期刊
JOURNAL OF ENDOCRINOLOGY
卷 243, 期 2, 页码 149-160出版社
BIOSCIENTIFICA LTD
DOI: 10.1530/JOE-19-0201
关键词
glucagon; obesity; fasting; insulin resistance
资金
- National Institutes of Health [K99-AG055649, F32-DK107058, DK56341, DK20579, RR024992]
- JDRF [2SRA2016149QR]
- Novo Nordisk Research Foundation
- Janssen RD
- Pershing Square Foundation
- [R01-DK55758]
- [R01-DK099110]
- [P01-DK088761-01]
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.
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