1914-P: Prolonged (12-Hour) Glucagon Infusion Stimulates Adipocyte Lipolysis and Inflammation In Vivo in Humans

Hyperglucagonemia is a characteristic feature of T2DM and contributes to the metabolic disturbances. Although some rodent studies have suggested that glucagon stimulates lipolysis in adipocytes, the long-term effect of hyperglucagonemia on adipose tissue metabolism and glucose homeostasis in vivo in humans is unclear. The aim of the present study was to examine the effect of 12-hour glucagon infusion on hepatic glucose production (HGP) and adipocyte metabolism in healthy individuals. 8 NGT subjects (5M/3F, age=35±5, BMI = 24±1) received a 12-hour (6PM to 6AM) glucagon infusion (6ng/kg/min) with 3-³H-glucose infusion followed by subcutaneous adipose tissue biopsy at 6AM. On a different day the subjects returned for a repeat study with infusion (6PM to 6AM) of normal saline. Plasma glucagon increased from 57±3 to 219±21 pg/ml. Plasma glucose increased transiently after the start of glucagon and declined to baseline levels at 6AM. Plasma insulin levels increased significantly following glucagon compared to saline (20±7 vs. 8±3 mU/L, p<0.05) and remained elevated at 6AM. Basal HGP (3.2±0.1 vs. 2.9±0.1 mg/kg/min, p<0.01) and fasting plasma FFA concentrations (0.70±0.1 vs. 0.39±0.1 mM, p<0.01) were increased after 12-hour glucagon infusion despite increased plasma insulin levels, indicating severe hepatic and adipocyte insulin resistance. Lipolysis-related gene expression in adipose tissue biopsy were upregulated following 12-hour glucagon infusion (ATGL, 1.14±0.07 vs. 0.77±0.03; HSL, 1.17±0.03 vs. 0.9±0.13; MGL, 1.2±0.04 vs. 0.82±0.2, all p<0.05). Plasma concentration of inflammatory markers were also increased after 12-hour glucagon infusion (IL-1β, 0.65±0.05 vs. 0.49±0.05 pg/mL; TNF-α, 2.03±0.23 vs. 1.75±0.17 pg/mL, both p<0.05). Overall, these results demonstrate that prolonged physiologic hyperglucagonemia causes marked hepatic and adipocyte insulin resistances, stimulates lipolysis and increases plasma FFA, and induces adipocyte and systemic inflammation.