Glucagon regulates hepatic kisspeptin to impair insulin secretion.
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.
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.
Woo-Jin
WJ
Song
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.
Prosenjit
P
Mondal
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.
Andrew
A
Wolfe
Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Laura C
LC
Alonso
Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Rachel
R
Stamateris
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.
Benny W T
BW
Ong
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.
Owen C
OC
Lim
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.
Kil S
KS
Yang
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.
Sally
S
Radovick
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.
Horacio J
HJ
Novaira
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Emily A
EA
Farber
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Charles R
CR
Farber
Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Stephen D
SD
Turner
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.
Mehboob A
MA
Hussain
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D055785:Gene Knockdown Techniques; D005934:Glucagon / Q000378:metabolism* / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D059648:Kisspeptins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008156:Luciferases; D051379:Mice; D016688:Mice, Inbred NOD; D008954:Models, Biological
D007328:Insulin; C491407:Kiss1 protein, mouse; D059648:Kisspeptins; D005934:Glucagon; D008156:Luciferases