Diabetes Mellitus===
*Both genetic and environmental contributions lead to immune-mediated loss of beta cell function resulting in hyperglycemia and life-long insulin dependence. In an individual at risk (human leukocyte antigen (HLA) haplotype accounts for 30% to 50% of their genetic risk. More than 50 other genes have been found through candidate gene and genome-wide association studies. 
*Both genetic and environmental factors lead to immune-mediated loss of beta cell functions resulting in hyperglycemia and life-long insulin dependence. A "triggering" insult in the form of maternal and intrauterine environment, exposure to viruses, host microbiome, diet and many other factors are thought to contribute towards disease susceptibility by initiating a process that recruits antigen-presenting cells to transport beta cell self-antigens to autoreactive T cells. Through failures of self-tolerance, these T cells mediate beta-cell killing and inflammation leading to insulinopenia and symptomatic DM.  
*A "triggering" insult (e.g., maternal and intrauterine environment, exposure to viruses, host microbiome, diet and many other factors are thought to contribute to disease susceptibility) is suspected to initiate a process that recruits antigen-presenting cells to transport beta cell self-antigens to autoreactive T cells. Through failures of self-tolerance, these T cells mediate beta-cell killing and inflammation leading to insulinopenia and symptomatic diabetes. Recently, preclinical stages of type 1 diabetes have been recognized.  
*Recently, preclinical stages of T1DM have been discovered and divided into 3 different stages as described in the following '''Table 2'''.  
**Stage 1:Pre-symptomatic DM1 with positive autoimmunity (two or more autoantibodies against the islet) and normal blood glucose. This corresponds to the immunological disease phase and, in many cases, progression to the clinical disease occurs in a period between 8 to 10 years.
 
**Stage 2: Pre-symptomatic DM1 with positive autoimmunity (two or more autoantibodies against the islet) and pre-diabetic dysglycemia (abnormal fasting glucose and/or reduced glucose tolerance in the OGTT). This corresponds to the almost irreversible stage of the disease, with functional loss of beta cells and the beginning of metabolic disease. The risk of symptomatic disease within a period of 5 years is approximately 75%, reaching 100% over a lifetime.
{| class="wikitable"
**Stage 3: Symptomatic DM1, with positive autoimmunity (two or more autoantibodies against the islet) and diabetic dysglycemia (diabetic fasting glucose and/or diabetic OGTT, increase in HbA1c). This corresponds to the autoimmune acceleration stage of the disease, with the presence of typical signs and symptoms of DM1. Progression of the symptomatic phase of DM1 can further be classified as: a) initial phase); b) established DM1 phase; c) established DM1 phase with chronic complications.
|+Table 2: Staging of T1DM
*Progression through these stages may take years. Although the pre-clinical staging is not usually clinically relevant, research focusing on interventions in the pre-clinical groups may prove to delay or prevent the onset of type 1 diabetes.
|-
! Stage !! Features
|-
| '''Stage 1''' ||
*Pre-symptomatic DM1: It corresponds to the immunological disease phase with a positive autoimmunity which may progress to the clinical disease over a period of 8 to 10 years.<ref name="Gottlieb2015">{{cite journal|last1=Gottlieb|first1=Peter A.|title=What defines disease in an age of genetics and biomarkers?|journal=Current Opinion in Endocrinology & Diabetes and Obesity|volume=22|issue=4|year=2015|pages=296–299|issn=1752-296X|doi=10.1097/MED.0000000000000172}}</ref>
*Diagnostic criteria: ›2 autoantibodies against the islet; No IGT or IFG; Normal blood glucose level
|-
| '''Stage 2''' ||
*Pre-symptomatic DM1: It corresponds to the almost irreversible stage of the disease with functional loss of beta cells and the beginning of metabolic disease with positive autoimmunity (two or more autoantibodies against the islet) and pre-diabetic dysglycemia. The risk of symptomatic disease within a period of 5 years is approximately 75%, reaching 100% over a lifetime.<ref name="Gottlieb2015">{{cite journal|last1=Gottlieb|first1=Peter A.|title=What defines disease in an age of genetics and biomarkers?|journal=Current Opinion in Endocrinology & Diabetes and Obesity|volume=22|issue=4|year=2015|pages=296–299|issn=1752-296X|doi=10.1097/MED.0000000000000172}}</ref><ref name="InselDunne2015">{{cite journal|last1=Insel|first1=Richard A.|last2=Dunne|first2=Jessica L.|last3=Atkinson|first3=Mark A.|last4=Chiang|first4=Jane L.|last5=Dabelea|first5=Dana|last6=Gottlieb|first6=Peter A.|last7=Greenbaum|first7=Carla J.|last8=Herold|first8=Kevan C.|last9=Krischer|first9=Jeffrey P.|last10=Lernmark|first10=Åke|last11=Ratner|first11=Robert E.|last12=Rewers|first12=Marian J.|last13=Schatz|first13=Desmond A.|last14=Skyler|first14=Jay S.|last15=Sosenko|first15=Jay M.|last16=Ziegler|first16=Anette-G.|title=Staging Presymptomatic Type 1 Diabetes: A Scientific Statement of JDRF, the Endocrine Society, and the American Diabetes Association|journal=Diabetes Care|volume=38|issue=10|year=2015|pages=1964–1974|issn=0149-5992|doi=10.2337/dc15-1419}}</ref>
* Diagnostic criteria: ›2 autoantibodies; Dysglycemia: IFG and/or IGT; FPG 100–125 mg/dL (5.6–6.9 mmol/L); 2-h PG 140–199 mg/dL (7.8–11.0 mmol/L); A1C 5.7–6.4% (39–47 mmol/mol) or ≥10% increase in A1C
|-
| '''Stage 3''' ||
*Symptomatic DM1: It corresponds to the autoimmune acceleration stage of the disease with positive autoimmunity (two or more autoantibodies against the islet) and diabetic dysglycemia (diabetic fasting glucose and/or diabetic OGTT, increase in HbA1c). Progression of the symptomatic phase of DM1 can further be classified as following:<ref name="Gottlieb2015">{{cite journal|last1=Gottlieb|first1=Peter A.|title=What defines disease in an age of genetics and biomarkers?|journal=Current Opinion in Endocrinology & Diabetes and Obesity|volume=22|issue=4|year=2015|pages=296–299|issn=1752-296X|doi=10.1097/MED.0000000000000172}}</ref><ref name="InselDunne2015">{{cite journal|last1=Insel|first1=Richard A.|last2=Dunne|first2=Jessica L.|last3=Atkinson|first3=Mark A.|last4=Chiang|first4=Jane L.|last5=Dabelea|first5=Dana|last6=Gottlieb|first6=Peter A.|last7=Greenbaum|first7=Carla J.|last8=Herold|first8=Kevan C.|last9=Krischer|first9=Jeffrey P.|last10=Lernmark|first10=Åke|last11=Ratner|first11=Robert E.|last12=Rewers|first12=Marian J.|last13=Schatz|first13=Desmond A.|last14=Skyler|first14=Jay S.|last15=Sosenko|first15=Jay M.|last16=Ziegler|first16=Anette-G.|title=Staging Presymptomatic Type 1 Diabetes: A Scientific Statement of JDRF, the Endocrine Society, and the American Diabetes Association|journal=Diabetes Care|volume=38|issue=10|year=2015|pages=1964–1974|issn=0149-5992|doi=10.2337/dc15-1419}}</ref><ref name="CouperHaller2014">{{cite journal|last1=Couper|first1=Jennifer J|last2=Haller|first2=Michael J|last3=Ziegler|first3=Annette-G|last4=Knip|first4=Mikael|last5=Ludvigsson|first5=Johnny|last6=Craig|first6=Maria E|title=Phases of type 1 diabetes in children and adolescents|journal=Pediatric Diabetes|volume=15|issue=S20|year=2014|pages=18–25|issn=1399543X|doi=10.1111/pedi.12188}}</ref>
**Initial phase);
**Established DM1 phase;  
**Established DM1 phase with chronic complications
*Diagnostic criteria: Clinical symptoms; Diabetes by standard criteria
|}
*Although the pre-clinical staging is not usually clinically relevant and progression through these stages may take years; however, research focusing on interventions in the pre-clinical groups may prove to delay or prevent the onset of T1DM.<ref name= "typ1">{{cite journal|title=13. Children and Adolescents: Standards of Medical Care in Diabetes—2019|journal=Diabetes Care|volume=42|issue=Supplement 1|year=2019|pages=S148–S164|issn=0149-5992|doi=10.2337/dc19-S013}}</ref>


===Type 2 Diabetes Mellitus===
===Type 2 Diabetes Mellitus===
*Hyperglycemia results when there is a relative lack of insulin compared to glucose in the blood. In type 2 diabetes mellitus, insulin resistance first leads to increased insulin production by the beta cells of the pancreas. When the beta cells are unable to produce enough insulin to maintain euglycemia, hyperglycemia results. Hyperglycemia has damaging effects to multiple organs, including kidneys, eyes, heart, and nerves. Further, hyperglycemia puts children at risk for other electrolyte disturbances
*Insulin resistance state initially leads to an increased insulin production by the remaining beta cells of the pancreas. When the beta cells are unable to produce enough insulin to maintain euglycemia, hyperglycemia results. Thereby, hyperglycemia results when there is a relative lack of insulin production compared to glucose levels in the blood which put damaging effects to multiple organs, including kidneys, eyes, heart, and nerves; and further puts children at risk for other electrolyte disturbances. <ref name="Hernández-MontoyaSoriano-Flores2019">{{cite journal|last1=Hernández-Montoya|first1=Dewi|last2=Soriano-Flores|first2=Antonio|last3=Esparza-Aguilar|first3=Marcelino|last4=Benjet|first4=Corina|last5=Llanes-Díaz|first5=Nathaly|title=Variation in incidence of type 2 diabetes mellitus: time series of Mexican adolescents|journal=Annals of Epidemiology|volume=30|year=2019|pages=15–21|issn=10472797|doi=10.1016/j.annepidem.2018.11.006}}</ref>


==Differentiating [disease name] from other Diseases==
==Differentiating Diseases<ref name= "ped t1 ch">Los E, Wilt AS. Diabetes Mellitus Type 1 In Children. [Updated 2020 Jun 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441918/</ref>==
*Salicylate toxicity
*Salicylate toxicity
*Pheochromocytoma
*Pheochromocytoma
Line 101: Line 127:
==Epidemiology and Demographics==
==Epidemiology and Demographics==


===Type 1 Diabetes Mellitus===
===Type 1 Diabetes Mellitus<ref name= "ped t1 ch">Los E, Wilt AS. Diabetes Mellitus Type 1 In Children. [Updated 2020 Jun 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441918/</ref>===
*Type 1 diabetes may be diagnosed at nearly any age, though peaks in presentation occur between ages 5 to 7 and around puberty. There appears to be seasonal variation with more cases diagnosed in fall and winter. Unlike most autoimmune disorders, type 1 diabetes is slightly more common in boys and men. In the past several decades, type 1 diabetes incidence and prevalence has increased in most age, sex, and race/ethnic groups with some of the fastest growth in young children. There is significant variability in incidence based on geography and ethnicity. For example, the incidence in Finland is 60 per 100,000 person-years, while in China it is 0.1 per 100,000. In the United States, there are approximately 20 to 30 new diagnoses per 100,000 person-years. These incidences have increased by 200% to 300% in the past several decades. In the United States, there are now more than 1.25 million people living with type 1 diabetes., and around 500,000 are children. If a child has type 1 diabetes, concordance in another sibling is around 5%. In fraternal twins, it is around 10% to 30%, and with identical twins, it is 40% to 50%. Children of adults with type 1 diabetes are at an approximately 5% to 8% risk. In the United States, the general population risk is approximately 0.3%.
*'''Age:''' It may be diagnosed at nearly any age, though peaks in presentation occur between ages 5 to 7 and around puberty.  
*'''Gender:''' Unlike most autoimmune disorders, T1DM is slightly more common in boys and men.  
*'''Incidence and prevalence:''' In the past several decades, it has increased in most age, sex, and race/ethnic groups with some of the rapid growth in young children. There is significant variability in incidence based on geography and ethnicity. For example, the incidence in Finland is 60 per 100,000 person-years, while in China it is 0.1 per 100,000. In the United States, the general population risk is ~0.3% with ~20 to 30 new diagnoses per 100,000 person-years; thereby leaving more than 1.25 million people and around 500,000 children living with T1DM. These incidences have increased by 200% to 300% in the past several decades. <ref name="AtkinsonEisenbarth2014">{{cite journal|last1=Atkinson|first1=Mark A|last2=Eisenbarth|first2=George S|last3=Michels|first3=Aaron W|title=Type 1 diabetes|journal=The Lancet|volume=383|issue=9911|year=2014|pages=69–82|issn=01406736|doi=10.1016/S0140-6736(13)60591-7}}</ref> 
*'''Seasonal variation:''' There appears to be seasonal variation with more cases diagnosed in fall and winter.
*'''Family association:''' If a child has T1DM, concordance in another sibling is around 5%. In fraternal twins, it is around 10% to 30%, and with identical twins, it is 40% to 50%. Children of adults with T1DM are at an approximately 5% to 8% risk.<ref name="TrioloFouts2019">{{cite journal|last1=Triolo|first1=Taylor M.|last2=Fouts|first2=Alexandra|last3=Pyle|first3=Laura|last4=Yu|first4=Liping|last5=Gottlieb|first5=Peter A.|last6=Steck|first6=Andrea K.|title=Identical and Nonidentical Twins: Risk and Factors Involved in Development of Islet Autoimmunity and Type 1 Diabetes|journal=Diabetes Care|volume=42|issue=2|year=2019|pages=192–199|issn=0149-5992|doi=10.2337/dc18-0288}}</ref>


===Type 2 Diabetes Mellitus===
===Type 2 Diabetes Mellitus===
*Type 1 diabetes remains the most prevalent form of diabetes in children. However, type 2 diabetes mellitus is estimated to occur in one in three (20% to 33%) of new diagnoses of diabetes in children today. The rate of type 2 diabetes mellitus in children continues to rise even as the obesity rates have plateaued in these age groups. Risk factors include high-risk ethnicity (African American, Hispanic, Native Americans, Pacific Islanders, Asian Americans), a positive first-degree relative with the disorder, obesity, low birth weight, mother with gestational diabetes, and female sex. It is more likely to be diagnosed during adolescence when insulin resistance is common due to multiple factors including hormonal changes.
*It is estimated to occur in one in three (20% to 33%) of new diagnoses of diabetes in children today.  
*The rate continues to rise even as the obesity rates have plateaued in these age groups.  
*'''Risk factors:''' High-risk ethnicity (African American, Hispanic, Native Americans, Pacific Islanders, Asian Americans), a positive first-degree relative with the disorder, obesity, low birth weight, mother with gestational DM, and female sex. It is more likely to be diagnosed during adolescence when insulin resistance is common due to multiple factors including hormonal changes. <ref name="JensenDabelea2018">{{cite journal|last1=Jensen|first1=Elizabeth T.|last2=Dabelea|first2=Dana|title=Type 2 Diabetes in Youth: New Lessons from the SEARCH Study|journal=Current Diabetes Reports|volume=18|issue=6|year=2018|issn=1534-4827|doi=10.1007/s11892-018-0997-1}}</ref> <ref name="PelhamHanks2019">{{cite journal|last1=Pelham|first1=James Heath|last2=Hanks|first2=Lynae|last3=Aslibekyan|first3=Stella|last4=Dowla|first4=Shima|last5=Ashraf|first5=Ambika P.|title=Higher hemoglobin A1C and atherogenic lipoprotein profiles in children and adolescents with type 2 diabetes mellitus|journal=Journal of Clinical & Translational Endocrinology|volume=15|year=2019|pages=30–34|issn=22146237|doi=10.1016/j.jcte.2018.11.006}}</ref>


==Risk Factors==
==Risk Factors==


===Type 1 Diabetes Mellitus===
===Type 1 Diabetes Mellitus===
*Despite HLA genes exerting a greater role in the etiology, other genes also contribute to the genetic effect, although the type of inheritance still remains unknown. Currently, the main markers of susceptibility to DM1 are considered to be class II HLA haplotypes DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2 serotype) and DRB1*0401-DQA1*0301-DQB1*0302 (DR4-DQ8 serotype), while DRB1*0403 is negatively associated with DM1, and may protect or slow the progression to clinical disease.
*Recurrence among siblings of a patient with DM1 is 5%, which means a risk 15 times higher, reaching 65-70% between monozygotic twins, or even higher if the index case has developed the disease in childhood.
*Genome-wide association studies have already identified more than 40 gene loci associated with the DM1 phenotype, generally involved in autoimmunity, the production and metabolism of insulin, and also the survival of the pancreatic beta cells.
*Genes such as IL2, CD25, INS, IL18RAP, IL10, IFH1, and PTPN22 appear to exert an influence on the speed of progression to DM1 after the onset of autoimmunity against the islet,24 and predictive algorithms for DM1 that also incorporated non-HLA genetic markers such as the PTPN22 or the INS gene increased the capacity to predict risk, especially in individuals with the DR3/DR4 haplotype in the general population.
*Some potential risk factors such as early fetal events, viral infections during the intrauterine or postnatal period, early exposure to the components of cow’s milk, and other nutritional factors could trigger the autoimmune process.


