Probes for INS

Insulin-induced hypoglycemia in diabetes is associated with impaired glucagon secretion. Here 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 perfusions to assess insulin and glucagon secretion during hypoglycemia or hyperglycemic conditions. Insulin infusion hypoglycemic clamps were performed with or without GPR119 agonist pre-treatment to assess glucagon counter-regulation in healthy and STZ-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 KO mice to evaluate whether the pharmacologic 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 counter-regulatory 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 diabetic patients remains to be established.