Glucagon Response to Prandial Insulin Administration in Persons With Type 1 Diabetes

Summary

Glucagon regulation and response in persons with T1D at the basal state and in response to various stimuli remains unclear. Dr. Philip Cryer has previously reported that, in T1D young adults with a course of the disease of 16+9 years, the absence of endogenous insulin secretion results in increased glucagon secretion after a mixed meal, concluding that endogenous insulin reciprocally regulates the alpha-cell glucagon secretion and also suggesting that glucagon dysregulation may play an important role in post-prandial hyperglycemia in T1D. Interestingly, recent research on human islets have shown that insulin inhibits counter-regulatory glucagon secretion by a paracrine effect mediated by SGLT2-dependent stimulation of somatostatin release. An important gap in our knowledge is whether the timing of prandial insulin doses affects the glucagon response to a hyperglycemic stimulus in patients with T1D who have undetectable C-peptide. Whether appropriately timed exogenous insulin can modify the glucagon response to glucose fluctuations has not been studied. As such, this pilot study aims to characterize the glucagon response to meal-time hyperglycemia and to compare the difference in glucagon secretion when mealtime bolus insulin is given before the meal versus after the meal with the objective of understanding factors that contribute to the peak post-prandial blood glucose and AUC of blood glucose after a mixed meal in this target population.

Timeline

Start

2020-02-13

Primary completion

2020-07-01

Completion

2020-07-01

Publications

• Background Cryer PE. Minireview: Glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology. 2012 Mar;153(3):1039-48. doi: 10.1210/en.2011-1499. Epub 2011 Dec 13.
• Background Cooperberg BA, Cryer PE. Insulin reciprocally regulates glucagon secretion in humans. Diabetes. 2010 Nov;59(11):2936-40. doi: 10.2337/db10-0728. Epub 2010 Aug 23.
• Background Vergari E, Knudsen JG, Ramracheya R, Salehi A, Zhang Q, Adam J, Asterholm IW, Benrick A, Briant LJB, Chibalina MV, Gribble FM, Hamilton A, Hastoy B, Reimann F, Rorsman NJG, Spiliotis II, Tarasov A, Wu Y, Ashcroft FM, Rorsman P. Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion. Nat Commun. 2019 Jan 11;10(1):139. doi: 10.1038/s41467-018-08193-8.
• Background Schiffrin A, Suissa S, Weitzner G, Poussier P, Lalla D. Factors predicting course of beta-cell function in IDDM. Diabetes Care. 1992 Aug;15(8):997-1001. doi: 10.2337/diacare.15.8.997.
• Background Yosten GLC. Alpha cell dysfunction in type 1 diabetes. Peptides. 2018 Feb;100:54-60. doi: 10.1016/j.peptides.2017.12.001.
• Background Porksen S, Nielsen LB, Kaas A, Kocova M, Chiarelli F, Orskov C, Holst JJ, Ploug KB, Hougaard P, Hansen L, Mortensen HB; Hvidore Study Group on Childhood Diabetes. Meal-stimulated glucagon release is associated with postprandial blood glucose level and does not interfere with glycemic control in children and adolescents with new-onset type 1 diabetes. J Clin Endocrinol Metab. 2007 Aug;92(8):2910-6. doi: 10.1210/jc.2007-0244. Epub 2007 May 22.
• Background Brown RJ, Sinaii N, Rother KI. Too much glucagon, too little insulin: time course of pancreatic islet dysfunction in new-onset type 1 diabetes. Diabetes Care. 2008 Jul;31(7):1403-4. doi: 10.2337/dc08-0575.

Drugs

Indications