*Systematic reviews of observational studies have identified certain protective factors against the development of DM1, such as breast milk, atopy, and attending day care as indicative of early infections. There are also some risk factors, such as advanced maternal age, birth by cesarean section, and lower birth order.
*'''Genetics:'''
**Type of inheritance still remains unknown despite of knowing HLA genes and other genes contributing to the genetic effect.
**Currently, the main markers of susceptibility to T1DM are considered to be class II HLA haplotypes '''DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2 serotype)''' and '''DRB1*0401-DQA1*0301-DQB1*0302 (DR4-DQ8 serotype)''', while '''DRB1*0403''' is negatively associated with T1DM, and may protect or slow the progression to clinical disease.<ref name="ErlichValdes2008">{{cite journal|last1=Erlich|first1=H.|last2=Valdes|first2=A. M.|last3=Noble|first3=J.|last4=Carlson|first4=J. A.|last5=Varney|first5=M.|last6=Concannon|first6=P.|last7=Mychaleckyj|first7=J. C.|last8=Todd|first8=J. A.|last9=Bonella|first9=P.|last10=Fear|first10=A. L.|last11=Lavant|first11=E.|last12=Louey|first12=A.|last13=Moonsamy|first13=P.|title=HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk: Analysis of the Type 1 Diabetes Genetics Consortium Families|journal=Diabetes|volume=57|issue=4|year=2008|pages=1084–1092|issn=0012-1797|doi=10.2337/db07-1331}}</ref>
**Genes such as '''IL2, CD25, INS, IL18RAP, IL10, IFH1, and PTPN22''' appear to exert an influence on the speed of progression to T1DM after the onset of autoimmunity against the islet; and predictive algorithms for T1DM that also incorporated non-HLA genetic markers such as the PTPN22 or the INS gene increased the capacity to predict risk, especially in individuals with the DR3/DR4 haplotype in the general population. <ref name="AchenbachHummel2013">{{cite journal|last1=Achenbach|first1=P.|last2=Hummel|first2=M.|last3=Thümer|first3=L.|last4=Boerschmann|first4=H.|last5=Höfelmann|first5=D.|last6=Ziegler|first6=A. G.|title=Characteristics of rapid vs slow progression to type 1 diabetes in multiple islet autoantibody-positive children|journal=Diabetologia|volume=56|issue=7|year=2013|pages=1615–1622|issn=0012-186X|doi=10.1007/s00125-013-2896-y}}</ref><ref name="SteckWong2012">{{cite journal|last1=Steck|first1=A. K.|last2=Wong|first2=R.|last3=Wagner|first3=B.|last4=Johnson|first4=K.|last5=Liu|first5=E.|last6=Romanos|first6=J.|last7=Wijmenga|first7=C.|last8=Norris|first8=J. M.|last9=Eisenbarth|first9=G. S.|last10=Rewers|first10=M. J.|title=Effects of Non-HLA Gene Polymorphisms on Development of Islet Autoimmunity and Type 1 Diabetes in a Population With High-Risk HLA-DR,DQ Genotypes|journal=Diabetes|volume=61|issue=3|year=2012|pages=753–758|issn=0012-1797|doi=10.2337/db11-1228}}</ref>
**Genome-wide association studies have already identified more than 40 gene loci associated with the T1DM phenotype involved in autoimmunity, the production and metabolism of insulin, and the survival of the pancreatic beta cells. <ref name="BarrettClayton2009">{{cite journal|last1=Barrett|first1=Jeffrey C|last2=Clayton|first2=David G|last3=Concannon|first3=Patrick|last4=Akolkar|first4=Beena|last5=Cooper|first5=Jason D|last6=Erlich|first6=Henry A|last7=Julier|first7=Cécile|last8=Morahan|first8=Grant|last9=Nerup|first9=Jørn|last10=Nierras|first10=Concepcion|last11=Plagnol|first11=Vincent|last12=Pociot|first12=Flemming|last13=Schuilenburg|first13=Helen|last14=Smyth|first14=Deborah J|last15=Stevens|first15=Helen|last16=Todd|first16=John A|last17=Walker|first17=Neil M|last18=Rich|first18=Stephen S|title=Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes|journal=Nature Genetics|volume=41|issue=6|year=2009|pages=703–707|issn=1061-4036|doi=10.1038/ng.381}}</ref>
**Recurrence among siblings of a patient with T1DM1 5%, which means a risk 15 times higher, reaching 65-70% between monozygotic twins, or even higher if the index case has developed the disease in childhood. <ref name="RedondoJeffrey2008">{{cite journal|last1=Redondo|first1=Maria J.|last2=Jeffrey|first2=Joy|last3=Fain|first3=Pamela R.|last4=Eisenbarth|first4=George S.|last5=Orban|first5=Tihamer|title=Concordance for Islet Autoimmunity among Monozygotic Twins|journal=New England Journal of Medicine|volume=359|issue=26|year=2008|pages=2849–2850|issn=0028-4793|doi=10.1056/NEJMc0805398}}</ref>


*On the other hand, the role of the metabolism of vitamin D remains unclear. The frequency of DM1 in childhood has already been associated with estimates of the wealth of populations, such as the gross domestic product, suggesting that lifestyle habits related to wealth may be responsible for changes in these trends.
*'''Environmental:'''
**''Risk factors'' such as early fetal events, viral infections during the intrauterine or postnatal period, early exposure to the components of cow’s milk, and attending day care as indicative of early infections could trigger the autoimmune process.<ref name="ÅkerblomVaarala2002">{{cite journal|last1=Åkerblom|first1=Hans K.|last2=Vaarala|first2=Outi|last3=Hyöty|first3=Heikki|last4=Ilonen|first4=Jorma|last5=Knip|first5=Mikael|title=Environmental factors in the etiology of type 1 diabetes|journal=American Journal of Medical Genetics|volume=115|issue=1|year=2002|pages=18–29|issn=01487299|doi=10.1002/ajmg.10340}}</ref>
**''Maternal risk factors'' includes advanced maternal age, birth by cesarean section, and lower birth order. <ref name="CardwellStene2009">{{cite journal|last1=Cardwell|first1=C. R.|last2=Stene|first2=L. C.|last3=Joner|first3=G.|last4=Bulsara|first4=M. K.|last5=Cinek|first5=O.|last6=Rosenbauer|first6=J.|last7=Ludvigsson|first7=J.|last8=Jane|first8=M.|last9=Svensson|first9=J.|last10=Goldacre|first10=M. J.|last11=Waldhoer|first11=T.|last12=Jarosz-Chobot|first12=P.|last13=Gimeno|first13=S. G.A.|last14=Chuang|first14=L.-M.|last15=Parslow|first15=R. C.|last16=Wadsworth|first16=E. J.K.|last17=Chetwynd|first17=A.|last18=Pozzilli|first18=P.|last19=Brigis|first19=G.|last20=Urbonaite|first20=B.|last21=Sipetic|first21=S.|last22=Schober|first22=E.|last23=Devoti|first23=G.|last24=Ionescu-Tirgoviste|first24=C.|last25=de Beaufort|first25=C. E.|last26=Stoyanov|first26=D.|last27=Buschard|first27=K.|last28=Patterson|first28=C. C.|title=Maternal Age at Birth and Childhood Type 1 Diabetes: A Pooled Analysis of 30 Observational Studies|journal=Diabetes|volume=59|issue=2|year=2009|pages=486–494|issn=0012-1797|doi=10.2337/db09-1166}}</ref><ref name="CardwellStene2008">{{cite journal|last1=Cardwell|first1=C. R.|last2=Stene|first2=L. C.|last3=Joner|first3=G.|last4=Cinek|first4=O.|last5=Svensson|first5=J.|last6=Goldacre|first6=M. J.|last7=Parslow|first7=R. C.|last8=Pozzilli|first8=P.|last9=Brigis|first9=G.|last10=Stoyanov|first10=D.|last11=Urbonaitė|first11=B.|last12=Šipetić|first12=S.|last13=Schober|first13=E.|last14=Ionescu-Tirgoviste|first14=C.|last15=Devoti|first15=G.|last16=de Beaufort|first16=C. E.|last17=Buschard|first17=K.|last18=Patterson|first18=C. C.|title=Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies|journal=Diabetologia|volume=51|issue=5|year=2008|pages=726–735|issn=0012-186X|doi=10.1007/s00125-008-0941-z}}</ref><ref name="CardwellStene2010">{{cite journal|last1=Cardwell|first1=C. R.|last2=Stene|first2=L. C.|last3=Joner|first3=G.|last4=Bulsara|first4=M. K.|last5=Cinek|first5=O.|last6=Rosenbauer|first6=J.|last7=Ludvigsson|first7=J.|last8=Svensson|first8=J.|last9=Goldacre|first9=M. J.|last10=Waldhoer|first10=T.|last11=Jarosz-Chobot|first11=P.|last12=Gimeno|first12=S. G.|last13=Chuang|first13=L.-M.|last14=Roberts|first14=C. L.|last15=Parslow|first15=R. C.|last16=Wadsworth|first16=E. J.|last17=Chetwynd|first17=A.|last18=Brigis|first18=G.|last19=Urbonaite|first19=B.|last20=Sipetic|first20=S.|last21=Schober|first21=E.|last22=Devoti|first22=G.|last23=Ionescu-Tirgoviste|first23=C.|last24=de Beaufort|first24=C. E.|last25=Stoyanov|first25=D.|last26=Buschard|first26=K.|last27=Radon|first27=K.|last28=Glatthaar|first28=C.|last29=Patterson|first29=C. C.|title=Birth order and childhood type 1 diabetes risk: a pooled analysis of 31 observational studies|journal=International Journal of Epidemiology|volume=40|issue=2|year=2010|pages=363–374|issn=0300-5771|doi=10.1093/ije/dyq207}}</ref>
**''Socioeconomic status:'' The frequency of T1DM in childhood has been associated with estimates of the wealth of populations, such as the gross domestic product, suggesting that lifestyle habits related to wealth may be responsible for changes in these trends.<ref name="PattersonDahlquist2001">{{cite journal|last1=Patterson|first1=C. C.|last2=Dahlquist|first2=G.|last3=Soltész|first3=G.|last4=Green|first4=A.|title=Is childhood-onset Type I diabetes a wealth-related disease? An ecological analysis of European incidence rates|journal=Diabetologia|volume=44|issue=S3|year=2001|pages=B9–B16|issn=0012-186X|doi=10.1007/PL00002961}}</ref>
**Vitamin D levels: A correlation between T1DM and vitamin D remains unclear.<ref name="RaabGiannopoulou2014">{{cite journal|last1=Raab|first1=Jennifer|last2=Giannopoulou|first2=Eleni Z.|last3=Schneider|first3=Simone|last4=Warncke|first4=Katharina|last5=Krasmann|first5=Miriam|last6=Winkler|first6=Christiane|last7=Ziegler|first7=Anette-Gabriele|title=Prevalence of vitamin D deficiency in pre-type 1 diabetes and its association with disease progression|journal=Diabetologia|volume=57|issue=5|year=2014|pages=902–908|issn=0012-186X|doi=10.1007/s00125-014-3181-4}}</ref>


==Natural History and Prognosis==
==Natural History and Prognosis==
*The natural history of diabetes involves increased risk for acute and severe complications alongwith chronic microvascular and macrovascular complications that negatively affect the quality of life and survival of these patients. Because the risk of diabetes-related complications is related to the duration of the disease, prompt diagnosis and appropriate therapy are important.
*'''Natural history:''' It involves an increased risk for acute and severe complications alongwith chronic microvascular and macrovascular complications that negatively affect the quality of life and survival of diabetic patients. A prompt diagnosis and appropriate therapy is important as the risk of diabetes-related complications is related to the duration of the disease. Moreover, the psychosocial impact of living with diabetes can be a challenge for any child and any family; and is particularly burdensome to those with maladaptive coping skills which can sometimes manifest as poor glycemic control.<ref>{{cite journal|title=Diagnosis and Classification of Diabetes Mellitus|journal=Diabetes Care|volume=36|issue=Supplement_1|year=2012|pages=S67–S74|issn=0149-5992|doi=10.2337/dc13-S067}}</ref>
*The psychosocial impact of living with diabetes can be a challenge for any child and any family but is particularly burdensome to those with maladaptive coping skills. The result can sometimes be manifest as poor glucose control.
*'''Prognosis:''' T1DM has high morbidity and mortality. The life expectancy is reduced by 10-20 years for many individuals; and ~1 million people die every year as a result of diabetes, two-thirds of which lives in the developing countries. About one-third of patients with newly-diagnosed T1DM present with diabetic ketoacidosis (DKA) which has a mortality rate of around 0.3-0.5% despite aggressive treatment.<ref name= "ped t1 ch">Los E, Wilt AS. Diabetes Mellitus Type 1 In Children. [Updated 2020 Jun 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441918/</ref> <ref>Narayan KMV, Zhang P, Williams D, Engelgau M, Imperatore G, Kanaya A, et al. How should developing countries manage diabetes? CMAJ. 2006; 175(7):733-6</ref>
*Approximately 1 million people die every year as a result of diabetes, two-thirds of which in developing countries.
*Type 1 diabetes has high morbidity and mortality. The life expectancy is reduced by 10-20 years for many individuals. Children particulary die from DKA chiefly due to delayed diagnosis.


==Complications==
==Complications==
*DKA and hypoglycemia are the most significant acute complications of diabetes and its treatment, and both complications pose a significant risk of morbidity and mortality. Diabetes mellitus causes damage to the microvascular circulation, which results in tissue and organ damage, most notably in the retina, kidneys, and nerves. Due to these microvascular complications, diabetes mellitus is a leading cause of blindness, end-stage renal disease, and neuropathy. There also is a significant increase in the risk of atherosclerotic vascular disease in individuals who have diabetes. This macrovascular disease is responsible for strokes and heart attacks being the most common causes of death in these patients.
*'''Acute complications:''' Diabetic Ketoacidosis (DKA) and hypoglycemia are the most significant acute complications of diabetes and its treatment which poses a significant risk of morbidity and mortality.  
 
*'''Chronic complications:'''
*Risk reduction: Both the microvascular and macrovascular complications of diabetes are related to the hyperglycemia that persists even with disease treatment. The development of chronic complications also depends on the duration of diabetes, generally taking decades for clinically significant complications to appear. Therefore, although some late adolescents who have early onset of diabetes may show early evidence of complications (eg, nonproliferative retinopathy, microalbuminuria [urinary albumin excretion of 30 to 300 mg/d], or changes in nerve conduction), it is extremely uncommon for a child to have significant diabetic microvascular or macrovascular complications. Nonetheless, glycemic control should be maximized in children who have diabetes to minimize their risk of long-term complications as they age. Clinical trials, including the Diabetes Control and Complications Trial (DCCT), have demonstrated that the lower the hemoglobin A1c (HbA1c) that a patient maintains, reflecting a lower average blood glucose concentration, the lower the risk of microvascular complications. An improvement in HbA1c of 1% (reflecting a decrease in mean glucose concentrations of 30 to 35 mg/dL [1.67 to 2.9 mmol/L]) decreases the risk of long-term complications by approximately 20% to 50%. There is no threshold for this effect; that is, a lower HbA1c always is better in terms of lowering the risk of long-term complications. However, the absolute risk reduction is less at lower HbA1c values, and lower average glucose values increase the risk of the acute complications of hypoglycemia. Therefore, diabetes management involves a balancing of the long-term benefit of lowering the average glucose concentration with avoiding the acute complication of hypoglycemia.
**Both the microvascular and macrovascular complications, which generally take decades for clinically significant presentations to appear, are related to the duration of diabetes and hyperglycemia that persists even with disease treatment.  
 
**Although some late adolescents with an early onset of DM may show early evidence of complications (eg, nonproliferative retinopathy, microalbuminuria [urinary albumin excretion of 30 to 300 mg/d], or changes in nerve conduction); however, it is extremely uncommon for a child to have significant diabetic microvascular or macrovascular complications. Therefore, glycemic control should be maximized in diabetic children to minimize their risk of long-term complications as they age. <ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref>
===Hypoglycemia===
*'''Risk reduction:'''
*Hypoglycemia, a blood glucose concentration less than 60 mg/dL (3.3 mmol/L), occurs frequently in children treated for type 1 diabetes. It is caused by the inability to match the minute-to-minute changes in insulin requirements with current therapy, resulting in periods when insulin action exceeds insulin requirements. Patients who have lower average blood glucose concentrations may have more frequent episodes of hypoglycemia. The severity of hypoglycemic symptoms depends on both the degree of hypoglycemia and the rapidity of its development. The adrenergic symptoms of hypoglycemia include sweating, trembling, hunger, and palpitations; the neuroglycopenic symptoms include headache, lightheadedness, dizziness, diplopia, and confusion. With severe hypoglycemia, coma and seizures can occur.
**Clinical trials, including the DCCT, have demonstrated that the lower the HbA1c levels which reflects a lower average blood glucose concentration, and hence, the lower the risk of microvascular complications.  
**An improvement in HbA1c of 1% (reflecting a decrease in mean glucose concentrations of 30 to 35 mg/dL [1.67 to 2.9 mmol/L]) decreases the risk of long-term complications by approximately 20% to 50%. There is no threshold for this effect; that is, a lower HbA1c always is better in terms of lowering the risk of long-term complications.  
**However, the absolute risk reduction is less at lower HbA1c values, and lower average glucose values increase the risk of the acute complications of hypoglycemia. Therefore, diabetes management involves a balancing of the long-term benefit of lowering the average glucose concentration with avoiding the acute complication of hypoglycemia.<ref>{{cite journal|title=Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial|journal=The Journal of Pediatrics|volume=125|issue=2|year=1994|pages=177–188|issn=00223476|doi=10.1016/S0022-3476(94)70190-3}}</ref> <ref name="Nathan2013">{{cite journal|last1=Nathan|first1=David M.|title=The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Overview|journal=Diabetes Care|volume=37|issue=1|year=2013|pages=9–16|issn=0149-5992|doi=10.2337/dc13-2112}}</ref>


*Mild-to-moderate hypoglycemia is treated by ingesting 10 to 15 g of glucose (eg, 4 oz of juice or nondiet soft drink). Hypoglycemia in infants and young children and moderate reactions resulting in confusion in older children require that caregivers, teachers, coaches, and others be prepared to assist in the recognition and treatment of hypoglycemia. Severe reactions require treatment with intramuscular or subcutaneous glucagon (1 mg, except for infants �10 kg, in whom 0.5 mg is given). Because hypoglycemia can occur away from home, a source of glucose to treat it (eg, a tube of cake frosting) and a glucagon emergency kit always should be available.
===Hypoglycemia <ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref>===
*'''Hypoglycemia:''' A blood glucose concentration of ‹60 mg/dL (3.3 mmol/L) which occurs frequently in T1DM. It is caused by the inability to match the minute-to-minute changes in insulin requirements with current therapy; thereby resulting in periods when insulin action exceeds insulin requirements. Therefore, patients who have lower average blood glucose concentrations may have more frequent episodes of hypoglycemia.
*'''Clinical presentation:''' It's severity depends upon both the degree of hypoglycemia and the rapidity of its development. The adrenergic symptoms include sweating, trembling, hunger, and palpitations; and the neuroglycopenic symptoms include headache, lightheadedness, dizziness, diplopia, and confusion. Coma and seizures can occur in severe hypoglycemic episode.
*'''Treatment:''' Hypoglycemia in infants and young children and moderate reactions resulting in confusion in older children require that caregivers, teachers, coaches, and others be prepared to assist in the recognition and treatment of hypoglycemia.  
**''Mild-to-moderate cases:'' Treated by ingesting 10 to 15 g of glucose (eg, 4 oz of juice or nondiet soft drink).
**''Severe cases:'' Intramuscular or subcutaneous glucagon (1 mg, except for infants ‹10 kg, in whom 0.5mg is given). <ref name="pmid21969805">{{cite journal| author=Kedia N| title=Treatment of severe diabetic hypoglycemia with glucagon: an underutilized therapeutic approach. | journal=Diabetes Metab Syndr Obes | year= 2011 | volume= 4 | issue=  | pages= 337-46 | pmid=21969805 | doi=10.2147/DMSO.S20633 | pmc=3180523 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21969805  }} </ref>
**A source of glucose snack (eg, a tube of cake frosting) and a glucagon emergency kit always should be available to treat it as hypoglycemia can occur away from home.<ref name="pmid21969805">{{cite journal| author=Kedia N| title=Treatment of severe diabetic hypoglycemia with glucagon: an underutilized therapeutic approach. | journal=Diabetes Metab Syndr Obes | year= 2011 | volume= 4 | issue=  | pages= 337-46 | pmid=21969805 | doi=10.2147/DMSO.S20633 | pmc=3180523 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21969805  }} </ref>


