Diet‐induced obesity enhances the glycaemic response to glucagon in male C57BL/6J mice

Although the impact of obesity on the action of insulin has been studied extensively, little is known about how obesity affects the action of its counter‐regulatory hormone, glucagon. The purpose of this study was to determine whether diet‐induced obesity alters in vivo glucagon responsiveness, independent of insulin action. To study diet‐induced obesity, C57BL/6J male mice were fed a normal chow diet or a Western diet for 16 weeks. Glucagon responsiveness was determined by assessing the blood glucose response to glucagon (25 µg/kg) while insulin secretion was inhibited by octreotide (1 mg/kg). Body composition was assessed by nuclear magnetic resonance spectroscopy. Insulin sensitivity was assessed by an insulin‐assisted glucose tolerance test. As expected, the Western diet resulted in an increase in adiposity and a decrease in insulin sensitivity. Contrary to our initial hypothesis, diet‐induced obesity increased glucagon responsiveness, as evidenced by significantly higher blood glucose levels following glucagon administration, resulting in a greater area under the curve in mice fed a Western diet compared with mice fed a normal chow diet. In a preclinical model of obesity and insulin resistance, our study indicates that the glycaemic response to glucagon is enhanced when insulin secretion is inhibited with octreotide, arguing against the idea of impaired glucagon responsiveness. Future studies can use this approach to identify alterations in glucagon signalling that might explain the enhanced glucose response to glucagon.