Glucagon regulates hepatic kisspeptin to impair insulin secretion.

ABSTRACT: Early in the pathogenesis of type 2 diabetes mellitus (T2DM), dysregulated glucagon secretion from pancreatic ? cells occurs prior to impaired glucose-stimulated insulin secretion (GSIS) from ? cells. However, whether hyperglucagonemia is causally linked to ? cell dysfunction remains unclear. Here we show that glucagon stimulates via cAMP-PKA-CREB signaling hepatic production of the neuropeptide kisspeptin1, which acts on ? cells to suppress GSIS. Synthetic kisspeptin suppresses GSIS in vivo in mice and from isolated islets in a kisspeptin1 receptor-dependent manner. Kisspeptin1 is increased in livers and in serum from humans with T2DM and from mouse models of diabetes mellitus. Importantly, liver Kiss1 knockdown in hyperglucagonemic, glucose-intolerant, high-fat-diet fed, and Lepr(db/db) mice augments GSIS and improves glucose tolerance. These observations indicate a hormonal circuit between the liver and the endocrine pancreas in glycemia regulation and suggest in T2DM a sequential link between hyperglucagonemia via hepatic kisspeptin1 to impaired insulin secretion.

SUBMITTER: Song WJ 

PROVIDER: S-EPMC4058888 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature