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GPR119 Agonism Increases Glucagon Secretion During Insulin-Induced Hypoglycemia.
- Source :
-
Diabetes [Diabetes] 2018 Jul; Vol. 67 (7), pp. 1401-1413. Date of Electronic Publication: 2018 Apr 18. - Publication Year :
- 2018
-
Abstract
- Insulin-induced hypoglycemia in diabetes is associated with impaired glucagon secretion. In this study, we tested whether stimulation of GPR119, a G-protein-coupled receptor expressed in pancreatic islet as well as enteroendocrine cells and previously shown to stimulate insulin and incretin secretion, might enhance glucagon secretion during hypoglycemia. In the study, GPR119 agonists were applied to isolated islets or perfused pancreata to assess insulin and glucagon secretion during hypoglycemic or hyperglycemic conditions. Insulin infusion hypoglycemic clamps were performed with or without GPR119 agonist pretreatment to assess glucagon counterregulation in healthy and streptozotocin (STZ)-induced diabetic rats, including those exposed to recurrent bouts of insulin-induced hypoglycemia that leads to suppression of hypoglycemia-induced glucagon release. Hypoglycemic clamp studies were also conducted in GPR119 knockout (KO) mice to evaluate whether the pharmacological stimulatory actions of GPR119 agonists on glucagon secretion during hypoglycemia were an on-target effect. The results revealed that GPR119 agonist-treated pancreata or cultured islets had increased glucagon secretion during low glucose perfusion. In vivo, GPR119 agonists also significantly increased glucagon secretion during hypoglycemia in healthy and STZ-diabetic rats, a response that was absent in GPR119 KO mice. In addition, impaired glucagon counterregulatory responses were restored by a GPR119 agonist in STZ-diabetic rats that were exposed to antecedent bouts of hypoglycemia. Thus, GPR119 agonists have the ability to pharmacologically augment glucagon secretion, specifically in response to hypoglycemia in diabetic rodents. Whether this effect might serve to diminish the occurrence and severity of iatrogenic hypoglycemia during intensive insulin therapy in patients with diabetes remains to be established.<br /> (© 2018 by the American Diabetes Association.)
- Subjects :
- Adult
Animals
Cells, Cultured
Diabetes Mellitus, Experimental drug therapy
Diabetes Mellitus, Experimental metabolism
Glucose Tolerance Test
Humans
Hypoglycemic Agents adverse effects
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Rats
Rats, Wistar
Receptors, G-Protein-Coupled genetics
Streptozocin
Young Adult
Glucagon metabolism
Hypoglycemia chemically induced
Hypoglycemia metabolism
Insulin adverse effects
Receptors, G-Protein-Coupled agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 67
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 29669745
- Full Text :
- https://doi.org/10.2337/db18-0031