Type 2 diabetes mellitus is thought to develop from an interaction between environmental and genetic factors. We examined whether clinical or genetic factors or both could predict progression to diabetes in two prospective cohorts. We genotyped 16 single-nucleotide polymorphisms (SNPs) and examined clinical factors in 16,061 Swedish and 2770 Finnish subjects. Type 2 diabetes developed in 2201 (11.7%) of these subjects during a median follow-up period of 23.5 years. We also studied the effect of genetic variants on changes in insulin secretion and action over time. Strong predictors of diabetes were a family history of the disease, an increased body-mass index, elevated liver-enzyme levels, current smoking status, and reduced measures of insulin secretion and action. Variants in 11 genes (TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX) were significantly associated with the risk of type 2 diabetes independently of clinical risk factors; variants in 8 of these genes were associated with impaired beta-cell function. The addition of specific genetic information to clinical factors slightly improved the prediction of future diabetes, with a slight increase in the area under the receiver-operating-characteristic curve from 0.74 to 0.75; however, the magnitude of the increase was significant (P=1.0×10⁻⁴). The discriminative power of genetic risk factors improved with an increasing duration of follow-up, whereas that of clinical risk factors decreased. As compared with clinical risk factors alone, common genetic variants associated with the risk of diabetes had a small effect on the ability to predict the future development of type 2 diabetes. The value of genetic factors increased with an increasing duration of follow-up.

Genetic variants in the gene encoding for transcription factor-7–like 2 (TCF7L2) have been associated with type 2 diabetes (T2D) and impaired β cell function, but the mechanisms have remained unknown. We therefore studied prospectively the ability of common variants in TCF7L2 to predict future T2D and explored the mechanisms by which they would do this. Scandinavian subjects followed for up to 22 years were genotyped for 3 SNPs (rs7903146, rs12255372, and rs10885406) in TCF7L2, and a subset of them underwent extensive metabolic studies. Expression of TCF7L2 was related to genotype and metabolic parameters in human islets. The CT/TT genotypes of SNP rs7903146 strongly predicted future T2D in 2 independent cohorts (Swedish and Finnish). The risk T allele was associated with impaired insulin secretion, incretin effects, and enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in T2D, particularly in carriers of the TT genotype. Overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. In conclusion, the increased risk of T2D conferred by variants in TCF7L2 involves the enteroinsular axis, enhanced expression of the gene in islets, and impaired insulin secretion.

Type 2 diabetes (T2D) is a multifactorial disease in which environmental triggers interact with genetic variants in the predisposition to the disease. A number of common variants have been associated with T2D but our knowledge of their ability to predict T2D prospectively is limited. By using a Cox proportional hazard model, common variants in the PPARG (P12A), CAPN10 (SNP43 and 44), KCNJ11 (E23K), UCP2 (−866G>A), and IRS1 (G972R) genes were studied for their ability to predict T2D in 2,293 individuals participating in the Botnia study in Finland. After a median follow-up of 6 y, 132 (6%) persons developed T2D. The hazard ratio for risk of developing T2D was 1.7 (95% confidence interval [CI] 1.1–2.7) for the PPARG PP genotype, 1.5 (95% CI 1.0–2.2) for the CAPN10 SNP44 TT genotype, and 2.6 (95% CI 1.5–4.5) for the combination of PPARG and CAPN10 risk genotypes. In individuals with fasting plasma glucose ≥ 5.6 mmol/l and body mass index ≥ 30 kg/m², the hazard ratio increased to 21.2 (95% CI 8.7–51.4) for the combination of the PPARG PP and CAPN10 SNP43/44 GG/TT genotypes as compared to those with the low-risk genotypes with normal fasting plasma glucose and body mass index < 30 kg/m². We demonstrate in a large prospective study that variants in the PPARG and CAPN10 genes predict future T2D. Genetic testing might become a future approach to identify individuals at risk of developing T2D.

Dissecting the genetics of complex polygenic diseases in which environmental factors interact with genetic variants in the predisposition to the disease has not been a trivial task and success has been limited. The purpose of this review is to provide insights into recent advances in genetics of type 2 diabetes. In the past year, together the consortia of several genome-wide association studies for type 2 diabetes have identified 19 common variants increasing susceptibility to disease. Most novel loci seem to influence the capacity of beta-cells to increase insulin secretion in response to increase in insulin resistance or body weight. Combined genetic information ultimately might aid in personalized prediction of disease risk; however, genetic tests cannot be offered yet to predict disease. The main reason is that the increased risk associated with each risk variant is small. We have only begun to explore the role of rare variants with stronger effects or copy number variations in the pathogenesis of type 2 diabetes. Rapid progress in the genetics of type 2 diabetes has significantly improved our understanding of disease pathogenesis and provided promising opportunities for drug discoveries over the coming years.

The purpose of this review is to provide a comprehensive evaluation of the most important type 2 diabetes gene to date, transcription factor 7 like-2. An important step to find genetic causes of type 2 diabetes in 2006 was the identification of the fact that variants in the gene encoding transcription factor 7 like-2 reproducibly increase susceptibility to type 2 diabetes in almost all populations studied. This gene has since then emerged as the most important type 2 diabetes gene. Genetic variants in transcription factor 7 like-2 confer a strong risk of type 2 diabetes possibly mediated by altering expression of transcription factor 7 like-2 in pancreatic islets. Risk variants in the transcription factor 7 like-2 influence insulin secretions both in vitro and in vivo. The risk T allele of this single nucleotide polymorphism also seems to have effects on the enteroinsular axis and the relationship between the incretin hormone glucose-dependent insulinotropic peptide and its target hormones, glucagon and insulin. Given transcription factor 7 like-2s' central role in the Wnt signaling pathway, it would be important to define whether the variant is associated with increased or decreased Wnt signaling. The fact that transcription factor 7 like-2 is by far the strongest type 2 diabetes susceptibility gene to date emphasizes the importance of exploring the potential of manipulating this pathway in future treatment of the disease.

Genome-wide association studies (GWAS) have emerged as a powerful approach for identifying susceptibility loci associated with polygenetic diseases such as type 2 diabetes mellitus (T2DM). However, it is still a daunting task to prioritize single nucleotide polymorphisms (SNPs) from GWAS for further replication in different population. Several recent studies have shown that genetic variation often affects gene-expression at proximal (cis) as well as distal (trans) genomic locations by different mechanisms such as altering rate of transcription or splicing or transcript stability.