3 years ago

Circulating Glucagon 1-61 Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production

Circulating Glucagon 1-61 Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production
Bo Feldt-Rasmussen, Asger Lund, Maria N. Gabe, Daniel Hornburg, Carolyn F. Deacon, Felix Meissner, Emilie Balk-Møller, Nils B. Jørgensen, Mette M. Rosenkilde, Marie Winther-Sørensen, Kirstine N. Bojsen-Møller, Bolette Hartmann, Tina Jorsal, Katrine D. Galsgaard, Tina Vilsbøll, Jens J. Holst, Reidar Albrechtsen, Sten Madsbad, Thomas Idorn, Maria Svane, Filip K. Knop, Lærke S. Gasbjerg, Mads Hornum, Nicolai J. Wewer Albrechtsen, Rasmus Eliasen, Christian Z. Jensen, Rune E. Kuhre, Matthias Mann, Carsten Dirksen

Summary

Glucagon is secreted from pancreatic α cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1-61 is secreted in subjects with obesity, both before and after gastric bypass surgery, with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in β cells demonstrated that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in vivo. We conclude that glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion.

Publisher URL: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31466-3

DOI: 10.1016/j.celrep.2017.10.034

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