Diabetic ketoacidosis pathophysiology: Difference between revisions

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{{Diabetic ketoacidosis}}
{{Diabetic ketoacidosis}}
{{CMG}}
{{CMG}}; {{AE}}{{HK}}


==Overview==
==Overview==
Development of diabetic ketoacidosis (DKA) is the result of a relative or absolute deficiency of [[insulin]] and an excess of [[glucagon]]. In [[diabetic]] patients, this leads to a shift from an [[anabolic]] state to a [[catabolic]] state. This leads to activation of various [[enzymes]] that cause an increase in [[blood]] [[glucose]] levels (via [[glycogenolysis]] and [[gluconeogenesis]]) and [[blood]] [[ketone]] levels (via [[lipolysis]]). The severe [[hyperglycemia]] results in [[glucosuria]] and [[osmotic diuresis]] leading to a state of [[dehydration]]. [[Muscle wasting]] is a consequence of [[proteolysis]] due an excess of counter-regulatory hormones ([[glucagon]], [[catecholamines]] and [[cortisol]]).


==Pathophysiology==
==Pathophysiology==
Diabetic ketoacidosis (DKA) results from insulin deficiency from new-onset diabetes (usually type 1 diabetes), insulin noncompliance, prescription or illicit drug use, and increased insulin need because of any condition. DKA features [[hyperglycemia]], [[acidosis]], and high levels of circulating [[ketone bodies]]. When there is no or minute amounts of circulating [[insulin]], for example in type 1 diabetes or less commonly in type 2 diabetes, the consequence is an elevation of counter-regulatory hormones/stress hormones (glucagon, catecholamines, cortisol, and growth hormone). This process eventually leads to the development of DKA.
Diabetic ketoacidosis (DKA) is the result of [[insulin]] deficiency from new-onset [[diabetes]] (usually [[Diabetes mellitus type 1|type 1 diabetes]]), [[insulin]] noncompliance, prescription or illicit drug use, and increased [[insulin]] need because of any condition. DKA features [[hyperglycemia]], [[acidosis]], and high levels of circulating [[ketone bodies]]. When there is no or minute amounts of circulating [[insulin]], for example in [[Diabetes mellitus type 1|type 1 diabetes]] or less commonly in [[Diabetes mellitus type 2|type 2 diabetes]], the consequence is an elevation of counter-regulatory hormones/[[Stress hormone|stress hormones]] ([[glucagon]], [[catecholamines]], [[cortisol]], and [[growth hormone]]). This process eventually leads to the development of DKA.<ref name="pmid126685463">{{cite journal |vauthors=Chiasson JL, Aris-Jilwan N, Bélanger R, Bertrand S, Beauregard H, Ekoé JM, Fournier H, Havrankova J |title=Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state |journal=CMAJ |volume=168 |issue=7 |pages=859–66 |year=2003 |pmid=12668546 |pmc=151994 |doi= |url=}}</ref>


== Pathogenesis ==
== Pathogenesis ==


=== Insulin deficiency ===
=== Insulin deficiency ===
* In type 1 diabetics there is immune-associated destruction of insulin-producing pancreatic β cells, which leads to no or decreased levels of insulin in the body. This leads to a major pre-disposition to the development of DKA in this patient population.
* In [[Diabetes mellitus type 1|type 1 diabetics]] there is [[Immune-mediated disease|immune]]-associated destruction of [[insulin]]-producing [[Pancreas|pancreatic β cells]], which leads to no or decreased levels of [[insulin]] in the body. This leads to a major pre-disposition to the development of DKA in this patient population.<ref name="pmid21248163">{{cite journal |vauthors=van Belle TL, Coppieters KT, von Herrath MG |title=Type 1 diabetes: etiology, immunology, and therapeutic strategies |journal=Physiol. Rev. |volume=91 |issue=1 |pages=79–118 |year=2011 |pmid=21248163 |doi=10.1152/physrev.00003.2010 |url=}}</ref>
* In type 2 diabetics, although the major mechanism of hyperglycemia is peripheral insulin resistance and there is some basal production of insulin; patients may develop a failure of pancreatic β cells at late stages of the disease. This is rare but may lead to development of DKA in these patients.
* In [[Diabetes mellitus type 2|type 2 diabetics]], although the major mechanism of [[hyperglycemia]] is peripheral [[insulin]] resistance and there is some basal production of [[insulin]]; patients may develop a failure of [[Pancreas|pancreatic β cells]] at late stages of the [[disease]]. This is rare but may lead to development of DKA in these patients.<ref name="pmid15925010">{{cite journal |vauthors=Leahy JL |title=Pathogenesis of type 2 diabetes mellitus |journal=Arch. Med. Res. |volume=36 |issue=3 |pages=197–209 |year=2005 |pmid=15925010 |doi=10.1016/j.arcmed.2005.01.003 |url=}}</ref>
* The major effect of insulin deficiency is decreased intra-cellular glucose utilization and mobilization of body sources of glucose by counter-regulatory or stress hormones namely, glucagon, catecholamines, cortisol and growth hormone. This eventually leads to a large increase in blood glucose levels and ketonemia.
* The major effect of [[insulin]] deficiency is decreased [[Intracellular|intra-cellular]] [[glucose]] utilization and mobilization of body sources of [[glucose]] by counter-regulatory or [[Stress hormone|stress hormones]] namely, [[glucagon]], [[catecholamines]], [[cortisol]] and [[growth hormone]]. This eventually leads to a large increase in [[blood]] [[glucose]] levels and [[ketonemia]].<ref name="pmid6511925">{{cite journal |vauthors=Gelfand RA, Matthews DE, Bier DM, Sherwin RS |title=Role of counterregulatory hormones in the catabolic response to stress |journal=J. Clin. Invest. |volume=74 |issue=6 |pages=2238–48 |year=1984 |pmid=6511925 |pmc=425416 |doi=10.1172/JCI111650 |url=}}</ref>


