Obesity dysregulates Fasting-Induced changes in glucagon secretion

Hyperglucagonemia, a hallmark in obesity and insulin resistance promotes hepatic glucose output, exacerbating hyperglycemia and thus predisposing to the development type 2 diabetes. As such, glucagon signaling is a key target for new therapeutics to manage insulin resistance. We evaluated glucagon homeostasis in lean and obese mice and people. In lean mice, fasting for 24 h caused a rise i n glucagon. In contrast, a decrease in serum glucagon compared to baseline was observed in diet-induced obese mice between 8 and 24 h of fasting. Fasting decreased serum ins ulin in both lean and obese mice. Accordingly, the glucagon:insulin ratio was unaffect ed by fasting in obese mice but increased in lean mice. Re-feeding (2 h) restored hype rglucagonemia in obese mice. Pancreatic perfusion studies confirm that fasting (16 h) d ecreases pancreatic glucagon secretion in obese mice. Consistent with our findings i n the mouse, a mixed meal increased serum glucagon and insulin concentrations in obese humans, both of which decreased with time after a meal. Consequently, fasting and re-feeding less robustly affected glucagon:insulin ratios in obese compared to l ean participants. The glucoregulatory disturbance in obesity may be driven by inappropriate regulation of glucagon by fasting and a static glucagon:insulin ratio.