TY - JOUR

T1 - Glucose and Amino Acid Metabolism in Mice Depend Mutually on Glucagon and Insulin Receptor Signaling

AU - Galsgaard, Katrine D

AU - Winther-Sørensen, Marie

AU - Pedersen, Jens

AU - Kjeldsen, Sasha A S

AU - Rosenkilde, Mette M

AU - Wewer Albrechtsen, Nicolai J

AU - Holst, Jens J

PY - 2019

Y1 - 2019

N2 - Glucagon and insulin are important regulators of blood glucose. The importance of insulin receptor signaling for alpha cell secretion and of glucagon receptor signaling for beta cell secretion is widely discussed and of clinical interest. Amino acids are powerful secretagogues for both hormones, and glucagon controls amino acid metabolism through ureagenesis. The role of insulin in amino acid metabolism is less clear. Female C57BL/6JRj mice received an insulin receptor antagonist (IRA) (S961, 30 nmol/kg), a glucagon receptor antagonist (GRA) (25-2648, 100 mg/kg), or GRA+IRA three hours before intravenous administration of similar volumes of saline, glucose (0.5 g/kg), or amino acids (1 µmol/g) while anesthetized with isoflurane. IRA caused basal hyperglycemia, hyperinsulinemia, and hyperglucagonemia. Unexpectedly, IRA lowered basal plasma concentrations of amino acids, whereas GRA increased amino acids, lowered glycemia, and increased glucagon, but did not influence insulin concentrations. After administration of GRA+IRA, insulin secretion was significantly reduced compared to IRA administration alone. Blood glucose responses to a glucose- and amino acid- challenge were similar after vehicle and GRA+IRA administration, but greater after IRA and lower after GRA. Anesthesia may have influenced the results, which otherwise strongly suggest that both hormones are essential for the maintenance of glucose homeostasis and that the secretion of both is regulated by powerful negative feedback mechanisms. In addition, insulin limits glucagon secretion, while endogenous glucagon stimulates insulin secretion, revealed during lack of insulin autocrine feedback. Finally, glucagon receptor signaling seems to be of greater importance for amino acid metabolism than insulin receptor signaling.

AB - Glucagon and insulin are important regulators of blood glucose. The importance of insulin receptor signaling for alpha cell secretion and of glucagon receptor signaling for beta cell secretion is widely discussed and of clinical interest. Amino acids are powerful secretagogues for both hormones, and glucagon controls amino acid metabolism through ureagenesis. The role of insulin in amino acid metabolism is less clear. Female C57BL/6JRj mice received an insulin receptor antagonist (IRA) (S961, 30 nmol/kg), a glucagon receptor antagonist (GRA) (25-2648, 100 mg/kg), or GRA+IRA three hours before intravenous administration of similar volumes of saline, glucose (0.5 g/kg), or amino acids (1 µmol/g) while anesthetized with isoflurane. IRA caused basal hyperglycemia, hyperinsulinemia, and hyperglucagonemia. Unexpectedly, IRA lowered basal plasma concentrations of amino acids, whereas GRA increased amino acids, lowered glycemia, and increased glucagon, but did not influence insulin concentrations. After administration of GRA+IRA, insulin secretion was significantly reduced compared to IRA administration alone. Blood glucose responses to a glucose- and amino acid- challenge were similar after vehicle and GRA+IRA administration, but greater after IRA and lower after GRA. Anesthesia may have influenced the results, which otherwise strongly suggest that both hormones are essential for the maintenance of glucose homeostasis and that the secretion of both is regulated by powerful negative feedback mechanisms. In addition, insulin limits glucagon secretion, while endogenous glucagon stimulates insulin secretion, revealed during lack of insulin autocrine feedback. Finally, glucagon receptor signaling seems to be of greater importance for amino acid metabolism than insulin receptor signaling.

U2 - 10.1152/ajpendo.00410.2018

DO - 10.1152/ajpendo.00410.2018

M3 - Journal article

C2 - 30807215

VL - 316

SP - E660-E673

JO - American Journal of Physiology - Endocrinology and Metabolism

JF - American Journal of Physiology - Endocrinology and Metabolism

SN - 0193-1849

IS - 4

ER -