Insulin and Glucagon Interaction Studied by Separate and Combined Receptor Antagonism

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Insulin and glucagon are mutually influencing not only the actions of each other but also the secretion, which makes it very complicated to unravel their roles in integrated metabolism. Having studied in detail the actions of glucagon receptor antagonism in mice, we decided also to study the effects of insulin receptor antagonism and their combination. Female C57BL/6J mice (n=72) were administered an insulin receptor antagonist (IRA) (S961, 30 nmol/kg), a glucagon receptor antagonist (GRA) (25-2648, 100 mg/kg), or both IRA and GRA (IRA+GRA) three hours before intravenous administration of saline, glucose (0.5g/kg) or amino acids (1 µmol/g) (both antagonists were generous gifts from Novo Nordisk A/S). As expected, IRA caused hyperglycemia (15.6±1.0 mM vs. 8.4±0.3mM, P<0.0001) and hyperinsulinemia (51.07±3.44ng/mL vs. 0.72±1.19ng/mL, P<0.0001) at fasting, but reduced glucose-induced inhibition of glucagon secretion (dAUC0-20 min; -114.0±24.0min × pM vs. dAUC0-20 min; -211.8±10.4 min × pM, P<0.0001). GRA treatment resulted in mild hypoglycemia (P=0.03), hyperglucagonemia (P=0.04), and did not influence insulin secretion (P=0.9) at fasting. However, after administration of both IRA and GRA, insulin secretion was significantly reduced (31.36±3.0 ng/mL vs. 51.07±3.44 ng/mL, P<0.0001). Finally, GRA+IRA administration resulted in blood glucose concentrations equal to those of vehicle treated mice upon a glucose challenge (tAUC0-20 min; 342.7±29.3 mmol × min vs. 353.1±39.1 mmol × min, P=0.6). In conclusion, using both glucagon and insulin receptor antagonists, it can be demonstrated in mice that both hormones are essential for the maintenance of fasting glucose metabolism and that the secretion of both is regulated by powerful negative feedback mechanisms. Insulin contributes to glucose-induced inhibition of glucagon secretion, while glucagon has a positive effect on insulin secretion. Disclosure K.D. Galsgaard: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. M. Winther-Soerensen: None. N.J. Wewer Albrechtsen: Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Other Relationship; Self; Mercodia, Alpco. J. Pedersen: None.