Postprandial hypoglycaemia after gastric bypass in type 2 diabetes: pathophysiological mechanisms and clinical implications.

Abstract

Aims/hypothesis: Postprandial hypoglycaemia (PPHG) is a frequent late complication of Roux-en-Y gastric bypass (RYGB) in people without diabetes. We aimed to examine the pathogenetic mechanisms of PPHG and its clinical consequences in people with a history of type 2 diabetes.

Methods: In this case-control study, 24 participants with type 2 diabetes treated with RYGB (14 women; median [IQR] age 53.5 [13.8] years, BMI 29.3 [6.3] kg/m², HbA_1c 36.0 [6.2] mmol/mol [5.4% (0.6%)]) underwent a dual-tracer, frequently sampled, 300 min, 75 g OGTT for the diagnosis of PPHG (glucose nadir <3.0 mmol/l, or <3.3 mmol/l with symptoms). Plasma glucose, glucose tracers, insulin, C-peptide, glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon, adrenaline (epinephrine), noradrenaline (norepinephrine), cortisol and NEFAs were measured. Mathematical models were implemented to estimate glucose metabolic fluxes and beta cell function. ECG recordings, cognitive testing and hypoglycaemia awareness assessments were repeated during the OGTT. Glycaemic levels and dietary habits were assessed under free-living conditions.

Results: PPHG occurred in 12 (50%) participants, mostly without symptoms, due to excessive tracer-derived glucose clearance (mean group difference ± SE in AUC_{0-180 min} +261±72 ml min^-1 kg^-1 × min) driven by higher whole-body insulin sensitivity and early glucose-stimulated hyperinsulinaemia, the latter depending on lower insulin clearance and enhanced beta cell function, regardless of incretin hormones. PPHG participants also had defective counterregulatory hormone responses to hypoglycaemia, preventing a physiological increase in endogenous glucose production and the appearance of symptoms and signs of sympathetic cardiovascular activation and neuroglycopenia. PPHG was associated with more frequent and prolonged hypoglycaemia on 14 day continuous glucose monitoring and alterations in free-living dietary habits.

Conclusions: Our results demonstrate that post-bypass PPHG occurs frequently in individuals with a history of type 2 diabetes, often without warning symptoms, and expose its complex pathogenetic mechanisms, revealing potential therapeutic targets.