Jump to content

User:Jthibaudeau/sandbox

From Wikipedia, the free encyclopedia

Add Glucagon Secretion/regulation section to Glucagon

Cite review article Alpha cell dysfunction in type 1 diabetes for explanation of glucagon secretion and model for a visual diagram [1]

  • The alpha cell has surface receptors for islet insulin and Zinc, autonomic neurotransmitters, GABAA, Somatostatin, and Epinephrine.



"Complications" section of Diabetes mellitus type 1 :[edit]

Alpha cell Dysfunction:[edit]

Onset of Autoimmune Diabetes is accompanied by impaired ability to regulate the hormone glucagon[2], which acts in antagonism with insulin to regulate blood sugar and metabolism. While the causes and mechanisms are still being studied and hypotheses abound, what is clear and agreed upon is that progressive beta cell destruction leads to dysfunction in the neighboring alpha cells, exacerbating excursions away from euglycemia in both directions; overproduction of glucagon after meals causes sharper hyperglycemia, and failure to stimulate glucagon upon incipient hypoglycemia prevents a glucagon-mediated rescue of glucose levels.[3]

Hyperglucagonemia:[edit]

Onset of type 1 diabetes is followed by an increase in postprandial glucagon secretion. Increases have been measured up to 37% during the first year of diagnosis, while c-peptide levels (indicative of islet-derived insulin), decline by up to 45%.[4] Insulin production will continue to fall as the immune system follows its course of progressive beta cell destruction, and islet-derived insulin will continue to be replaced by therapeutic exogenous insulin. Simultaneously, there is measurable alpha cell hypertrophy and hyperplasia in the early overt stage of the disease, leading to expanded alpha cell mass. This, together with failing beta cell insulin secretion, begins to account for rising glucagon levels that contribute to hyperglycemia.[1] Some researchers believe glucagon dysregulation to be the primary cause of early stage hyperglycemia.[5] Leading hypotheses for the cause of postprandial hyperglucagonemia suggest that exogenous insulin therapy is inadequate to replace the lost intraislet signalling to alpha cells previously mediated by beta cell-derived pulsatile insulin secretion.[6][7] Under this working hypothesis intensive insulin therapy has attempted to mimic natural insulin secretion profiles in exogenous insulin infusion therapies.[8]

Hypoglycemic glucagon impairment[edit]

Hypoglycemia in type 1 diabetics is often a result of over-administered insulin therapy, though being in a fasting state, exercising without proper adjustment of insulin, sleep, and alcohol can also contribute.[9] The normal counter regulatory responses to hypoglycemia are impaired in type 1 diabetics. Glucagon secretion is normally increased upon falling glucose levels, but normal glucagon response to hypoglycemia is blunted when measured in type 1 diabetics and compared to healthy individuals experiencing an equal insulin-induced hypoglycemic trigger.[10][11] Beta cell glucose sensing and subsequent suppression of administered insulin secretion is absent, leading to islet hyperinsulinemia which inhibits glucagon release.[10][12]

Autonomic inputs to alpha cells are much more important for glucagon stimulation in the moderate to severe ranges of hypoglycemia, yet the autonomic response is blunted in a number of ways. Recurrent hypoglycemia leads to metabolic adjustments in the glucose sensing areas of the brain, shifting the threshold for counter regulatory activation of the sympathetic nervous system to lower glucose concentration.[12] This is known as hypoglycemic unawareness. Subsequent hypoglycemia is met with impairment in sending of counter regulatory signals to the islets and adrenal cortex. This accounts for the lack of glucagon stimulation and epinephrine release that would normally stimulate and enhance glucose release and production from the liver, rescuing the diabetic from severe hypoglycemia, coma, and death. Numerous hypotheses have been produced in the search for a cellular mechanism of hypoglycemic unawareness, and a consensus has yet to be reached.[13] The major hypotheses are summarized in the following table: [14][12][13]

Hypothesized Mechanisms of Hypoglycemic Unawareness
Glycogen Supercompensation Increased glycogen stores in astrocytes might contribute supplementary glycosyl units for metabolism, counteracting the central nervous system perception of hypoglycemia.
Enhanced Glucose Metabolism Altered glucose transport and enhanced metabolic efficiency upon recurring hypoglycemia relieves oxidative stress that would activate sympathetic response.
Alternative Fuel Hypothesis Decreased reliance on glucose, supplementation of lactate from astrocytes, or ketones meet metabolic demands and reduce stress to brain.
Brain Neuronal Communication Hypothalamic inhibitory GABA normally decreases during hypoglycemia, disinhibiting signals for sympathetic tone. Recurrent episodes of hypoglycemia result in increased basal GABA which fails to decrease normally during subsequent hypoglycemia. Inhibitory tone remains and sympathetic tone is not increased.

In addition, autoimmune diabetes is characterized by a loss of islet specific sympathetic innervation. This loss constitutes an 80-90% reduction of islet sympathetic nerve endings, happens early in the progression of the disease, and is persistent though the life of the patient. It is linked to the autoimmune aspect of type 1 diabetics and fails to occur in type 2 diabetics. Early in the autoimmune event, the axon pruning is activated in islet sympathetic nerves. Increased BDNF and ROS that result from insulitis and beta cell death stimulate the p75 neurotrophin receptor (p75NTR), which acts to prune off axons. Axons are normally protected from pruning by activation of tropomyosin receptor kinase A (Trk A) receptors by NGF, which in islets is primarily produced by beta cells. Progressive autoimmune beta cell destruction therefore causes both the activation of pruning factors and the loss of protective factors to the islet sympathetic nerves. This unique form of neuropathy is a hallmark of type 1 diabetes, and plays a part in the loss of glucagon rescue of severe hypoglycemia. [15]