===Ketonemia and Ketonuria===
===Ketonemia and Ketonuria===
*The presence of urine or blood ketones should be assessed whenever there is persistent, significant hyperglycemia (eg, blood glucose�250 mg/dL [13.9 mmol/L] in spite of the administration of corrective doses of insulin). Urine or blood ketones also should be tested whenever the child feels ill, particularly with nausea and vomiting.
*'''Indications:''' The presence of urine or blood ketones should be assessed in the following conditions:<ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref><ref name="MesaSalcedo2006">{{cite journal|last1=Mesa|first1=Jordi|last2=Salcedo|first2=Dolores|last3=Calle|first3=Hermenegildo de la|last4=Delgado|first4=Elías|last5=Nóvoa|first5=Javier|last6=Hawkins|first6=Federico|last7=Navarrete|first7=Gerardo S.|last8=Parramón|first8=Mónica|last9=Acosta|first9=Domingo|title=Detection of ketonemia and its relationship with hyperglycemia in type 1 diabetic patients|journal=Diabetes Research and Clinical Practice|volume=72|issue=3|year=2006|pages=292–297|issn=01688227|doi=10.1016/j.diabres.2005.10.008}}</ref>
*Aggressive treatment with additional insulin is necessary once ketosis develops to prevent deterioration into DKA. Rapid-acting insulin at doses of 10% to 20% of the total daily requirement should be given every 3 to 4 hours until the ketones are cleared. Care must be taken to avoid causing hypoglycemia in a child who is not able to take sufficient caloric intake because of illness. Blood glucose and ketones should be measured frequently (at least every 3 to 4 h). Extra fluids are given to maintain hydration, which also helps excrete excess glucose and ketoacids. If solid foods cannot be eaten, sugar-containing foods such as soda, juice, gelatin dessert, and popsicles can be given to maintain some caloric intake and prevent hypoglycemia. During some illnesses, the usual daily insulin doses, adjusted for intake and glucose concentrations, can be continued. For illnesses in which oral intake is more disrupted, when ketones have developed, or for more significant illnesses, it may be best to treat with more frequent, small doses of insulin; typical doses may be 5% to 10% of the total daily dose every 3 to 4 hours, increasing to 10% to 20% of the total daily dose every 3 to 4 hours if ketones are present.
**Persistent and significant hyperglycemia (eg, blood glucose ›250 mg/dL [13.9 mmol/L]) in spite of the administration of corrective doses of insulin  
*Persistent vomiting, or a refusal or inability to take fluids or food orally, requires an emergency department or office visit. Glucagon must be available to treat hypoglycemia during an illness. The usual dose is administered for significant hypoglycemia. Because such doses of glucagon frequently cause significant nausea and vomiting, further compromising the ability to ingest food, smaller doses may be more effective for less severe hypoglycemia due to poor intake: 10 mcg/year of age (minimum 20 mcg, maximum 150 mcg); if there is no response in 30 minutes, a repeat at twice the dose can be attempted.
**Child feels ill particularly with nausea and vomiting.
*'''Treatment:''' Persistent vomiting, or a refusal or inability to take fluids or food orally, requires an emergency department or office visit. Aggressive treatment with additional insulin is necessary once ketosis develops to prevent deterioration into DKA.<ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref>
**Rapid-acting insulin at doses of 10% to 20% of the total daily requirement should be given every 3 to 4 hours until the ketones are cleared.  
**Extra fluids are given to maintain hydration and excrete excess glucose and ketoacids.
**Blood glucose and ketones should be measured frequently at least every 3 to 4 h.  
**During some illnesses, the usual daily insulin doses, adjusted for intake and glucose concentrations, can be continued.  
**For illnesses with disrupted oral intake and ketones development; treat with more frequent small doses of insulin; typical doses may be 5-10% of the total daily dose every 3 to 4 hours and further increasing to 10-20% of the total daily dose every 3 to 4 hours if ketones are present.
**'''Hypoglycemic episodes:'''
***Care must be taken to avoid causing hypoglycemia in a child who is not able to take sufficient caloric intake due to illness.
***If solid foods cannot be eaten, sugar-containing foods such as soda, juice, gelatin dessert, and popsicles can be given to maintain some caloric intake and prevent hypoglycemia.  
***'''Glucagon:''' The usual dose must be administered for significant hypoglycemia during an illness. Because such doses frequently cause significant nausea and vomiting, and thereby further compromising the ability to ingest food. Hence, smaller doses may be more effective for less severe hypoglycemia due to poor intake: 10 mcg/year of age (minimum 20 mcg, maximum 150 mcg); and a repeat at twice the dose can be attempted if there is no response in 30 minutes.<ref name="pmid21969805">{{cite journal| author=Kedia N| title=Treatment of severe diabetic hypoglycemia with glucagon: an underutilized therapeutic approach. | journal=Diabetes Metab Syndr Obes | year= 2011 | volume= 4 | issue=  | pages= 337-46 | pmid=21969805 | doi=10.2147/DMSO.S20633 | pmc=3180523 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21969805  }} </ref>


===Diabetes Ketoacidosis===
===Diabetes Ketoacidosis===
*DKA is a state of metabolic decompensation that results from profound insulin deficiency. DKA is the most common cause of death in children who have type 1 diabetes and is associated with a significant risk of morbidity. Early identification and treatment are key to minimizing the risks. For a child who is not known to have diabetes, the diagnosis of DKA must be considered with the presentation of vomiting and dehydration, particularly in the presence of an altered sensorium or in the absence of other indicators of a viral infection (such as fever and diarrhea). Diabetes mellitus always should be considered when there is a preceding history of polydipsia and polyuria. For a child who has a known diagnosis of diabetes mellitus, ketones should be measured when the child is significantly ill, if there is vomiting, or if there is persistent hyperglycemia. During a ketotic illness, referral for medical care (rather than continued home management) should be considered if the patient begins to vomit. Medical attention is necessary if the patient has deep respirations or is unable to stand.
*DKA is an acute complication usually associated with new-onset T1DM, insulin omission, and increased levels of stress-related counterregulatory hormones/cytokines (e.g., infection). <ref name="HaynesHermann2017">{{cite journal|last1=Haynes|first1=Aveni|last2=Hermann|first2=Julia M.|last3=Miller|first3=Kellee M.|last4=Hofer|first4=Sabine E.|last5=Jones|first5=Timothy W.|last6=Beck|first6=Roy W.|last7=Maahs|first7=David M.|last8=Davis|first8=Elizabeth A.|last9=Holl|first9=Reinhard W.|title=Severe hypoglycemia rates are not associated with HbA1c: a cross-sectional analysis of 3 contemporary pediatric diabetes registry databases|journal=Pediatric Diabetes|volume=18|issue=7|year=2017|pages=643–650|issn=1399543X|doi=10.1111/pedi.12477}}</ref>
 
*'''Indications:'''
===Associated autoimmune disease===
**It must be considered in a child who is not known to have diabetes but presenting with vomiting and dehydration particularly in the presence of an altered sensorium or in the absence of other indicators of a viral infection such as fever and diarrhea.  
*Associated autoimmune disease, particularly thyroid dysfunction, occurs with greater frequency in individuals who have type 1 diabetes. Thyroid-stimulating hormone (TSH) should be measured shortly after diagnosis and may be measured subsequently every 1 to 2 years. TSH also should be measured whenever any thyroid-related signs or symptoms occur. Thyroxine concentrations and thyroid antibodies also may be assessed. Although rare, autoimmune adrenal hypofunction can occur, and symptoms to suggest this disorder should prompt appropriate testing.
**It should be always considered in cases where there is a preceding history of polydipsia and polyuria.
*'''Ketotic episode:''' For a diabetic child, ketones should be measured when the child is significantly ill, if there is vomiting, or if there is persistent hyperglycemia. During a ketotic illness, referral for medical care should be considered if the patient begins to vomit. Medical attention is necessary if the patient has deep respirations or is unable to stand. Early identification and treatment are key to minimizing the further risks and complications.<ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref><ref name="WolfsdorfGlaser2006">{{cite journal|last1=Wolfsdorf|first1=J.|last2=Glaser|first2=N.|last3=Sperling|first3=M. A.|title=Diabetic Ketoacidosis in Infants, Children, and Adolescents: A consensus statement from the American Diabetes Association|journal=Diabetes Care|volume=29|issue=5|year=2006|pages=1150–1159|issn=0149-5992|doi=10.2337/dc06-9909}}</ref>


*Celiac disease also occurs more frequently in children who have type 1 diabetes; all patients should be screened for this disorder at least once and any time poor growth and gastrointestinal symptoms occur. Tissue transglutaminase and antiendomysial antibodies are more sensitive and specific than antigliadin antibodies. Also, because these are immunoglobulin A (IgA) antibodies, it is important to assure that the individual patient is not IgA-deficient by measuring IgA concentrations.
===Associated autoimmune disease<ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref>===
*'''Thyroid dysfunction:''' It occurs with greater frequency in individuals with T1DM. Thyroid-stimulating hormone (TSH) should be ordered shortly after diagnosis of DM and may be measured subsequently every 1 to 2 years. TSH should be also measured whenever any thyroid-related signs or symptoms develops. Thyroxine concentrations and thyroid antibodies also may be assessed. <ref name="UmpierrezLatif2003">{{cite journal|last1=Umpierrez|first1=G. E.|last2=Latif|first2=K. A.|last3=Murphy|first3=M. B.|last4=Lambeth|first4=H. C.|last5=Stentz|first5=F.|last6=Bush|first6=A.|last7=Kitabchi|first7=A. E.|title=Thyroid Dysfunction in Patients With Type 1 Diabetes: A longitudinal study|journal=Diabetes Care|volume=26|issue=4|year=2003|pages=1181–1185|issn=0149-5992|doi=10.2337/diacare.26.4.1181}}</ref>
*'''Celiac disease:''' It also occurs more frequently in children with T1DM. All patients should be screened at least once and any time poor growth and gastrointestinal symptoms reported. Tissue transglutaminase and antiendomysial antibodies are more sensitive and specific than antigliadin antibodies. Moreover, it is important to assure that the individual patient is not IgA-deficient by measuring IgA concentrations because these are immunoglobulin A (IgA) antibodies. <ref name="SudMarcon2010">{{cite journal|last1=Sud|first1=Shama|last2=Marcon|first2=Margaret|last3=Assor|first3=Esther|last4=Palmert|first4=MarkR|last5=Daneman|first5=Denis|last6=Mahmud|first6=FaridH|title=Celiac Disease and Pediatric Type 1 Diabetes: Diagnostic and Treatment Dilemmas|journal=International Journal of Pediatric Endocrinology|volume=2010|issue=1|year=2010|pages=161285|issn=1687-9856|doi=10.1155/2010/161285}}</ref>


===Growth Disturbance===
===Growth Disturbance<ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref>===
*Linear growth is affected negatively by poor diabetic control. Decreased growth velocity, crossing percentiles downward for height and weight, eventual short stature, and delayed skeletal and sexual maturation are associated with chronic undertreatment with insulin. An extreme form of this effect—the Mauriac syndrome or diabetic dwarfism—occurs rarely and usually is associated with hepatomegaly. Height and weight should be measured at every appointment and plotted on growth curves so deviations from normal velocities can be detected early. Alternatively, treatment with excessive insulin doses often leads to excessive weight gain, causing the weight curve to cross percentiles upward. Maintenance of normal growth curves for height and weight is an important goal of diabetes management.
*Height and weight should be measured at every appointment and plotted on growth curves so deviations from normal velocities can be detected early.  
*Decreased growth velocity, crossing percentiles downward for height and weight, eventual short stature, and delayed skeletal and sexual maturation are associated with chronic undertreatment with insulin. Thus, a linear growth is affected negatively by poor diabetic control.
*'''Mauriac syndrome or diabetic dwarfism:''' An extreme form of this effect occurs rarely but usually associated with hepatomegaly.<ref name="JainKant2013">{{cite journal|last1=Jain|first1=Rajesh|last2=Kant|first2=Saket|last3=Prakash|first3=Ved|last4=Madhu|first4=SV|title=Mauriac syndrome: A rare complication of type 1 diabetes mellitus|journal=Indian Journal of Endocrinology and Metabolism|volume=17|issue=4|year=2013|pages=764|issn=2230-8210|doi=10.4103/2230-8210.113780}}</ref>
*Alternatively, treatment with excessive insulin doses often leads to excessive weight gain; thereby causing the weight curve to cross percentiles upward. <ref name="BaskaranVolkening2015">{{cite journal|last1=Baskaran|first1=Charumathi|last2=Volkening|first2=Lisa K|last3=Diaz|first3=Monica|last4=Laffel|first4=Lori M|title=A decade of temporal trends in overweight/obesity in youth with type 1 diabetes after the Diabetes Control and Complications Trial|journal=Pediatric Diabetes|volume=16|issue=4|year=2015|pages=263–270|issn=1399543X|doi=10.1111/pedi.12166}}</ref>
*Hence, maintenance of normal growth curves for height and weight is an important goal of diabetes management.


===Retinopathy===
===Retinopathy===
*Retinopathy usually is not seen before 5 to 10 years of diabetes duration. Recommendations from the American Diabetes Association are for the first ophthalmologic examination to occur once the child is at least 10 years old and has had diabetes for 3 to 5 years. Yearly follow-up examinations generally are recommended. Poor metabolic control, elevated blood pressure, smoking, albuminuria, and elevated lipid values are risk factors for retinopathy. Diabetes duration and pregnancy also are associated with increased risk.
*It is usually not seen before 5-10 years of diabetes duration.  
*'''Risk factors:''' Poor metabolic control, elevated blood pressure, smoking, albuminuria, and elevated lipid values.
*'''Recommendations:''' ADA recommends the first ophthalmologic examination once the child is at least 10 years old and/or has had diabetes for 3 to 5 years. Then, yearly follow-up examinations are suggested. <ref name="ChiangMaahs2018">{{cite journal|last1=Chiang|first1=Jane L.|last2=Maahs|first2=David M.|last3=Garvey|first3=Katharine C.|last4=Hood|first4=Korey K.|last5=Laffel|first5=Lori M.|last6=Weinzimer|first6=Stuart A.|last7=Wolfsdorf|first7=Joseph I.|last8=Schatz|first8=Desmond|title=Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association|journal=Diabetes Care|volume=41|issue=9|year=2018|pages=2026–2044|issn=0149-5992|doi=10.2337/dci18-0023}}</ref>


===Nephropathy===
===Nephropathy===
*A significant minority of patients who have type 1 diabetes eventually develops end-stage renal disease, necessitating dialysis or transplantation. All patients who have type 1 diabetes should be monitored by urine microalbumin determination at least annually beginning after the child is 10 years old and has had diabetes for 5 years. Because hypertension accelerates the progression of nephropathy, blood pressure should be monitored several times a year, and hypertension should be treated aggressively. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are recommended for treatment of hypertension. If hypertension, overt proteinuria, or elevation in serum creatinine or urea nitrogen values is found, monitoring of renal function several times each year and consultation with a nephrologist are warranted. Microalbuminuria (30 to 299 mg of albumin per gram of creatinine on spot urine) is a marker for early nephropathy. Two of three urine specimens that have elevated values, measured on different days, are needed for confirmation. Whether using angiotensin-converting enzyme inhibitors in normotensive individuals prevents or retards nephropathy is not known. Patients should avoid other risk factors for nephropathy, such as smoking.
*All patients with T1DM should be monitored by urine microalbumin determination atleast annually beginning after the child is 10 years old and has had diabetes for 5 years due to the higher likelihood of developing end-stage renal disease which might necessitates dialysis or transplantation.<ref name="ChiangMaahs2018">{{cite journal|last1=Chiang|first1=Jane L.|last2=Maahs|first2=David M.|last3=Garvey|first3=Katharine C.|last4=Hood|first4=Korey K.|last5=Laffel|first5=Lori M.|last6=Weinzimer|first6=Stuart A.|last7=Wolfsdorf|first7=Joseph I.|last8=Schatz|first8=Desmond|title=Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association|journal=Diabetes Care|volume=41|issue=9|year=2018|pages=2026–2044|issn=0149-5992|doi=10.2337/dci18-0023}}</ref>
*Hypertension accelerates the progression of nephropathy; therefore, blood pressure should be monitored several times a year and hypertension should be treated aggressively.
*Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are recommended for treatment of hypertension. <ref name="de BoerBangalore2017">{{cite journal|last1=de Boer|first1=Ian H.|last2=Bangalore|first2=Sripal|last3=Benetos|first3=Athanase|last4=Davis|first4=Andrew M.|last5=Michos|first5=Erin D.|last6=Muntner|first6=Paul|last7=Rossing|first7=Peter|last8=Zoungas|first8=Sophia|last9=Bakris|first9=George|title=Diabetes and Hypertension: A Position Statement by the American Diabetes Association|journal=Diabetes Care|volume=40|issue=9|year=2017|pages=1273–1284|issn=0149-5992|doi=10.2337/dci17-0026}}</ref> <ref name="MarcovecchioChiesa2017">{{cite journal|last1=Marcovecchio|first1=M. Loredana|last2=Chiesa|first2=Scott T.|last3=Bond|first3=Simon|last4=Daneman|first4=Denis|last5=Dawson|first5=Sarah|last6=Donaghue|first6=Kim C.|last7=Jones|first7=Timothy W.|last8=Mahmud|first8=Farid H.|last9=Marshall|first9=Sally M.|last10=Neil|first10=H. Andrew W.|last11=Dalton|first11=R. Neil|last12=Deanfield|first12=John|last13=Dunger|first13=David B.|title=ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes|journal=New England Journal of Medicine|volume=377|issue=18|year=2017|pages=1733–1745|issn=0028-4793|doi=10.1056/NEJMoa1703518}}</ref>
*'''Microalbuminuria''' (30-299 mg of albumin per gram of creatinine on spot urine) is a marker for early nephropathy. Two of three urine specimens that have elevated values, measured on different days, are needed for confirmation. Patients should avoid other risk factors for nephropathy such as smoking, NSAIDs, etc. <ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref>
*If hypertension, overt proteinuria, or elevation in serum creatinine or urea nitrogen values is found; renal functions should be done several times each year and consultation with a nephrologist are warranted.


