Diabetes mellitus type 2 natural history, complications, and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]Anahita Deylamsalehi, M.D.[3] Fatemeh Dehghani Firouzabadi, MD [4] Javaria Anwer M.D.[5]

Overview

If diabetes mellitus type 2 is left untreated, it may result in hyperosmolar hyperglycemic state (HHS) and in rare circumstances, diabetic ketoacidosis (DKA). These are classified as acute complications of diabetes. Chronic complications of diabetes mellitus include microvascular and macrovascular complications. Early diagnosis and prompt treatment of these complications may result in improved prognosis and less long term morbidity and mortality.

Natural History

• Type 2 diabetes may go unnoticed for years because symptoms are typically mild, non-existent or sporadic, and usually there are no ketoacidotic episodes. However, severe long-term complications can result from unnoticed type 2 diabetes, including renal failure due to diabetic nephropathy, vascular disease (including coronary artery disease), visual changes due to diabetic retinopathy, loss of sensation or pain due to diabetic neuropathy, and liver damage from non-alcoholic steatohepatitis secondary to metabolic syndrome.
• Untreated DM type 2 may also result in acute complications such as hyperosmolar hyperglycemic state (HHS) and in rare circumstances, diabetic ketoacidosis (DKA).

Complications

• Complications of diabetes mellitus type 2 are divided in to 2 major groups:

Acute complications

• Acute complications include diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS).
• These complications are seen in type 2 diabetes but HHS is more common and usually is seen in old age with limited therapeutic resources.

Chronic complications

• The following table summarizes the chronic complications of diabetes.

Chronic complications of Diabetes Type Organ system Compliaction Microvascular complications Eye Retinopathy (nonproliferative/proliferative) Macular edema Nervous system Sensory and motor neuropathy (mono and polyneuropathy) Autonomic neuropathy Kidneys Nephropathy (albuminuria and declining renal function) Macrovascular complications Coronary and vascular Coronary heart disease Peripheral arterial disease CNS Cerebrovascular disease Others Gastrointestinal (GI) Gastroparesis Diarrhea Fatty liver disease Genitourinary Uropathy Sexual dysfunction HEENT Hearing loss Periodontal disease Skin Pigmented pretibial patches Eye Cataracts Glaucoma CNS Depression Cognitive impairment Dementia

• Unlike Type 1 diabetes, there is little tendency toward ketoacidosis in Type 2 diabetes, though it is not unknown. One effect that can occur is non ketotic hyperglycemia. Complex and multi-factorial metabolic changes lead to damage and function impairment of many organs, most importantly the cardiovascular system in both types. This leads to substantially increased morbidity and mortality in both Type 1 and Type 2 patients, but the two have quite different origins and treatments despite the similarity in complications.
• Type 2 diabetes has been related to reduction in verbal fluency and memory in a period of ~ 5 years. Furthermore, type 2 diabetes is related to earlier onset of dementia. Ten years follow up of diabetic patients in their midlife demonstrated rapid decline in global cognitive function, executive function and processing speed compared to normal population. Diabetic patients have higher chance of earlier onset of brain atrophy, included hippocampal and medial temporal atrophy.

Heart Disease and Stroke

• People with diabetes are more prone to heart and blood vessel disease. Diabetes carries an increased risk for heart attack, stroke, and complications related to poor circulation.
• Diabetic patients are more vulnerable to atherosclerosis, compared to normal population. They also have higher chance of severe heart failure development due to diabetic cardiomyopathy.
• 2 out of 3 people with diabetes die from heart disease or stroke.
• Diabetes management is more than control of blood glucose. People with diabetes must also manage blood pressure and cholesterol and talk to their healthcare provider to learn about other ways to reduce their chances for heart attacks and stroke. Lifestyle changes, such as healthy diet and being physically active, as well as taking medication can help. Many people find that changing what they eat can make a big difference in their blood glucose, blood pressure, and cholesterol levels.
• There is no need to perform screening exercise stress testing in asymptomatic diabetic patients and annual assessment for blood pressure, fasting lipid profile and smoking history is recommended for all patients.
• Diabetic patients have higher carotid intima-media thickness (CIMT), heart rate and QTc interval compared to normal population. Furthermore, investigations demonstrated lower flow-mediated dilatation (FMD) at the brachial artery and higher prevalence of left ventricle hypertrophy and diastolic dysfunction in diabetic patients.
• There are some data suggesting how diabetes mellitus can lead to cardiac complications. One of them suggests that high blood glucose can increase circulating fatty acids and subsequently activates cardiomyocyte's PPARα. The augmented PPARα activity will increase fatty acid oxidation, which ultimately decreases cardiac fatty acid oxidation capacity. Reduction in cardiac fatty acid oxidation capacity causes intramyocardial lipid accumulation and ensuing cardiomyocyte lipotoxicity. Another explanation is pyruvate dehydrogenase inhibition due to PDK4 induction, fatty acid and ketone bodies, which result in glycolytic intermediates accumulation in a diabetic heart.

