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.
Woo-Jin Song  1 ,  Prosenjit Mondal  1 ,  Andrew Wolfe  2 ,  Laura C Alonso  3 ,  Rachel Stamateris  3 ,  Benny W T Ong  1 ,  Owen C Lim  1 ,  Kil S Yang  1 ,  Sally Radovick  4 ,  Horacio J Novaira  4 ,  Emily A Farber  5 ,  Charles R Farber  5 ,  Stephen D Turner  6 ,  Mehboob A Hussain  7
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: [email protected].
PMID: 24703698 DOI: 10.1016/j.cmet.2014.03.005
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.

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