Dysregulated glucagon signaling contributes to hypoglycemia after vertical sleeve gastrectomy in mice

After bariatric surgery, many individuals experience debilitating bouts of hypoglycemia, termed post-bariatric hypoglycemia (PBH). Our mouse model of vertical sleeve gastrectomy (VSG) mimics key aspects of PBH in humans. As glucagon is a key element of the counterregulatory hormonal response to hypoglycemia, the objective of this manuscript is to understand if glucagon responses and sensitivity are altered after VSG in mice.

Mice underwent sham or VSG surgery. We measured glucagon responses to insulin-induced hypoglycemia and mixed meal tolerance tests. We then measured glucose and insulin responses to different doses of exogenous glucagon in fed and fasted states. Lastly, we performed in vitro experiments to examine glucagon responses to glucose and amino acids.

Postprandial glucagon levels were elevated in mice after VSG, but glucose responses to low doses of exogenous glucagon were blunted in the fasted and postprandial state. Administration of low dose glucagon in the fed state led to hypoglycemia in some VSG mice in parallel with stimulation of insulin release. This effect was partially prevented by pretreatment with the GLP-1 receptor antagonist exendin9-39. In islets isolated from VSG mice, glucagon release in response to high glucose was suppressed, but glucagon responses to alanine and high glucose were not different compared to sham controls.

Altogether, our data suggest both glucagon responses, and sensitivity to exogenous glucagon are altered by VSG. The glucagon dysregulation was not observed in isolated islets suggesting gut signaling may be critical in driving glucagon responses after VSG.