Hyperosmolar hyperglycemic state pathophysiology: Difference between revisions
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{{CMG}}; {{AE}} {{HS}} | {{CMG}}; {{AE}} {{HS}} | ||
==Overview== | ==Overview== | ||
The hyperosmolar hyperglycemic state (HHS) is the result of relative [[insulin]] deficiency and excess of | The hyperosmolar hyperglycemic state (HHS) is the result of relative [[insulin]] deficiency and excess of counter-regulatory hormones like [[glucagon]], [[growth hormone]], [[catecholamine]], and [[Cortisol|cortisol.]] The decrease in [[insulin]]-to-[[glucagon]] ratio puts the body in the [[Catabolic|catabolic state]] and leads to [[hyperglycemic]] and [[hyperosmolar]] state. The [[hyperglycemia]] is secondary to activation of [[gluconeogenesis]], [[glycogenolysis]] and decreased peripheral utilization of [[glucose]]. The increase in [[plasma osmolality]] is secondary to [[osmotic diuresis]] and [[dehydration]]. Advanced age and other underlying [[comorbidities]] such as [[congestive heart failure]] or [[chronic kidney disease]], decrease in [[fluid]] intake and osmotic diuresis leading to activation of [[Renin-angiotensin system|renal angiotensin aldosterone system (RAAS)]] further aggravate the increase in [[plasma osmolality]]. There is enough endogenous [[insulin]] [[secretion]] in the hyperglycemic hyperosmolar state (HHS) to prevent unrestrained [[ketosis]] but not enough to prevent [[hyperglycemia]]. | ||
==Pathophysiology== | ==Pathophysiology== | ||
===Glucose homeostasis=== | ===Glucose homeostasis=== | ||
====Anabolic state during meals==== | ====[[Anabolic]] state during meals==== | ||
*During fed state, high glycemic levels cause increased [[insulin]] release from [[Pancreatic|pancreatic beta cells.]] | *During fed-state, high [[glycemic]] levels cause increased [[insulin]] release from [[Pancreatic|pancreatic beta cells.]] | ||
*Increased [[insulin]] levels inhibit [[glucagon]] from pancreatic [[Alpha cells|alpha]] cells which | *Increased [[insulin]] levels inhibit the secretion of [[glucagon]] from [[pancreatic]] [[Alpha cells|alpha]] cells which leads to increased [[insulin]]-to-[[glucagon]] ratio.<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> | ||
*High insulin-to-glucagon ratio favors [[anabolic]] state during which insulin mediated uptake of glucose occurs in liver and | *High [[insulin]]-to-[[glucagon]] ratio favors [[anabolic]] state, during which [[insulin]] mediated uptake of [[glucose]] occurs in the [[liver]] and [[muscles]] where it is stored as [[glycogen]]. | ||
*Insulin dependent uptake of glucose also drives [[potassium]] into the cells. | *[[Insulin]] dependent uptake of [[glucose]] also drives [[potassium]] into the [[Cells (biology)|cells]]. | ||
*The high insulin-to-glucagon ratio also favors uptake of [[Amino acid|amino acids]] by muscle. | *The high [[insulin]]-to-[[glucagon]] ratio also favors uptake of [[Amino acid|amino acids]] by [[muscle]]. | ||
====Catabolic state between meals==== | ====[[Catabolic]] state between meals==== | ||
*Between meals, the decrease in insulin and rise in glucagon leads to low plasma insulin-to-glucagon ratio which favors the [[catabolic]] state. | *Between meals, the decrease in [[insulin]] and rise in [[glucagon]] leads to low [[plasma]] [[insulin]]-to-[[glucagon]] ratio which favors the [[catabolic]] state. | ||
*During catabolic state, | *During [[catabolic]] state, there is a breakdown of [[glycogen]] in the [[liver]] and [[muscles]] and [[gluconeogenesis]] is initiated in the [[liver]]. | ||
*Both these processes maintain plasma glucose concentration | *Both these processes maintain [[plasma]] [[glucose]] concentration within normal range. | ||
*The low insulin-to-glucagon ratio also favors [[lipolysis]] and [[ketone]] body formation. | *The low [[insulin]]-to-[[glucagon]] ratio also favors [[lipolysis]] and [[ketone]] body formation. | ||
*Several insulin-independent tissues | *Several [[insulin]]-independent [[Tissue (biology)|tissues]] such as the [[brain]] and [[kidneys]] utilize [[glucose]] as a major source of energy, regardless of the [[insulin]]-to-[[glucagon]] ratio. | ||
===Pathogenesis=== | ===Pathogenesis=== | ||
The progression to hyperosmolar hyperglycemic state (HHS) can occur due to the reduction in the net effective concentration of insulin relative to glucagon and other [[Counterregulatory hormone|counterregulatory]] stress hormones ([[Catecholamine|catecholamines]], [[cortisol]], and [[growth hormone]]), which can be seen in a multitude of settings.<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><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><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> | The progression to hyperosmolar hyperglycemic state (HHS) can occur due to the reduction in the net effective concentration of insulin relative to glucagon and other [[Counterregulatory hormone|counterregulatory]] stress hormones ([[Catecholamine|catecholamines]], [[cortisol]], and [[growth hormone]]), which can be seen in a multitude of settings.<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><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><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> | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Husnain Shaukat, M.D [2]
Overview
The hyperosmolar hyperglycemic state (HHS) is the result of relative insulin deficiency and excess of counter-regulatory hormones like glucagon, growth hormone, catecholamine, and cortisol. The decrease in insulin-to-glucagon ratio puts the body in the catabolic state and leads to hyperglycemic and hyperosmolar state. The hyperglycemia is secondary to activation of gluconeogenesis, glycogenolysis and decreased peripheral utilization of glucose. The increase in plasma osmolality is secondary to osmotic diuresis and dehydration. Advanced age and other underlying comorbidities such as congestive heart failure or chronic kidney disease, decrease in fluid intake and osmotic diuresis leading to activation of renal angiotensin aldosterone system (RAAS) further aggravate the increase in plasma osmolality. There is enough endogenous insulin secretion in the hyperglycemic hyperosmolar state (HHS) to prevent unrestrained ketosis but not enough to prevent hyperglycemia.
