ABSTRACT
Type 2 diabetes mellitus (T2DM) is a heterogeneous metabolic disease occurring with concomitant or interdependent defects of both insulin secretion and action (1). T2DM results from a complex interplay of genetic and environmental factors influencing a number of intermediate traits of relevance to the diabetic phenotype (such as b-cell mass, insulin secretion, insulin action, fat distribution, and obesity) (2). It is now well recognized that T2DM is composed of many different subtypes where genetic susceptibility is strongly associated with environmental factors at one end of the spectrum, which are common polygenic T2DM forms, and highly genetic forms, defined as monogenic diabetes, at the other end (3). Although the current rise in T2DM prevalence is greatly driven by lifestyle changes, the inherent susceptibility to T2DM is well established and attributable to complex genetic determinants (4). In polygenic T2DM, the simultaneous action of several susceptibility alleles or multiple combinations of frequent variants at several loci may have deleterious effects when predisposing environmental factors are present. At the opposite side of human T2DM genetics, several monogenic forms of diabetes have been identified, such as maturity-onset diabetes of the young (MODY) (5), maternally inherited diabetes and deafness (MIDD) (6), and neonatal diabetes mellitus (NDM) (7). Moreover, retrospective studies showed that low birth weight is associated with insulin resistance and T2DM in adulthood, likely resulting from a metabolic adaptation to poor fetal nutrition (8). However, the identification of gene variants contributing both to variation in fetal growth and to the susceptibility to T2DM suggest that this metabolic ‘‘programing’’ could also be partly genetically determined (9).
