Glucagon regulates hepatic kisspeptin to impair insulin secretion

Woo-Jin Song; Prosenjit Mondal; Andrew Wolfe; Laura C Alonso; Rachel Stamateris; Benny W T Ong; Owen C Lim; Kil S Yang; Sally Radovick; Horacio J Novaira; Emily A Farber; Charles R Farber; Stephen D Turner; Mehboob A Hussain

doi:10.1016/j.cmet.2014.03.005

Glucagon regulates hepatic kisspeptin to impair insulin secretion

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Gene Expression Regulation / drug effects
Gene Expression Regulation / physiology*
Gene Knockdown Techniques
Glucagon / metabolism*
Glucagon / pharmacology
Gluconeogenesis / drug effects
Gluconeogenesis / physiology*
Immunohistochemistry
Insulin / metabolism*
Insulin Secretion
Kisspeptins / blood
Kisspeptins / genetics
Kisspeptins / metabolism*
Liver / metabolism*
Luciferases
Mice
Mice, Inbred NOD
Models, Biological

Substances

Insulin
Kiss1 protein, mouse
Kisspeptins
Glucagon
Luciferases

Associated data

GEO/GSE48815

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding