Obesity dysregulates fasting-induced changes in glucagon secretion

Jennifer H. Stern, Gordon I. Smith, Shiuwei Chen, Roger H. Unger, Samuel Klein, Philipp E. Scherer

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1 Scopus citations


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.

Original languageEnglish
Pages (from-to)149-160
Number of pages12
JournalJournal of Endocrinology
Issue number2
StatePublished - Nov 1 2019


  • fasting
  • glucagon
  • insulin resistance
  • obesity

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    Stern, J. H., Smith, G. I., Chen, S., Unger, R. H., Klein, S., & Scherer, P. E. (2019). Obesity dysregulates fasting-induced changes in glucagon secretion. Journal of Endocrinology, 243(2), 149-160. https://doi.org/10.1530/JOE-19-0201