| First Author | Song WJ | Year | 2014 |
| Journal | Cell Metab | Volume | 19 |
| Issue | 4 | Pages | 667-81 |
| PubMed ID | 24703698 | Mgi Jnum | J:213148 |
| Mgi Id | MGI:5582975 | Doi | 10.1016/j.cmet.2014.03.005 |
| Citation | Song WJ, et al. (2014) Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab 19(4):667-81 |
| abstractText | Early in the pathogenesis of type 2 diabetes mellitus (T2DM), dysregulated glucagon secretion from pancreatic alpha cells occurs prior to impaired glucose-stimulated insulin secretion (GSIS) from beta cells. However, whether hyperglucagonemia is causally linked to beta cell dysfunction remains unclear. Here we show that glucagon stimulates via cAMP-PKA-CREB signaling hepatic production of the neuropeptide kisspeptin1, which acts on beta 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. |
