Cell Metab. 19, 667–681 (2014)

Elevated pancreatic glucagon secretion by pancreatic α cells precedes impairment of glucose-stimulated insulin secretion (GSIS) from β cells in type 2 diabetes, but whether there is a direct connection between these two events has not been clear. To search for a connection, Song et al. developed a mouse model that selectively mimics the effects of elevated glucagon signaling in the liver—an organ that is known to respond to the activity of pancreatic α and β cells—and found evidence for a serum factor that suppressed GSIS in vitro. In comparative microarray analyses, transcripts encoding the hepatic peptide kisspeptin1 were more abundant in the model than in wild-type mice. In cultured hepatocytes and in mice, glucagon treatment led to elevated kisspeptin1 production only if glucagon receptor was expressed on hepatocytes. A synthetic version of kisspeptin1 suppressed GSIS in wild-type mice but not in mice with a pancreas-specific deletion of the kisspeptin receptor, indicating that the hepatic peptide acts on cells in the pancreas. In mice fed a high-fat diet, shRNA-mediated knockdown of kisspeptin1 in the liver or selective knockout of the kisspeptin1 receptor in the pancreas increased GSIS and improved glucose tolerance compared with scrambled shRNA or no knockout, respectively. Taken together, the findings define an α cell–liver–β cell endocrine circuit based on the peptide kisspeptin1 that causally links dysregulated glucagon secretion with impaired GSIS in diabetes.