We reproduced the association of diabetes-associated variants with proinsulin/insulin ratios, and also examined the association of a TCF7L2 haplotype with obesity in the Framingham Heart Study (FHS).
In the family-based study, variation in TCF7L2 increased the risk of diabetes about three-fold (HR 1.75 per allele, 95% CI 1.3-2.4; p = 0.0006), and decreased the mean age at diabetes diagnosis by 7 years.
Thus, diabetes-associated TCF7L2 gene variation predicts the success of lifestyle intervention in terms of weight loss and determines individual susceptibility toward environmental factors.
The transcription factor TCF7L2 is particularly strongly associated with risk for diabetes and appears to be fundamentally important in both canonical Wnt signaling and beta-cell functioning.
We investigated the association between the TCF7L2rs7903146 polymorphism and incident IFG defined as fasting serum glucose levels of 100-125 mg/dL (5.6-6.9 mmol/L) in 1377 African American and 5152 Caucasian participants without diabetes and IFG at intake who participated in the Atherosclerosis Risk in Communities (ARIC) Study from 1987 to 1989 and were followed for 9 years.
In contrast, variants near insulin-like growth factor-binding protein 2 (IGFBP2), CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1), solute carreir family 30 (zinc transporter), member 8 (SLC30A8), hematopoietically-expressed homeobox (HHEX), and transcription factor 7-like2 (TCF7L2) were clearly associated with diabetes; no evidence for an association to CAC was observable.
Maternal GCK and TCF7L2 variants are associated with glucose levels known to carry an increased risk of adverse pregnancy outcome in women without overt diabetes.
TCF7L2diabetes risk variants, either as single-nucleotide polymorphisms or as haplotypes, detrimentally influence β-cell function and might play a role in determining the metabolic phenotype of patients with newly diagnosed type 2 diabetes.
Our data suggest that patients with diabetes risk alleles in TCF7L2 have an altered hypoglycaemic response to SUs resulting in earlier secondary failure.
In subjects without known diabetes (n=961) recruited from the Chennai Urban Rural Epidemiology Study (CURES), OGTT, IDRS, and genotyping of rs12255372 (G/T) and rs7903146(C/T) of TCF7L2 polymorphisms were done.
The TCF7L2 was associated with susceptibility for gestational diabetes independently of the presence of HLA-DQB1*0602 and islet cell autoantibodies and other factors such as maternal age, number of pregnancies, family history of diabetes and other HLA-DQ genotypes.
The combination of a lack of impact of the TCF7L2 genotypes on the ability to lose weight, but the presence of a consistent effect on the proinsulin:insulin ratio over the course of DPP, suggests that high-risk genotype carriers at this locus can successfully lose weight to counter diabetes risk despite persistent deficits in insulin production.
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).
Controlling for diabetes status, participants with the TT genotype of TCF7L2 (n= 12) performed worse on tests of attention/executive function/processing speed than those with the CC (n= 46) and CT (n= 53) genotypes, despite no between-group differences in demographic or medical variables.