1951-P: Prolonged (12-Hour) Glucagon Infusion Leads to Transient Elevation of Plasma Glucose but Sustained Elevation of Hepatic Glucose Production

Recently, novel non-glycemic effects of glucagon have been described. Although short-term glucagon infusion is well known to elevate plasma glucose levels, long-term effect of increased plasma glucagon on glucose and lipid metabolism is unclear. The aim of the present study was to evaluate the effect of 12-hour glucagon infusion on hepatic glucose production and lipid metabolism in healthy NGT individuals. 8 NGT subjects (5M/3F, age=35± 5 years, BMI = 24 ± 1 kg/m2, HbA1c 5.2± 0.1%) received an 2-hour (75gram) OGTT. On a different day subjects received a 12-hour (6PM to 6 AM) glucagon infusion (3ng/kg/minutes) with the measurement of hepatic glucose production (HGP) with 3-3H-glucose on the following morning from 6-10 AM. HGP in glucagon infused subjects was compared to values in 20 age/gender/weight matched NGT subjects studied after an overnight fast from 6-10 AM. Plasma glucose, insulin, C-peptide, glucagon, and FFA concentrations were obtained every 15 minutes during OGTT. Plasma glucagon concentrations increased from 40 ± 4 to 120 ± 34 pg/ml at 6 AM. Plasma glucose increased 2 hours after the start of infusion from 95 ± 6 to 111 ± 6 mg/dl (p<0.005); after 12 hours of glucagon infusion the plasma glucose concentration declined to the mean baseline levels. After 12-hour glucagon infusion (6 AM), plasma insulin and C-peptide were not significantly changed. Basal hepatic glucose production was significantly higher following prolonged (12-hour) glucagon infusion compared to NGT control subjects following 12-hour overnight fast (3.1 ± 0.1 vs. 2.2 ± 0.2 mg/kg/minutes, p<0.05). Plasma FFA concentrations did not change following 12-hour glucagon infusion (0.629±0.1 vs. 0.670±0.2mml/l, p=ns). Thus 12-hour glucagon infusion led to higher basal rate of HGP, but unchanged plasma FFA levels. These results demonstrate that prolonged physiologic hyperglucagonemia results in a transient elevation of plasma glucose concentration but sustained increase in hepatic glucose production.