Plasma GDF15 increases during hyperinsulinemic hypoglycemia in humans with post-bariatric hypoglycemia and after insulin exposure in mice

Post-bariatric hypoglycemia (PBH), characterized by excessive postprandial incretin and insulin secretion, is a common complication of bariatric surgery. Here, we investigate the relationship between PBH and growth differentiation factor 15 (GDF15) in individuals with PBH after Roux-en-Y gastric bypass (RYGB), post-RYGB individuals who remain asymptomatic (Asx), and individuals with overweight/obesity but without history of surgery (Ow/Ob). Fasting plasma GDF15 is higher in PBH vs. Ow/Ob and further increases postprandially, coinciding with hypoglycemia symptoms. During a hyperinsulinemic hypoglycemic clamp, GDF15 progressively increases in PBH and correlates with hypoglycemia survey symptoms, including weakness, difficulty concentrating, feeling cold, and tingling lips. In mice, insulin-induced hypoglycemia also results in elevated GDF15 levels, and exogenous recombinant GDF15 (rGDF15) reduces food intake in response to hypoglycemia. Our data suggest that GDF15 modulates the counterregulatory response to hypoglycemia in both PBH individuals and mice and that elevated GDF15 levels contribute to hypoglycemia-related postprandial symptoms. This study was registered at ClinicalTrials.gov (NCT04428866).