=== Increased lipolysis and ketogenesis ===
=== Increased [[lipolysis]] and [[ketogenesis]] ===
'''<u>Basic enzymes involved</u>'''
'''<u>Basic enzymes involved</u>'''
* The rate of lipolysis and ketogenesis depends upon the action of three enzymes:  
* The rate of [[lipolysis]] and [[ketogenesis]] depends upon the action of three [[enzymes]]:<ref name="urlKetone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes - Laffel - 1999 - Diabetes/Metabolism Research and Reviews - Wiley Online Library">{{cite web |url=http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1520-7560(199911/12)15:6%3C412::AID-DMRR72%3E3.0.CO;2-8/full |title=Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes - Laffel - 1999 - Diabetes/Metabolism Research and Reviews - Wiley Online Library |format= |work= |accessdate=}}</ref> <ref name="pmid14641008">{{cite journal |vauthors=Holm C |title=Molecular mechanisms regulating hormone-sensitive lipase and lipolysis |journal=Biochem. Soc. Trans. |volume=31 |issue=Pt 6 |pages=1120–4 |year=2003 |pmid=14641008 |doi=10.1042/ |url=}}</ref><ref name="pmid17313320">{{cite journal |vauthors=Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS |title=Regulation of lipolysis in adipocytes |journal=Annu. Rev. Nutr. |volume=27 |issue= |pages=79–101 |year=2007 |pmid=17313320 |pmc=2885771 |doi=10.1146/annurev.nutr.27.061406.093734 |url=}}</ref><ref name="pmid16545081">{{cite journal |vauthors=Brownsey RW, Boone AN, Elliott JE, Kulpa JE, Lee WM |title=Regulation of acetyl-CoA carboxylase |journal=Biochem. Soc. Trans. |volume=34 |issue=Pt 2 |pages=223–7 |year=2006 |pmid=16545081 |doi=10.1042/BST20060223 |url=}}</ref><ref name="pmid15968460">{{cite journal |vauthors=Tong L |title=Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery |journal=Cell. Mol. Life Sci. |volume=62 |issue=16 |pages=1784–803 |year=2005 |pmid=15968460 |doi=10.1007/s00018-005-5121-4 |url=}}</ref>
** Hormone-sensitive lipase (or triglyceride lipase), which is found in peripheral adipocytes
** '''[[Hormone-sensitive lipase]]''' (or triglyceride lipase), which is found in peripheral [[adipocytes]]
** Acetyl CoA carboxylase, which is found in the liver
** '''Acetyl CoA carboxylase''', which is found in the [[liver]]
** Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS), which is also found in the liver
** '''Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase''' (mHS), which is also found in the [[liver]]


* Insulin and glucagon play the key roles in regulating lipolysis and ketogenesis by acting in opposition to each other.
* [[Insulin]] and [[glucagon]] play the key roles in regulating [[lipolysis]] and [[ketogenesis]] by acting in opposition to each other.<ref name="pmid20733001">{{cite journal |vauthors=Choi SM, Tucker DF, Gross DN, Easton RM, DiPilato LM, Dean AS, Monks BR, Birnbaum MJ |title=Insulin regulates adipocyte lipolysis via an Akt-independent signaling pathway |journal=Mol. Cell. Biol. |volume=30 |issue=21 |pages=5009–20 |year=2010 |pmid=20733001 |pmc=2953052 |doi=10.1128/MCB.00797-10 |url=}}</ref><ref name="pmid6122545">{{cite journal |vauthors=Foster DW, McGarry JD |title=The regulation of ketogenesis |journal=Ciba Found. Symp. |volume=87 |issue= |pages=120–31 |year=1982 |pmid=6122545 |doi= |url=}}</ref><ref name="pmid4808635">{{cite journal |vauthors=Liljenquist JE, Bomboy JD, Lewis SB, Sinclair-Smith BC, Felts PW, Lacy WW, Crofford OB, Liddle GW |title=Effects of glucagon on lipolysis and ketogenesis in normal and diabetic men |journal=J. Clin. Invest. |volume=53 |issue=1 |pages=190–7 |year=1974 |pmid=4808635 |pmc=301453 |doi=10.1172/JCI107537 |url=}}</ref>
 