Kidney Disease

• South Asian population are more prone to develop diabetic nephropathy, compared to the Caucasian population.
• In a study done in China, 21.3% of diabetic patients developed chronic kidney disease.
• There are some data suggesting that there is a faster rate of renal function deterioration in diabetic kidney disease (DKD) or diabetic kidney disease (DKD) superimposed on nondiabetic renal disease (NDRD), compared to nondiabetic renal disease.
• There is a possible relationship between polymorphisms within the Carnosine Dipeptidase 1 (CNDP1) gene and diabetic nephropathy development.

• Diabetes can damage the filtering ability of kidneys. High levels of blood sugar make the kidneys filter too much blood. All this extra work is hard on the filters. After many years, they start to leak. Useful protein is lost in the urine. Having small amounts of protein in the urine is called microalbuminuria. When kidney disease is diagnosed early, (during microalbuminuria), several treatments may keep kidney disease from getting worse. Having larger amounts is called macroalbuminuria. When kidney disease is caught later (during macroalbuminuria), end-stage renal disease (ESRD) usually follows. In time, the stress of overwork causes the kidneys to lose their filtering ability. Waste products then start to build up in the blood. Finally, the kidneys fail. This failure, ESRD, is very serious. A person with ESRD needs to have a kidney transplant or to have the blood filtered by machine (dialysis). Diabetic kidney disease can be prevented by keeping blood sugar in the target range.
• A study done on Chinese population found an association between elevated tyrosine level and increased likelihood of diabetic nephropathy.
• There are some data that support uNCR (urinary neutrophil gelatinase-associated lipocalin (uNGAL)/Cr ratio) as a possible diagnostic tool for suspected diabetic kidney disease or in patients that required confirmatory kidney biopsy. Based on these data, diabetic patients with uNCR ratio more than 60.685 ng/mg has 7.595 times higher probability of nephrotic-range proteinuria compared to the group with uNCR≤60.685 ng/mg.

Eye Complications

• People with diabetes are 40% more likely to suffer from glaucoma than people without diabetes.
• The duration of diabetes is directly related to higher risk of glaucoma development. Thus risk also increases with age. Glaucoma occurs when pressure builds up in the eye, and vision is gradually lost because the retina and nerve are damaged.
• Many people without diabetes get cataracts, but people with diabetes are 60% more likely to develop this eye condition. People with diabetes also tend to get cataracts at a younger age and have them progress faster. With cataracts, there is clouding of the clear lens of the eye, which blocks light.
• Diabetic retinopathy is a general term for all disorders of the retina caused by diabetes. In nonproliferative retinopathy, capillaries in the back of the eye balloon and form pouches. Nonproliferative retinopathy can move through three stages (mild, moderate, and severe), as more and more blood vessels become blocked. In some people, retinopathy progresses after several years to a more serious form, called proliferative retinopathy which can lead to blindness caused by retinal detachment. People who keep their blood sugar levels closer to normal are less likely to have retinopathy or have milder forms.
• A study done on hospitalized diabetic patients showed that rapid HbA1c reduction is related to higher chance of proliferative retinopathy, while gradual decrease is safe.
• A cross-sectional study demonstrated a positive association between retinopathy development and myostatin level in diabetic patients.
• Prevention of severe hypoglycemia, smoking cessation and maintaining renal function have been introduced as factors that prevent visual loss in diabetic patients.
• Apoptosis of retinal pigmented epithelial cells (RPEs) is one of the possible mechanisms of diabetic retinopathy development. A molecule named miR-203a-3p has been recognized as an important regulator of CoCl2-induced RPEs apoptosis. Deregulation of this molecule may serve as a path for limiting diabetic retinopathy.
• Recommendations for ophthalmologic screening is at the time of diagnosis and then yearly in the presence of retinopathy. Otherwise, ophthalmologic examinations can be done every 2 years if there is no sign of retinopathy.

