GPR119 Agonism Increases Glucagon Secretion During Insulin-Induced Hypoglycemia
| Autor: | Margaret Wu, Aleksandr Petrov, Liangsu Wang, Yuyan Ding, Nina Xiaoyan Li, David E. Kelley, Ge Dai, Tamara Dlugos, Robert S. Sherwin, Harold B. Wood, Mark D. Erion, Liming Yang, Timothy J. Kowalski, Stacey N. Brown |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine endocrine system medicine.medical_specialty endocrine system diseases Endocrinology Diabetes and Metabolism medicine.medical_treatment Incretin Hypoglycemia Glucagon Streptozocin Diabetes Mellitus Experimental Receptors G-Protein-Coupled Mice Young Adult 03 medical and health sciences Diabetes mellitus Internal medicine Internal Medicine medicine Animals Humans Hypoglycemic Agents Insulin Rats Wistar Cells Cultured Mice Knockout Glucose tolerance test medicine.diagnostic_test business.industry Glucagon secretion nutritional and metabolic diseases Glucose Tolerance Test Middle Aged medicine.disease Streptozotocin Pharmacology and Therapeutics Rats Mice Inbred C57BL 030104 developmental biology Endocrinology business hormones hormone substitutes and hormone antagonists medicine.drug |
| Zdroj: | Diabetes. 67:1401-1413 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db18-0031 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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