A Potential Role for Endogenous Glucagon in Preventing Post-Bariatric Hypoglycemia
Carolina B. Lobato, Sofia S. Pereira, Marta Guimarães, Bolette Hartmann, Nicolai J. Wewer Albrechtsen, Linda Hilsted, Jens J. Holst, Mário Nora, Mariana P. Monteiro
Abstract
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 ( N =23) in a single tertiary hospital presenting PBH symptoms ( Sym , n =14) and asymptomatic weight-matched controls ( Asy , n =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 Sym and Asy groups ( p =1.000). Re-grouped according to glucose nadir during the MMTT ( Hypo n =11 vs NoHypo n =12; nadir <3.05 mmol/l vs ≥3.05 mmol/l), subjects presented no differences in anthropometric (BMI: p =0.527) or metabolic features (HbA 1c : p =0.358), yet distinct meal-elicited hormone dynamics were identified. Postprandial glucose excursion and peak glucose levels were similar ( p >0.05), despite distinct late glycemic outcomes (t=60 min and t=90 min: p <0.01), with overall greater glycemic variability in Hypo group (minimum-to-maximum glucose ratio: p <0.001). Hypo group meal-triggered hormone profile was characterized by lower early glucagon (t=15 min: p <0.01) and higher insulin (t=30 min: p <0.05, t=45 min: p <0.001), C-peptide (t=30 min: p <0.01, t=45 min: p <0.001, t=60 min: p <0.05), and GLP-1 (t=45 min: p <0.05) levels. Hyperinsulinemia was an independent risk factor for hypoglycemia ( p <0.05). After adjusting for hyperinsulinemia, early glucagon correlated with glycemic nadir ( p <0.01), and prevented postprandial hypoglycemia ( p <0.05). A higher insulin to glucagon balance in Hypo was observed ( p <0.05). No differences were observed in total AA, GIP or NT excursions ( p >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.