* [[Insulin]] inhibits [[ketogenesis]] by causing the [[dephosphorylation]] of [[hormone-sensitive lipase]] ([[Hormone-sensitive lipase|HSL]]) and leads to [[lipogenesis]] by stimulating acetyl CoA carboxylase.<ref name="pmid14641008">{{cite journal |vauthors=Holm C |title=Molecular mechanisms regulating hormone-sensitive lipase and lipolysis |journal=Biochem. Soc. Trans. |volume=31 |issue=Pt 6 |pages=1120–4 |year=2003 |pmid=14641008 |doi=10.1042/ |url=}}</ref>
* Insulin inhibits ketogenesis by causing the dephosphorylation of hormone-sensitive lipase (HSL) and leads to lipogenesis by stimulating acetyl CoA carboxylase.
* In the [[adipose tissue]], [[dephosphorylation]] of [[hormone-sensitive lipase]] ([[Hormone sensitive lipase|HSL]]) decreases the degradation of [[triglycerides]] into [[fatty acids]] and [[glycerol]], the [[rate-limiting step]] in the release of [[free fatty acids]] from the [[adipocyte]]. This subsequently reduces the amount of [[substrate]] that is available for [[ketogenesis]].<ref name="pmid4146798">{{cite journal |vauthors=Halestrap AP, Denton RM |title=Insulin and the regulation of adipose tissue acetyl-coenzyme A carboxylase |journal=Biochem. J. |volume=132 |issue=3 |pages=509–17 |year=1973 |pmid=4146798 |pmc=1177615 |doi= |url=}}</ref>
* In the adipose tissue, dephosphorylation of hormone-sensitive lipase (HSL) decreases the degradation of triglycerides into fatty acids and glycerol, the rate-limiting step in the release of free fatty acids from the adipocyte. This subsequently reduces the amount of substrate that is available for ketogenesis.
* [[Insulin]] also [[Dephosphorylation|dephosphorylates]] the [[inhibitory]] sites on acetyl CoA carboxylase leading to [[enzyme]] activation and increased production of [[Malonyl-CoA|malonyl CoA]]. [[Malonyl-CoA|Malonyl CoA]] [[Inhibitor|inhibits]] [[beta oxidation]] of [[fatty acids]] thereby decreasing [[ketogenesis]].<ref name="pmid4146798">{{cite journal |vauthors=Halestrap AP, Denton RM |title=Insulin and the regulation of adipose tissue acetyl-coenzyme A carboxylase |journal=Biochem. J. |volume=132 |issue=3 |pages=509–17 |year=1973 |pmid=4146798 |pmc=1177615 |doi= |url=}}</ref>
* Insulin also dephosporylates the inhibitory sites on acetyl CoA carboxylase leading to enzyme activation and increased production of malonyl CoA. Malonyl CoA inhibits beta oxidation of fatty acids thereby decreasing ketogenesis.
* [[Glucagon]] stimulates [[ketogenesis]] by causing the [[phosphorylation]] of both [[hormone-sensitive lipase]] ([[Hormone-sensitive lipase|HSL]]) and acetyl CoA carboxylase via [[cyclic AMP]]-dependent [[protein kinase]]. in the [[adipocytes]], [[phosphorylation]] of [[lipase]] by [[cyclic AMP]]-dependent [[protein kinase]] causes degradation of [[triglycerides]] into [[fatty acids]].<ref name="pmid6122545">{{cite journal |vauthors=Foster DW, McGarry JD |title=The regulation of ketogenesis |journal=Ciba Found. Symp. |volume=87 |issue= |pages=120–31 |year=1982 |pmid=6122545 |doi= |url=}}</ref><ref name="pmid2858203">{{cite journal |vauthors=Holland R, Hardie DG, Clegg RA, Zammit VA |title=Evidence that glucagon-mediated inhibition of acetyl-CoA carboxylase in isolated adipocytes involves increased phosphorylation of the enzyme by cyclic AMP-dependent protein kinase |journal=Biochem. J. |volume=226 |issue=1 |pages=139–45 |year=1985 |pmid=2858203 |pmc=1144686 |doi= |url=}}</ref>
* Glucagon stimulates ketogenesis by causing the phosphorylation of both hormone-sensitive lipase (HSL) and acetyl CoA carboxylase via cyclic AMP-dependent protein kinase. in the adipocytes, phosphorylation of lipase by cyclic AMP-dependent protein kinase causes degradtion of trigycerides into fatty acids.
* In [[Hepatocyte|hepatocytes]], [[phosphorylation]] of [[Acetyl-CoA carboxylase|acetyl CoA carboxylase]] by [[cyclic AMP]]-dependent [[protein kinase]] decreases the production of [[Malonyl-CoA|malonyl CoA]] which subsequently stimulates [[fatty acid]] uptake by the [[mitochondria]] of the [[Cell (biology)|cells]] for [[oxidation]], and thus increases the amount of [[substrate]] available for [[ketogenesis]].
* In hepatocytes, phosphorylation of acetyl CoA carboxylase by cyclic AMP-dependent protein kinase decreases the production of malonyl CoA which subsequently stimulates fatty acid uptake by the mitochondria for oxidation, and thus increases the amount of substrate available for ketogenesis.
* The activity of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) is increased by [[starvation]] and a high-fat [[Diet (nutrition)|diet]], and it is decreased by [[insulin]].<ref name="pmid7902069">{{cite journal |vauthors=Serra D, Casals N, Asins G, Royo T, Ciudad CJ, Hegardt FG |title=Regulation of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase protein by starvation, fat feeding, and diabetes |journal=Arch. Biochem. Biophys. |volume=307 |issue=1 |pages=40–5 |year=1993 |pmid=7902069 |doi=10.1006/abbi.1993.1557 |url=}}</ref>
* The activity of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) is increased by starvation and a high-fat diet, and it is decreased by insulin.
'''<u>Ketosis and acedemia in DKA</u>'''
'''<u>Ketosis and acedemia in DKA</u>'''
* Insulin deficiency is the most important regulator of ketogenesis.  
* [[Insulin]] deficiency is the most important regulator of [[ketogenesis]].  
* Lipolysis is mediated by hormone-sensitive lipase in adipose tissue. Hormone-sensitive lipase is activated by both insulin deficiency and the rise in counter-regulatory hormones in DKA.<ref name="urlwww.niddk.nih.gov">{{cite web |url=https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/Documents/Diabetes%20in%20America%202nd%20Edition/chapter13.pdf |title=www.niddk.nih.gov |format= |work= |accessdate=}}</ref>
* [[Lipolysis]] is mediated by [[hormone-sensitive lipase]] in [[adipose tissue]]. [[Hormone-sensitive lipase]] is activated by both [[insulin]] deficiency and the rise in counter-regulatory hormones in DKA.<ref name="urlwww.niddk.nih.gov">{{cite web |url=https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/Documents/Diabetes%20in%20America%202nd%20Edition/chapter13.pdf |title=www.niddk.nih.gov |format= |work= |accessdate=}}</ref>
* In the liver of patients with active DKA, the deficiency of insulin and the high levels of counter-regulatory hormones (mainly glucagon) act synergistically to decrease the re-esterification of FFA  and to increase the processes by which FFA are transported into mitochondria where they are converted into ketone bodies. FFA transport into hepatic mitochondria is enhanced by glucagon-mediated decrease in the cytosolic malonyl-CoA, which removes inhibition of carnitine palmitoyltransferase 1 (CPT1).
* In the [[liver]] of patients with active DKA, the deficiency of [[insulin]] and the high levels of counter-regulatory hormones (mainly [[glucagon]]) act [[Synergy|synergistically]] to decrease the re-esterification of [[free fatty acids]] ([[Fatty acid|FFA]]) and to increase the processes by which [[FFA]]<nowiki/>s are transported into [[mitochondria]] where they are converted into [[ketone bodies]]. [[FFA]] transport into [[hepatic]] [[mitochondria]] is enhanced by [[glucagon]]-mediated decrease in the cytosolic [[malonyl-CoA]], which removes inhibition of [[Carnitine palmitoyltransferase I|carnitine palmitoyltransferase 1]]      ([[Carnitine palmitoyltransferase I|CPT1]]).<ref name="pmid19694967">{{cite journal |vauthors=Schreurs M, Kuipers F, van der Leij FR |title=Regulatory enzymes of mitochondrial beta-oxidation as targets for treatment of the metabolic syndrome |journal=Obes Rev |volume=11 |issue=5 |pages=380–8 |year=2010 |pmid=19694967 |doi=10.1111/j.1467-789X.2009.00642.x |url=}}</ref><ref name="pmid124319">{{cite journal |vauthors=DiMarco JP, Hoppel C |title=Hepatic mitochondrial function in ketogenic states. Diabetes, starvation, and after growth hormone administration |journal=J. Clin. Invest. |volume=55 |issue=6 |pages=1237–44 |year=1975 |pmid=124319 |pmc=301878 |doi=10.1172/JCI108042 |url=}}</ref>
* Excessive amounts of fatty acyl CoA derivatives are oxidized to form ketone bodies, and large quantities of 3-hydroxybutyrate and acetoacetate are released into the blood.
* Excessive amounts of fatty acyl CoA derivatives are [[oxidized]] to form [[ketone bodies]], and large quantities of 3-hydroxybutyrate and [[acetoacetate]] are released into the [[blood]].
* Ketone bodies are acidic and lead to a decrease in pH of the body (acedemia).
* [[Ketone bodies]] are [[acidic]] in nature and lead to a decrease in pH of the body ([[Acidosis|acedemia]]).
 
