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

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

Research output: Contribution to journalArticle

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1082-1089
Number of pages8
JournalDiabetes
Volume61
Issue number5
DOIs
StatePublished - May 2012

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Smushkin, G., Sathananthan, M., Sathananthan, A., Man, C. D., Micheletto, F., Zinsmeister, A. R., Cobelli, C., & Vella, A. (2012). Diabetes-associated common genetic variation and its association with GLP-1 concentrations and response to exogenous GLP-1. Diabetes, 61(5), 1082-1089. https://doi.org/10.2337/db11-1732