Age-related obesity is associated with enhanced glucagon action in male C57BL/6J mice

The impact of aging on insulin action has been studied extensively; however, the effect of aging on the action of its counter-regulatory hormone, glucagon, is not established. The purpose of this study was to determine if aging alters in vivo glucagon responsiveness, independent of insulin action. To accomplish this, glucagon (60 ug/Kg lean body mass) was administered while insulin secretion was inhibited by Octreotide (1mg/Kg body mass) in young (YG, 4-6 months) and aged (AG, 19-21 months) male C57BL6/J mice. In addition, body composition was assessed by nuclear magnetic resonance spectroscopy and insulin sensitivity was assessed by an insulin-assisted glucose tolerance (IAGT) test. AG mice had significantly higher body mass (48.2±2.28 vs. 36.0±1.18 g, p=0.0002), fat mass (23.5±3.5 vs. 8.31±1.46 g, p=0.0004), and %body fat (49.2±4.0 vs. 22.3±3.35%, p=0.0001) when compared to YG mice. AG mice also had significantly lower lean body mass (19.0±1.04 vs. 22.1±0.70, p=0.026). AG mice appear to be insulin resistant as evidenced by higher glucose levels during the IAGT test (ANOVA: age effect, p = 0.04). Glucagon responsiveness was increased significantly in AG compared to YG mice, as shown by significantly higher blood glucose levels following glucagon administration (ANOVA: age effect, p=0.001). Glucagon responsiveness area under the curve (AUC) was highly related to body mass (r=0.74), fat mass (r =0.82), and %body fat (r=0.79), indicating that obesity likely plays an important role in the age-related changes in glucagon action. Our findings demonstrate that when insulin secretion is acutely blocked with Octreotide, age-related obesity promotes an exaggerated glucose response to glucagon, rather than glucagon resistance. These results may lead to new targets to treat metabolic dysfunction-associated steatohepatitis (MASH), a disease whose prevalence is increased in older individuals. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.