Hyperosmolar hyperglycemic state pathophysiology: Difference between revisions

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*All these situations may cause a decrease effective [[insulin]]-to-[[glucagon]] ratio which may lead to [[hyperosmolarity]] and [[hyperglycemia]] seen in the hyperosmolar hyperglycemic state (HHS).
*All these situations may cause a decrease effective [[insulin]]-to-[[glucagon]] ratio which may lead to [[hyperosmolarity]] and [[hyperglycemia]] seen in the hyperosmolar hyperglycemic state (HHS).
====Hyperglycemia in hyperosmolar hyperglycemic state (HHS)====
====Hyperglycemia in hyperosmolar hyperglycemic state (HHS)====
Hyperglycemia in HHS  develops as a result of three processes:<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="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><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><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><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><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><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><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><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><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>   
Hyperglycemia in HHS  develops as a result of three processes:<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/bst0311120|url=}}</ref><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><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><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><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><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><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><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><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><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>   
=====(a) Increased gluconeogenesis=====  
=====(a) Increased gluconeogenesis=====  
*[[Gluconeogenesis]] takes place in the liver and it increases in HHS due to:
*[[Gluconeogenesis]] takes place in the liver and it increases in HHS due to:
Line 48: Line 48:
=====(c) Impaired [[glucose]] utilization by peripheral [[Tissue (biology)|tissues]]=====
=====(c) Impaired [[glucose]] utilization by peripheral [[Tissue (biology)|tissues]]=====
*The low [[insulin]]-to-[[glucagon]] ratio also decrease the [[insulin]] dependent uptake of [[glucose]] 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)====
====[[Lipid]] and [[ketone]] [[metabolism]] in hyperosmolar hyperglycemic state (HHS)====
The main mechanisms involved in [[ketone]] [[metabolism]] in hyperosmolar hyperglycemic state include the following:<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><ref name="urlDiabetic Ketoacidosis: Evaluation and Treatment - American Family Physician" /><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><ref name="pmid7902069" /><ref name="pmid2312732">{{cite journal| author=Arner P, Kriegholm E, Engfeldt P, Bolinder J| title=Adrenergic regulation of lipolysis in situ at rest and during exercise. | journal=J Clin Invest | year= 1990 | volume= 85 | issue= 3 | pages= 893-8 | pmid=2312732 | doi=10.1172/JCI114516 | pmc=296507 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2312732  }} </ref><ref name="pmid8817110">{{cite journal |vauthors=Bolinder J, Sjöberg S, Arner P |title=Stimulation of adipose tissue lipolysis following insulin-induced hypoglycaemia: evidence of increased beta-adrenoceptor-mediated lipolytic response in IDDM |journal=Diabetologia |volume=39 |issue=7 |pages=845–53 |year=1996 |pmid=8817110 |doi= |url=}}</ref>
The main mechanisms involved in [[ketone]] [[metabolism]] in hyperosmolar hyperglycemic state include the following:<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><ref name="urlDiabetic Ketoacidosis: Evaluation and Treatment - American Family Physician" /><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><ref name="pmid7902069" /><ref name="pmid2312732">{{cite journal| author=Arner P, Kriegholm E, Engfeldt P, Bolinder J| title=Adrenergic regulation of lipolysis in situ at rest and during exercise. | journal=J Clin Invest | year= 1990 | volume= 85 | issue= 3 | pages= 893-8 | pmid=2312732 | doi=10.1172/JCI114516 | pmc=296507 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2312732  }} </ref><ref name="pmid8817110">{{cite journal |vauthors=Bolinder J, Sjöberg S, Arner P |title=Stimulation of adipose tissue lipolysis following insulin-induced hypoglycaemia: evidence of increased beta-adrenoceptor-mediated lipolytic response in IDDM |journal=Diabetologia |volume=39 |issue=7 |pages=845–53 |year=1996 |pmid=8817110 |doi= |url=}}</ref>

Revision as of 15:31, 17 October 2017

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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

Catabolic state between meals

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 counter-regulatory stress hormones (catecholamines, cortisol, and growth hormone), which may be seen in a multitude of settings:[2][3][4]

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]

(a) Increased gluconeogenesis
(b) Increased glycogenolysis
(c) Impaired glucose utilization by peripheral tissues

Lipid and ketone metabolism in hyperosmolar hyperglycemic state (HHS)

The main mechanisms involved in ketone metabolism in hyperosmolar hyperglycemic state include the following:[16][17][11][18][10][19][20]

Hyperosmolarity in hyperosmolar hyperglycemic state (HHS)

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. 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.
  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. 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.
  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. Holm C (2003). "Molecular mechanisms regulating hormone-sensitive lipase and lipolysis". Biochem. Soc. Trans. 31 (Pt 6): 1120–4. doi:10.1042/bst0311120. PMID 14641008.
  7. 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.
  8. Foster DW, McGarry JD (1982). "The regulation of ketogenesis". Ciba Found. Symp. 87: 120–31. PMID 6122545.
  9. 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. 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. 11.0 11.1 "Diabetic Ketoacidosis: Evaluation and Treatment - American Family Physician".
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. Ruderman NB, Goodman MN (1974). "Inhibition of muscle acetoacetate utilization during diabetic ketoacidosis". Am. J. Physiol. 226 (1): 136–43. PMID 4203779.
  17. 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.
  18. "www.niddk.nih.gov" (PDF).
  19. 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.
  20. 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.
  21. 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.
  22. 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.

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