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A reduced incretin effect mediated by the rs7903146 variant in the TCF7L2 Gene is an early marker of beta-cell dysfunction in obese youth

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posted on 24.08.2020 by Alfonso Galderisi, Domenico Trico, Bridget Pierpont, Veronika Shabanova, Stephanie Samuels, Chiara Dalla Man, Brittany Galuppo, Nicola Santoro, Sonia Caprio
Background. The risk genotype for the common variant rs7903146 of the transcription factor-7-like-2 gene (TCF7L2) has been found to affect the incretin response in healthy and obese adults, however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146 variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, beta-cell function relative to insulin sensitivity, the Gastrointestinal Induced Glucose Disposal (GIGD) in obese youths with normal and impaired glucose tolerance.

Methods Thirty nine non-diabetic obese adolescents (15[14,18] years; BMI 37[33, 43]kg/m2) were genotyped for the rs7903146 of TCF7L2 and underwent a 3-hour OGTT followed by an iso-glycemic intravenous glucose infusion (iso-IVGTT) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation.

The incretin effect was measured as 100*(AUC-SROGTT – AUC-SRiso-IVGTT)/AUC-SROGTT [AUC-SR=AUC of C-peptide secretion rate]. Participants were grouped into tertiles according to the percentage incretin effect (High-, Moderate- and Low-incretin effect) to describe their metabolic phenotype.

Results The presence of T risk allele for TCF7L2 was associated with a markedly reduced

incretin effect compared to the wild type genotype(0.3[-7.2,14] vs 37.8[12.5-52.4], p<0.002) When the cohort was stratified by incretin effect, the High-, Moderate- and Low-incretin groups did not differ with respect to anthropometric features, while the Low-incretin group exhibited higher 1-h glucose (p=0.015), a reduced disposition index, insulin sensitivity and insulin clearance, compared with the High-incretin group. Gastrointestinal induced glucose disposal (GIGD) was reduced in the Low-incretin group (p=0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp.

Conclusion A reduced incretin effect and its association with the TCF7L2 variant rs7903146 identify an early metabolic phenotype in obese non-diabetic youths, featured by a higher plasma glucose peak at 1hr, lower insulin secretion, sensitivity and clearance, and gastrointestinal glucose disposal.

Funding

This study was supported by the National Institutes of Health, National Institute of Child Health and Human Development (grants R01-HD-40787, R01DK111038, R01-HD-28016, and K24-HD-01464 to S.C. and R01-DK-114504 to N.S.), the National Center for Research Resources (Clinical and Translational Science Award [grant UL1-RR-0249139] to S.C.), the American Diabetes Association (Distinguished Clinical Scientist Award to S.C.), the National Institute of Diabetes and Digestive and Kidney Diseases (grant R01-DK-111038 to S.C.; grant R01-DK-114504-01A; K12-AWDA10768 and GR103182); the Robert Leet Patterson and Clara Guthrie Patterson Trust Mentored Research Award, the Cassa Di Risparmio di Padova e Rovigo and the Italian Ministry for Education under the initiative "Departments of Excellence" (Law 232/2016). This article’s contents are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health.

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