  1. ^ a b Yosten, Gina L.C. (2018-02). "Alpha cell dysfunction in type 1 diabetes". Peptides. 100: 54–60. doi:10.1016/j.peptides.2017.12.001. ISSN 0196-9781. {{cite journal}}: Check date values in: |date= (help)
  2. ^ Farhy, Leon S.; McCall, Anthony L. (July 2015). "Glucagon – the new 'insulin' in the pathophysiology of diabetes". Current Opinion in Clinical Nutrition and Metabolic Care. 18 (4): 407–414. doi:10.1097/mco.0000000000000192. ISSN 1363-1950.
  3. ^ Yosten, Gina L.C. (2018-02). "Alpha cell dysfunction in type 1 diabetes". Peptides. 100: 54–60. doi:10.1016/j.peptides.2017.12.001. {{cite journal}}: Check date values in: |date= (help)
  4. ^ Brown, R. J.; Sinaii, N.; Rother, K. I. (2008-07-01). "Too Much Glucagon, Too Little Insulin: Time course of pancreatic islet dysfunction in new-onset type 1 diabetes". Diabetes Care. 31 (7): 1403–1404. doi:10.2337/dc08-0575. ISSN 0149-5992. PMC 2453684. PMID 18594062.{{cite journal}}: CS1 maint: PMC format (link)
  5. ^ Unger, Roger H.; Cherrington, Alan D. (Jan 2012). "Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover". The Journal of Clinical Investigation. 122 (1): 4–12. doi:10.1172/JCI60016. ISSN 1558-8238. PMC 3248306. PMID 22214853.
  6. ^ Meier, J. J.; Kjems, L. L.; Veldhuis, J. D.; Lefebvre, P.; Butler, P. C. (2006-04-01). "Postprandial Suppression of Glucagon Secretion Depends on Intact Pulsatile Insulin Secretion: Further Evidence for the Intraislet Insulin Hypothesis". Diabetes. 55 (4): 1051–1056. doi:10.2337/diabetes.55.04.06.db05-1449. ISSN 0012-1797.
  7. ^ Cooperberg, B. A.; Cryer, P. E. (2009-12-01). "β-Cell-Mediated Signaling Predominates Over Direct α-Cell Signaling in the Regulation of Glucagon Secretion in Humans". Diabetes Care. 32 (12): 2275–2280. doi:10.2337/dc09-0798. ISSN 0149-5992. PMC 2782990. PMID 19729529.{{cite journal}}: CS1 maint: PMC format (link)
  8. ^ Paolisso, G.; Sgambato, S.; Torella, R.; Varricchio, M.; Scheen, A.; D'Onofrio, F.; Lefèbvre, P. J. (June 1988). "Pulsatile Insulin Delivery is More Efficient Than Continuous Infusion in Modulating Islet Cell Function in Normal Subjects and Patients with Type 1 Diabetes". The Journal of Clinical Endocrinology & Metabolism. 66 (6): 1220–1226. doi:10.1210/jcem-66-6-1220. ISSN 0021-972X.
  9. ^ "Diabetic hypoglycemia - Symptoms and causes". Mayo Clinic. Retrieved 2019-12-23.
  10. ^ a b Banarer, S.; McGregor, V. P.; Cryer, P. E. (2002-04-01). "Intraislet Hyperinsulinemia Prevents the Glucagon Response to Hypoglycemia Despite an Intact Autonomic Response". Diabetes. 51 (4): 958–965. doi:10.2337/diabetes.51.4.958. ISSN 0012-1797.
  11. ^ Raju, B.; Cryer, P. E. (2005-03-01). "Loss of the Decrement in Intraislet Insulin Plausibly Explains Loss of the Glucagon Response to Hypoglycemia in Insulin-Deficient Diabetes: Documentation of the Intraislet Insulin Hypothesis in Humans". Diabetes. 54 (3): 757–764. doi:10.2337/diabetes.54.3.757. ISSN 0012-1797.
  12. ^ a b c Tesfaye, Nolawit; Seaquist, Elizabeth R. (2010-10-29). "Neuroendocrine responses to hypoglycemia". Annals of the New York Academy of Sciences. 1212 (1): 12–28. doi:10.1111/j.1749-6632.2010.05820.x. ISSN 0077-8923.
  13. ^ a b Reno, Candace M.; Litvin, Marina; Clark, Amy L.; Fisher, Simon J. (Mar 2013). "Defective Counterregulation and Hypoglycemia Unawareness in Diabetes". Endocrinology and Metabolism Clinics of North America. 42 (1): 15–38. doi:10.1016/j.ecl.2012.11.005. PMC 3568263. PMID 23391237.{{cite journal}}: CS1 maint: PMC format (link)
  14. ^ Martín-Timón, Iciar; Del Cañizo-Gómez, Francisco Javier (2015-07-10). "Mechanisms of hypoglycemia unawareness and implications in diabetic patients". World Journal of Diabetes. 6 (7): 912–926. doi:10.4239/wjd.v6.i7.912. ISSN 1948-9358. PMC 4499525. PMID 26185599.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  15. ^ Mundinger, Thomas O.; Taborsky, Gerald J. (2016-10). "Early sympathetic islet neuropathy in autoimmune diabetes: lessons learned and opportunities for investigation". Diabetologia. 59 (10): 2058–2067. doi:10.1007/s00125-016-4026-0. ISSN 0012-186X. PMC 6214182. PMID 27342407. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
Retrieved from "https://en.wikipedia.org/w/index.php?title=User:Jthibaudeau/sandbox&oldid=932604925"