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Generation of High Quality Chromatin Immunoprecipitation DNA Template for High-throughput Sequencing (ChIP-seq)
Published on: April 19, 2013
TCF7L2 polymorphisms modulate proinsulin levels and beta-cell function in a British Europid population.
Ruth J F Loos1, Paul W Franks, Richard W Francis
1Medical Research Council Epidemiology Unit, Strangeways Research Laboratory, Cambridge, UK. ruth.loos@mrc-epid.cam.ac.uk
Diabetes
|April 10, 2007
Summary
Genetic variations in TCF7L2 increase type 2 diabetes risk by impairing proinsulin processing in pancreatic beta cells. This leads to higher proinsulin levels and reduced insulin secretion, particularly at 60 minutes during an oral glucose tolerance test.
Area of Science:
- Genetics
- Endocrinology
- Metabolic Diseases
Background:
- Common T-cell transcription factor (TCF)7L2 gene polymorphisms are linked to type 2 diabetes risk.
- The precise mechanisms underlying this association remain largely unknown.
Purpose of the Study:
- To investigate the association between TCF7L2 single nucleotide polymorphisms (SNPs) and measures of insulin sensitivity and secretion.
- To elucidate the role of TCF7L2 in proinsulin processing and beta-cell function.
Main Methods:
- Analysis of four TCF7L2 SNPs, including rs7903146, in 1,697 participants from the population-based MRC-Ely study.
- Measurement of fasting proinsulin, insulin levels, and responses during an oral glucose tolerance test (OGTT).
- Assessment of beta-cell function using homeostasis model assessment (HOMA-B).
Main Results:
- The T-allele of rs7903146 was strongly associated with increased fasting proinsulin and 32,33 split proinsulin levels.
- A reduced insulin response was observed at 60-min OGTT in T-allele carriers, but not at 30-min.
- The T-allele correlated with higher A1C and reduced beta-cell function (HOMA-B).
Conclusions:
- TCF7L2 risk allele may predispose to type 2 diabetes by impairing beta-cell proinsulin processing.
- This impairment leads to elevated proinsulin and diminished insulin secretion during OGTT.
- Findings suggest a novel mechanism linking TCF7L2 variants to diabetes pathogenesis via proinsulin processing defects.
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