Diabetic Neuropathy and Nerve Damage

• One of the most common complications of diabetes is diabetic neuropathy. Neuropathy means damage to the nerves that run throughout the body, connecting the spinal cord to muscles, skin, blood vessels, and other organs.
• There are two common types of nerve damage. The first is sensorimotor neuropathy, also known as peripheral neuropathy. This can cause tingling, pain, numbness, or weakness in feet and hands. The second is called autonomic neuropathy. The latter type can lead to:
  • Digestive problems such as feeling full, nausea,
  • Vomiting, diarrhea, or constipation
  • Uropathy
  • Sexual dysfunction
  • Dizziness or faint
  • Loss of the typical warning signs of a heart attack
  • Loss of the warning signs of low blood glucose
  • Increased or decreased sweating
  • Cranial neuropathies

• People with diabetes can also have what is called focal neuropathy. In this kind of nerve damage, a nerve or a group of nerves is affected, causing sudden weakness or pain. It can lead to double vision, a paralysis on one side of the face called Bell's palsy, or pain in the front of the thigh or other parts of the body.
• People with diabetes also are at risk for compressed nerves. Carpal tunnel syndrome is a common cause of numbness and tingling in the fingers and can lead to muscle pain and weakness as well. Keeping blood glucose levels in the target range can prevent or delay further damage.
• Diabetic patients may experience impairment in the muscle endurance, regardless of neuropathy presence. On the contrary, explosive and maximal muscle strength is related to presence and severity of neuropathic complications in diabetic patients.

Foot Complications

• Although it can hurt, diabetic nerve damage can also lessen the ability to feel pain, heat, and cold. A foot injury may go unnoticed until the skin breaks down and becomes infected.
• Nerve damage can also lead to changes in the shape of feet and toes. Ulcers occur most often on the ball of the foot or on the bottom of the big toe.
• Neglecting foot ulcers can result in infections, which can eventually lead to limb loss.
• Screening for peripheral vascular disease should be performed by checking the distal pulses.
  Test for sensation should be performed by using:
  • A Semmes-Weinstein 5.07 (10 g) monofilament at specific sites to detect loss of sensation in the foot

Evaluation of sensation with a 10g monofilament at specific sites, case courtesy by Joselyn Rojas "Peripheral and Autonomic Neuropathy in an Adolescent with Type 1 Diabetes Mellitus: Evidence of Symptom Reversibility after Successful Correction of Hyperglycemia".

• • Vibration using a 128-Hz tuning fork

Evaluation of vibratory sense with a 128-Hz tuning fork, case courtesy by Nitin Kapoor"Approach to diabetic neuropathy".

• • Pinprick sensation
  • Ankle reflexes
• A study done on diabetic patients with foot ulcer showed that piRNA, a factor related to better wound healing, have been elevated in wounds of diabetic who received negative pressure wound treatment(NPWT).
• A meta-analysis done on 2020 suggested that autologous platelet-rich plasma treatment for diabetic foot ulcer enhances complete wound healing and speeds up the healing process. This study reported that this method doesn't increase the rate of side effects.

