Proliferator-activated receptor gamma Pro12Ala interacts with the insulin receptor substrate 1 Gly972Arg and increase the risk of insulin resistance and diabetes in the mixed ancestry population from South Africa

Abstract

Background: The peroxisome proliferator-activated receptor gamma (PPARG), Pro12Ala and the insulin receptor substrate (IRS1), Gly972Arg confer opposite effects on insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the independent and joint effects of PPARG Pro12Ala and IRS1 Gly972Arg on markers of insulin resistance and T2DM in an African population with elevated risk of T2DM. In all 787 (176 men) mixed-ancestry adults from the Bellville-South community in Cape Town were genotyped for PPARG Pro12Ala and IRS1 Gly972Arg by two independent laboratories. Glucose tolerance status and insulin resistance/sensitivity were assessed. Results: Genotype frequencies were 10.4% (PPARG Pro12Ala) and 7.7% (IRS1 Gly972Arg). Alone, none of the polymorphisms predicted prevalent T2DM, but in regression models containing both alleles and their interaction term, PPARG Pro12 conferred a 64% higher risk of T2DM. Furthermore PPARG Pro12 was positively associated in adjusted linear regressions with increased 2-hour post-load insulin in non-diabetic but not in diabetic participants. Conclusion:The PPARG Pro12 is associated with insulin resistance and this polymorphism interacts with IRS1 Gly972Arg, to increase the risk of T2DM in the mixed-ancestry population of South Africa. Our findings require replication in a larger study before any generalisation and possible application for risk stratification.

Contribution of ENPP1, TCF7L2, and FTO polymorphisms to type 2 diabetes in mixed ancestry ethnic population of South Africa

“…However, in the present study we did not find any significant association between ENPP1 SNPs and indicators of insulin resistance/sensitivity. Instead, in a previous study we demonstrated that the PPARGPro12 allele was associated with insulin resistance in this mixed ancestry cohort 21 . Like ENPP1, PPARG plays a role in insulin sensitivity.…”

“…Although few number of T2DM susceptibility genes discovered through candidate gene, linkage analyses, and GWA studies elsewhere have been replicated in African studies [16][17][18][19][20][21] , it must also be emphasized that many other association studies failed to show significant and replicable findings [22][23][24] . Therefore in this study we investigated three genes, namely, TCF7L2, FTO, and ENPP1 as risk factors for T2DM in a South African ethnic population group of Mixed-ancestry (Coloureds) with a unique genetic architecture.…”

Interaction between peroxisome proliferator-activated receptor gamma polymorphism and obesity on type 2 diabetes in a Chinese Han population

“…Al-Safar et al [20] also suggested that confirmed that Pro12Ala mutation in PPARG2 is not associated with T2DM risk in this population. In a study for South Africa population, Vergotine et al [21] reported that the Pro12Ala of PPARG2 is significantly associated with insulin resistance and this polymorphism interacts with IRS1 Gly972Arg, to increase the risk of T2DM. Hahn et al [22] indicated that our data confirm a beneficial effect of the PPARG1 12Ala allele on insulin resistance and glucose metabolism in PCOS women.…”

Association of the PPARγ2 Pro12Ala and C1431T Polymorphisms with Type 2 Diabetes and Diabetic Retinopathy in a Sample of Egyptian Patients

“…Among several genetic variants of the PPARγ2 gene, two polymorphisms; Pro12Ala of the exon B (rs1801282) and the C1431T silent substitution (rs3856806) in the exon 6, are the most frequently occurring SNPs and have been associated with various diseases [13][14][15][16][17][18][19][20][21]. The association of Pro12Ala polymorphism with T2D, insulin resistance, obesity and metabolic disorders has been reported in several studies [24][25][26]. The C1431T polymorphism has also been studied in relation to obesity, diabetes and coronary heart disease [18,[25][26][27].…”