American Diabetes Association
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Genetic evidence of causal relation between intestinal glucose absorption and early postprandial glucose response: a Mendelian randomization study

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posted on 2024-03-18, 16:52 authored by Simon Peschard, Violeta Raverdy, Pierre Bauvin, Rebecca Goutchtat, Veronique Touche, Bruno Derudas, Celine Gheeraert, Julie Dubois-Chevalier, Robert Caiazzo, Gregory Baud, Camille Marciniak, Helene Verkindt, Naima Oukhouya Daoud, Carel W Le Roux, Philippe Lefebvre, Bart Staels, Sophie Lestavel, François Pattou

The post-prandial glucose response is an independent risk factor for type 2 diabetes. Observationally, early glucose response after an oral glucose challenge has been linked to intestinal glucose absorption, largely influenced by the expression of sodium-glucose-co-transporter-1 (SGLT1). This study utilizes Mendelian randomization (MR) to estimate the causal effect of intestinal SGLT1 expression on early glucose response. Involving 1547 subjects with class II/III obesity from the ABOS cohort, the study employs SGLT1 genotyping, oral glucose tolerance tests, and jejunal biopsies to measure SGLT1 expression. A loss-of-function SGLT1 haplotype served as the instrumental variable, with intestinal SGLT1 expression as the exposure and the change in 30-minute post-load glycemia from fasting glycemia (∆30 glucose) as the outcome. Results showed that 12.8% of the 1,342 genotyped patients carried the SGLT1 loss-of-function haplotype, associated with a mean ∆30 glucose reduction of -0.41 mmol/L and a significant decrease in intestinal SGLT1 expression. The observational study linked a one standard deviation decrease in SGLT1 expression to a ∆30 glucose reduction of -0.097 mM/L. MR analysis paralleled these findings, associating a statistically significant reduction in genetically instrumented intestinal SGLT1 expression with a ∆30 glucose decreases of -0.353. In conclusion, the MR analysis provides genetic evidence that reducing intestinal SGLT1 expression causally lowers early post-load glucose response. This finding has a potential translational impact on managing early glucose response in type 2 diabetes


This work was supported by the “Programme d’Investissement d’Avenir” (PRECINASH, ANR-16-RHUS-0006; European Genomic Institute for Diabetes, ANR-10-LABX-0046), Lille University (WILL-CHAlRES-23-001), Fondation de la Recherche Médicale (EQU202303016330 PATTOU), EU Horizon 2020 research and innovation program (Innovative Medicines Initiative 2, project SOPHIA 875534), Fondation Francophone pour la Recherche sur le Diabète (FFRD 2015).


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