===Neuropathy===
===Neuropathy===
*Symptomatic diabetic neuropathy, peripheral or autonomic, is uncommon in children and adolescents who have type 1 diabetes. Changes in nerve conduction, however, may be seen after 4 to 5 years of having diabetes. Overall, neuropathy is a common type 1 diabetes complication, and its frequency increases with the duration of disease and degree of hyperglycemia. Improvements in glycemic control may improve neuropathic symptoms.
*Symptomatic diabetic neuropathy, peripheral or autonomic, is uncommon in children and adolescents with T1DM.  
*Changes in nerve conduction may be seen after 4-5 years of having diabetes; and thereby increasing the risk of development of neuropathy with the duration of disease and degree of hyperglycemia. Hence, improvements in glycemic control may improve neuropathic symptoms.
*'''Recommendations:''' Consider an annual comprehensive foot exam for the adolescent at the start of puberty or at age 10 years, whichever is earlier, once the youth has had type 1 diabetes for 5 years. <ref name="Pop-BusuiBoulton2016">{{cite journal|last1=Pop-Busui|first1=Rodica|last2=Boulton|first2=Andrew J.M.|last3=Feldman|first3=Eva L.|last4=Bril|first4=Vera|last5=Freeman|first5=Roy|last6=Malik|first6=Rayaz A.|last7=Sosenko|first7=Jay M.|last8=Ziegler|first8=Dan|title=Diabetic Neuropathy: A Position Statement by the American Diabetes Association|journal=Diabetes Care|volume=40|issue=1|year=2016|pages=136–154|issn=0149-5992|doi=10.2337/dc16-2042}}</ref>


===Macrovascular Complications===
===Macrovascular Complications===
*Patients who have type 1 diabetes tend to have coronary artery, cerebrovascular, and peripheral vascular disease more often, at an earlier age, and more extensively than the nondiabetic population. Hypertension, elevated blood lipid concentrations, and cigarette smoking are other risk factors for developing macrovascular complications. Risk factors should be analyzed, including lipid panels, blood pressure measurements, and determination of smoking status, and treatment instituted as indicated. A strong admonition against smoking and referral to an appropriate program for patients who already are smokers is crucial. Studies continue to show that lower lowdensity lipoprotein (LDL) values are beneficial in lowering the risk of vascular disease, and recommendations continue to evolve. Screening with fasting lipid measurements should begin in children at age 12 years if there is no concerning family history and at diagnosis (after establishing metabolic control) when there is a positive family history for lipid abnormalities or early cardiovascular events.
*T1DM patients tend to have coronary artery, cerebrovascular, and peripheral vascular disease more often, at an earlier age, and more extensively than the nondiabetic population. Hypertension, elevated blood lipid concentrations, and cigarette smoking are other risk factors for developing macrovascular complications.  
 
*Risk factors should be analyzed including lipid panels, blood pressure measurements, and determination of smoking status, and treatment instituted as indicated.  
*Current recommendations are to treat children older than age 10 years who have LDL cholesterol concentrations at or above 160 mg/dL (4.14 mmol/L) and to consider treatment if the LDL value is at or above 130 mg/dL (3.37 mmol/L) if other risk factors are present. The goal is to achieve an LDL value below 100 mg/dL (2.59 mmol/L) . Although bile acid sequestrants may be recommended as the first treatment in children, they are poorly tolerated, and effective therapeutic data are lacking. Thus, statins should be considered, with appropriate monitoring. Of course, dietary counseling and blood glucose control are important parts of management.
*Studies have show that '''lower lowdensity lipoprotein (LDL)''' values are beneficial in lowering the risk of vascular disease and recommendations continue to evolve.
*'''Recommendations:'''
**''Screening'' with fasting lipid measurements should begin as the following:<ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref>
***Children at age 12 years with no concerning family history; or
***At the time of diagnosis after establishing metabolic control in cases with a positive family history for lipid abnormalities or early cardiovascular events.
**''Current recommendation goal'' is to achieve an LDL value below 100 mg/dL (2.59 mmol/L); and to treat the following:<ref name="ChiangMaahs2018">{{cite journal|last1=Chiang|first1=Jane L.|last2=Maahs|first2=David M.|last3=Garvey|first3=Katharine C.|last4=Hood|first4=Korey K.|last5=Laffel|first5=Lori M.|last6=Weinzimer|first6=Stuart A.|last7=Wolfsdorf|first7=Joseph I.|last8=Schatz|first8=Desmond|title=Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association|journal=Diabetes Care|volume=41|issue=9|year=2018|pages=2026–2044|issn=0149-5992|doi=10.2337/dci18-0023}}</ref>
***Children older than age 10 years who have LDL cholesterol concentrations at or above 160 mg/dL (4.14 mmol/L); or
***LDL value is at or above 130 mg/dL (3.37 mmol/L) if other risk factors are present.  
*Bile acid sequestrants may be recommended as the first treatment in children; however, they are poorly tolerated and effective therapeutic data are lacking. Thus, statins should be considered with appropriate monitoring. <ref name="MarcovecchioChiesa2017">{{cite journal|last1=Marcovecchio|first1=M. Loredana|last2=Chiesa|first2=Scott T.|last3=Bond|first3=Simon|last4=Daneman|first4=Denis|last5=Dawson|first5=Sarah|last6=Donaghue|first6=Kim C.|last7=Jones|first7=Timothy W.|last8=Mahmud|first8=Farid H.|last9=Marshall|first9=Sally M.|last10=Neil|first10=H. Andrew W.|last11=Dalton|first11=R. Neil|last12=Deanfield|first12=John|last13=Dunger|first13=David B.|title=ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes|journal=New England Journal of Medicine|volume=377|issue=18|year=2017|pages=1733–1745|issn=0028-4793|doi=10.1056/NEJMoa1703518}}</ref>
*Additionally, dietary counseling and blood glucose control are important parts of management.


==Diagnosis==
==Diagnosis==
===Diagnostic Criteria===
===Diagnostic Criteria===
*Metabolic tests that evaluate insulin secretion ability and glycemic state are also used as criteria for predicting the functional reserve of beta cells and the clinical onset of DM1; they include: a) the intravenous glucose tolerance test (IGTT); b) the oral glucose tolerance test (OGTT); c) glycated hemoglobin concentrations (HbA1c). The diagnostic criteria of glucose disorders according to the American Diabetes Association (ADA) – 20165 are presented in Table 1.
*Metabolic tests predicting insulin secretion ability, glycemic state, the functional reserve of beta cells, and the clinical onset of T1DM are as follows:
 
**Intravenous glucose tolerance test (IGTT);
**Oral glucose tolerance test (OGTT);  
**Glycated hemoglobin concentrations (HbA1c).  
* The American Diabetes Association (ADA) recommends the following diagnostic criteria for the diagnosis of glucose disorders in '''Table 3'''<ref>{{cite journal|title=2. Classification and Diagnosis of Diabetes|journal=Diabetes Care|volume=39|issue=Supplement 1|year=2016|pages=S13–S22|issn=0149-5992|doi=10.2337/dc16-S005}}</ref>
{| class="wikitable"
{| class="wikitable"
|+Diagnostic criteria of glucose disorders according to the American Diabetes Association (ADA) – 2016
|+Table 3: Diagnostic criteria of glucose disorders according to the American Diabetes Association (ADA) – 2016
|-
|-
! Diagnosis !! Fasting blood glucose (mg/dL) !! 2H-OGTT (mg/dL) !! HbA1c (%)
! Diagnosis !! Fasting blood glucose (mg/dL) !! 2H-OGTT (mg/dL) !! HbA1c (%)
Line 185: Line 260:
| Diabetes mellitus || ≥ 126 || ≥ 200 || ≥ 6.5
| Diabetes mellitus || ≥ 126 || ≥ 200 || ≥ 6.5
|}
|}
2H-OGTT: 120 minute time of the oral glucose tolerance test; HbA1c: glycated hemoglobin evaluated by laboratory test aligned with that used by the Diabetes Control and Complications Trial (DCCT).
* 2H-OGTT: 120 minute time of the oral glucose tolerance test;  
* HbA1c: glycated hemoglobin evaluated by laboratory test aligned with the Diabetes Control and Complications Trial (DCCT).


===History and Physical Examination===
===History and Physical Examination===
*At presentation, children usually have a history of polyuria, polydipsia and weight loss for days to months. Re-emergence of bedwetting, nocturia, and a need to leave classes in school to use the bathroom are complaints that suggest polyuria.
*'''Presenting signs and symptoms:''' Polyuria, polydipsia and weight loss for days to months. Re-emergence of bedwetting, nocturia, and a need to leave classes in school to use the bathroom are complaints that suggest polyuria. However, some children may present with ketoacidosis associated with the smell of ketones, dehydration, abdominal pain, Kussmaul breathing, vomiting, coma and altered mental status. <ref name= "ped t1 ch">Los E, Wilt AS. Diabetes Mellitus Type 1 In Children. [Updated 2020 Jun 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441918/</ref>
*If the diagnosis is delayed, there may be vomiting, lethargy, altered mental status, dehydration, and acidosis.
*'''T2DM:''' These children most often present during asymptomatic screening. Children with T2DM are more likely than adults with the disorder to present in DKA (5% to 13%), especially if they are of ethnic minority descent. Adolescents with T2DM may also present in Hyperosmolar Hyperglycemic State (HHS).<ref name= "ped 2 ch">Tillotson CV, Bowden SA, Boktor SW. Pediatric Type 2 Diabetes Mellitus. [Updated 2020 Nov 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431046/</ref>  
*Some children will present with ketoacidosis that is associated with the smell of ketones, dehydration, abdominal pain, Kussmaul breathing, vomiting, coma and altered mental status.
*'''Follow up H&P:''' A medical provider will assess changes in diabetes status and life circumstances affecting diabetes management, for example, school experience, changes in patterns of exercise and diet, the developmental stage of the child, their participation in diabetes care tasks, family and home life changes, and adherence to therapy. It also focus on assessing issues related to glucose monitoring, insulin delivery (e.g., lipodystrophy, skin tolerance to medical adhesives on diabetes technology), and screening for symptoms of associated medical issues such as thyroid dysfunction or celiac disease. <ref name= "typ1">{{cite journal|title=13. Children and Adolescents: Standards of Medical Care in Diabetes—2019|journal=Diabetes Care|volume=42|issue=Supplement 1|year=2019|pages=S148–S164|issn=0149-5992|doi=10.2337/dc19-S013}}</ref> <ref name="PhelanLange2018">{{cite journal|last1=Phelan|first1=Helen|last2=Lange|first2=Karin|last3=Cengiz|first3=Eda|last4=Gallego|first4=Patricia|last5=Majaliwa|first5=Edna|last6=Pelicand|first6=Julie|last7=Smart|first7=Carmel|last8=Hofer|first8=Sabine E.|title=ISPAD Clinical Practice Consensus Guidelines 2018: Diabetes education in children and adolescents|journal=Pediatric Diabetes|volume=19|year=2018|pages=75–83|issn=1399543X|doi=10.1111/pedi.12762}}</ref>
*Children with type 2 diabetes mellitus most often present during asymptomatic screening. Children with type 2 diabetes mellitus are more likely than adults with the disorder to present in DKA (5% to 13%), especially if they are of ethnic minority descent. Adolescents with type 2 diabetes mellitus may also present in Hyperosmolar Hyperglycemic State (HHS).  
*Physical exam findings can include acanthosis nigricans (dark, velvety rash present in the axillae and neck). The American Diabetes Association recommends screening children at 10 years old or at the start of puberty in children who are obese (> 95th percentile BMI for age) or are overweight (BMI > 85th percentile for age or > 120% ideal body weight) and have two risk factors. These factors can be positive family history, high-risk ethnicity, signs of insulin resistance (polycystic ovary syndrome (PCOS), acanthosis, symptoms), or history of maternal gestational diabetes mellitus
*History and physical also focus on assessing issues related to glucose monitoring, insulin delivery (e.g., lipodystrophy, skin tolerance to medical adhesives on diabetes technology), and screening for symptoms of associated medical issues such as thyroid dysfunction or celiac disease. As most children with type 1 diabetes are otherwise healthy, history and physical is usually limited to assessment of pertinent diabetes care.
*At regular visits, the provider will assess changes in diabetes status and life circumstances affecting diabetes management, for example, school experience, changes in patterns of exercise and diet, the developmental stage of the child, their participation in diabetes care tasks, family and home life changes, and adherence to therapy.


===Diagnostic Evaluation===
===Diagnostic Evaluation===
*The American Diabetes Association recommends screening for type 2 diabetes mellitus  every three years starting at age ten years (or at the onset of puberty) for patients who are:
*'''Screening criteria:''' The American Diabetes Association (ADA) recommends screening for T2DM every three years starting at ten years of age or puberty onset for the following patients:<ref name="LeeFermin2017">{{cite journal|last1=Lee|first1=Arthur M.|last2=Fermin|first2=Cyrelle R.|last3=Filipp|first3=Stephanie L.|last4=Gurka|first4=Matthew J.|last5=DeBoer|first5=Mark D.|title=Examining trends in prediabetes and its relationship with the metabolic syndrome in US adolescents, 1999–2014|journal=Acta Diabetologica|volume=54|issue=4|year=2017|pages=373–381|issn=0940-5429|doi=10.1007/s00592-016-0958-6}}</ref> <ref name="HagmanDanielsson2016">{{cite journal|last1=Hagman|first1=E|last2=Danielsson|first2=P|last3=Brandt|first3=L|last4=Ekbom|first4=A|last5=Marcus|first5=C|title=Association between impaired fasting glycaemia in pediatric obesity and type 2 diabetes in young adulthood|journal=Nutrition & Diabetes|volume=6|issue=8|year=2016|pages=e227–e227|issn=2044-4052|doi=10.1038/nutd.2016.34}}</ref> <ref name="OesterKloppenborg2016">{{cite journal|last1=Oester|first1=Ida Margrethe Bach|last2=Kloppenborg|first2=Julie Tonsgaard|last3=Olsen|first3=Birthe Susanne|last4=Johannesen|first4=Jesper|title=Type 2 diabetes mellitus in Danish children and adolescents in 2014|journal=Pediatric Diabetes|volume=17|issue=5|year=2016|pages=368–373|issn=1399543X|doi=10.1111/pedi.12291}}</ref>
**Obese (body mass index (BMI) greater than or equal to the 95th percentile for age)
**''Obese'' (body mass index (BMI) greater than or equal to the 95th percentile for age)
**Overweight (BMI greater than or equal to the 85thpercentile) and have at lease two risk factors (positive family history, higher risk race or ethnicity, signs of insulin resistance, maternal history of gestational DM).  
**''Overweight'' (BMI greater than or equal to the 85th percentile or > 120% ideal body weight)  
**''Two risk factors'' which includes positive family history, high-risk ethnicity, signs of insulin resistance (polycystic ovary syndrome (PCOS), acanthosis, symptoms), or history of maternal gestational DM.


*Diagnostic criteria:
*'''Diagnostic criteria:'''
**Random plasma blood glucose 200 mg/dl or greater with symptoms of polyuria, polydipsia, or weight loss.
**''Random plasma blood glucose'' 200 mg/dl or greater with symptoms of polyuria, polydipsia, or weight loss.
**Fasting blood glucose of 126 mg/dl or higher in an asymptomatic patient.  
**''Fasting blood glucose'' of 126 mg/dl or higher in an asymptomatic patient.  
**Oral glucose tolerance test with blood sugar 200 mg/dl or greater at two hours post ingestion.
**''Oral glucose tolerance test'' with blood sugar 200 mg/dl or greater at two hours post ingestion.
**Hemoglobin A1c > 6.5%.  
**''Hemoglobin A1c'' > 6.5%.  


*If the diagnosis between type 1 and type 2 diabetes mellitus is not clear, helpful labs include fasting insulin or c peptide (both usually high or normal in type 2 diabetes mellitus, low in type 1 diabetes mellitus ), and autoantibodies for type 1 diabetes mellitus.
*'''Doubtful diagnosis:''' Laboratory tests such as fasting insulin or C peptide (both usually high or normal in T2DM, and low in T1DM); and autoantibodies for T1DM can be ordered to differentiate between T1DM and T2DM. However, Islet cell antibodies are only found in about 5% of children and are not specific markers; hence, they are not usually measured to make the diagnosis of T1DM. <ref name= "ped 2 ch">Tillotson CV, Bowden SA, Boktor SW. Pediatric Type 2 Diabetes Mellitus. [Updated 2020 Nov 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431046/</ref> <ref name= "ped t1 ch">Los E, Wilt AS. Diabetes Mellitus Type 1 In Children. [Updated 2020 Jun 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441918/</ref> 
*Screening for thyroid disorders is performed at regular intervals and screening for celiac disease is typically done as well, although the frequency is not established.  
*'''Multidisciplinary screening:''' Regular screening for lipid disorders, microalbuminuria, retinopathy, thyroid disorders and celiac disease are recommended based on the duration and status of diabetes control. Assessment of mental health and psychosocial factors are equally important.<ref name="typ1">{{cite journal|title=13. Children and Adolescents: Standards of Medical Care in Diabetes—2019|journal=Diabetes Care|volume=42|issue=Supplement 1|year=2019|pages=S148–S164|issn=0149-5992|doi=10.2337/dc19-S013}}</ref>
*Regular screening for lipid disorders, microalbuminuria, and retinopathy are recommended based on the duration of diabetes.  
*Assessment of mental health and psychosocial factors are also important.
*Islet cell antibodies are not usually measured to make the diagnosis of type 1 diabetes. These antibodies are only found in about 5% of children and are not specific markers. One should obtain a baseline lipid profile. In addition, urinary albumin should start at age 12 as these children are susceptible to end-stage renal disease.


