Diabetic ketoacidosis pathophysiology: Difference between revisions
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* [[Diabetes mellitus type 1|Type 1 diabetes mellitus]] | * [[Diabetes mellitus type 1|Type 1 diabetes mellitus]] | ||
* [[Diabetes mellitus type 2|Type 2 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
- 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.[2]
- 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.[3]
- 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.[4]
Increased lipolysis and ketogenesis
Basic enzymes involved
- The rate of lipolysis and ketogenesis depends upon the action of three enzymes:[5] [6][7][8][9]
- Hormone-sensitive lipase (or triglyceride lipase), which is found in peripheral adipocytes
- Acetyl CoA carboxylase, which is 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.[10][11][12]
- Insulin inhibits ketogenesis by causing the dephosphorylation of hormone-sensitive lipase (HSL) and leads to lipogenesis by stimulating acetyl CoA carboxylase.[6]
- 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.[13]
- Insulin also dephosphorylates 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.[13]
- 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 degradation of triglycerides into fatty acids.[11][14]
- 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 of the cells 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, and it is decreased by insulin.[15]
Ketosis and acedemia in DKA
- 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.[16]
- 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 free fatty acids (FFA) and to increase the processes by which FFAs 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).[17][18]
- 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 in nature and lead to a decrease in pH of the body (acedemia).
- In DKA the ratio of 3-hydroxybutyrate to acetoacetate rises to 3:1 or higher (to as high as 10:1).[19]
- Insulin deficiency also acts to reduce renal clearance of ketone bodies via unclear mechanisms.[20][21]
Increased blood glucose level
Basic enzymes involved
- Glycogen and proteins are catabolized to form glucose.[19]
- 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 (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 dephosphorylates 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.[22]
- Glucagon triggers production of cyclic adenosine monophosphate (cAMP), which activates a cAMP-dependent protein kinase. This kinase phosphorylates the PFK-2and FBPase-2 enzymes. This causes activation of FBPase-2 activity and inhibition of PFK-2 activity, thereby decreasing the levels of fructose 2,6-bisphosphate in the cell. With decreasing amounts of fructose 2,6-bisphosphate, glycolysis is inhibited while gluconeogenesis is activated.[23]
Hyperglycemia in DKA
- In DKA, due to a profound insulin deficiency, here is an excess of counter-regulatory hormones/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 non-ketotic state, which is found in type 2 diabetics.[24]
- The increased serum glucose may lead to osmotic diuresis in patient leading to dehydration and weakness.[25]
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).
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
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ "Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes - Laffel - 1999 - Diabetes/Metabolism Research and Reviews - Wiley Online Library".
- ↑ 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. - ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 11.0 11.1 Foster DW, McGarry JD (1982). "The regulation of ketogenesis". Ciba Found. Symp. 87: 120–31. PMID 6122545.
- ↑ 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.
- ↑ 13.0 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.
- ↑ 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.
- ↑ 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.
- ↑ "www.niddk.nih.gov" (PDF).
- ↑ 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.
- ↑ 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.
- ↑ 19.0 19.1 "Diabetic Ketoacidosis: Evaluation and Treatment - American Family Physician".
- ↑ Ruderman NB, Goodman MN (1974). "Inhibition of muscle acetoacetate utilization during diabetic ketoacidosis". Am. J. Physiol. 226 (1): 136–43. PMID 4203779.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.