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. 2025 Feb;68(2):444-459.
doi: 10.1007/s00125-024-06312-3. Epub 2024 Nov 29.

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

Domenico Tricò  1   2 , Luca Sacchetta  3   4 , Eleni Rebelos  3   4   5 , Noemi Cimbalo  3   4 , Martina Chiriacò  3   4   6 , Diego Moriconi  3 , Lorenzo Nesti  3   4 , Giulia Nesti  3   4 , Silvia Frascerra  3   4 , Maria T Scozzaro  3   4 , Giuseppe Daniele  3 , Simona Baldi  3   4 , Andrea Mari  7 , Monica Nannipieri  3 , Andrea Natali  3   4
Affiliations

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

Domenico Tricò et al. Diabetologia. 2025 Feb.

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, HbA1c 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 AUC0-180 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.

Keywords: Bariatric surgery; Beta cell function; Diabetes remission; Glucose absorption; Glucose intolerance; Glucose kinetics; Hypertriglyceridaemia; Hypoglycaemia; Insulin clearance; Insulin resistance; Insulin secretion; Metabolic surgery; Type 2 diabetes.

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Conflict of interest statement

Acknowledgements: We are deeply grateful to all participants for their consent and willingness to participate in this study. We gratefully acknowledge S. Amiel (Department of Diabetes, King’s College of London, London, UK) for her constructive comments and insightful discussion on the research questions and study design. Preliminary data were presented as an abstract at the 60th Annual Meeting of the EASD in 2024. Data availability: The data that support the study findings are available from the corresponding author on request. Funding: This research was funded by the European Foundation for the Study of Diabetes (EFSD Rising Star Fellowship supported by EFSD/Novo Nordisk to DT) and by the European Society for Clinical Nutrition and Metabolism (ESPEN Research Fellowship to DT). Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: DT designed the study protocol, conducted experiments, acquired and analysed data and wrote the manuscript. LS, ER, NC, MC and LN conducted experiments and acquired data. GN revised and analysed the self-reported food diaries. DM and GD recruited participants and provided substantial contributions to the interpretation of data. SB, SF and MTS conducted experiments and analysed blood samples. AM performed glucose tracer and beta cell function modelling. MN and AN revised the study protocol, recruited participants, supervised the study and share last authorship. All authors commented on and approved the final version of the manuscript. DT and AN are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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