==Treatment==
==Treatment==
===Medical Therapy===
*The management requires a diabetes healthcare team consisting of the medical provider, nurse, diabetes educator, dietician, social worker, and psychologist. However, not all specialties are always available, convenient, or covered by insurance.
*Type 1
*During an initial phase of management, frequent contact between the child and family and medical team through in-office visits is required while being treatment is adjusted; and the family learns the daily management tasks of caring for a child with diabetes as it needs a long-term day to day treatment decisions.
*Type 2
*'''Social worker''': Involved to ensure that the child has adequate support and finances for treatment.
*Lifestyle management
*'''Exercise specialist:''' Teach the child about beneficial exercises.
*'''Diabetic nurse:''' Assess the child's growth, blood pressure and injection site at every home visit; and assist with the care coordination between the patient and family with the medical providers. A mental health nurse provide counseling if a child with diabetes become depressed.
*All diabetics should be referred to an ophthalmologist, nephrologist, cardiologist and a neurologist for baseline workup of their respective organ systems. <ref name= "ped t1 ch">Los E, Wilt AS. Diabetes Mellitus Type 1 In Children. [Updated 2020 Jun 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441918/</ref>
 
===Type 1 Diabetes Mellitus===
*'''Insulin delivery:''' It is done by multiple daily injections (MDI) or an insulin pump to simulate endogenous insulin physiology. <ref name= "ped t1 ch">Los E, Wilt AS. Diabetes Mellitus Type 1 In Children. [Updated 2020 Jun 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441918/</ref>
**'''Multiple daily injections:''' Basal insulin is given once or twice daily, and bolus insulin typically injected at meals three or more times daily based on carbohydrate content and current blood glucose.
**'''Insulin pumps:''' They deliver rapid-acting insulin only and provide a basal rate of insulin that is either programmed or automatically adjusted based on continuous glucose monitor input in some pumps, and mealtime insulin is typically calculated based on mealtime inputs of carbohydrate and current blood glucose.
*'''Honeymoon period:''' Patients usually have some remaining beta cells at the time of diagnosis of the diabetes. Hence, insulin requirements often decline temporarily 1 to 3 months after diagnosis. During this honeymoon period, dose requirements may drop to less than 0.5 units/kg/day which may lasts several months occasionally for 12 months or more. However, most patients who have type 1 diabetes have no significant insulin production except during the honeymoon period; therefore, most preadolescent children need about 0.5 to 1.0 units/kg/day and adolescents usually requires about 0.8 to 1.2 units/kg/day due to increased insulin resistance during puberty. <ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref> <ref name="Abdul-RasoulHabib2006">{{cite journal|last1=Abdul-Rasoul|first1=Majedah|last2=Habib|first2=Hessa|last3=Al-Khouly|first3=Maha|title='The honeymoon phase' in children with type 1 diabetes mellitus: frequency, duration, and influential factors|journal=Pediatric Diabetes|volume=7|issue=2|year=2006|pages=101–107|issn=1399-543X|doi=10.1111/j.1399-543X.2006.00155.x}}</ref>
*'''Insulin:''' All insulin is manufactured by recombinant DNA technology based on the amino acid sequence of human insulin which are elaborated in '''Table 4'''.<ref name="ChiangMaahs2018">{{cite journal|last1=Chiang|first1=Jane L.|last2=Maahs|first2=David M.|last3=Garvey|first3=Katharine C.|last4=Hood|first4=Korey K.|last5=Laffel|first5=Lori M.|last6=Weinzimer|first6=Stuart A.|last7=Wolfsdorf|first7=Joseph I.|last8=Schatz|first8=Desmond|title=Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association|journal=Diabetes Care|volume=41|issue=9|year=2018|pages=2026–2044|issn=0149-5992|doi=10.2337/dci18-0023}}</ref>
{| class="wikitable"
|+Table 4: Types of insulin preparations and approximate insulin action profiles
|-
! Insulin type !! Onset of action (h) !! Peak of action (h) !! Duration of action (h)
|-
|Rapid-acting analogs
*Aspart (Novolog)
*Lispro (Humalog)
*Glulisine (Apidra)
||
 
*0.25–0.5
*0.25–0.5
*0.25–0.5
||
 
*1–3
*1–3
*1–3
||
 
*3–5
*3–5
*3–5
|-
| Regular insulin ||
*0.5–1
||
*2–4
||
*5–8
|-
| Intermediate-acting: NPH ||
*2–4
||
*4–8
||
*12–18
|-
| Long-acting analogs
*Detemir (Levemir)
*Glargine (Lantus, Basaglar, Toujeo)
*Degludec (Tresiba)
||
 
*2–4
*2–4
*2–4
||
 
*none
*none
*none
||
 
*12–24
*up to 24
*›24
|}
 
*'''Split/mixed regimens:''' It require at least two injections per day of short- and intermediate-acting insulin (a mix of NPH and regular/rapid) being administered shortly before breakfast and dinner to achieve satisfactory metabolic control. When split/mixed regimens are used, patients usually need about two thirds of their total dose in the morning and one third in the evening. The doses usually are split between one-third regular/rapid-acting insulin and two thirds NPH to one-half/one-half. More regular/rapid-acting insulin may be required in the morning because of the dawn phenomenon which is caused by normal nocturnal increases in some counter-regulatory hormones that lead to reduced insulin sensitivity in the early morning. <ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref> <ref name="Davidson2015">{{cite journal|last1=Davidson|first1=Mayer B.|title=Insulin Therapy: A Personal Approach|journal=Clinical Diabetes|volume=33|issue=3|year=2015|pages=123–135|issn=0891-8929|doi=10.2337/diaclin.33.3.123}}</ref>
 
*'''Basal/bolus regimens:''' It aims to achieve more physiologic insulin concentrations with less between-meal insulin action.
**Basal insulin: It provides baseline or fasting insulin needs, which are usually about 50% of total daily insulin requirements, by either rapid-acting insulin given with the basal rate of an insulin pump or with once- or twice daily injections of detemir or glargine. 
**Bolus insulin: It is provided by acute doses of rapid-acting insulin either through injections or through bolus doses given by an insulin pump to cover food requirements and to correct hyperglycemia. It has two parts to the dose: the amount of insulin needed to cover the carbohydrates in the meal and the amount of insulin needed to correct for a blood glucose concentration outside of the target range.
**The Basal/bolus doses are based on empiric formulas, and modifications can be made once responses to starting doses are assessed. 
**The insulin-to-carbohydrate ratio, which may differ for each patient and for different times of day, is the insulin requirement for each gram of carbohydrate in a meal.
**The correction or sensitivity factor is how much the individual patient’s blood glucose values fall when given 1 unit of insulin.
**Thus, the premeal bolus dose equals the insulin-to-carbohydrate ratio multiplied by the grams of carbohydrate to be eaten plus the insulin sensitivity factor multiplied by the amount that the blood glucose needs to fall from the preprandial value to reach the target range.
**Target ranges, for example, may be set at 80 to 120 mg/dL (4.4 to 6.7 mmol/L) for daytime and 100 to 150 mg/dL (5.6 to 8.3 mmol/L) at bedtime. When converting a child from a two- or three-injection regimen with NPH to a basal/bolus regimen, the total daily dose is usually lower, and recommendations are to use 50% to 80% of the NPH dose for the initial basal insulin dose, with the lower percentages used for younger children.<ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref> <ref name="GargRosenstock2005">{{cite journal|last1=Garg|first1=Satish K.|last2=Rosenstock|first2=Julio|last3=Ways|first3=Kirk|title=Optimized Basal-Bolus Insulin Regimens in Type 1 Diabetes: Insulin Glulisine Versus Regular Human Insulin in Combination with Basal Insulin Glargine|journal=Endocrine Practice|volume=11|issue=1|year=2005|pages=11–17|issn=1530891X|doi=10.4158/EP.11.1.11}}</ref>
*'''Automated Insulin Delivery:''' The combination of continuous glucose sensors with insulin pumps has enabled the development of automated insulin delivery systems (“closed-loop” or “artificial pancreas” devices). “Hybrid” closed-loop systems, which modulate basal insulin delivery based on sensor glucose levels, have increased time spent within target glucose ranges, reduced hyper- and hypoglycemia exposure, lowered A1C levels, and improved measures of quality of life in both adult and adolescent subjects. However, transition of automated insulin delivery from research to clinical care will require patient and provider education to optimize outcomes.<ref name="KovatchevCheng2017">{{cite journal|last1=Kovatchev|first1=Boris|last2=Cheng|first2=Peiyao|last3=Anderson|first3=Stacey M.|last4=Pinsker|first4=Jordan E.|last5=Boscari|first5=Federico|last6=Buckingham|first6=Bruce A.|last7=Doyle|first7=Francis J.|last8=Hood|first8=Korey K.|last9=Brown|first9=Sue A.|last10=Breton|first10=Marc D.|last11=Chernavvsky|first11=Daniel|last12=Bevier|first12=Wendy C.|last13=Bradley|first13=Paige K.|last14=Bruttomesso|first14=Daniela|last15=Del Favero|first15=Simone|last16=Calore|first16=Roberta|last17=Cobelli|first17=Claudio|last18=Avogaro|first18=Angelo|last19=Ly|first19=Trang T.|last20=Shanmugham|first20=Satya|last21=Dassau|first21=Eyal|last22=Kollman|first22=Craig|last23=Lum|first23=John W.|last24=Beck|first24=Roy W.|title=Feasibility of Long-Term Closed-Loop Control: A Multicenter 6-Month Trial of 24/7 Automated Insulin Delivery|journal=Diabetes Technology & Therapeutics|volume=19|issue=1|year=2017|pages=18–24|issn=1520-9156|doi=10.1089/dia.2016.0333}}</ref> <ref name="MesserForlenza2018">{{cite journal|last1=Messer|first1=Laurel H.|last2=Forlenza|first2=Gregory P.|last3=Wadwa|first3=R. Paul|last4=Weinzimer|first4=Stuart A.|last5=Sherr|first5=Jennifer L.|last6=Hood|first6=Korey K.|last7=Buckingham|first7=Bruce A.|last8=Slover|first8=Robert H.|last9=Maahs|first9=David M.|title=The dawn of automated insulin delivery: A new clinical framework to conceptualize insulin administration|journal=Pediatric Diabetes|volume=19|issue=1|year=2018|pages=14–17|issn=1399543X|doi=10.1111/pedi.12535}}</ref>
 
*'''Adjunctive therapies:''' Pramlintide, an analog of the pancreatic polypeptide amylin, has been shown to improve glycemic control when added to insulin in adults with type 1 diabetes primarily through dampening glycemic excursions by suppressing glucagon secretion and delaying gastric emptying. However, neither pramlintide nor other potentially useful adjuncts, such as glucagon like peptide 1 receptor agonists (e.g., liraglutide, exenatide) or sodium–glucose cotransporter 2 inhibitors, have been thoroughly studied in the pediatric population with type 1 diabetes, and none have been approved yet for use in this population by the FDA. <ref name="ChiangMaahs2018">{{cite journal|last1=Chiang|first1=Jane L.|last2=Maahs|first2=David M.|last3=Garvey|first3=Katharine C.|last4=Hood|first4=Korey K.|last5=Laffel|first5=Lori M.|last6=Weinzimer|first6=Stuart A.|last7=Wolfsdorf|first7=Joseph I.|last8=Schatz|first8=Desmond|title=Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association|journal=Diabetes Care|volume=41|issue=9|year=2018|pages=2026–2044|issn=0149-5992|doi=10.2337/dci18-0023}}</ref> <ref name="WeyerMaggs2001">{{cite journal|last1=Weyer|first1=C.|last2=Maggs|first2=D.|last3=Young|first3=A.|last4=Kolterman|first4=O.|title=Amylin Replacement With Pramlintide as an Adjunct to Insulin Therapy in Type 1 and Type 2 Diabetes Mellitus: A Physiological Approach Toward Improved Metabolic Control|journal=Current Pharmaceutical Design|volume=7|issue=14|year=2001|pages=1353–1373|issn=13816128|doi=10.2174/1381612013397357}}</ref>
 
===Type 2 Diabetes Mellitus===
 
*'''Pharmacological agents:''' Metformin and insulin are the only medications for use in children and adolescents.<ref name= "ped 2 ch">Tillotson CV, Bowden SA, Boktor SW. Pediatric Type 2 Diabetes Mellitus. [Updated 2020 Nov 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431046/</ref>
**'''Metformin:''' It is first-line therapy along with in combination with diet and exercise in children 10 years and older. It should be initiated at a dosage of 500 mg per day, regardless of the patient’s weight, then titrated in 500 mg intervals over four weeks to the maximum dosage of 2,000 mg per day. The gradual increase of the medication and taking it with food helps to prevent gastrointestinal side effects.
**'''Insulin:''' Insulin may be beneficial for these patients on a short-term basis; subsequently can be discontinued after initiating metformin therapy and lifestyle changes. A basal/bolus regimen like in T1DM may be used, but typically T2DM patients require higher doses (2-3 unit/kg/day). However, it must be initiated in the following scenarios:
***Patient has signs of ketosis or ketoacidosis
***Random plasma glucose levels of 250 mg/dL (13.9 mmol/L) or greater
***A1C level is greater than 9%
***Diagnosis of type 1 vs. type 2 is not clear.
 
===Lifestyle management===
*Lifestyle management is important for pediatric patients with diabetes to enable health maintenance, CVD prevention, and glycemic control.
 
====Nutrition====
*Dietary management should be individualized: family habits, food preferences, religious or cultural needs, schedules, physical activity, and the patient’s and family’s abilities in numeracy, literacy, and self-management level.
*Dietitian visits should include assessment for changes in food preferences over time, access to food, growth and development, weight status, cardiovascular risk, and potential for eating disorders.
*Current consensus recommends the following: <ref name= "ped t1 ch">Los E, Wilt AS. Diabetes Mellitus Type 1 In Children. [Updated 2020 Jun 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441918/</ref>
**'''Carbohydrates''': 50-55% of the daily energy intake but simple carbohydrates like sucrose should not make up more than 10% of the total.
**'''Fats:''' ~30% of the daily energy intake.
**'''Protein:''' 10-15% of the daily energy intake.
*Most carbohydrate calories should be complex carbohydrates, and the fat portion should emphasize low amounts of cholesterol and saturated fats.
*'''Split/ mixed insulin regimens:''' For patients using this regimen, timing of meals is important to minimize blood glucose variability. <ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref>
**'''Mid-afternoon snacks:''' In addition to the usual three meals, they are necessary because they coincide with the typical peak of the morning NPH insulin dose and with most after-school sports activities.
**'''Bedtime snacks:''' They are important for most children receiving evening NPH doses.
**'''Midmorning snacks:''' They are useful in preschool-age children, but most school-age children find such snacks disruptive to their school routine. This snack usually is not recommended after a child begins elementary school.
 
====Physical activity and Exercise====
*Exercise is recommended with the goal of 60 min of moderate- to vigorous intensity aerobic activity daily along with vigorous muscle-strengthening and bone-strengthening activities at least 3 days per week.
*'''Hypoglycemia during exercise:'''
**'''Deranged intrinsic balance:''' The type, intensity, and duration of exercise trigger the release of multiple hormones such as insulin, glucagon, catecholamines, and glucocorticoids to mediate the fuel metabolism. Pancreatic islet cells achieve euglycemia by balancing peripheral glucose uptake and hepatic glucose production. However, this intrinsic balance does not exist in T1DM. Exogenous insulin administration inhibits hepatic glucose production and promotes exercise-induced glucose uptake, thereby both triggering hypoglycemia.
**'''Lag effect:''' Intense exercise increases hypoglycemia risk during, immediately following, and 6–12 h after physical activity namely the “lag effect”. This lag likely results from a combination of improved insulin sensitivity following exercise, blunted counterregulatory hormone release, and increased glucose uptake bythe liver and skeletal muscles to replenish glycogen stores. Impaired counterregulatory hormone release in pediatric patients may include blunting during sleep, antecedent hypoglycemia, and autonomic failure. Delayed hypoglycemia often occurs at night following afternoon physical activities. Therefore, exercise-induced hypoglycemia and fear of hypoglycemia may limit desire to participate in exercise. <ref name="McMahonFerreira2007">{{cite journal|last1=McMahon|first1=Sarah K.|last2=Ferreira|first2=Luis D.|last3=Ratnam|first3=Nirubasini|last4=Davey|first4=Raymond J.|last5=Youngs|first5=Leanne M.|last6=Davis|first6=Elizabeth A.|last7=Fournier|first7=Paul A.|last8=Jones|first8=Timothy W.|title=Glucose Requirements to Maintain Euglycemia after Moderate-Intensity Afternoon Exercise in Adolescents with Type 1 Diabetes Are Increased in a Biphasic Manner|journal=The Journal of Clinical Endocrinology & Metabolism|volume=92|issue=3|year=2007|pages=963–968|issn=0021-972X|doi=10.1210/jc.2006-2263}}</ref>
**'''Preventive measures:''' Education about prevention and management of potential hypoglycemia during and after exercise is essential, including pre-exercise glucose levels of 90–250 mg/dL (5–13 mmol/L) and accessible carbohydrates snacks, individualized according to the type/intensity of the planned physical activity. Strategies to prevent hypoglycemia during exercise, after exercise, and overnight following exercise are as follows:
***Reduce prandial insulin dosing for the meal/snack preceding exercise
***Increase carbohydrate intake
***Eating bedtime snacks
***Use of CGM
***Reduce basal insulin doses
***10-15 g of carbohydrate may prevent hypoglycemia during low- to moderate-intensity aerobic activities (30-60 min) in fasting patient <ref name="RiddellMilliken2011">{{cite journal|last1=Riddell|first1=Michael C.|last2=Milliken|first2=Jill|title=Preventing Exercise-Induced Hypoglycemia in Type 1 Diabetes Using Real-Time Continuous Glucose Monitoring and a New Carbohydrate Intake Algorithm: An Observational Field Study|journal=Diabetes Technology & Therapeutics|volume=13|issue=8|year=2011|pages=819–825|issn=1520-9156|doi=10.1089/dia.2011.0052}}</ref>
***0.5–1.0 g of carbohydrates/kg per hour of exercise (~30-60 g) may prevent hypoglycemia due to relative hyperinsulinemia after insulin boluses which is similar to carbohydrate requirements to optimize performance in athletes without T1DM. <ref name="AdolfssonMattsson2015">{{cite journal|last1=Adolfsson|first1=Peter|last2=Mattsson|first2=Stig|last3=Jendle|first3=Johan|title=Evaluation of glucose control when a new strategy of increased carbohydrate supply is implemented during prolonged physical exercise in type 1 diabetes|journal=European Journal of Applied Physiology|volume=115|issue=12|year=2015|pages=2599–2607|issn=1439-6319|doi=10.1007/s00421-015-3251-4}}</ref> 
*'''Hyperglycemia during exercise:''' It may occur during high-intensity exercise such as sprints or resistance training when there is inadequate delivery of exogenous insulin and/or an excess of counterregulatory hormones that increase hepatic glucose production and inhibit glucose uptake into skeletal muscle. Intense activity should be postponed with marked hyperglycemia (glucose≥350mg/dL [19.4mmol/L]), moderate to large urine ketones, and/or b-hydroxybutyrate ›1.5 mmol/L. Caution may be needed when b-hydroxybutyrate levels are ≥0.6 mmol/L. <ref name="ColbergSigal2016">{{cite journal|last1=Colberg|first1=Sheri R.|last2=Sigal|first2=Ronald J.|last3=Yardley|first3=Jane E.|last4=Riddell|first4=Michael C.|last5=Dunstan|first5=David W.|last6=Dempsey|first6=Paddy C.|last7=Horton|first7=Edward S.|last8=Castorino|first8=Kristin|last9=Tate|first9=Deborah F.|title=Physical Activity/Exercise and Diabetes: A Position Statement of the American Diabetes Association|journal=Diabetes Care|volume=39|issue=11|year=2016|pages=2065–2079|issn=0149-5992|doi=10.2337/dc16-1728}}</ref>
*Hence, frequent glucose monitoring before, during, and after exercise, with or without CGM use, is important to prevent, detect, and treat hypoglycemia and hyperglycemia with exercise.
 