* In DKA the ratio of 3-hydroxybutyrate to [[acetoacetate]] rises to 3:1 or higher (to as high as 10:1).<ref name="urlDiabetic Ketoacidosis: Evaluation and Treatment - American Family Physician">{{cite web |url=http://www.aafp.org/afp/2013/0301/p337.html |title=Diabetic Ketoacidosis: Evaluation and Treatment - American Family Physician |format= |work= |accessdate=}}</ref>
* In DKA the ratio of 3-hydroxybutyrate to acetoacetate rises to 3:1 or higher (to as high as 10:1).
* [[Insulin]] deficiency also acts to reduce [[renal clearance]] of [[ketone bodies]] via unclear mechanisms.<ref name="pmid4203779">{{cite journal |vauthors=Ruderman NB, Goodman MN |title=Inhibition of muscle acetoacetate utilization during diabetic ketoacidosis |journal=Am. J. Physiol. |volume=226 |issue=1 |pages=136–43 |year=1974 |pmid=4203779 |doi= |url=}}</ref><ref name="pmid3918903">{{cite journal |vauthors=Féry F, Balasse EO |title=Ketone body production and disposal in diabetic ketosis. A comparison with fasting ketosis |journal=Diabetes |volume=34 |issue=4 |pages=326–32 |year=1985 |pmid=3918903 |doi= |url=}}</ref>
* Insulin deficiency also acts to reduce renal clearance of ketone bodies via unclear mechanisms.<ref name="pmid4203779">{{cite journal |vauthors=Ruderman NB, Goodman MN |title=Inhibition of muscle acetoacetate utilization during diabetic ketoacidosis |journal=Am. J. Physiol. |volume=226 |issue=1 |pages=136–43 |year=1974 |pmid=4203779 |doi= |url=}}</ref><ref name="pmid3918903">{{cite journal |vauthors=Féry F, Balasse EO |title=Ketone body production and disposal in diabetic ketosis. A comparison with fasting ketosis |journal=Diabetes |volume=34 |issue=4 |pages=326–32 |year=1985 |pmid=3918903 |doi= |url=}}</ref>


