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. 2012 May;61(5):1082-9.
doi: 10.2337/db11-1732. Epub 2012 Mar 28.

Diabetes-associated common genetic variation and its association with GLP-1 concentrations and response to exogenous GLP-1

Galina Smushkin  1 , Matheni Sathananthan, Airani Sathananthan, Chiara Dalla Man, Francesco Micheletto, Alan R Zinsmeister, Claudio Cobelli, Adrian Vella
Affiliations

Diabetes-associated common genetic variation and its association with GLP-1 concentrations and response to exogenous GLP-1

Galina Smushkin et al. Diabetes. 2012 May.

Abstract

The mechanisms by which common genetic variation predisposes to type 2 diabetes remain unclear. The disease-associated variants in TCF7L2 (rs7903146) and WFS1 (rs10010131) have been shown to affect response to exogenous glucagon-like peptide 1 (GLP-1), while variants in KCNQ1 (rs151290, rs2237892, and rs2237895) alter endogenous GLP-1 secretion. We set out to validate these observations using a model of GLP-1-induced insulin secretion. We studied healthy individuals using a hyperglycemic clamp and GLP-1 infusion. In addition, we measured active and total GLP-1 in response to an oral challenge in nondiabetic subjects. After genotyping the relevant single nucleotide polymorphisms, generalized linear regression models and repeated-measures ANCOVA models incorporating potential confounders, such as age and BMI, were used to assess the associations, if any, of response with genotype. These variants did not alter GLP-1 concentrations in response to oral intake. No effects on β-cell responsiveness to hyperglycemia and GLP-1 infusion were apparent. Diabetes-associated variation (T allele at rs7903146) in TCF7L2 may impair the ability of hyperglycemia to suppress glucagon (45 ± 2 vs. 47 ± 2 vs. 60 ± 5 ng/L for CC, CT, and TT, respectively, P = 0.02). In nondiabetic subjects, diabetes-associated genetic variation does not alter GLP-1 concentrations after an oral challenge or its effect on insulin secretion.

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Figures

FIG. 1.
FIG. 1.
A–E: Effect of genotype on β-cell responsivity indices in response to hyperglycemia (120 min), hyperglycemia and 0.75 pmol/kg/min GLP-1 (180 min), hyperglycemia and 1.5 pmol/kg/min GLP-1 (240 min), and peak response to hyperglycemia and GLP-1 infusion (Peak). *Nominal significance for a given time point.
FIG. 2.
FIG. 2.
Effect of genotype on GIR (A), glucose concentrations (B), C-peptide (C), ISR (D), and glucagon concentrations (E) during hyperglycemia and GLP-1 infusion. *Nominal significance for a given time point.
FIG. 3.
FIG. 3.
A–E: Effect of genotype on active GLP-1 concentrations and total GLP-1 concentrations in response to a 75-g OGTT. *Nominal significance for a given time point.
FIG. 4.
FIG. 4.
A–E: Effect of genotype on glucagon concentrations during a 75-g OGTT.
See this image and copyright information in PMC

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