Hepatic Kisspeptin Secretion Impairs Insulin Secretion from Pancreatic Bets Cell. Kisspeptin Receptor GPR54 Antagonist for Treatment of Prediabetes and Diabetes Mellitus in Humans.

Unmet Need
Glucagon and insulin work together to keep blood glucose levels balanced. Glucagon stimulates the liver to secrete glucose while insulin suppresses glucose release. If the body does not regulate glucose levels properly, Type 2 diabetes mellitus (T2DM) will develop. Type 2 diabetes mellitus is a world-wide epidemic, projected to affect 1/3 of people in the U.S. by the year 2050. Many countries spend as much as 10% of their healthcare budget on treating diabetes and its complications. T2DM is characterized by high blood sugar, a relative lack of insulin and insulin resistance, an inability of their liver cells to respond to insulin so that the liver will inappropriately release glucose into the blood. T2DM patients also have dysregulated glucagon secretion. Prolonged activation of glucagon receptors can result in impaired glucose-stimulated insulin secretion (GSIS). The exact mechanisms behind defective GSIS and defective glucagon secretion are still unclear. Discovering these mechanisms could identify novel treatment targets for type 2 diabetes and help treat an ever-growing disease epidemic.
 
Technology Overview
Johns Hopkins researchers found that stimulating liver glucagon receptors produces the neurotransmitter kisspeptin. Kisspeptin circulates to the pancreas and binds to the GPR54 receptor which strongly suppresses pancreatic beta-cell GSIS, impairing glucose homeostasis.  Treatment of a diabetic mouse model with a GPR54 receptor antagonist dramatically improved glucose tolerance, identifying a possible novel type 2 diabetes treatment target.
 
Stage of Development
Hopkins researchers found glucose intolerant and diabetic mouse models had elevated hepatic Kiss1 expression and kisspeptin serum activity. The kisspeptin receptor GPR54 was detected at high levels in mouse pancreatic islets. Using a specific GPR54 receptor antagonist, researchers ameliorated diabetes mellitus and glucose tolerance in a mouse model of diabetes mellitus.
 
Publications
Song WJ et al. Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab. 2014 Apr 1;19(4):667-81
 
Wolfe A and Hussain MA. The Emerging Role(s) for Kisspeptin in Metabolism in Mammals. Front Endocrinol (Lausanne). 2018 Apr 24;9:184.
 

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