=== Increased blood glucose level ===
=== Increased blood glucose level ===
Other effects of insulin include stimulation of the formation of [[glycogen]] from glucose and inhibition of glycogenolysis;  stimulation of [[fatty acid]] (FA) production from stored lipids <!-- animals lack the enxyme machinery to do this -- "synthesis from glucose" --> and inhibition of FA release into the blood; stimulation of FA uptake and storage; inhibition of protein [[catabolism]] and of gluconeogenesis, in which glucose is synthesised (mostly from some amino acid types, released by protein catabolism). A lack of insulin therefore has significant effects, all of which contribute to increasing blood glucose levels, to increased fat metabolism and protein degradation. Fat metabolism is one of the underlying causes of DKA.
'''<u>Basic enzymes involved</u>'''
* [[Glycogen]] and [[proteins]] are [[Catabolism|catabolized]] to form [[glucose]].<ref name="urlDiabetic Ketoacidosis: Evaluation and Treatment - American Family Physician">{{cite web |url=http://www.aafp.org/afp/2013/0301/p337.html |title=Diabetic Ketoacidosis: Evaluation and Treatment - American Family Physician |format= |work= |accessdate=}}</ref>
* Increased [[lipolysis]], [[proteolysis]], [[glycogenolysis]] and decreased [[glucose]] utilization lead to an increased [[glucose]] concentration in [[blood]].
* The following [[enzymes]] are involved in these processes:
** [[Glycogenolysis]]: '''[[Glycogen phosphorylase]].'''
** [[Gluconeogenesis]]: '''[[Phosphofructokinase 2|Phosphofructokinase-2]] ([[Phosphofructokinase 2|PFK-2]])''' and '''fructose bisposphatase-2 (FB-2)''' which control the production of [[fructose 2,6-bisphosphate]] (an allosteric modifier of the activity of '''[[phosphofructokinase-1]] (PFK-1)''' and '''[[fructose 1,6-bisphosphatase]] (FBPase-1)''', which control [[gluconeogenesis]] and [[glycolysis]]).
* [[Insulin]] inhibits [[glycogen phosphorylase]], leading to decreased [[blood]] [[glucose]] and [[Dephosphorylation|dephosphorylates]] [[Phosphofructokinase 2|PFK-2]] leading to its activation and inhibiting the FBPase-2 activity. With increased [[fructose 2,6-bisphosphate]] present, activation of PFK-1 occurs to stimulate [[glycolysis]] while inhibiting [[gluconeogenesis]].<ref name="pmid442206">{{cite journal |vauthors=Bulman GM, Arzo GM, Nassimi MN |title=An outbreak of tropical theileriosis in cattle in Afghanistan |journal=Trop Anim Health Prod |volume=11 |issue=1 |pages=17–20 |year=1979 |pmid=442206 |doi= |url=}}</ref>
* [[Glucagon]] triggers production of [[cyclic adenosine monophosphate]] ([[Cyclic adenosine monophosphate|cAMP]]), which activates a [[cAMP-dependent protein kinase]]. This [[kinase]] [[phosphorylates]] the [[Phosphofructokinase 2|PFK-2]]<nowiki/>and FBPase-2 [[enzymes]]. This causes activation of FBPase-2 activity and [[inhibition]] of [[Phosphofructokinase 2|PFK-2]] activity, thereby decreasing the levels of [[fructose 2,6-bisphosphate]] in the [[Cell (biology)|cell]]. With decreasing amounts of [[fructose 2,6-bisphosphate]], [[glycolysis]] is inhibited while [[gluconeogenesis]] is activated.<ref name="pmid6286362">{{cite journal |vauthors=Pilkis SJ, El-Maghrabi MR, McGrane M, Pilkis J, Claus TH |title=Regulation by glucagon of hepatic pyruvate kinase, 6-phosphofructo 1-kinase, and fructose-1,6-bisphosphatase |journal=Fed. Proc. |volume=41 |issue=10 |pages=2623–8 |year=1982 |pmid=6286362 |doi= |url=}}</ref>
'''<u>Hyperglycemia in DKA</u>'''
* In DKA, due to a profound [[insulin]] deficiency, here is an excess of counter-regulatory hormones/[[Stress hormone|stress hormones]], for example, [[glucagon]], [[cortisol]], [[catecholamines]] and [[growth hormone]] which all lead to an increase production of [[glucose]] in the body.
* The [[serum]] [[glucose]] level in DKA is usually > 250 mg/dl but usually < 1000 mg/dl. Values exceeding 1000 mg/dl are usually found in [[Hyperosmolar hyperglycemic state|hyperosmolar non-ketotic state]], which is found in [[Diabetes mellitus type 2|type 2 diabetics]].<ref name="pmid12668546">{{cite journal |vauthors=Chiasson JL, Aris-Jilwan N, Bélanger R, Bertrand S, Beauregard H, Ekoé JM, Fournier H, Havrankova J |title=Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state |journal=CMAJ |volume=168 |issue=7 |pages=859–66 |year=2003 |pmid=12668546 |pmc=151994 |doi= |url=}}</ref>
* The increased [[serum]] [[glucose]] may lead to [[osmotic diuresis]] in patient leading to [[dehydration]] and weakness.<ref name="pmid126685462">{{cite journal |vauthors=Chiasson JL, Aris-Jilwan N, Bélanger R, Bertrand S, Beauregard H, Ekoé JM, Fournier H, Havrankova J |title=Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state |journal=CMAJ |volume=168 |issue=7 |pages=859–66 |year=2003 |pmid=12668546 |pmc=151994 |doi= |url=}}</ref>


