期刊
CELL METABOLISM
卷 19, 期 4, 页码 667-681出版社
CELL PRESS
DOI: 10.1016/j.cmet.2014.03.005
关键词
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资金
- National Institutes of Health
- Swami International Institute for Medical Education
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-PKACREB 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.
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