A New Player in Glucose Counterregulation: the Glycemic Effects of Neuronostatin through GPR107 and Enhanced Glucagon Secretion

Abstract

Regulation of blood glucose is a tightly controlled system with numerous players, woven by both hyperglycemic and hypoglycemic agents that interact in secretion and signaling mechanisms. However, this complex system is deranged in both Type 1 and Type 2 Diabetes, in the response to hyperglycemia (insulin) and hypoglycemia (counterregulatory factors such as glucagon). In treating diabetes with insulin and antidiabetic agents, there is significant risk of hypoglycemia due to improper dosing or inadequate food intake. In addition, repeated bouts of hypoglycemia diminish the counterregulatory response and blunt awareness of symptoms, creating a vicious cycle of unawareness and increasingly severe hypoglycemia. There is great need for better understanding of the players and mechanisms in blood glucose maintenance, and specifically in diabetic hypoglycemia. We recently identified a novel peptide, neuronostatin (NST), encoded in the somatostatin prohormone and found in all somatostatin‐positive tissues. However, the activity of NST is functionally distinct from other prosomatostatin products. Furthermore, it appears the physiologic stimuli of the peptides are different and that the peptides are sequestered in separate secretory vesicles. Our group identified the orphan GPCR, GPR107, as a cognate receptor of NST. Through an interaction with GPR107, NST enhanced glucagon release from isolated islets and immortalized alpha cells. NST also reduced release of insulin in response to high glucose conditions in isolated islets. Based off our findings, we hypothesized that NST is a component of the pancreatic arm of the counterregulatory response. In support of our hypothesis, an infusion of NST substantially increased plasma glucose levels over 30 minutes in male rats, and diminished the insulin response to hyperglycemia in a glucose tolerance test. Additionally, antagonism of the glucagon receptor did not prevent the hyperglycemic effects of NST, suggesting the peptide can act independent of glucagon to increase blood glucose. In insulin‐induced hypoglycemia, NST blunts the drop in blood glucose, further reinforcing the role of NST in counterregulation. The secretion of NST release also appears tied to glucose levels. Fasting blood glucose raised plasma NST levels in rats and humans, and exposure to low glucose stimulated NST release from human islets. Further experiments will confirm the regulatory mechanisms involved in the release of NST, and the importance of its receptor, GPR107. We propose that NST could represent a novel therapeutic target for the treatment and prevention of hypoglycemia in diabetes. Support or Funding Information This work was funded by the NIDDK and the Helmsley Charitable Trust.