====Education and Family involvement====
*Diabetes comprehensive education about the disease aspects and its potential acute and long-term complications is life-long for patients, families, and the diabetes team.
*They must understand details of insulin action, including duration and timing and dose adjustments, injection and insertion techniques, electronics and mechanics of insulin pumps, dietary information, blood glucose monitoring and interpretation, and urine ketone checks and appropriate interventions.
*'''Family-centered education''' is culturally appropriate to improve medication adherence and successful implications of lifestyle changes. <ref name="VendittiTan2018">{{cite journal|last1=Venditti|first1=E.M.|last2=Tan|first2=K.|last3=Chang|first3=N.|last4=Laffel|first4=L.|last5=McGinley|first5=G.|last6=Miranda|first6=N.|last7=Tryggestad|first7=J.B.|last8=Walders-Abramson|first8=N.|last9=Yasuda|first9=P.|last10=Delahanty|first10=L.|title=Barriers and strategies for oral medication adherence among children and adolescents with Type 2 diabetes|journal=Diabetes Research and Clinical Practice|volume=139|year=2018|pages=24–31|issn=01688227|doi=10.1016/j.diabres.2018.02.001}}</ref>
*Education about diabetes must be appropriate to the child’s age and the family’s educational background. Responsibility for diabetes self-care skills (eg, insulin injections) should be shifted gradually from parent to child, and when the child shows interest and readiness to take responsibility. Premature shifting of responsibility may result in deterioration of metabolic control. Sharing responsibilities and attending support groups and camps for children who have T1DM can help with psychological adjustment. The psychosocial effects of diabetes should be addressed to help children and adolescents cope with the disease. <ref name="CookePlotnick2008">{{cite journal|last1=Cooke|first1=David W.|last2=Plotnick|first2=Leslie|title=Type 1 Diabetes Mellitus in Pediatrics|journal=Pediatrics in Review|volume=29|issue=11|year=2008|pages=374–385|issn=0191-9601|doi=10.1542/pir.29-11-374}}</ref>
 
===Assessment of Glycemic control===
*'''A1C monitoring:''' It should be measured at 3-month intervals to assess their overall glycemic control with a target of ‹7.5%; but should be individualized based on the needs and situation of the patient and family. With increasing use of continuous glucose monitoring (CGM) devices, outcomes other than A1C, such as time with glucose in target range and frequency of hypoglycemia, should be considered in the overall assessment of glycemic control. <ref name="RewersPillay2014">{{cite journal|last1=Rewers|first1=Marian J|last2=Pillay|first2=Kuben|last3=de Beaufort|first3=Carine|last4=Craig|first4=Maria E|last5=Hanas|first5=Ragnar|last6=Acerini|first6=Carlo L|last7=Maahs|first7=David M|title=Assessment and monitoring of glycemic control in children and adolescents with diabetes|journal=Pediatric Diabetes|volume=15|issue=S20|year=2014|pages=102–114|issn=1399543X|doi=10.1111/pedi.12190}}</ref>
*'''Blood glucose monitoring:''' Blood glucose levels should be monitored multiple times daily up to 6–10 times/day including premeal and pre-bedtime; and as needed for safety reasons in specific situations such as exercise, driving, illness, or the presence of hypoglycemic symptoms. <ref name="MillerBeck2013">{{cite journal|last1=Miller|first1=K. M.|last2=Beck|first2=R. W.|last3=Bergenstal|first3=R. M.|last4=Goland|first4=R. S.|last5=Haller|first5=M. J.|last6=McGill|first6=J. B.|last7=Rodriguez|first7=H.|last8=Simmons|first8=J. H.|last9=Hirsch|first9=I. B.|title=Evidence of a Strong Association Between Frequency of Self-Monitoring of Blood Glucose and Hemoglobin A1c Levels in T1D Exchange Clinic Registry Participants|journal=Diabetes Care|volume=36|issue=7|year=2013|pages=2009–2014|issn=0149-5992|doi=10.2337/dc12-1770}}</ref>
*'''Blood/Urinary Ketone Monitoring:''' Blood or urine ketone levels should be measured in the setting of prolonged/severe hyperglycemia or acute illness to determine if treatment adjustment or urgent care referral is needed. <ref name="ChiangMaahs2018">{{cite journal|last1=Chiang|first1=Jane L.|last2=Maahs|first2=David M.|last3=Garvey|first3=Katharine C.|last4=Hood|first4=Korey K.|last5=Laffel|first5=Lori M.|last6=Weinzimer|first6=Stuart A.|last7=Wolfsdorf|first7=Joseph I.|last8=Schatz|first8=Desmond|title=Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association|journal=Diabetes Care|volume=41|issue=9|year=2018|pages=2026–2044|issn=0149-5992|doi=10.2337/dci18-0023}}</ref>
*'''Continuous glucose monitoring (CGM):''' CGM should be considered in all children and adolescents with T1DM, whether using injections or insulin pump therapy, as an additional tool to help improve glycemic control. <ref name="Laffel2016">{{cite journal|last1=Laffel|first1=Lori|title=Improved Accuracy of Continuous Glucose Monitoring Systems in Pediatric Patients with Diabetes Mellitus: Results from Two Studies|journal=Diabetes Technology & Therapeutics|volume=18|issue=S2|year=2016|pages=S2-23–S2-33|issn=1520-9156|doi=10.1089/dia.2015.0380}}</ref>
 
===Anticipatory Guidance===
 
*'''Immunization:''' Diabetic children should receive all immunizations in accordance with the recommendations of the Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention; including annual vaccination against influenza for children with DM who are at least 6 months of age, and one dose of 23-valent pneumococcal polysaccharide vaccine (Pneumovax) at least eight weeks after previous dose of 13-valent pneumococcal conjugate vaccine (Prevnar 13). The child and adolescent vaccination schedule is available at www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html <ref>https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fvaccines%2Fschedules%2Fhcp%2Fchild-adolescent.html</ref>
 
*'''Growth:''' Normal linear growth and appropriate weight gain throughout childhood and adolescence are considered as a measurement markers of general health and metabolic control. Height and weight should be tracked via appropriate growth charts at regular visit available at www.cdc.gov/growthcharts/clinical_charts.htm. Overweight and obesity are emerging issues in youth with T1DM and should be considered as part of dietary counseling. <ref>https://www.cdc.gov/growthcharts/clinical_charts.htm</ref>
 
*'''Multidisciplinary evaluation:''' All people with diabetes should have regular dilated eye exams (to examine for diabetic retinopathy), urine microalbumin screening (to evaluate for renal involvement), hyperlipidemia screens/treatment, hypertension screening/treatment, liver function tests, sleep apnea evaluation, and regular assessment of psychosocial adherence, self-management skills, dietary needs, and physical activity level at appropriate intervals.


===Surgery===
*'''Smoking:''' Elicit a smoking history at initial and follow-up diabetes visits; discourage smoking in youth who do not smoke; and encourage smoking cessation in those who do smoke and referral to an appropriate smoking cessation program should be given. <ref name="ChiangMaahs2018">{{cite journal|last1=Chiang|first1=Jane L.|last2=Maahs|first2=David M.|last3=Garvey|first3=Katharine C.|last4=Hood|first4=Korey K.|last5=Laffel|first5=Lori M.|last6=Weinzimer|first6=Stuart A.|last7=Wolfsdorf|first7=Joseph I.|last8=Schatz|first8=Desmond|title=Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association|journal=Diabetes Care|volume=41|issue=9|year=2018|pages=2026–2044|issn=0149-5992|doi=10.2337/dci18-0023}}</ref>


===Prevention===
*'''Transition from pediatric to adult care:''' Pediatric diabetes providers should begin to prepare youth for transition in early adolescence at least 1 year before the transition to adult health care. Both pediatric and adult diabetes care providers should provide support and resources for transitioning young adults. <ref name="PetersLaffel2011">{{cite journal|last1=Peters|first1=Anne|last2=Laffel|first2=Lori|title=Diabetes Care for Emerging Adults: Recommendations for Transition From Pediatric to Adult Diabetes Care Systems: Table 1|journal=Diabetes Care|volume=34|issue=11|year=2011|pages=2477–2485|issn=0149-5992|doi=10.2337/dc11-1723}}</ref>


==References==
==References==
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[[Category:Pediatrics]]
[[Category:Pediatrics]]
[[Category:Primary care]]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Jaspinder Kaur, MBBS[2]

Synonyms and keywords: Pediatric Diabetes Mellitus (DM)

Overview

Diabetes mellitus (DM) is the metabolic homeostasis disorder regulated by insulin which causes abnormalities in the carbohydrate and lipid metabolism. Type 1 diabetes (also called juvenile-onset diabetes mellitus, DM1, T1DM, and insulin-dependent diabetes mellitus) is considered an immuno-mediated disease that results in a gradual destruction of insulin-producing pancreatic beta cells, and subsequently leads to their complete loss and total dependence on exogenous insulin. The etiology and natural history of T1DM are not yet completely known; however, the genetic and environmental factors are likely responsible for the underlying damage. The genetic effect probably contributes 70 to 75% in the susceptibility to T1DM; while, environmental factors possibly initiates or stimulates the process resulting in the destruction of the beta cells and the disease onset. The disease process begins months to years before the onset of clinical signs such as polyuria, polydipsia, weight loss, and diabetic ketoacidosis. Clinical presentation usually begins at any age; however, most patients will be diagnosed before the age of 30 years. Type 2 diabetes mellitus (T2DM) is characterized by two underlying defects. The earliest abnormality being an insulin resistance which initially compensated with an increase in insulin secretion. Thereafter, T2DM develops due to a defect in insulin secretion that prevents such secretion from matching the increased requirements imposed by an initial insulin-resistant state. Therefore, T1DM results from an absolute insulin deficiency, and relative deficiency in T2DM. Although, the percentage of DM cases in children and adolescents caused by T2DM has risen in the past 1 to 2 decades; however, T1DM remains the most common form of DM in children. Acute and chronic complications including renal failure, retinopathy, neuropathy, and cardiovascular disease are related to and likely caused by the hyperglycemic state. Recombinant insulin analogs, insulin pumps, and newer devices for home monitoring have drastically improved the ability to control glucose concentrations in patients with DM. However, the feedback control in the healthy state that allows minute-to-minute regulation of insulin secretion cannot be recapitulated with current diabetes therapies; thereby achieving the full metabolic normalization not yet possible and making some degree of hyperglycemia persists in virtually all patients with diabetes.

Historical Perspective

  • 400–500 A.D.: Indian physicians named it madhumeha (‘honey urine’) as ants are attracted by urine sweetness. The ancient Indian physician, Sushruta, and the surgeon Charaka discovered the two forms of DM which are later classified as Type I and Type 2 diabetes. [1] [2]
  • 1889: Von Mering and Minkowski while experimenting on dogs found that removal of the pancreas led to diabetes. [3]
  • 1921: Banting, Best and Collip while working in Macleod’s laboratory ligated the pancreatic duct which resulted in the destruction of the exocrine pancreas while leaving the islets intact. They used canine insulin extracts in their animal experiment to reverse induced diabetes; and thereby, conclusively established that the deficiency of insulin was the cause of diabetes. [4]
  • 1922: The discovery of insulin by Canadian surgeon Banting and his assistant Best was made. Following experimentation on dogs, their life-saving infusion of a bovine extract of insulin developed by their biochemist colleague, Collip to a 14-year-old boy, Leonard Thompson, in 1922 at the Toronto General Hospital emerged as a sensation in the world of diabetic therapy. [4]
  • 1960-1969: Urine strips in the 1960s and the automated ‘doit-yourself’ measurement of blood glucose through glucometers produced by Ames Diagnostics in 1969 brought glucose control from the emergency room to the patient’s living room. [5]
  • 1980: Graham Bell manufactured the first human insulin. [6]
  • 1982: The first biosynthetic insulin (humulin) was developed by Eli Lilly. [7]
  • 1986: Eisenbarth proposed the pathophysiological model of T1DM as a gradual deficiency of insulin production resulting from the autoimmune T cells mediated destruction of pancreatic beta cells in individuals genetically susceptible to the disease who were born with a normal number of beta cells; but undergo a process of cell destruction after being exposed to the precipitating environmental factors. [8]
  • November 14: Since 2007, Banting’s colossal contribution has been globally recognized by the declaration of his birthday on November 14 as the World Diabetes Day. [9]

Classification

Diabetes mellitus in children has been classified into the following forms:

  • Type 1 Diabetes mellitus (T1DM)
  • Type 2 Diabetes mellitus (T2DM)
  • Monogenic diabetes: Neonatal diabetes, MODY-maturity onset diabetes of the young, mitochondrial diabetes, and lipoatrophic diabetes[10]
  • Diabetes secondary to other pancreatic diseases, endocrinopathies, infections and cytotoxic drugs[10]
  • Diabetes related to certain genetic syndromes[10]
Table 1: Characteristics of prevalent forms of primary diabetes in children and adolescents[11] [12][13]
Features Type 1 diabetes Type 2 diabetes MODY* Atypical diabetes**
Prevalence ~85% ~12% ~1–4% ≥10% in African American
Age at onset Throughout childhood and adolescence Puberty; rare ‹10 years ‹25 years Pubertal
Onset Acute severe Insidious to severe Gradual Acute severe
DKA at onset ~30% ~6% Not typical Common
Affected relative 5–10% 60–90% 50–90% ›75%
Female:male 1:1 1.1–1.8:1 1:1 Variable
Inheritance Polygenic Polygenic Autosomal dominant Autosomal dominant
HLA-DR3/4 Association No association No association No association
Ethnicity All, Caucasian at highest risk All¶ All African American/Asian
Insulin (C-peptide) secretion Decreased/absent Variable Variably decreased Variably decreased
Insulin sensitivity Normal when controlled Decreased Normal Normal
Insulin dependence Permanent Variable Variable Intermittent
Obesity No† ›90% Uncommon Varies with population
Acanthosis nigricans No Common No† No†
Islet autoantibodies Yes§ No No No
  • *MODY is maturity-onset diabetes in the young or monogenic diabetes.
  • **Atypical diabetes is also referred to as Flatbush diabetes, type 1.5 diabetes, ketosis-prone diabetes, and idiopathic T1DM.
  • ¶In North America, T2DM predominates in African American, Hispanic, Native American, and Canadian First Nations children and adolescents; and is also more common in Asian and South Asian than in Caucasian individuals.
  • †Mirrors rate in general population.
  • §Diabetes-associated (islet) autoantibodies to insulin, islet cell cytoplasmic, glutamic acid decarboxylase, or tyrosine phosphatase (insulinoma-associated) antibody (IA-2, ICA512, ZnT8 antibodies in 85–95%) at diagnosis.