Gastroparesis

• Gastroparesis is a disorder affecting patient with both type 1 and type 2 diabetes, defined as delayed gastric emptying in the absence of any obstruction.
• It occurs when gastric nerves are damaged. The vagus nerve controls the movement of food through the digestive tract. If the vagus nerve is damaged, the muscles of the stomach and intestines do not function normally, which leads to stasis of food.
• Gastroparesis can make diabetes worse by making it more difficult to manage blood glucose level. When gastric emptying has been delayed, intestinal absorption of nutrition will be postponed too, which consequently will cause delay in blood glucose elevation. This can cause a mismatch between insulin or other postprandial anti-diabetic drugs which may present as uncontroled postprandial blood glucose level.
• The following is a list of some complications related to gastroparesis:
  • Mallory–Weiss tear from chronic nausea and vomiting
  • Malnutrition
  • Formation of bezoar
    • Food particles can harden into solid masses called bezoars that may cause nausea, vomiting, and GI obstruction in the stomach. Bezoars can be dangerous if they block food passage within the Gastrointestinal tract.
  • Esophagitis
  • Hypovolemia and consequent acute kidney injury
  • Electrolyte disturbances
  • Hyperglycemia emergencies such as diabetic ketoacidosis and hyperosmolar hyperglycemic state
  • If food stays too long in the stomach, it can cause problems like bacterial overgrowth due to food fermentation

Hypoglycemia, Hyperglycemia, and a High Risk for Diabetic Comas

• Although intensive therapy improves numerous diabetic complications, it can lead to coma and hypoglycemic related seizure with a relative risk of 3.02.
• Hypoglycemia could be asymptomatic in some patients, however if symptomatic the symptoms include:
  • Shakiness and tremor
  • Paresthesia
  • Palpitation
  • Dizziness
  • Sweating
  • Hunger
  • Headache
  • Pale skin
  • Sudden moodiness or behavior changes, such as crying for no apparent reason
  • Anxiety
  • Clumsy or jerky movements
  • Difficulty paying attention, or confusion
  • Tingling sensations around the mouth
  • Cognitive dysfunction, seizure and coma

COVID-19 infection

• Diabetes mellitus, specifically type 2 diabetes has been recognized as one of the most common comorbidities of COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It has been estimated that 20-25% of patients with COVID-19 had diabetes.
• SARS-CoV-2 infection has been linked with higher rate of hospitalization and mortality in diabetic patients compared to non-diabetics.
• Records from the Centers for Disease Control and Prevention (CDC) and other national health centers and hospitals state that diabetic patients with COVID-19 have up to 50% higher chance of death compared to non diabetics with this infection.
• Another study done in the US reports more than fourfold mortality rate elevation in COVID-19 in diabetic patients.
• Study on COVID-19 patients in intensive care unit showed a twofold increase in incidence of diabetes, compared to non-intensive care patients.
• Older age and high C-reactive protein (CPR) level are two risk factors that increase mortality rate in diabetic patients who become infected with SARS-CoV-2. Therefore, A study suggests usage of C-reactive protein (CRP) as a tool to identify patients with higher chance of dying during hospitalization.
• Sever COVID-19 in diabetic patients were related to higher levels of serum amyloid A (SAA) and low CD4+ T lymphocyte counts.
• Diabetic patients with SARS-CoV-2 infection have lower levels of the following, compared to non-diabetics:
  • Lymphocytes
  • Red blood cells (RBC)
  • Albumin
  • Hemoglobin

• Diabetic patients with SARS-CoV-2 infection have higher levels of the following, compared to non-diabetics:
  • Neutrophils
  • Erythrocyte sedimentation rate (ESR)
  • D-dimer
  • A-hydroxybutyrate dehydrogenase
  • Lactic dehydrogenase
  • Alanine aminotransferase (ALT)
  • Fibrinogen
  • C reactive protein
  • Ferritin
  • Interleukin-6 (IL-6)

Risk Factors

• Some possible factors that lead to more severe COVID-19 in diabetic patient have been summarized in the table below:

Confirmed factors	hypothesized factors
1- Glycemic instability 2- Immune deficiency (specially T-cell response) 3- Related comorbidities, like obesity and cardiac and renal disease	1- Chronic inflammation (elevated interleukin-6) 2- Elevated plasmin 3- Reduced ACE2 4- Increased furin (involved in virus entry into cell)

• Abnormal production of adipokines and cytokines like Tumor necrosis factor-alpha and interferon in diabetic patients have been associated with impairment in immune system and increased susceptibility to infections.

Complications:

• Diabetic patients with SARS-CoV-2 infection had higher rate of complications like acute respiratory distress syndrome (ARDS), septic shock, acute kidney injury, acute heart injury, requirement of oxygen inhalation, multi-organ failure and both non-invasive and invasive ventilation (eg, extracorporeal membrane oxygenation (ECMO)).

