Hyperosmolar hyperglycemic state pathophysiology: Difference between revisions

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{{Hyperosmolar hyperglycemic state}}
{{Hyperosmolar hyperglycemic state}}
 
{{CMG}}; {{AE}} {{HS}}
{{CMG}}; {{AE}}  
==Overview==
==Overview==
The exact pathogenesis of [disease name] is not fully understood.
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]].
 
OR
 
It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
 
OR
 
[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
 
OR
 
Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
 
OR
 
 
[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
 
OR
 
The progression to [disease name] usually involves the [molecular pathway].
 
OR
 
The pathophysiology of [disease/malignancy] depends on the histological subtype.


==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 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 which lead to increase insulin-to-glucagon ratio.
*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 muscle which is stored as glycogen.
*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 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, the breakdown of glycogen in the liver and muscle and gluconeogenesis by the liver occurs.  
*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 in the normal range.
*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 like brain and kidneys use glucose regardless of the insulin-to-glucagon ratio.
*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 stress hormones (catecholamines, cortisol, and growth hormone), which can be seen in a multitude of settings.
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|counter-regulatory stress hormones]] ([[Catecholamine|catecholamines]], [[cortisol]], and [[growth hormone]]), which may 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>
*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 1 diabetes|type 1 diabetics]], there is an [[Immune-mediated disease|immune-mediated]] destruction of [[insulin]]-producing [[Beta cells|pancreatic β cells]], which leads to either an absolute or relative deficiency 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.  
*In [[Type 2 diabetes|type 2 diabetics]], although the major mechanism of [[hyperglycemia]] is [[Insulin resistance|peripheral insulin resistance]] and there is some basal production of [[insulin]]; patients may develop a failure of [[Beta cells|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).  
*Increased levels of [[Stress hormone|counter-regulatory stress hormones]] may also cause [[insulin resistance]]. The levels of [[Stress hormone|counter-regulatory stress hormones]] may increase during an acute illness (e.g., [[infections]] such as [[Urinary tract infection|UTI]] or [[pneumonia]], [[Myocardial infarction|myocardial infarction [MI]]], or [[pancreatitis]]), stress (e.g., [[surgery]] or [[trauma]]), when [[Stress hormone|counter-regulatory hormones]] are given as therapy (e.g., [[dexamethasone]]), and as a result of their overproduction (eg, in [[Cushing's 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.
*Some [[Pharmacological|pharmacologic agents]] may also cause [[insulin resistance]]. Notable [[pharmacologic]] agents which may lead to [[insulin resistance]] include:
*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).
**[[Antipsychotics]] (such as [[clozapine]], [[olanzapine]], [[risperidone]])
====Hyperglycemia in HHS====
**[[Immunosuppressive agents]] (such as [[cyclosporine]], [[interferon]], [[pentamidine]])
Hyperglycemia in HHS  develops as a result of three processes:  
**[[Sympathomimetic agents]] (such as [[albuterol]], [[dobutamine]], [[terbutaline]])
=====Increased gluconeogenesis=====  
*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).
*Gluconeogenesis takes place in the liver and it increases in HHS due to:
====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/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="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=====  
*[[Gluconeogenesis]] takes place in the liver and it increases in HHS due to:
**Increased gluconeogenic precursors, such as:       
**Increased gluconeogenic precursors, such as:       
***Amino acids (alanine and glutamine), which are increased due to proteolysis and decreased protein synthesis.
***[[Amino acid|Amino acids]] ([[alanine]] and [[glutamine]]), which are increased due to [[proteolysis]] and decreased [[protein synthesis]].
***Lactate, which comes from muscle glycogenolysis
***[[Lactate]], which comes from [[muscle]] [[glycogenolysis]].
***Glycerol, which comes from lipolysis.  
***[[Glycerol]], which comes from [[lipolysis]].  
**Increased activity of gluconeogenic enzymes, which are further stimulated by stress hormones; include:
**Increased activity of [[Gluconeogenesis|gluconeogenic enzymes]], which are further stimulated by [[Stress hormone|stress hormones]] including:
***Phosphoenolpyruvate carboxykinase (PEPCK)
***[[Phosphoenolpyruvate carboxykinase|Phosphoenolpyruvate carboxykinase (PEPCK)]]
***Fructose-1,6-Biphosphatase
***[[Fructose 1,6-bisphosphatase|Fructose-1,6-Biphosphatase]]
***Pyruvate carboxylase
***[[Pyruvate carboxylase]]
***Glucose-6-phosphatase
***[[Glucose-6-phosphatase]]
*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]] ([[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.
*The low [[insulin]]-to-[[glucagon]] ratio also inhibits production of an important metabolic regulator, [[Fructose 2,6-bisphosphate|fructose-2,6-biphosphate]] ([[Fructose-2,6-bisphosphate 2-phosphatase|FBPase-2]]) by triggering the production of [[cyclic adenosine monophosphate]] ([[Cyclic adenosine monophosphate|cAMP]]), which activates a [[cAMP-dependent protein kinase]]. This [[kinase]] [[phosphorylates]] the phosphofructokinase 2 ([[Phosphofructokinase 2|PFK-2]]) <nowiki/>and [[Fructose bisphosphatase|FBPase-2]] [[enzymes]] which leads to activation of [[Fructose bisphosphatase|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.
*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.
*Reduction of [[Fructose 2,6-bisphosphate|fructose-2,6-biphosphate]] stimulates the activity of [[Fructose 1,6-bisphosphatase|fructose-1,6-bisphosphatase]] (an [[enzyme]] that converts [[Fructose 1,6-bisphosphate|fructose-1,6-biphosphate]] to [[Fructose 6-phosphate|fructose-6-phosphate]]) and inhibits [[phosphofructokinase]] ([[Phosphofructokinase 2|PFK]]), the [[Rate limiting step|rate-limiting enzyme]] in the [[glycolytic]] pathway.
=====(b) Increased [[glycogenolysis]]=====
*The low [[insulin]]-to-[[glucagon]] ratio promotes [[glycogenolysis]] by stimulating [[glycogen phosphorylase]], a key [[enzyme]] of [[Glycogenolysis|glycogen breakdown]].
=====(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]].


