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

Glucagon is secreted from pancreatic a 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 b 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

Protocol for assessing the effects of exogenous hormone administration on human postprandial glucose metabolism, appetite sensations, and food intake

Summary: Here, we present a protocol for a randomized, double-blind, placebo-controlled, crossover trial to evaluate the effects of a continuous intravenous infusion of a native liver-derived hormone, liver-expressed antimicrobial peptide 2 (LEAP2), on postprandial glucose metabolism, appetite and satiety sensations, and ad libitum food intake in humans. We describe the preparation of the exogenous hormone administration and participants. We then detail the liquid mixed meal, ad libitum meal test, and blood sampling procedures for assessing postprandial glucose metabolism and food intake.For complete details on the use and execution of this protocol, please refer to Hagemann et al. (2022).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics