Understanding type 2 diabetes: from genetics to epigenetics

Abstract

The known genetic variability (common DNA polymorphisms) does not account either for the current epidemics of type 2 diabetes or for the family transmission of this disorder. However, clinical, epidemiological and, more recently, experimental evidence indicates that environmental factors have an extraordinary impact on the natural history of type 2 diabetes. Some of these environmental hits are often shared in family groups and proved to be capable to induce epigenetic changes which alter the function of genes affecting major diabetes traits. Thus, epigenetic mechanisms may explain the environmental origin as well as the familial aggregation of type 2 diabetes much easier than common polymorphisms. In the murine model, exposure of parents to environmental hits known to cause epigenetic changes reprograms insulin sensitivity as well as beta-cell function in the progeny, indicating that certain epigenetic changes can be transgenerationally transmitted. Studies from different laboratories revealed that, in humans, lifestyle intervention modulates the epigenome and reverts environmentally induced epigenetic modifications at specific target genes. Finally, specific human epigenotypes have been identified which predict adiposity and type 2 diabetes with much greater power than any polymorphism so far identified. These epigenotypes can be recognized in easily accessible white cells from peripheral blood, indicating that, in the future, epigenetic profiling may enable effective type 2 diabetes prediction. This review discusses recent evidence from the literature supporting the immediate need for further investigation to uncover the power of epigenetics in the prediction, prevention and treatment of type 2 diabetes.

Specific CpG hyper-methylation leads to Ankrd26 gene down-regulation in white adipose tissue of a mouse model of diet-induced obesity

“…Epigenetic modifications represent a common mechanism through which both genetic and environmental exposures impact on the susceptibility to obesity and T2D262728. Recent evidence has underlined the potential importance of epigenetic regulation of gene expression and function in obesity26.…”

The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell–Centric Classification Schema

“…Though research is nascent, implicated environmental factors have included endocrine disruptors (56), food additives (52), abnormal gut biome (38,39,57), and ingested advanced glycation end products (58). There is also evidence that certain environmental factors may epigenetically alter the genotype in reproductive cells, producing inheritable DM factors in future generations (59,60) (Fig. 2).…”

“…In our model, as typical in obesity, IR is a monogenic or, more commonly, a polygenic disorder (59). Additional contributing factors to IR may include inflammation (48–51), changes in the gut microbiota (37–40), and brain-modulated changes in metabolism (51,61,62).…”

Shared genetic etiology underlying Alzheimer's disease and type 2 diabetes

“…Both T2D and AD are complex diseases, each involving multiple etiologic contributing factors (Gautrin and Gauthier, 1989; Henriksen et al, 2011; Jiang et al, 2013; Morris et al, 2014; Onso-Magdalena et al, 2011; Raciti et al, 2015). Among these, genetic predisposition factors are known to play important roles in both T2D and AD (Chouraki and Seshadri, 2014; Prasad and Groop, 2015; Raciti et al, 2015; Tanzi, 2012).…”

“…Among these, genetic predisposition factors are known to play important roles in both T2D and AD (Chouraki and Seshadri, 2014; Prasad and Groop, 2015; Raciti et al, 2015; Tanzi, 2012). We hypothesize that T2D may share common underlying genetic etiologies with AD, and that the presence of these shared T2D/AD genetic etiologies in a subset of individuals may contribute to the development of T2D in these individuals, as well as the development of AD over the long-term.…”