title: Diabetes-associated common genetic variation and its association with GLP-1 concentrations and response to exogenous GLP-1.
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.
authors.affiliation: Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Galina
authors.initials: G
authors.lastname: Smushkin
authors.forename: Matheni
authors.initials: M
authors.lastname: Sathananthan
authors.forename: Airani
authors.initials: A
authors.lastname: Sathananthan
authors.forename: Chiara
authors.initials: C
authors.lastname: Dalla Man
authors.forename: Francesco
authors.initials: F
authors.lastname: Micheletto
authors.forename: Alan R
authors.initials: AR
authors.lastname: Zinsmeister
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
authors.forename: Adrian
authors.initials: A
authors.lastname: Vella
mesh_terms: D002096:C-Peptide / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006801:Humans; D006943:Hyperglycemia; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D002096:C-Peptide; D007328:Insulin; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D008565:Membrane Proteins; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; C114987:wolframin protein; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose