Title | Glucagon regulates hepatic kisspeptin to impair insulin secretion. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Song W-J, Mondal P, Wolfe A, Alonso LC, Stamateris R, Ong BWT, Lim OC, Yang KS, Radovick S, Novaira HJ, Farber EA, Farber CR, Turner SD, Hussain MA |
Journal | Cell Metab |
Volume | 19 |
Issue | 4 |
Pagination | 667-81 |
Date Published | 2014 Apr 01 |
ISSN | 1932-7420 |
Keywords | Animals, Gene Expression Regulation, Gene Knockdown Techniques, Glucagon, Gluconeogenesis, Immunohistochemistry, Insulin, Insulin Secretion, Kisspeptins, Liver, Luciferases, Mice, Mice, Inbred NOD, Models, Biological |
Abstract | Early in the pathogenesis of type 2 diabetes mellitus (T2DM), dysregulated glucagon secretion from pancreatic α cells occurs prior to impaired glucose-stimulated insulin secretion (GSIS) from β cells. However, whether hyperglucagonemia is causally linked to β cell dysfunction remains unclear. Here we show that glucagon stimulates via cAMP-PKA-CREB signaling hepatic production of the neuropeptide kisspeptin1, which acts on β 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. |
DOI | 10.1016/j.cmet.2014.03.005 |
Alternate Journal | Cell Metab. |
PubMed ID | 24703698 |
PubMed Central ID | PMC4058888 |
Grant List | P30 NS050274 / NS / NINDS NIH HHS / United States R01 DK095140 / DK / NIDDK NIH HHS / United States R01 HD068777 / HD / NICHD NIH HHS / United States P30 DK079637 / DK / NIDDK NIH HHS / United States R01 DK081472 / DK / NIDDK NIH HHS / United States U01 HD066432 / HD / NICHD NIH HHS / United States P60 DK079637 / DK / NIDDK NIH HHS / United States R01 DK101591 / DK / NIDDK NIH HHS / United States F32 HD008222 / HD / NICHD NIH HHS / United States R01 AR057759 / AR / NIAMS NIH HHS / United States |