34-OR: Postprandial Glucagon Action in the Human Brain

While elevated fasting glucagon is linked to hyperglycemia, the impact of postprandial changes in glucagon is less clear. Recent findings suggest potential metabolic benefits of rising glucagon after oral glucose intake. In addition to the prominent hepatic action of the hormone, animal data indicate that glucagon signaling in the brain contributes to its effects on whole-body metabolism. To elucidate the translational relevance of these findings, we studied postprandial effects of glucagon on the human brain. We performed oral glucose tolerance tests combined with fMRI to quantify brain activity and connectivity at fasting, 30- and 60-minutes post glucose load in 29 volunteers. In 14 out of 22 volunteers with physiologically suppressed glucagon during OGTT, a second OGTT with low-dose glucagon infusion was performed (0.5 pmol/kg/min). All participants had their first OGTT with intravenous saline infusion. This was compared to 7 participants with endogenous rising glucagon during OGTT. 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 the OGTT significantly increased postprandial brain responsivity in the hippocampal gyrus and in brain regions important for the regulation of food intake and systemic metabolism (i.e. hypothalamus, nucleus accumbens, midbrain). Postprandial brain responsivity 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. Our findings demonstrate postprandial effects of glucagon in metabolically relevant human brain areas. This may underly the promising effects on body weight achieved with upcoming pharmacological multi-agonists that activate the glucagon receptor. Disclosure R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. A.Peter: None. M.Heni: Advisory Panel; Boehringer-Ingelheim, Sanofi, Research Support; Boehringer Ingelheim Inc., Speaker's Bureau; Lilly, Bayer Inc., Sanofi, Boehringer-Ingelheim, Novo Nordisk, Amryt Pharma Plc. S.Kullmann: None. J.Hummel: None. R.Veit: None. K.Prystupa: Other Relationship; Berlin-Chemie AG. E.Hosenfeld: None. A.L.Birkenfeld: None. H.Häring: None. H.Preissl: None.