===Muscle Wasting===
=== Muscle wasting ===
Muscle wasting occurs primarily due to the lack of inhibition of protein catabolism; insulin inhibits the breakdown of proteins and, since muscle tissue is protein, a lack of insulin encourages muscle wasting, releasing amino acids both to produce glucose (by gluconeogenesis) and for the synthesis of ATP via partial respiration of the remaining amino acids.
* [[Muscle wasting]] occurs primarily due to the lack of [[inhibition]] of [[protein]] [[catabolism]].
In those suffering from starvation, blood glucose concentrations are low due to both low consumption of carbohydrates and because most of the glucose available is being used as a source of energy by tissues unable to use most other sources of energy, such as neurons in the brain. Since insulin lowers blood glucose levels, the normal bodily mechanism here is to prevent insulin secretion, thus leading to similar fat and protein catabolic effects as in [[Type I diabetes|type 1 diabetes]]. Thus the muscle wastage visible in those suffering from starvation also occurs in [[Type I diabetes|type 1 diabetics]], normally resulting in weight loss.
* [[Insulin]] inhibits the breakdown of [[proteins]] and, since [[muscle tissue]] is [[protein]], a lack of [[insulin]] encourages [[muscle wasting]], releasing [[amino acids]] both to produce [[glucose]] (by [[gluconeogenesis]]).
'''Pathophysiology of diabetic ketoacidosis at a glance'''
{{familytree/start}}
{{familytree | | | | | | | | | A01 | | | | | |A01='''Profound [[insulin]] deficiency/[[stress]]/[[infection]]'''}}
{{familytree | | | | | | | | | |!| | | | | | | | }}
{{familytree | | | | | | | | | B01 | | | | | |B01=Increased levels of counter-regulatory hormones ([[glucagon]], [[catecholamines]], [[cortisol]])}}
{{familytree | | |,|-|-|-|-|-|-|+|-|-|-|-|-|-|.| }}
{{familytree | | C01 | | | | | C02 | | | | | C03 |C01=Increased [[lipolysis]]|C02=Increased [[proteolysis]], decreased [[protein synthesis]] (increased availability of gluconeogenic substrates)|C03=Increased [[glycogenolysis]]}}
{{familytree | | |!| | | | | | |!| | | | | | |!| | }}
{{familytree | |D01| | | | |D02| | | | |D03|D01= Increased [[ketogenesis]] '''([[acidosis]])'''|D02= Increased [[gluconeogenesis]] '''([[hyperglycemia]])'''|D03= '''[[Hyperglycemia]]'''}}
{{familytree | | | | | | | | | |!| | | | | | |!| | }}
{{familytree | | | | | | | | |E01| | | | |E02|E01='''[[Glucosuria]] and [[dehydration]]'''|E02='''[[Glucosuria]] and [[dehydration]]''' }}
{{familytree/end}}


