Obesity dysregulates fasting-induced changes in glucagon secretion. Issue 2 (November 2019)

• Record Type: Journal Article
• Authors: Stern, Jennifer H; Smith, Gordon I; Chen, Shiuwei; Unger, Roger H; Klein, Samuel; Scherer, Philipp E
• Is Part Of: Journal of endocrinology. Volume 243:Issue 2(2019)
• Page Start: 149
• Page End: 160
• Publication Date: 2019-11
• Subjects: glucagon -- obesity -- fasting -- insulin resistance; Endocrinology -- Periodicals; 616.4005
• DOI: 10.1530/JOE-19-0201
• Languages: English
• ISSNs: 0022-0795

Abstract

Abstract : 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 in 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 insulin in both lean and obese mice. Accordingly, the glucagon:insulin ratio was unaffected by fasting in obese mice but increased in lean mice. Re-feeding (2 h) restored hyperglucagonemia in obese mice. Pancreatic perfusion studies confirm that fasting (16 h) decreases pancreatic glucagon secretion in obese mice. Consistent with our findings in 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 lean participants. The glucoregulatory disturbance in obesity may be driven by inappropriate regulation of glucagon by fasting and a static glucagon:insulin ratio.