Postprandial Glucagon Action in the Human Brain

ABSTRACT Aims Elevated fasting glucagon is linked to hyperglycemia, but postprandial glucagon effects are less understood. Recent evidence suggests metabolic benefits of rising glucagon after oral glucose intake, potentially impacting brain‐mediated whole‐body metabolism. To elucidate the translational relevance of these findings, we studied postprandial effects of glucagon on the human brain. Materials and Methods We performed oral glucose tolerance tests (OGTT) combined with functional magnetic resonance imaging to quantify brain activity and connectivity at fasting, 30 and 120 min post glucose load in 30 volunteers. In 14 participants with suppressed glucagon, low‐dose glucagon infusion mimicked non‐suppressed glucagon after OGTT. This was compared to 7 participants with endogenous rising glucagon during OGTT. Results Low‐dose glucagon infusion did not elevate plasma glucose levels during OGTT. Also, no changes in insulin sensitivity and insulin secretion were observed. However, experimentally elevating glucagon during OGTT in individuals with physiological suppression of glucagon significantly increased postprandial brain responsivity in the hippocampal gyrus and in brain regions important for the homeostatic and hedonic regulation of food intake as well as systemic metabolism (i.e., hypothalamus and ventral striatum). Most postprandial brain responsiveness during glucagon infusion was directionally consistent with the findings in persons with endogenously rising glucagon. Moreover, the postprandial brain response correlated with the rise in glucagon, regardless of exogenous or endogenous source of glucagon. Although the overall glucagon trajectory during OGTT was not significantly different over the full 0–150 min period, the groups differed at key post‐challenge timepoints and in integrated glucagon exposure. Together with the infusion and correlation analyses, this supports a relationship between postprandial glucagon and brain responsivity, while more subtle differences in glucagon kinetics will require larger studies. Conclusions Our findings demonstrate postprandial effects of glucagon in metabolically relevant human brain areas. This may underlie the promising effects on body weight achieved with pharmacological multi‐agonists that activate the glucagon receptor.