===Brain===
== Associated Conditions ==
Normally, ketone bodies are produced in minuscule quantities, feeding only part of the energy needs of the [[heart]] and brain. In DKA, the body enters a starving state. Eventually, neurons (and so the brain) switch from using glucose as a primary fuel source to using ketone bodies. As a result, the bloodstream is filled with an increasing amount of glucose that it cannot use (as the liver continues [[gluconeogenesis]] and exporting the glucose so made). This significantly increases its [[osmolality]]. At the same time, massive amounts of ketone bodies are produced, which, in addition to increasing the osmolar load of the blood, are [[acid]]ic. As a result, the [[pH]] of the blood begins to move downward towards an acidotic state. The normal pH of human blood is 7.35-7.45, in acidosis the pH dips below 7.35.  Very severe acidosis may be as low as 6.9-7.1.  The acidic shift in the blood is significant because the proteins (i.e. body tissues, enzymes, etc.) in the body will be permanently denatured by a pH that is either too high or too low, thereby leading to widespread tissue damage, organ failure, and eventually death. Glucose begins to spill into the [[urine]] as the proteins responsible for reclaiming it from urine (the SGLT family) reach maximum capacity (the renal threshold for glucose). As glucose is excreted in the urine, it takes a great deal of body water with it, resulting in dehydration.  Dehydration further concentrates the blood and worsens the increased osmolality of the blood.  Severe dehydration forces water out of cells and into the bloodstream to keep vital [[organ (biology)|organs]] perfused.  This shift of intracellular water into the bloodstream occurs at a cost as the cells themselves need the water to complete chemical reactions that allow the cells to function.
The following conditions are associated with diabetic ketoacidosis (DKA):
* [[Diabetes mellitus type 1|Type 1 diabetes mellitus]]
* [[Diabetes mellitus type 2|Type 2 diabetes mellitus]]


==References==
==References==

Latest revision as of 03:55, 9 November 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Development of diabetic ketoacidosis (DKA) is the result of a relative or absolute deficiency of insulin and an excess of glucagon. In diabetic patients, this leads to a shift from an anabolic state to a catabolic state. This leads to activation of various enzymes that cause an increase in blood glucose levels (via glycogenolysis and gluconeogenesis) and blood ketone levels (via lipolysis). The severe hyperglycemia results in glucosuria and osmotic diuresis leading to a state of dehydration. Muscle wasting is a consequence of proteolysis due an excess of counter-regulatory hormones (glucagon, catecholamines and cortisol).

Pathophysiology

Diabetic ketoacidosis (DKA) is the result of insulin deficiency from new-onset diabetes (usually type 1 diabetes), insulin noncompliance, prescription or illicit drug use, and increased insulin need because of any condition. DKA features hyperglycemia, acidosis, and high levels of circulating ketone bodies. When there is no or minute amounts of circulating insulin, for example in type 1 diabetes or less commonly in type 2 diabetes, the consequence is an elevation of counter-regulatory hormones/stress hormones (glucagon, catecholamines, cortisol, and growth hormone). This process eventually leads to the development of DKA.[1]

Pathogenesis

Insulin deficiency

Increased lipolysis and ketogenesis

Basic enzymes involved

Ketosis and acedemia in DKA

Increased blood glucose level

Basic enzymes involved

Hyperglycemia in DKA

Muscle wasting

Pathophysiology of diabetic ketoacidosis at a glance

 
 
 
 
 
 
 
 
Profound insulin deficiency/stress/infection
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Increased levels of counter-regulatory hormones (glucagon, catecholamines, cortisol)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Increased lipolysis
 
 
 
 
Increased proteolysis, decreased protein synthesis (increased availability of gluconeogenic substrates)
 
 
 
 
Increased glycogenolysis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Increased ketogenesis (acidosis)
 
 
 
 
Increased gluconeogenesis (hyperglycemia)
 
 
 
 
Hyperglycemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glucosuria and dehydration
 
 
 
 
Glucosuria and dehydration

Associated Conditions

The following conditions are associated with diabetic ketoacidosis (DKA):

