A Potential Role for Endogenous Glucagon in Preventing Post-Bariatric Hypoglycemia.

Obesity and obesity-related diseases are major public health concerns that have been exponentially growing in the last decades. Bariatric surgery is an effective long-term treatment to achieve weight loss and obesity comorbidity remission. Post-bariatric hypoglycemia (PBH) is a late complication of bariatric surgery most commonly reported after Roux-en-Y gastric bypass (RYGB). PBH is the end result of postprandial hyperinsulinemia but additional endocrine mechanisms involved are still under debate. Our aim was to characterize entero-pancreatic hormone dynamics associated with postprandial hypoglycemia after RYGB. Individuals previously submitted to RYGB (=23) in a single tertiary hospital presenting PBH symptoms (, =14) and asymptomatic weight-matched controls (, =9) were enrolled. Participants underwent a mixed-meal tolerance test (MMTT) to assess glucose, total amino acids (total AA), insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and neurotensin (NT). We found that hypoglycemia during the MMTT was equally frequent in  and  groups (=1.000). Re-grouped according to glucose nadir during the MMTT ( =11 vs  =12; nadir <3.05 mmol/l vs ≥3.05 mmol/l), subjects presented no differences in anthropometric (BMI: =0.527) or metabolic features (HbA: =0.358), yet distinct meal-elicited hormone dynamics were identified. Postprandial glucose excursion and peak glucose levels were similar (>0.05), despite distinct late glycemic outcomes (t=60 min and t=90 min: <0.01), with overall greater glycemic variability in group (minimum-to-maximum glucose ratio: <0.001).  group meal-triggered hormone profile was characterized by lower early glucagon (t=15 min: <0.01) and higher insulin (t=30 min: <0.05, t=45 min: <0.001), C-peptide (t=30 min: <0.01, t=45 min: <0.001, t=60 min: <0.05), and GLP-1 (t=45 min: <0.05) levels. Hyperinsulinemia was an independent risk factor for hypoglycemia (<0.05). After adjusting for hyperinsulinemia, early glucagon correlated with glycemic nadir (<0.01), and prevented postprandial hypoglycemia (<0.05). A higher insulin to glucagon balance in was observed (<0.05). No differences were observed in total AA, GIP or NT excursions (>0.05). In sum, after RYGB, postprandial hyperinsulinemia is key in triggering PBH, but a parallel and earlier rise in endogenous glucagon might sustain the inter-individual variability in glycemic outcome beyond the effect of hyperinsulinism, advocating a potential pivotal role for glucagon in preventing hyperinsulinemic hypoglycemia.