Fasting-Induced Changes in Glucagon Secretion Are Dysregulated in Obesity

Hyperglucagonemia is a hallmark in obesity and type 2 diabetes (T2DM). Suppression of glucagon signaling improves glycemic control in T2DM. We evaluated glucagon homeostasis in lean and obese mice and people. Discordant with the canonical rise in glucagon with fasting, our studies show that fasting (4, 8, 16 and 24 h) caused a progressive decrease in serum glucagon in diet-induced obese, hyperglucagonemic mice (P<0.01), yet a progressive increase in serum glucagon in lean mice (P<0.01). Serum insulin decreased with fasting in both lean and obese mice (P<0.01). Accordingly, fasting increased the glucagon:insulin ratio in the lean mouse (P<0.01), but did not affect the glucagon:insulin ratio in the obese mouse. Two hours of re-feeding restored hyperglucagonemia in obese mice (P<0.01). Pancreatic perfusion studies in obese, hyperglucagonemic mice confirm that 16 h of fasting decreases pancreatic glucagon secretion (P<0.01). Consistent with our findings in the mouse, fasting decreased (P<0.05) serum glucagon in obese participants. In contrast, fasting increased serum glucagon concentrations in lean participants (P<0.05). As expected, fasting decreased serum insulin in both lean and obese participants (P<0.05 for both). As a result, fasting induced a more robust rise in the glucagon:insulin ratio in lean compared to obese participants (P<0.01). In addition, mixed meal feeding increased serum glucagon in people with obesity. These findings suggest that the metabolic pathophysiology of obesity may be driven by inappropriate meal-induced regulation of glucagon, resulting in a relatively static glucagon:insulin ratio. Disclosure J.H. Stern: None. G.I. Smith: None. R.H. Unger: None. S. Klein: Stock/Shareholder; Self; Aspire Bariatrics. Consultant; Self; Pfizer Inc.. Research Support; Self; Merck & Co., Inc., Johnson & Johnson Services, Inc., REMD Biotherapeutics. P.E. Scherer: None.