• Optimal metabolic control reduce the chance of complications in concurrent diabetes mellitus and COVID-19 in outpatients.

Management Considerations:

• Evaluation of electrolytes, blood glucose, blood PH, blood ketones or beta-hydroxybutyrate should be considered in patients in intensive care unit (ICU).
• Since hypokalemia is a feature of COVID-19 (possibly as a result of high angiotensin 2 concentration and consequent hyperaldosteronism), potassium level should be checked (especially in concurrent insulin treatment).
  • Severe hypokalaemia, which is defined as measures lower than 2∙5 mEq/L, has been related to elevated mortality rate in hospitalized patients.
• Plasma glucose concentration goal for diabetic outpatients infected with SARS-CoV-2 is 72-144 mg/dl, while plasma glucose concentration of patients in intensive care unit is recommended to be maintained between 72 and 180 mg/dl.
• Treatment with insulin was associated with poor prognosis in diabetic patients with COVID-19. Although, Insulin is the choice agent to control blood glucose in hospitalized diabetic patients with COVID-19.
• Possible β cell damage caused by SARS-CoV-2 can cause to insulin deficiency, which explain increased insulin requirement in these patients. Due to elevated insulin consumption, intravenous infusion must be considered.
• Although angiotensin-converting enzyme II (ACE) expression has been reduced in COVID-19, treatment with ACE inhibitors (ACEI) or angiotensin II type-I receptor blockers (ARB) in diabetic patient with hypertension had no significant difference compared to other anti-hypertensive treatments based on one study. On the other hand, another study done on diabetic patients showed higher risk of SARS-CoV-2 infection with ACE2-increasing drugs. Elevated ACE2 level can ease the entry of virus. Therefore It is hypothesized that medications like, Angiotensin-converting-enzyme inhibitors (ACEI), angiotensin II type-I receptor blockers (ARB), thiazolidinediones and ibuprofen augment the risk of a severe and lethal SARS-CoV-2 infection.
• Due to increased risk of chronic kidney disease and acute kidney injury, renal function should be monitored in patients who take metformin. There is also a recommendation to stop Metformin use in a patient with poor oral intake and vomiting. There are other data that suggest metformin as a possibly helpful anti-diabetic agent in concurrent SARS-CoV-2 infection. Since metformin leads to less elevation in interleukin-6 level, compared to other anti-diabetic agents. These data also assert an association between metformin use and albumin level elevation and a lower COVID-19 related death in patients who took metformin.
• A hypothesis state that since Sodium glucose cotransporter 2 (SGLT-2) inhibitors decrease lactate production and subsequently increase the cytosolic pH, they interfere with virus entry into the cells. Conversely, based on another study Sodium glucose cotransporter 2 (SGLT-2) inhibitors are also indirectly responsible for high ACE2 level, which is attributed as a risk factor for SARS-CoV-2 infection. High ACE2 level can be further elevated by concurrent Angiotensin-converting-enzyme inhibitors (ACEI) use. Current database suggests benefit from discontinuation of Sodium glucose cotransporter 2 (SGLT-2) inhibitors in diabetic patient with COVID-19.
• Initiation of Sodium-glucose-co-transporter 2 inhibitors should be avoided in respiratory illnesses.
• Although lactic acidosis due to metformin use and euglycaemic or moderate hyperglycaemic diabetic ketoacidosis associated with Sodium-glucose-co-transporter 2 inhibitors are rare, their usage has not been recommended. Nevertheless, there is no need to stop these medications prophylactically in diabetic patients with no sign of COVID-19.
• Dipeptidyl peptidase-4 inhibitors has been well tolerated in some diabetic patients with concurrent SARS-CoV-2 infection. It can be continue in mild to moderate COVID-19, nevertheless it is better to be discontinued in sever cases.
• Use of thiazolidinediones has been linked with increased fluid retention and congestive heart failure in diabetic patients with SARS-CoV-2 infection. Pioglitazone use can be continued in mild or moderate COVID-19.
• Dehydration in diabetic patients with COVID-19 should be avoided. Based on a practical recommendation, medications with possible dehydration side effect like Metformin, Sodium-glucose-co-transporter 2 inhibitors and Glucagon-like peptide-1 receptor agonists should be avoided to prevent further complications.
• A summary of anti-diabetic medications in diabetic patients with SARS-CoV-2 infection:

Anti-diabetic medication	Relation to ACE2 expression	Advantage	Disadvantage
Metformin	None	Lower level of IL-6 Higher albumin level Lower COVID-19 related death Potential cardiovascular benefits	Higher chance of lactic acidosis and renal dysfunction higher chance of dehydration
Pioglitazone	Increased ACE2 production in animal models	Reduction in proinflammatory cytokines Lower chance of lung injury	Increased chance of SARS-CoV-2 infection due to ACE2 overexpression
Sulfonylurea	None	No specific advantage has been found in patients with COVID-19	Higher chance of hypoglycemia
Dipeptidyl peptidase-4 inhibitors	None	Some anti-inflammatory properties are reported	No specific disadvantage has been found in patients with COVID-19
Sodium-glucose-co-transporter 2 inhibitors	Increased ACE2 production by kidney in human studies	Decreased oxidative stress Anti-inflammatory effects	Higher chance of hypovolemia
Glucagon-like peptide-1 receptor agonists	Liraglutide has been linked with elevated ACE2 production in lung and heart in animal models	Potential cardiovascular benefits	Higher chance of dehydration higher chance of gastrointestinal side effects
Insulin	Increased Renal ACE2 production in animal models	Anti-inflammatory effects	No specific disadvantage has been found in patients with COVID-19

Prognosis

• Diabetes mellitus has been the seventh leading cause of death in the united states in 2015. Based on data reported by CDC, mortality rate has 2 fold increase in diabetic patients compared to non-diabetics at the same age.
• Depending on the extent of the disease, the time of diagnosis and glycemic control, the prognosis may varies.
• Timely diagnosis and prompt treatment with preventive measures will result in good prognosis, conversely delayed diagnosis or inadequate treatment may lead to multiple and severe complications such as limb amputation, blindness, coronary artery disease or renal failure.
• It seems that targeting multiple risk factors is more successful in prognosis improvement, compared to concentrating on one single factor.
• Based on a Cohort study, cardiac disease and cancer related deaths are the most common etiologies of death in diabetic patients.
• Premature death have been reported due to heart attack, stroke and kidney disease.
• Due to kidney failure, some patients may become dependent on dialysis or need a kidney transplant.
• Hypoglycemia is another worrisome complication in diabetic patients which can be a consequence of over treatment and both the healthcare provider and the patient must be aware of it.
• There are some strong results that state treatment with lipid-lowering agents like statins are able to significantly improve prognosis of diabetic patients with coronary heart disease (CHD).
• United Kingdom Prospective Diabetes Study (UKPDS), which followed 5000 patients with type 2 diabetes, demonstrated fewer microvascular complications when intense treatment were used. Nevertheless rates of macrovascular disease didn't change except in obese patients on metformin monotherapy, possibly due to myocardial infarction risk reduction.
• Steno-2 study in Denmark also reported lower rate of cardiovascular disease and related death, end-stage renal disease progression, and need for retinal photo-coagulation in patients who received intensive treatment.
• It has been estimated that for every 1% of HbA1C elevation, there is a 66% increase in mortality rate. On the other hand, HbA1C lower than 6% has been related to better outcome in diabetic patients.
• One study suggests that HbA1C measured 3 months after diabetes mellitus type 2 diagnosis, can predict the subsequent mortality of these patients.
• A study proposed single-photon CT myocardial perfusion (SPECT) imaging as a possible predictive tool for cardiovascular events and subsequent cardiac death in asymptomatic patients with diabetes mellitus.
• In old diabetic patients with concurrent myocardial infarction a significant increase have been reported in their 5-year mortality rate. Conversely, in young diabetic patients with concurrent myocardial infarction, the mortality rate is strongly related to duration of diabetes mellitus. Furthermore, a cohort study suggests diabetes mellitus as an independent predictor of cardiac related complications and mortality in the first year after myocardial infarction.
• *Based on a meta-analysis by Palmer et al., SGLT-2 inhibitors and GLP-1 receptor agonists, together for the treatment of DM type 2, reduce mortality, non-fatal myocardial infarction, and serious hyperglycemia, and renal failure.

References

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