Hyperosmolar hyperglycemic state pathophysiology: Difference between revisions

Jump to navigation Jump to search
No edit summary
No edit summary
Line 20: Line 20:
*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.
*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|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 diabetes|type 1 diabetics]], there is an immune-associated destruction of insulin-producing [[Beta cells|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 diabetes|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|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 [[genitourinary]] or [[pulmonary]], [[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 [[Pharmacological|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]])
**[[Immunosuppressive agents]] (such as [[cyclosporine]], [[interferon]], [[pentamidine]])
**[[Sympathomimetic agents]] (such as [[albuterol]], [[dobutamine]], [[terbutaline]])
*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/ |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>   

Revision as of 16:08, 2 October 2017

Hyperosmolar hyperglycemic state Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Hyperosmolar hyperglycemic state from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic study of choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

Echocardiography and Ultrasound

CT scan

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Hyperosmolar hyperglycemic state pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Hyperosmolar hyperglycemic state pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Hyperosmolar hyperglycemic state pathophysiology

CDC on Hyperosmolar hyperglycemic state pathophysiology

Hyperosmolar hyperglycemic state pathophysiology in the news

Blogs on Hyperosmolar hyperglycemic state pathophysiology

Directions to Hospitals Treating Psoriasis

Risk calculators and risk factors for Hyperosmolar hyperglycemic state pathophysiology

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]

Increased gluconeogenesis
Increased glycogenolysis
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)

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

  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/ Check |doi= value (help). 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.

Template:WH Template:WS