Pathophysiology

Type 1 Diabetes Mellitus

  • Immune-mediated process:[14]
    • The autoimmune destruction of beta cells probably occurs over the course of months to years before diabetes develops.
    • ›80% of beta cells must be lost before significant glycemic control gets impaired.
    • As beta-cell loss progresses beyond that point, insulin is insufficiently secreted to maintain glucose and lipid homeostasis.
    • When glucose concentrations in the blood rise above ~180 mg/dL (10.0 mmol/L), glucosuria occurs leading to an osmotic diuresis that causes polyuria which further stimulates polydipsia to maintain euvolemia.
    • With further progression of insulin deficiency, there is an increase in lipolysis from fat cells as well as protein breakdown; thereby exaggerating the normal fasting state designed to provide alternative sources of fuel.
    • These complex mechanisms along with the caloric loss from glucosuria result in the hyperphagia and weight loss typical of the underlying undiagnosed diabetic state.
    • With profound insulin deficiency, the process devolves into ketoacidosis with marked hyperglycemia, dehydration driven by the glucosuric osmotic diuresis, and accumulation of ketoacids from the hepatic metabolism of the liberated fatty acids.
    • Hence, insufficient endogenous insulin leads to hyperglycemia, hyperglucagonemia, glucosuria, and without treatment, eventually ketosis, acidosis, dehydration, and death.
  • The Diabetes Control and Complications Trial (DCCT) was the pivotal study published in 1993 documenting the clear association of chronic hyperglycemia with long-term microvascular complications such retinopathy, neuropathy, and microalbuminuria (as a surrogate for nephropathy). Follow-up studies have documented the association of chronic hyperglycemia with macrovascular complications as well as all-cause mortality. Iatrogenic hypoglycemia, however, was identified as the major limiting factor to intensive glucose control. [15] [16] [17]

Type 2 Diabetes Mellitus

  • Obesity leads to peripheral insulin resistance and subsequently hyperglycemia. Apart from obesity, certain ethnicities carries higher risks of insulin resistance and beta cell dysfunction. Thereby, hyperglycemia leads to an osmotic diuresis (polyuria) which increases thirst (polydipsia); and this subsequent diuresis causes moderate to severe dehydration. Hence, prolonged hyperglycemia can produce two distinct emergent states in children with T2DM.[18]
  • Diabetic ketoacidosis: It is much more common in children with T2DM than adults. Lack of insulin inhibits the body's ability to use glucose for energy and reverts to breaking down fat for energy. This leads to ketosis, acidosis, and electrolyte abnormalities and may lead to coma and death. [19]
  • Hyperglycemic Hyperosmolar State (HHS): It is characterized by hypertonicity, extreme hyperglycemia (> 600 mg/dl), and severe dehydration resulting from continued osmotic diuresis and intravascular depletion. [19]

Etiology

Type 1 Diabetes Mellitus

  • Both genetic and environmental factors lead to immune-mediated loss of beta cell functions resulting in hyperglycemia and life-long insulin dependence. A "triggering" insult in the form of maternal and intrauterine environment, exposure to viruses, host microbiome, diet and many other factors are thought to contribute towards disease susceptibility by initiating a process that recruits antigen-presenting cells to transport beta cell self-antigens to autoreactive T cells. Through failures of self-tolerance, these T cells mediate beta-cell killing and inflammation leading to insulinopenia and symptomatic DM.
  • Recently, preclinical stages of T1DM have been discovered and divided into 3 different stages as described in the following Table 2.
Table 2: Staging of T1DM
Stage Features
Stage 1
  • Pre-symptomatic DM1: It corresponds to the immunological disease phase with a positive autoimmunity which may progress to the clinical disease over a period of 8 to 10 years.[20]
  • Diagnostic criteria: ›2 autoantibodies against the islet; No IGT or IFG; Normal blood glucose level
Stage 2
  • Pre-symptomatic DM1: It corresponds to the almost irreversible stage of the disease with functional loss of beta cells and the beginning of metabolic disease with positive autoimmunity (two or more autoantibodies against the islet) and pre-diabetic dysglycemia. The risk of symptomatic disease within a period of 5 years is approximately 75%, reaching 100% over a lifetime.[20][21]
  • Diagnostic criteria: ›2 autoantibodies; Dysglycemia: IFG and/or IGT; FPG 100–125 mg/dL (5.6–6.9 mmol/L); 2-h PG 140–199 mg/dL (7.8–11.0 mmol/L); A1C 5.7–6.4% (39–47 mmol/mol) or ≥10% increase in A1C
Stage 3
  • Symptomatic DM1: It corresponds to the autoimmune acceleration stage of the disease with positive autoimmunity (two or more autoantibodies against the islet) and diabetic dysglycemia (diabetic fasting glucose and/or diabetic OGTT, increase in HbA1c). Progression of the symptomatic phase of DM1 can further be classified as following:[20][21][22]
    • Initial phase);
    • Established DM1 phase;
    • Established DM1 phase with chronic complications
  • Diagnostic criteria: Clinical symptoms; Diabetes by standard criteria
  • Although the pre-clinical staging is not usually clinically relevant and progression through these stages may take years; however, research focusing on interventions in the pre-clinical groups may prove to delay or prevent the onset of T1DM.[23]

Type 2 Diabetes Mellitus

  • Insulin resistance state initially leads to an increased insulin production by the remaining beta cells of the pancreas. When the beta cells are unable to produce enough insulin to maintain euglycemia, hyperglycemia results. Thereby, hyperglycemia results when there is a relative lack of insulin production compared to glucose levels in the blood which put damaging effects to multiple organs, including kidneys, eyes, heart, and nerves; and further puts children at risk for other electrolyte disturbances. [24]

Differentiating Diseases[25]

  • Salicylate toxicity
  • Pheochromocytoma
  • Diabetes insipidus
  • Hyperthyroidism

Epidemiology and Demographics

Type 1 Diabetes Mellitus[25]

  • Age: It may be diagnosed at nearly any age, though peaks in presentation occur between ages 5 to 7 and around puberty.
  • Gender: Unlike most autoimmune disorders, T1DM is slightly more common in boys and men.
  • Incidence and prevalence: In the past several decades, it has increased in most age, sex, and race/ethnic groups with some of the rapid growth in young children. There is significant variability in incidence based on geography and ethnicity. For example, the incidence in Finland is 60 per 100,000 person-years, while in China it is 0.1 per 100,000. In the United States, the general population risk is ~0.3% with ~20 to 30 new diagnoses per 100,000 person-years; thereby leaving more than 1.25 million people and around 500,000 children living with T1DM. These incidences have increased by 200% to 300% in the past several decades. [26]
  • Seasonal variation: There appears to be seasonal variation with more cases diagnosed in fall and winter.
  • Family association: If a child has T1DM, concordance in another sibling is around 5%. In fraternal twins, it is around 10% to 30%, and with identical twins, it is 40% to 50%. Children of adults with T1DM are at an approximately 5% to 8% risk.[27]

Type 2 Diabetes Mellitus

  • It is estimated to occur in one in three (20% to 33%) of new diagnoses of diabetes in children today.
  • The rate continues to rise even as the obesity rates have plateaued in these age groups.
  • Risk factors: High-risk ethnicity (African American, Hispanic, Native Americans, Pacific Islanders, Asian Americans), a positive first-degree relative with the disorder, obesity, low birth weight, mother with gestational DM, and female sex. It is more likely to be diagnosed during adolescence when insulin resistance is common due to multiple factors including hormonal changes. [28] [29]

Risk Factors

Type 1 Diabetes Mellitus

  • Genetics:
    • Type of inheritance still remains unknown despite of knowing HLA genes and other genes contributing to the genetic effect.
    • Currently, the main markers of susceptibility to T1DM are considered to be class II HLA haplotypes DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2 serotype) and DRB1*0401-DQA1*0301-DQB1*0302 (DR4-DQ8 serotype), while DRB1*0403 is negatively associated with T1DM, and may protect or slow the progression to clinical disease.[30]
    • Genes such as IL2, CD25, INS, IL18RAP, IL10, IFH1, and PTPN22 appear to exert an influence on the speed of progression to T1DM after the onset of autoimmunity against the islet; and predictive algorithms for T1DM that also incorporated non-HLA genetic markers such as the PTPN22 or the INS gene increased the capacity to predict risk, especially in individuals with the DR3/DR4 haplotype in the general population. [31][32]
    • Genome-wide association studies have already identified more than 40 gene loci associated with the T1DM phenotype involved in autoimmunity, the production and metabolism of insulin, and the survival of the pancreatic beta cells. [33]
    • Recurrence among siblings of a patient with T1DM1 5%, which means a risk 15 times higher, reaching 65-70% between monozygotic twins, or even higher if the index case has developed the disease in childhood. [34]
  • Environmental:
    • Risk factors such as early fetal events, viral infections during the intrauterine or postnatal period, early exposure to the components of cow’s milk, and attending day care as indicative of early infections could trigger the autoimmune process.[35]
    • Maternal risk factors includes advanced maternal age, birth by cesarean section, and lower birth order. [36][37][38]
    • Socioeconomic status: The frequency of T1DM in childhood has been associated with estimates of the wealth of populations, such as the gross domestic product, suggesting that lifestyle habits related to wealth may be responsible for changes in these trends.[39]
    • Vitamin D levels: A correlation between T1DM and vitamin D remains unclear.[40]

Natural History and Prognosis

  • Natural history: It involves an increased risk for acute and severe complications alongwith chronic microvascular and macrovascular complications that negatively affect the quality of life and survival of diabetic patients. A prompt diagnosis and appropriate therapy is important as the risk of diabetes-related complications is related to the duration of the disease. Moreover, the psychosocial impact of living with diabetes can be a challenge for any child and any family; and is particularly burdensome to those with maladaptive coping skills which can sometimes manifest as poor glycemic control.[41]
  • Prognosis: T1DM has high morbidity and mortality. The life expectancy is reduced by 10-20 years for many individuals; and ~1 million people die every year as a result of diabetes, two-thirds of which lives in the developing countries. About one-third of patients with newly-diagnosed T1DM present with diabetic ketoacidosis (DKA) which has a mortality rate of around 0.3-0.5% despite aggressive treatment.[25] [42]

Complications

  • Acute complications: Diabetic Ketoacidosis (DKA) and hypoglycemia are the most significant acute complications of diabetes and its treatment which poses a significant risk of morbidity and mortality.
  • Chronic complications:
    • Both the microvascular and macrovascular complications, which generally take decades for clinically significant presentations to appear, are related to the duration of diabetes and hyperglycemia that persists even with disease treatment.
    • Although some late adolescents with an early onset of DM may show early evidence of complications (eg, nonproliferative retinopathy, microalbuminuria [urinary albumin excretion of 30 to 300 mg/d], or changes in nerve conduction); however, it is extremely uncommon for a child to have significant diabetic microvascular or macrovascular complications. Therefore, glycemic control should be maximized in diabetic children to minimize their risk of long-term complications as they age. [14]
  • Risk reduction:
    • Clinical trials, including the DCCT, have demonstrated that the lower the HbA1c levels which reflects a lower average blood glucose concentration, and hence, the lower the risk of microvascular complications.
    • An improvement in HbA1c of 1% (reflecting a decrease in mean glucose concentrations of 30 to 35 mg/dL [1.67 to 2.9 mmol/L]) decreases the risk of long-term complications by approximately 20% to 50%. There is no threshold for this effect; that is, a lower HbA1c always is better in terms of lowering the risk of long-term complications.
    • However, the absolute risk reduction is less at lower HbA1c values, and lower average glucose values increase the risk of the acute complications of hypoglycemia. Therefore, diabetes management involves a balancing of the long-term benefit of lowering the average glucose concentration with avoiding the acute complication of hypoglycemia.[43] [44]

Hypoglycemia [14]

  • Hypoglycemia: A blood glucose concentration of ‹60 mg/dL (3.3 mmol/L) which occurs frequently in T1DM. It is caused by the inability to match the minute-to-minute changes in insulin requirements with current therapy; thereby resulting in periods when insulin action exceeds insulin requirements. Therefore, patients who have lower average blood glucose concentrations may have more frequent episodes of hypoglycemia.
  • Clinical presentation: It's severity depends upon both the degree of hypoglycemia and the rapidity of its development. The adrenergic symptoms include sweating, trembling, hunger, and palpitations; and the neuroglycopenic symptoms include headache, lightheadedness, dizziness, diplopia, and confusion. Coma and seizures can occur in severe hypoglycemic episode.
  • Treatment: Hypoglycemia in infants and young children and moderate reactions resulting in confusion in older children require that caregivers, teachers, coaches, and others be prepared to assist in the recognition and treatment of hypoglycemia.
    • Mild-to-moderate cases: Treated by ingesting 10 to 15 g of glucose (eg, 4 oz of juice or nondiet soft drink).
    • Severe cases: Intramuscular or subcutaneous glucagon (1 mg, except for infants ‹10 kg, in whom 0.5mg is given). [45]
    • A source of glucose snack (eg, a tube of cake frosting) and a glucagon emergency kit always should be available to treat it as hypoglycemia can occur away from home.[45]

Ketonemia and Ketonuria

  • Indications: The presence of urine or blood ketones should be assessed in the following conditions:[14][46]
    • Persistent and significant hyperglycemia (eg, blood glucose ›250 mg/dL [13.9 mmol/L]) in spite of the administration of corrective doses of insulin
    • Child feels ill particularly with nausea and vomiting.
  • Treatment: Persistent vomiting, or a refusal or inability to take fluids or food orally, requires an emergency department or office visit. Aggressive treatment with additional insulin is necessary once ketosis develops to prevent deterioration into DKA.[14]
    • Rapid-acting insulin at doses of 10% to 20% of the total daily requirement should be given every 3 to 4 hours until the ketones are cleared.
    • Extra fluids are given to maintain hydration and excrete excess glucose and ketoacids.
    • Blood glucose and ketones should be measured frequently at least every 3 to 4 h.
    • During some illnesses, the usual daily insulin doses, adjusted for intake and glucose concentrations, can be continued.
    • For illnesses with disrupted oral intake and ketones development; treat with more frequent small doses of insulin; typical doses may be 5-10% of the total daily dose every 3 to 4 hours and further increasing to 10-20% of the total daily dose every 3 to 4 hours if ketones are present.
    • Hypoglycemic episodes:
      • Care must be taken to avoid causing hypoglycemia in a child who is not able to take sufficient caloric intake due to illness.
      • If solid foods cannot be eaten, sugar-containing foods such as soda, juice, gelatin dessert, and popsicles can be given to maintain some caloric intake and prevent hypoglycemia.
      • Glucagon: The usual dose must be administered for significant hypoglycemia during an illness. Because such doses frequently cause significant nausea and vomiting, and thereby further compromising the ability to ingest food. Hence, smaller doses may be more effective for less severe hypoglycemia due to poor intake: 10 mcg/year of age (minimum 20 mcg, maximum 150 mcg); and a repeat at twice the dose can be attempted if there is no response in 30 minutes.[45]

Diabetes Ketoacidosis

  • DKA is an acute complication usually associated with new-onset T1DM, insulin omission, and increased levels of stress-related counterregulatory hormones/cytokines (e.g., infection). [47]
  • Indications:
    • It must be considered in a child who is not known to have diabetes but presenting with vomiting and dehydration particularly in the presence of an altered sensorium or in the absence of other indicators of a viral infection such as fever and diarrhea.
    • It should be always considered in cases where there is a preceding history of polydipsia and polyuria.
  • Ketotic episode: For a diabetic child, ketones should be measured when the child is significantly ill, if there is vomiting, or if there is persistent hyperglycemia. During a ketotic illness, referral for medical care should be considered if the patient begins to vomit. Medical attention is necessary if the patient has deep respirations or is unable to stand. Early identification and treatment are key to minimizing the further risks and complications.[14][48]

Associated autoimmune disease[14]

  • Thyroid dysfunction: It occurs with greater frequency in individuals with T1DM. Thyroid-stimulating hormone (TSH) should be ordered shortly after diagnosis of DM and may be measured subsequently every 1 to 2 years. TSH should be also measured whenever any thyroid-related signs or symptoms develops. Thyroxine concentrations and thyroid antibodies also may be assessed. [49]
  • Celiac disease: It also occurs more frequently in children with T1DM. All patients should be screened at least once and any time poor growth and gastrointestinal symptoms reported. Tissue transglutaminase and antiendomysial antibodies are more sensitive and specific than antigliadin antibodies. Moreover, it is important to assure that the individual patient is not IgA-deficient by measuring IgA concentrations because these are immunoglobulin A (IgA) antibodies. [50]

Growth Disturbance[14]

  • Height and weight should be measured at every appointment and plotted on growth curves so deviations from normal velocities can be detected early.
  • Decreased growth velocity, crossing percentiles downward for height and weight, eventual short stature, and delayed skeletal and sexual maturation are associated with chronic undertreatment with insulin. Thus, a linear growth is affected negatively by poor diabetic control.
  • Mauriac syndrome or diabetic dwarfism: An extreme form of this effect occurs rarely but usually associated with hepatomegaly.[51]
  • Alternatively, treatment with excessive insulin doses often leads to excessive weight gain; thereby causing the weight curve to cross percentiles upward. [52]
  • Hence, maintenance of normal growth curves for height and weight is an important goal of diabetes management.

Retinopathy

  • It is usually not seen before 5-10 years of diabetes duration.
  • Risk factors: Poor metabolic control, elevated blood pressure, smoking, albuminuria, and elevated lipid values.
  • Recommendations: ADA recommends the first ophthalmologic examination once the child is at least 10 years old and/or has had diabetes for 3 to 5 years. Then, yearly follow-up examinations are suggested. [13]

Nephropathy

  • All patients with T1DM should be monitored by urine microalbumin determination atleast annually beginning after the child is 10 years old and has had diabetes for 5 years due to the higher likelihood of developing end-stage renal disease which might necessitates dialysis or transplantation.[13]
  • Hypertension accelerates the progression of nephropathy; therefore, blood pressure should be monitored several times a year and hypertension should be treated aggressively.
  • Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are recommended for treatment of hypertension. [53] [54]
  • Microalbuminuria (30-299 mg of albumin per gram of creatinine on spot urine) is a marker for early nephropathy. Two of three urine specimens that have elevated values, measured on different days, are needed for confirmation. Patients should avoid other risk factors for nephropathy such as smoking, NSAIDs, etc. [14]
  • If hypertension, overt proteinuria, or elevation in serum creatinine or urea nitrogen values is found; renal functions should be done several times each year and consultation with a nephrologist are warranted.

Neuropathy

  • Symptomatic diabetic neuropathy, peripheral or autonomic, is uncommon in children and adolescents with T1DM.
  • Changes in nerve conduction may be seen after 4-5 years of having diabetes; and thereby increasing the risk of development of neuropathy with the duration of disease and degree of hyperglycemia. Hence, improvements in glycemic control may improve neuropathic symptoms.
  • Recommendations: Consider an annual comprehensive foot exam for the adolescent at the start of puberty or at age 10 years, whichever is earlier, once the youth has had type 1 diabetes for 5 years. [55]

Macrovascular Complications

  • T1DM patients tend to have coronary artery, cerebrovascular, and peripheral vascular disease more often, at an earlier age, and more extensively than the nondiabetic population. Hypertension, elevated blood lipid concentrations, and cigarette smoking are other risk factors for developing macrovascular complications.
  • Risk factors should be analyzed including lipid panels, blood pressure measurements, and determination of smoking status, and treatment instituted as indicated.
  • Studies have show that lower lowdensity lipoprotein (LDL) values are beneficial in lowering the risk of vascular disease and recommendations continue to evolve.
  • Recommendations:
    • Screening with fasting lipid measurements should begin as the following:[14]
      • Children at age 12 years with no concerning family history; or
      • At the time of diagnosis after establishing metabolic control in cases with a positive family history for lipid abnormalities or early cardiovascular events.
    • Current recommendation goal is to achieve an LDL value below 100 mg/dL (2.59 mmol/L); and to treat the following:[13]
      • Children older than age 10 years who have LDL cholesterol concentrations at or above 160 mg/dL (4.14 mmol/L); or
      • LDL value is at or above 130 mg/dL (3.37 mmol/L) if other risk factors are present.
  • Bile acid sequestrants may be recommended as the first treatment in children; however, they are poorly tolerated and effective therapeutic data are lacking. Thus, statins should be considered with appropriate monitoring. [54]
  • Additionally, dietary counseling and blood glucose control are important parts of management.

Diagnosis

Diagnostic Criteria

  • Metabolic tests predicting insulin secretion ability, glycemic state, the functional reserve of beta cells, and the clinical onset of T1DM are as follows:
    • Intravenous glucose tolerance test (IGTT);
    • Oral glucose tolerance test (OGTT);
    • Glycated hemoglobin concentrations (HbA1c).
  • The American Diabetes Association (ADA) recommends the following diagnostic criteria for the diagnosis of glucose disorders in Table 3[56]
Table 3: Diagnostic criteria of glucose disorders according to the American Diabetes Association (ADA) – 2016
Diagnosis Fasting blood glucose (mg/dL) 2H-OGTT (mg/dL) HbA1c (%)
Normal 70 to 99 < 140 4.5 to 5.6
Prediabetes 100 to 125 140 to 199 5.7 to 6.4
Diabetes mellitus ≥ 126 ≥ 200 ≥ 6.5
  • 2H-OGTT: 120 minute time of the oral glucose tolerance test;
  • HbA1c: glycated hemoglobin evaluated by laboratory test aligned with the Diabetes Control and Complications Trial (DCCT).