=====Increased glycogenolysis=====  
====[[Lipid]] and [[ketone]] [[metabolism]] in hyperosmolar hyperglycemic state (HHS)====
*The low insulin-to-glucagon ratio promotes glycogenolysis by stimulating glycogen phosphorylase, a key enzyme of glycogen breakdown.  
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>
=====Impaired glucose utilization by peripheral tissues=====
*The low [[insulin]]-to-[[glucagon]] ratio affects [[lipid metabolism]] and mobilization because [[insulin]] normally promotes [[triglycerides]] clearance from circulation and inhibits [[lipolysis]].
The low insulin-to-glucagon ratio also decrease the insulin dependent uptake of glucose by peripheral tissues.
*The low [[insulin]]-to-[[glucagon]] ratio stimulates [[lipolysis]] from [[adipose tissue]] by activating [[Hormone-sensitive lipase|hormone - sensitive lipase]] ([[Hormone-sensitive lipase|HSL]]). This [[lipolysis]] leads to the abundant supply of [[Free fatty acids|free fatty acids (FFA)]] to the [[liver]].
*The [[Free fatty acids|free fatty acid]] levels may be as high in the hyperosmolar hyperglycemic state (HHS) as in [[Diabetic ketoacidosis|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 I|carnitine palmitoyltransferase 1 (CPT1)]].
*The activation of [[carnitine palmitoyltransferase I]] allows [[free fatty acids]] to cross the [[mitochondrial membrane]] in the form of fatty [[acyl-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 hyperglycemic nonketotic state, but findings of moderated [[ketonemia]] in several patients has lead to the use of current term.
====Hyperosmolarity in hyperosmolar hyperglycemic state (HHS)====
====Hyperosmolarity in hyperosmolar hyperglycemic state (HHS)====
 
*The [[hyperosmolar]] state in HHS is a combination of a decrease in total body water, loss of [[Electrolyte|electrolytes]], [[dehydration]], and [[hyperglycemia]].<ref name="pmid16694129">{{cite journal| author=Atchley DW, Loeb RF, Richards DW, Benedict EM, Driscoll ME| title=ON DIABETIC ACIDOSIS: A Detailed Study of Electrolyte Balances Following the Withdrawal and Reestablishment of Insulin Therapy. | journal=J Clin Invest | year= 1933 | volume= 12 | issue= 2 | pages= 297-326 | pmid=16694129 | doi=10.1172/JCI100504 | pmc=435909 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16694129  }} </ref><ref name="pmid24455475">{{cite journal| author=Vardeny O, Gupta DK, Claggett B, Burke S, Shah A, Loehr L et al.| title=Insulin resistance and incident heart failure the ARIC study (Atherosclerosis Risk in Communities). | journal=JACC Heart Fail | year= 2013 | volume= 1 | issue= 6 | pages= 531-6 | pmid=24455475 | doi=10.1016/j.jchf.2013.07.006 | pmc=3893700 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24455475  }} </ref>
==Genetics==
*The [[osmotic diuresis]] in HHS results when the [[glucose]] concentration reaches greater than 180 to 200 mg/dl.
*[Disease name] is transmitted in [mode of genetic transmission] pattern.
*A [[glucose]] concentration greater than 180 to 200 mg/dl saturates the reabsorbing capacity of the [[Proximal convoluted tubule|proximal tubular transport system]] in the [[kidneys]].
*Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
*The saturation of [[glucose]] transport system prevents further reabsorption and [[glucose]] eventually starts losing in the [[urine]] along with [[water]] and [[Electrolyte|electrolytes]] and causing a decrease in the total body water.
*The development of [disease name] is the result of multiple genetic mutations.
*The [[blood]] [[glucose]] concentration keeps on rising due to continued [[gluconeogenesis]], [[glycogenolysis]], and decrease in total body water which further increases the [[plasma osmolarity]].
==Associated Conditions==
*The increase in [[plasma]] [[osmolarity]] and water loss stimulates [[Antidiuretic hormone|antidiuretic hormone (ADH)]] [[secretion]], which leads to increased water reabsorption through the [[Collecting duct system|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.
==Gross Pathology==
*The decrease in effective circulatory volume due to dehydration leads to activation of [[Renin-angiotension aldosterone system|renal angiotensin aldosterone system (RAAS)]], which conserves water but further exacerbates [[hyperglycemia]] due to [[oliguria]] which decreases [[Renal Artery Stenosis|renal]] [[excretion]] of [[glucose]].
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
*The decrease in effective [[circulatory]] volume or [[hypotension]] eventually leads to [[coma]] due to a decrease in [[Tissue (biology)|tissue]] [[perfusion]], and the massive activation of [[Renin-angiotension aldosterone system|renal angiotensin aldosterone system]] eventually leading to a [[Renal failure|renal shutdown]].
 
==Microscopic Pathology==
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].


==References==
==References==
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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][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. ↑ 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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