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Cell Metab. 2014 Apr 1;19(4):667-81. doi: 10.1016/j.cmet.2014.03.005.

Glucagon regulates hepatic kisspeptin to impair insulin secretion.

Author information

1
Metabolism Division, Johns Hopkins University, CMSC Building 10-113, Baltimore, MD, 21287, USA; Diabetes Institute, Johns Hopkins University, CMSC Building 10-113, Baltimore, MD, 21287, USA; Department of Pediatrics, Johns Hopkins University, CMSC Building 10-113, Baltimore, MD, 21287, USA.
2
Division of Pediatric Endocrinology, Johns Hopkins University, CMSC Building 10-113, Baltimore, MD, 21287, USA; Department of Pediatrics, Johns Hopkins University, CMSC Building 10-113, Baltimore, MD, 21287, USA; Department of Physiology, Johns Hopkins University, CMSC Building 10-113, Baltimore, MD, 21287, USA.
3
Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA 01655, USA.
4
Division of Pediatric Endocrinology, Johns Hopkins University, CMSC Building 10-113, Baltimore, MD, 21287, USA; Department of Pediatrics, Johns Hopkins University, CMSC Building 10-113, Baltimore, MD, 21287, USA.
5
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
6
Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
7
Metabolism Division, Johns Hopkins University, CMSC Building 10-113, Baltimore, MD, 21287, USA; Diabetes Institute, Johns Hopkins University, CMSC Building 10-113, Baltimore, MD, 21287, USA; Department of Medicine, Johns Hopkins University, CMSC Building 10-113, Baltimore, MD, 21287, USA; Department of Pediatrics, Johns Hopkins University, CMSC Building 10-113, Baltimore, MD, 21287, USA; Department of Biological Chemistry, Johns Hopkins University, CMSC Building 10-113, Baltimore, MD, 21287, USA. Electronic address: mhussai4@jhmi.edu.

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.

PMID:
24703698
PMCID:
PMC4058888
DOI:
10.1016/j.cmet.2014.03.005
[Indexed for MEDLINE]
Free PMC Article

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