History and Physical Examination

  • Presenting signs and symptoms: Polyuria, polydipsia and weight loss for days to months. Re-emergence of bedwetting, nocturia, and a need to leave classes in school to use the bathroom are complaints that suggest polyuria. However, some children may present with ketoacidosis associated with the smell of ketones, dehydration, abdominal pain, Kussmaul breathing, vomiting, coma and altered mental status. [25]
  • T2DM: These children most often present during asymptomatic screening. Children with T2DM are more likely than adults with the disorder to present in DKA (5% to 13%), especially if they are of ethnic minority descent. Adolescents with T2DM may also present in Hyperosmolar Hyperglycemic State (HHS).[19]
  • Follow up H&P: A medical provider will assess changes in diabetes status and life circumstances affecting diabetes management, for example, school experience, changes in patterns of exercise and diet, the developmental stage of the child, their participation in diabetes care tasks, family and home life changes, and adherence to therapy. It also focus on assessing issues related to glucose monitoring, insulin delivery (e.g., lipodystrophy, skin tolerance to medical adhesives on diabetes technology), and screening for symptoms of associated medical issues such as thyroid dysfunction or celiac disease. [23] [57]

Diagnostic Evaluation

  • Screening criteria: The American Diabetes Association (ADA) recommends screening for T2DM every three years starting at ten years of age or puberty onset for the following patients:[58] [59] [60]
    • Obese (body mass index (BMI) greater than or equal to the 95th percentile for age)
    • Overweight (BMI greater than or equal to the 85th percentile or > 120% ideal body weight)
    • Two risk factors which includes positive family history, high-risk ethnicity, signs of insulin resistance (polycystic ovary syndrome (PCOS), acanthosis, symptoms), or history of maternal gestational DM.
  • Diagnostic criteria:
    • Random plasma blood glucose 200 mg/dl or greater with symptoms of polyuria, polydipsia, or weight loss.
    • Fasting blood glucose of 126 mg/dl or higher in an asymptomatic patient.
    • Oral glucose tolerance test with blood sugar 200 mg/dl or greater at two hours post ingestion.
    • Hemoglobin A1c > 6.5%.
  • Doubtful diagnosis: Laboratory tests such as fasting insulin or C peptide (both usually high or normal in T2DM, and low in T1DM); and autoantibodies for T1DM can be ordered to differentiate between T1DM and T2DM. However, Islet cell antibodies are only found in about 5% of children and are not specific markers; hence, they are not usually measured to make the diagnosis of T1DM. [19] [25]
  • Multidisciplinary screening: Regular screening for lipid disorders, microalbuminuria, retinopathy, thyroid disorders and celiac disease are recommended based on the duration and status of diabetes control. Assessment of mental health and psychosocial factors are equally important.[23]

Treatment

  • The management requires a diabetes healthcare team consisting of the medical provider, nurse, diabetes educator, dietician, social worker, and psychologist. However, not all specialties are always available, convenient, or covered by insurance.
  • During an initial phase of management, frequent contact between the child and family and medical team through in-office visits is required while being treatment is adjusted; and the family learns the daily management tasks of caring for a child with diabetes as it needs a long-term day to day treatment decisions.
  • Social worker: Involved to ensure that the child has adequate support and finances for treatment.
  • Exercise specialist: Teach the child about beneficial exercises.
  • Diabetic nurse: Assess the child's growth, blood pressure and injection site at every home visit; and assist with the care coordination between the patient and family with the medical providers. A mental health nurse provide counseling if a child with diabetes become depressed.
  • All diabetics should be referred to an ophthalmologist, nephrologist, cardiologist and a neurologist for baseline workup of their respective organ systems. [25]

Type 1 Diabetes Mellitus

  • Insulin delivery: It is done by multiple daily injections (MDI) or an insulin pump to simulate endogenous insulin physiology. [25]
    • Multiple daily injections: Basal insulin is given once or twice daily, and bolus insulin typically injected at meals three or more times daily based on carbohydrate content and current blood glucose.
    • Insulin pumps: They deliver rapid-acting insulin only and provide a basal rate of insulin that is either programmed or automatically adjusted based on continuous glucose monitor input in some pumps, and mealtime insulin is typically calculated based on mealtime inputs of carbohydrate and current blood glucose.
  • Honeymoon period: Patients usually have some remaining beta cells at the time of diagnosis of the diabetes. Hence, insulin requirements often decline temporarily 1 to 3 months after diagnosis. During this honeymoon period, dose requirements may drop to less than 0.5 units/kg/day which may lasts several months occasionally for 12 months or more. However, most patients who have type 1 diabetes have no significant insulin production except during the honeymoon period; therefore, most preadolescent children need about 0.5 to 1.0 units/kg/day and adolescents usually requires about 0.8 to 1.2 units/kg/day due to increased insulin resistance during puberty. [14] [61]
  • Insulin: All insulin is manufactured by recombinant DNA technology based on the amino acid sequence of human insulin which are elaborated in Table 4.[13]
Table 4: Types of insulin preparations and approximate insulin action profiles
Insulin type Onset of action (h) Peak of action (h) Duration of action (h)
Rapid-acting analogs
  • Aspart (Novolog)
  • Lispro (Humalog)
  • Glulisine (Apidra)
  • 0.25–0.5
  • 0.25–0.5
  • 0.25–0.5
  • 1–3
  • 1–3
  • 1–3
  • 3–5
  • 3–5
  • 3–5
Regular insulin
  • 0.5–1
  • 2–4
  • 5–8
Intermediate-acting: NPH
  • 2–4
  • 4–8
  • 12–18
Long-acting analogs
  • Detemir (Levemir)
  • Glargine (Lantus, Basaglar, Toujeo)
  • Degludec (Tresiba)
  • 2–4
  • 2–4
  • 2–4
  • none
  • none
  • none
  • 12–24
  • up to 24
  • ›24
  • Split/mixed regimens: It require at least two injections per day of short- and intermediate-acting insulin (a mix of NPH and regular/rapid) being administered shortly before breakfast and dinner to achieve satisfactory metabolic control. When split/mixed regimens are used, patients usually need about two thirds of their total dose in the morning and one third in the evening. The doses usually are split between one-third regular/rapid-acting insulin and two thirds NPH to one-half/one-half. More regular/rapid-acting insulin may be required in the morning because of the dawn phenomenon which is caused by normal nocturnal increases in some counter-regulatory hormones that lead to reduced insulin sensitivity in the early morning. [14] [62]
  • Basal/bolus regimens: It aims to achieve more physiologic insulin concentrations with less between-meal insulin action.
    • Basal insulin: It provides baseline or fasting insulin needs, which are usually about 50% of total daily insulin requirements, by either rapid-acting insulin given with the basal rate of an insulin pump or with once- or twice daily injections of detemir or glargine.
    • Bolus insulin: It is provided by acute doses of rapid-acting insulin either through injections or through bolus doses given by an insulin pump to cover food requirements and to correct hyperglycemia. It has two parts to the dose: the amount of insulin needed to cover the carbohydrates in the meal and the amount of insulin needed to correct for a blood glucose concentration outside of the target range.
    • The Basal/bolus doses are based on empiric formulas, and modifications can be made once responses to starting doses are assessed.
    • The insulin-to-carbohydrate ratio, which may differ for each patient and for different times of day, is the insulin requirement for each gram of carbohydrate in a meal.
    • The correction or sensitivity factor is how much the individual patient’s blood glucose values fall when given 1 unit of insulin.
    • Thus, the premeal bolus dose equals the insulin-to-carbohydrate ratio multiplied by the grams of carbohydrate to be eaten plus the insulin sensitivity factor multiplied by the amount that the blood glucose needs to fall from the preprandial value to reach the target range.
    • Target ranges, for example, may be set at 80 to 120 mg/dL (4.4 to 6.7 mmol/L) for daytime and 100 to 150 mg/dL (5.6 to 8.3 mmol/L) at bedtime. When converting a child from a two- or three-injection regimen with NPH to a basal/bolus regimen, the total daily dose is usually lower, and recommendations are to use 50% to 80% of the NPH dose for the initial basal insulin dose, with the lower percentages used for younger children.[14] [63]
  • Automated Insulin Delivery: The combination of continuous glucose sensors with insulin pumps has enabled the development of automated insulin delivery systems (“closed-loop” or “artificial pancreas” devices). “Hybrid” closed-loop systems, which modulate basal insulin delivery based on sensor glucose levels, have increased time spent within target glucose ranges, reduced hyper- and hypoglycemia exposure, lowered A1C levels, and improved measures of quality of life in both adult and adolescent subjects. However, transition of automated insulin delivery from research to clinical care will require patient and provider education to optimize outcomes.[64] [65]
  • Adjunctive therapies: Pramlintide, an analog of the pancreatic polypeptide amylin, has been shown to improve glycemic control when added to insulin in adults with type 1 diabetes primarily through dampening glycemic excursions by suppressing glucagon secretion and delaying gastric emptying. However, neither pramlintide nor other potentially useful adjuncts, such as glucagon like peptide 1 receptor agonists (e.g., liraglutide, exenatide) or sodium–glucose cotransporter 2 inhibitors, have been thoroughly studied in the pediatric population with type 1 diabetes, and none have been approved yet for use in this population by the FDA. [13] [66]

Type 2 Diabetes Mellitus

  • Pharmacological agents: Metformin and insulin are the only medications for use in children and adolescents.[19]
    • Metformin: It is first-line therapy along with in combination with diet and exercise in children 10 years and older. It should be initiated at a dosage of 500 mg per day, regardless of the patient’s weight, then titrated in 500 mg intervals over four weeks to the maximum dosage of 2,000 mg per day. The gradual increase of the medication and taking it with food helps to prevent gastrointestinal side effects.
    • Insulin: Insulin may be beneficial for these patients on a short-term basis; subsequently can be discontinued after initiating metformin therapy and lifestyle changes. A basal/bolus regimen like in T1DM may be used, but typically T2DM patients require higher doses (2-3 unit/kg/day). However, it must be initiated in the following scenarios:
      • Patient has signs of ketosis or ketoacidosis
      • Random plasma glucose levels of 250 mg/dL (13.9 mmol/L) or greater
      • A1C level is greater than 9%
      • Diagnosis of type 1 vs. type 2 is not clear.

Lifestyle management

  • Lifestyle management is important for pediatric patients with diabetes to enable health maintenance, CVD prevention, and glycemic control.

Nutrition

  • Dietary management should be individualized: family habits, food preferences, religious or cultural needs, schedules, physical activity, and the patient’s and family’s abilities in numeracy, literacy, and self-management level.
  • Dietitian visits should include assessment for changes in food preferences over time, access to food, growth and development, weight status, cardiovascular risk, and potential for eating disorders.
  • Current consensus recommends the following: [25]
    • Carbohydrates: 50-55% of the daily energy intake but simple carbohydrates like sucrose should not make up more than 10% of the total.
    • Fats: ~30% of the daily energy intake.
    • Protein: 10-15% of the daily energy intake.
  • Most carbohydrate calories should be complex carbohydrates, and the fat portion should emphasize low amounts of cholesterol and saturated fats.
  • Split/ mixed insulin regimens: For patients using this regimen, timing of meals is important to minimize blood glucose variability. [14]
    • Mid-afternoon snacks: In addition to the usual three meals, they are necessary because they coincide with the typical peak of the morning NPH insulin dose and with most after-school sports activities.
    • Bedtime snacks: They are important for most children receiving evening NPH doses.
    • Midmorning snacks: They are useful in preschool-age children, but most school-age children find such snacks disruptive to their school routine. This snack usually is not recommended after a child begins elementary school.

Physical activity and Exercise

  • Exercise is recommended with the goal of 60 min of moderate- to vigorous intensity aerobic activity daily along with vigorous muscle-strengthening and bone-strengthening activities at least 3 days per week.
  • Hypoglycemia during exercise:
    • Deranged intrinsic balance: The type, intensity, and duration of exercise trigger the release of multiple hormones such as insulin, glucagon, catecholamines, and glucocorticoids to mediate the fuel metabolism. Pancreatic islet cells achieve euglycemia by balancing peripheral glucose uptake and hepatic glucose production. However, this intrinsic balance does not exist in T1DM. Exogenous insulin administration inhibits hepatic glucose production and promotes exercise-induced glucose uptake, thereby both triggering hypoglycemia.
    • Lag effect: Intense exercise increases hypoglycemia risk during, immediately following, and 6–12 h after physical activity namely the “lag effect”. This lag likely results from a combination of improved insulin sensitivity following exercise, blunted counterregulatory hormone release, and increased glucose uptake bythe liver and skeletal muscles to replenish glycogen stores. Impaired counterregulatory hormone release in pediatric patients may include blunting during sleep, antecedent hypoglycemia, and autonomic failure. Delayed hypoglycemia often occurs at night following afternoon physical activities. Therefore, exercise-induced hypoglycemia and fear of hypoglycemia may limit desire to participate in exercise. [67]
    • Preventive measures: Education about prevention and management of potential hypoglycemia during and after exercise is essential, including pre-exercise glucose levels of 90–250 mg/dL (5–13 mmol/L) and accessible carbohydrates snacks, individualized according to the type/intensity of the planned physical activity. Strategies to prevent hypoglycemia during exercise, after exercise, and overnight following exercise are as follows:
      • Reduce prandial insulin dosing for the meal/snack preceding exercise
      • Increase carbohydrate intake
      • Eating bedtime snacks
      • Use of CGM
      • Reduce basal insulin doses
      • 10-15 g of carbohydrate may prevent hypoglycemia during low- to moderate-intensity aerobic activities (30-60 min) in fasting patient [68]
      • 0.5–1.0 g of carbohydrates/kg per hour of exercise (~30-60 g) may prevent hypoglycemia due to relative hyperinsulinemia after insulin boluses which is similar to carbohydrate requirements to optimize performance in athletes without T1DM. [69]
  • Hyperglycemia during exercise: It may occur during high-intensity exercise such as sprints or resistance training when there is inadequate delivery of exogenous insulin and/or an excess of counterregulatory hormones that increase hepatic glucose production and inhibit glucose uptake into skeletal muscle. Intense activity should be postponed with marked hyperglycemia (glucose≥350mg/dL [19.4mmol/L]), moderate to large urine ketones, and/or b-hydroxybutyrate ›1.5 mmol/L. Caution may be needed when b-hydroxybutyrate levels are ≥0.6 mmol/L. [70]
  • Hence, frequent glucose monitoring before, during, and after exercise, with or without CGM use, is important to prevent, detect, and treat hypoglycemia and hyperglycemia with exercise.

Education and Family involvement

  • Diabetes comprehensive education about the disease aspects and its potential acute and long-term complications is life-long for patients, families, and the diabetes team.
  • They must understand details of insulin action, including duration and timing and dose adjustments, injection and insertion techniques, electronics and mechanics of insulin pumps, dietary information, blood glucose monitoring and interpretation, and urine ketone checks and appropriate interventions.
  • Family-centered education is culturally appropriate to improve medication adherence and successful implications of lifestyle changes. [71]
  • Education about diabetes must be appropriate to the child’s age and the family’s educational background. Responsibility for diabetes self-care skills (eg, insulin injections) should be shifted gradually from parent to child, and when the child shows interest and readiness to take responsibility. Premature shifting of responsibility may result in deterioration of metabolic control. Sharing responsibilities and attending support groups and camps for children who have T1DM can help with psychological adjustment. The psychosocial effects of diabetes should be addressed to help children and adolescents cope with the disease. [14]

Assessment of Glycemic control

  • A1C monitoring: It should be measured at 3-month intervals to assess their overall glycemic control with a target of ‹7.5%; but should be individualized based on the needs and situation of the patient and family. With increasing use of continuous glucose monitoring (CGM) devices, outcomes other than A1C, such as time with glucose in target range and frequency of hypoglycemia, should be considered in the overall assessment of glycemic control. [72]
  • Blood glucose monitoring: Blood glucose levels should be monitored multiple times daily up to 6–10 times/day including premeal and pre-bedtime; and as needed for safety reasons in specific situations such as exercise, driving, illness, or the presence of hypoglycemic symptoms. [73]
  • Blood/Urinary Ketone Monitoring: Blood or urine ketone levels should be measured in the setting of prolonged/severe hyperglycemia or acute illness to determine if treatment adjustment or urgent care referral is needed. [13]
  • Continuous glucose monitoring (CGM): CGM should be considered in all children and adolescents with T1DM, whether using injections or insulin pump therapy, as an additional tool to help improve glycemic control. [74]

Anticipatory Guidance

  • Immunization: Diabetic children should receive all immunizations in accordance with the recommendations of the Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention; including annual vaccination against influenza for children with DM who are at least 6 months of age, and one dose of 23-valent pneumococcal polysaccharide vaccine (Pneumovax) at least eight weeks after previous dose of 13-valent pneumococcal conjugate vaccine (Prevnar 13). The child and adolescent vaccination schedule is available at www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html [75]
  • Growth: Normal linear growth and appropriate weight gain throughout childhood and adolescence are considered as a measurement markers of general health and metabolic control. Height and weight should be tracked via appropriate growth charts at regular visit available at www.cdc.gov/growthcharts/clinical_charts.htm. Overweight and obesity are emerging issues in youth with T1DM and should be considered as part of dietary counseling. [76]
  • Multidisciplinary evaluation: All people with diabetes should have regular dilated eye exams (to examine for diabetic retinopathy), urine microalbumin screening (to evaluate for renal involvement), hyperlipidemia screens/treatment, hypertension screening/treatment, liver function tests, sleep apnea evaluation, and regular assessment of psychosocial adherence, self-management skills, dietary needs, and physical activity level at appropriate intervals.
  • Smoking: Elicit a smoking history at initial and follow-up diabetes visits; discourage smoking in youth who do not smoke; and encourage smoking cessation in those who do smoke and referral to an appropriate smoking cessation program should be given. [13]
  • Transition from pediatric to adult care: Pediatric diabetes providers should begin to prepare youth for transition in early adolescence at least 1 year before the transition to adult health care. Both pediatric and adult diabetes care providers should provide support and resources for transitioning young adults. [77]

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