References

  1. ↑ Chiasson JL, Aris-Jilwan N, Bélanger R, Bertrand S, Beauregard H, Ekoé JM, Fournier H, Havrankova J (2003). "Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state". CMAJ. 168 (7): 859–66. PMC 151994. PMID 12668546.
  2. ↑ van Belle TL, Coppieters KT, von Herrath MG (2011). "Type 1 diabetes: etiology, immunology, and therapeutic strategies". Physiol. Rev. 91 (1): 79–118. doi:10.1152/physrev.00003.2010. PMID 21248163.
  3. ↑ Leahy JL (2005). "Pathogenesis of type 2 diabetes mellitus". Arch. Med. Res. 36 (3): 197–209. doi:10.1016/j.arcmed.2005.01.003. PMID 15925010.
  4. ↑ Gelfand RA, Matthews DE, Bier DM, Sherwin RS (1984). "Role of counterregulatory hormones in the catabolic response to stress". J. Clin. Invest. 74 (6): 2238–48. doi:10.1172/JCI111650. PMC 425416. PMID 6511925.
  5. ↑ "Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes - Laffel - 1999 - Diabetes/Metabolism Research and Reviews - Wiley Online Library".
  6. ↑ 6.0 6.1 Holm C (2003). "Molecular mechanisms regulating hormone-sensitive lipase and lipolysis". Biochem. Soc. Trans. 31 (Pt 6): 1120–4. doi:10.1042/ Check |doi= value (help). PMID 14641008.
  7. ↑ Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS (2007). "Regulation of lipolysis in adipocytes". Annu. Rev. Nutr. 27: 79–101. doi:10.1146/annurev.nutr.27.061406.093734. PMC 2885771. PMID 17313320.
  8. ↑ Brownsey RW, Boone AN, Elliott JE, Kulpa JE, Lee WM (2006). "Regulation of acetyl-CoA carboxylase". Biochem. Soc. Trans. 34 (Pt 2): 223–7. doi:10.1042/BST20060223. PMID 16545081.
  9. ↑ Tong L (2005). "Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery". Cell. Mol. Life Sci. 62 (16): 1784–803. doi:10.1007/s00018-005-5121-4. PMID 15968460.
  10. ↑ Choi SM, Tucker DF, Gross DN, Easton RM, DiPilato LM, Dean AS, Monks BR, Birnbaum MJ (2010). "Insulin regulates adipocyte lipolysis via an Akt-independent signaling pathway". Mol. Cell. Biol. 30 (21): 5009–20. doi:10.1128/MCB.00797-10. PMC 2953052. PMID 20733001.
  11. ↑ 11.0 11.1 Foster DW, McGarry JD (1982). "The regulation of ketogenesis". Ciba Found. Symp. 87: 120–31. PMID 6122545.
  12. ↑ Liljenquist JE, Bomboy JD, Lewis SB, Sinclair-Smith BC, Felts PW, Lacy WW, Crofford OB, Liddle GW (1974). "Effects of glucagon on lipolysis and ketogenesis in normal and diabetic men". J. Clin. Invest. 53 (1): 190–7. doi:10.1172/JCI107537. PMC 301453. PMID 4808635.
  13. ↑ 13.0 13.1 Halestrap AP, Denton RM (1973). "Insulin and the regulation of adipose tissue acetyl-coenzyme A carboxylase". Biochem. J. 132 (3): 509–17. PMC 1177615. PMID 4146798.
  14. ↑ Holland R, Hardie DG, Clegg RA, Zammit VA (1985). "Evidence that glucagon-mediated inhibition of acetyl-CoA carboxylase in isolated adipocytes involves increased phosphorylation of the enzyme by cyclic AMP-dependent protein kinase". Biochem. J. 226 (1): 139–45. PMC 1144686. PMID 2858203.
  15. ↑ Serra D, Casals N, Asins G, Royo T, Ciudad CJ, Hegardt FG (1993). "Regulation of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase protein by starvation, fat feeding, and diabetes". Arch. Biochem. Biophys. 307 (1): 40–5. doi:10.1006/abbi.1993.1557. PMID 7902069.
  16. ↑ "www.niddk.nih.gov" (PDF).
  17. ↑ Schreurs M, Kuipers F, van der Leij FR (2010). "Regulatory enzymes of mitochondrial beta-oxidation as targets for treatment of the metabolic syndrome". Obes Rev. 11 (5): 380–8. doi:10.1111/j.1467-789X.2009.00642.x. PMID 19694967.
  18. ↑ DiMarco JP, Hoppel C (1975). "Hepatic mitochondrial function in ketogenic states. Diabetes, starvation, and after growth hormone administration". J. Clin. Invest. 55 (6): 1237–44. doi:10.1172/JCI108042. PMC 301878. PMID 124319.
  19. ↑ 19.0 19.1 "Diabetic Ketoacidosis: Evaluation and Treatment - American Family Physician".
  20. ↑ Ruderman NB, Goodman MN (1974). "Inhibition of muscle acetoacetate utilization during diabetic ketoacidosis". Am. J. Physiol. 226 (1): 136–43. PMID 4203779.
  21. ↑ Féry F, Balasse EO (1985). "Ketone body production and disposal in diabetic ketosis. A comparison with fasting ketosis". Diabetes. 34 (4): 326–32. PMID 3918903.
  22. ↑ Bulman GM, Arzo GM, Nassimi MN (1979). "An outbreak of tropical theileriosis in cattle in Afghanistan". Trop Anim Health Prod. 11 (1): 17–20. PMID 442206.
  23. ↑ Pilkis SJ, El-Maghrabi MR, McGrane M, Pilkis J, Claus TH (1982). "Regulation by glucagon of hepatic pyruvate kinase, 6-phosphofructo 1-kinase, and fructose-1,6-bisphosphatase". Fed. Proc. 41 (10): 2623–8. PMID 6286362.
  24. ↑ Chiasson JL, Aris-Jilwan N, Bélanger R, Bertrand S, Beauregard H, Ekoé JM, Fournier H, Havrankova J (2003). "Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state". CMAJ. 168 (7): 859–66. PMC 151994. PMID 12668546.
  25. ↑ Chiasson JL, Aris-Jilwan N, Bélanger R, Bertrand S, Beauregard H, Ekoé JM, Fournier H, Havrankova J (2003). "Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state". CMAJ. 168 (7): 859–66. PMC 151994. PMID 12668546.

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