Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms

Dekker, J.M.; Fritsche, Andreas; Gallwitz, Baptist; Häring, HU; Holst, JJ; Machicao, Fausto; Nijpels, G.; Schäfer, Silke; Stefan, Norbert; Thamer, Claus; Hart, Leen 't; Tschritter, Otto; Haeften, Theo van

doi:10.1007/s00125-007-0871-1

Cited by 20 publications

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“…In the same study, 81 healthy male subjects with the diabetes-associated allele of TCF7L2 (at rs7903146) had an impaired insulin secretory response to infused GLP-1 and decreased glucagon secretion during a 24 h period (18). Although this is congruent with the Schäfer et al (8) study, it differs from our observation that after adjusting for age and sex, no differences in GLP-1–induced changes in β-cell responsiveness were attributable to TCF7L2 .…”

Section: Discussionsupporting

confidence: 76%

“…These were the diabetes-associated polymorphisms in TCF7L2 (8,17,18) and WFS1 (9) as well as three SNPs in KCNQ1 . In the case of KCNQ1 , the three SNPs studied are in Intron 15 and have been associated with type 2 diabetes and GLP-1 response to an OGTT (10).…”

Section: Resultsmentioning

confidence: 99%

“…Schäfer et al (8) have suggested that individuals with one or more diabetes-associated alleles in this locus have an impaired insulin secretory response to GLP-1 infusion during a hyperglycemic clamp. The same group of investigators has also suggested that WFS1 alters response to infused GLP-1 (9).…”

mentioning

confidence: 99%

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Diabetes-Associated Common Genetic Variation and Its Association With GLP-1 Concentrations and Response to Exogenous GLP-1

Smushkin

Sathananthan

et al. 2012

Diabetes

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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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Section: Discussionsupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

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Diabetes-Associated Common Genetic Variation and Its Association With GLP-1 Concentrations and Response to Exogenous GLP-1

Smushkin

Sathananthan

et al. 2012

Diabetes

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“…The association between diabetes and polymorphisms of the transcription factor TCF7L2, which is the most important type 2 diabetes gene identified to date, may have been due to impairment of insulin secretion (2,21,22), which was determined by a functional defect in the glucagon-like peptide 1-induced insulin b cell secretion (23), and decreased insulin exocytosis due For variables that were not normally distributed, median differences and their CIs were computed by using Wilcoxon's rank-sum test.…”

Section: Discussionmentioning

confidence: 99%

Effects of TCF7L2 polymorphisms on glucose values after a lifestyle intervention

Gambino²,

Ciccone³

et al. 2009

The American Journal of Clinical Nutrition

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“…Similar approaches have been undertaken to demonstrate that variation in TCF7L2 may alter response to infused GLP-1 [45] and that OCT1 may alter response to oral metformin [46]. In the former study insulin secretion in response to hyperglycemia and GLP-1 was utilized as an endpoint while glucose excursion after an oral glucose tolerance test was used in the latter.…”

Section: Variants Associated With Differential Response To Therapymentioning

confidence: 99%

Genetics of type 2 diabetes

Smushkin

Vella

2010

Current Opinion in Clinical Nutrition and Metabolic Care

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Purpose of review To provide an overview of the genetics of type 2 diabetes in the context of recent progress in the understanding of the genetic architecture of the disease and its applicability to the pathogenesis of the disease as well as efforts to individualize therapy in type 2 diabetes. Efforts are underway to understand how these loci alter measurable physiologic processes in nondiabetic humans. However, it is important to understand the potential pitfalls in such studies and the limitations underlying measurement of insulin secretion and action using qualitative methodologies. Recent findings The availability of large population-based cohorts and the ease with which large numbers of common genetic variants can be genotyped has enabled the discovery of multiple loci and pathways associated with type 2 diabetes. Recent efforts examining quantitative traits such as fasting glucose concentrations have led to the discovery of other genes likely to be important in the development of diabetes. Summary The past 4 years have witnessed a significant increase in our understanding of genetic predisposition to type 2 diabetes. Hopefully more progress will be made in applying this knowledge to the pathophysiology of type 2 diabetes in the coming years.

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Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms

Abstract: Unfortunately the dose of the GLP-1 bolus during the hyperglycaemic clamp was incorrectly given as 0.6 pmol/kg body weight, instead of 4.5 pmol/kg body weight.The authors apologise for this mistake.

Cited by 20 publications

References 0 publications

Diabetes-Associated Common Genetic Variation and Its Association With GLP-1 Concentrations and Response to Exogenous GLP-1

Diabetes-Associated Common Genetic Variation and Its Association With GLP-1 Concentrations and Response to Exogenous GLP-1

Effects of TCF7L2 polymorphisms on glucose values after a lifestyle intervention

Genetics of type 2 diabetes

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