Pathophysiology
Glucose homeostasis
Anabolic state during meals
- During fed-state, high glycemic levels cause increased insulin release from pancreatic beta cells.
- Increased insulin levels inhibit the secretion of glucagon from pancreatic alpha cells which leads to increased insulin-to-glucagon ratio.[1]
- High insulin-to-glucagon ratio favors anabolic state, during which insulin mediated uptake of glucose occurs in the liver and muscles where it is stored as glycogen.
- Insulin dependent uptake of glucose also drives potassium into the cells.
- The high insulin-to-glucagon ratio also favors uptake of amino acids by muscle.
Catabolic state between meals
- Between meals, the decrease in insulin and rise in glucagon leads to low plasma insulin-to-glucagon ratio which favors the catabolic state.
- During catabolic state, there is a breakdown of glycogen in the liver and muscles and gluconeogenesis is initiated in the liver.
- Both these processes maintain plasma glucose concentration within normal range.
- The low insulin-to-glucagon ratio also favors lipolysis and ketone body formation.
- Several insulin-independent tissues such as the brain and kidneys utilize glucose as a major source of energy, regardless of the insulin-to-glucagon ratio.
Pathogenesis
The progression to hyperosmolar hyperglycemic state (HHS) can occur due to the reduction in the net effective concentration of insulin relative to glucagon and other counterregulatory stress hormones (catecholamines, cortisol, and growth hormone), which can be seen in a multitude of settings.[2][3][4]
- In type 1 diabetics, there is an immune-associated destruction of insulin-producing pancreatic β cells, which leads to no or decreased levels of insulin in the body.
- 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.
- Increased levels of counterregulatory stress hormones can also cause insulin resistance. The levels of counterregulatory stress hormones can increase during an acute illness (eg, infections like genitourinary or pulmonary, myocardial infarction [MI], or pancreatitis), stress (eg, surgery or injuries), when counterregulatory hormones are given as therapy (eg, dexamethasone), and as a result of their overproduction (eg, in Cushing syndrome).
- Some pharmacologic agents can also cause insulin resistance. The notable pharmacologic agents which cause insulin resistance include antipsychotics like clozapine, olanzapine, risperidone or the immunosuppressive agents, such as cyclosporine, interferon, pentamidine and sympathomimetic agents like albuterol, dobutamine, terbutaline.
- All these situations can cause decrease effective insulin-to-glucagon ratio which can lead to hyperosmolarity and hyperglycemia seen in the hyperosmolar hyperglycemic state (HHS).
Hyperglycemia in hyperosmolar hyperglycemic state (HHS)
Hyperglycemia in HHS develops as a result of three processes:[5][6][7][7][8][9][10][11][12][13][14][15]
Increased gluconeogenesis
- Gluconeogenesis takes place in the liver and it increases in HHS due to:
- Increased gluconeogenic precursors, such as:
- Amino acids (alanine and glutamine), which are increased due to proteolysis and decreased protein synthesis.
- Lactate, which comes from muscle glycogenolysis
- Glycerol, which comes from lipolysis.
- Increased activity of gluconeogenic enzymes, which are further stimulated by stress hormones; include:
- Increased gluconeogenic precursors, such as:
- The low insulin-to-glucagon ratio also inhibits production of an important metabolic regulator, fructose-2,6-biphosphate by triggering the 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.
- Reduction of fructose-2,6-biphosphate stimulates the activity of fructose-1,6-bisphosphatase (an enzyme that converts fructose-1,6-biphosphate to fructose-6-phosphate) and inhibits phosphofructokinase, the rate-limiting enzyme in the glycolytic pathway.
Increased glycogenolysis
- The low insulin-to-glucagon ratio promotes glycogenolysis by stimulating glycogen phosphorylase, a key enzyme of glycogen breakdown.
Impaired glucose utilization by peripheral tissues
- The low insulin-to-glucagon ratio also decrease the insulin dependent uptake of glucose by peripheral tissues.
Lipid and ketone metabolism in hyperosmolar hyperglycemic state (HHS)
- The low insulin-to-glucagon ratio affects lipid metabolism and mobilization because insulin normally promotes triglycerides clearance from circulation and inhibits lipolysis.[16][17][11][18][10][19][20]
- The low insulin-to-glucagon ratio stimulates lipolysis from adipose tissue by activating hormone - sensitive lipase. This lipolysis leads to the abundant supply of free fatty acids (FFA) to the liver.
- The free fatty acid levels may be as high in the hyperosmolar hyperglycemic state (HHS) as in diabetic ketoacidosis (DKA).
- The increase in free fatty acids in the liver diverts the hepatic fatty acid metabolism toward the ketogenesis.
- The ketogenesis occurs in the hepatic mitochondria and the transport of free fatty acids across the mitochondrial membrane is enhanced by the glucagon-mediated decrease in the cytosolic malonyl-CoA, which removes inhibition of carnitine palmitoyltransferase 1 (CPT1).
- The activation of carnitine palmitoyltransferase I allow free fatty acids to cross the mitochondrial membrane in the form of CoA after their esterification with carnitine.
- The insulin-to-glucagon ratio in the hyperosmolar hyperglycemic state (HHS) does not decrease to a level where unrestrained ketoacidosis occurs.
- The hyperosmolar hyperglycemic state (HHS) was also named hyperosmolar hyperglycemia nonketotic state, but findings of moderated ketonemia in several patients lead to the current term.
Hyperosmolarity in hyperosmolar hyperglycemic state (HHS)
- The hyperosmolar state in HHS is a combination of a decrease in total body water, loss of electrolytes, dehydration, and hyperglycemia.[21][22]
- The osmotic diuresis in HHS results when the glucose concentration reaches greater than 180-200mg/dl.
- The glucose concentration greater than 180-200 mg /dl saturates the reabsorbing capacity of the proximal tubular transport system in the kidneys.
- The saturation of glucose transport system prevents further reabsorption and glucose eventually starts losing in the urine along with water and electrolytes and causing a decrease in the total body water.
- The blood glucose concentration keeps on rising due to continued gluconeogenesis, glycogenolysis, and decrease in total body water which further increases the plasma osmolarity.
- The increase in plasma osmolarity and water loss stimulates antidiuretic hormone (ADH) secretion, which leads to increase water reabsorption through the collecting ducts in the kidney.
- The renal water loss in the hyperosmolar hyperglycemic state (HHS) leads to dehydration especially in the elderly and in the patients who are dependent on others for care as they have decreased oral water intake.
- The decrease in effective circulatory volume due to dehydration leads to activation of renal angiotensin aldosterone system (RAAS), which conserves water but further exacerbates hyperglycemia due to oliguria which decreases renal excretion of glucose.
- The decrease in effective circulatory volume or hypotension eventually leads to coma due to the decrease in tissue perfusion, and the massive activation of renal angiotensin aldosterone system eventually leads to a renal shutdown.
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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ "Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes - Laffel - 1999 - Diabetes/Metabolism Research and Reviews - Wiley Online Library".
- ↑ 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. - ↑ 7.0 7.1 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.
- ↑ Foster DW, McGarry JD (1982). "The regulation of ketogenesis". Ciba Found. Symp. 87: 120–31. PMID 6122545.
- ↑ 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.
- ↑ 10.0 10.1 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.
- ↑ 11.0 11.1 "Diabetic Ketoacidosis: Evaluation and Treatment - American Family Physician".
- ↑ 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.
- ↑ 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.
- ↑ "www.niddk.nih.gov" (PDF).
- ↑ Arner P, Kriegholm E, Engfeldt P, Bolinder J (1990). "Adrenergic regulation of lipolysis in situ at rest and during exercise". J Clin Invest. 85 (3): 893–8. doi:10.1172/JCI114516. PMC 296507. PMID 2312732.
- ↑ Bolinder J, Sjöberg S, Arner P (1996). "Stimulation of adipose tissue lipolysis following insulin-induced hypoglycaemia: evidence of increased beta-adrenoceptor-mediated lipolytic response in IDDM". Diabetologia. 39 (7): 845–53. PMID 8817110.
- ↑ Atchley DW, Loeb RF, Richards DW, Benedict EM, Driscoll ME (1933). "ON DIABETIC ACIDOSIS: A Detailed Study of Electrolyte Balances Following the Withdrawal and Reestablishment of Insulin Therapy". J Clin Invest. 12 (2): 297–326. doi:10.1172/JCI100504. PMC 435909. PMID 16694129.
- ↑ Vardeny O, Gupta DK, Claggett B, Burke S, Shah A, Loehr L; et al. (2013). "Insulin resistance and incident heart failure the ARIC study (Atherosclerosis Risk in Communities)". JACC Heart Fail. 1 (6): 531–6. doi:10.1016/j.jchf.2013.07.006. PMC 3893700. PMID 24455475.