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

Publication date: 7 November 2017
Source:Cell Reports, Volume 21, Issue 6
Author(s): Nicolai J. Wewer Albrechtsen, Rune E. Kuhre, Daniel Hornburg, Christian Z. Jensen, Mads Hornum, Carsten Dirksen, Maria Svane, Lærke S. Gasbjerg, Nils B. Jørgensen, Maria N. Gabe, Emilie Balk-Møller, Reidar Albrechtsen, Marie Winther-Sørensen, Katrine D. Galsgaard, Felix Meissner, Tina Jorsal, Asger Lund, Tina Vilsbøll, Rasmus Eliasen, Kirstine N. Bojsen-Møller, Thomas Idorn, Carolyn F. Deacon, Filip K. Knop, Mette M. Rosenkilde, Bolette Hartmann, Bo Feldt-Rasmussen, Matthias Mann, Sten Madsbad, Jens J. Holst
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.

Graphical abstract

Teaser

Wewer Albrechtsen et al. identify a glucagon-like molecule, PG 1-61, in humans using mass-spectrometry-based proteomics. PG 1-61 activates the glucagon receptor, stimulates insulin secretion, and activates key gluconeogenic enzymes. In dysmetabolic conditions, PG 1-61 is upregulated and may therefore serve as a marker of alpha cell stress.


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