NEWSLETTER
Aetio-pathology of Type 2 Diabetes; genetics and environment
Prof. Abdul Basit, Dr. Shazia Kiran at BIDE. BMU
Diabetes Mellitus is a group of metabolic disorders characterized by chronic hyperglycemia. Within this group, T2DM describes the form of disease usually with onset in adult life and associated with insulin resistance and relative insulin deficiency.T2DM is of great importance to public health due to the burden of morbidity and mortality associated with this common disease.
Gene-environment interaction plays a major role in the aetiopathology of T2DM.Genetic involvement pattern is complicated as it is a polygenic disorder with multiple genes located on different chromosomes contributing to its susceptibility.
In the last few years there has been a great leap forward in our understanding of genetic forms of diabetes, how genetic variants predisposes to T2DM and how genetic testing can start to play a role in the outpatient management of diabetes. Many genes are involved in controlling our fuel intake and regulation. A mutation in any one gene will probably not lead to diabetes, but mutations in several genes could add up to pose an increased risk. Any two people with T2DM may have mutations in a different subset of genes, making it hard for researches to pinpoint high-risk mutations.
Until 2007, only three genes were consistently associated with T2DM: PPARγ, KCNJ11 and TCF7L2.In 2007, five whole genome- wide association studies were published, followed by the discovery of 11 genes consistently associated with T2DM.
Table 1. The history of gene discovery for T2DM |
|
Year |
Gene |
2000 |
PPARγ |
2001 |
KCNJ11 |
2006 |
TCF7L2 |
2007 |
CDKAL1, IGF2BP-2, CDKN2A/2B, H4EX, SLC30A, FTO |
2008 |
WFS1, JAZF1 |
Until last year, only two gene variants had robustly fulfilled the criteria for T2DM; P12A variant of PPARγ and E23K variant of Kir6.2 (KCNJ11). Researchers have found few gene mutations that influence diabetes risk in some families; one well studied gene is the Beta -3-adrenergic receptor gene. A mutation in this gene is TRP64ARG; people with this gene develop diabetes at an earlier age than others. Genetic factors also have an important role in determining Insulin Resistance as supported by the findings of decreased insulin activity and hyperinsulinemia among first degree non-diabetic relatives. It has also been proposed in certain studies that a genetically programmed insulin effect during embryogenesis determine fetal growth and provides a possible molecular link between birth weight and susceptibility to T2DM.The fact that T2DM is genetically heterogeneous disorder implies that several primary defects contribute to the susceptibility of the disease.
The identification of T2DM genes will improve our understanding of the molecular mechanisms that leads to chronic hyperglycemia and this could lead to the development of more specifically targeted anti-diabetic drugs or even gene based therapies.
Analysis of the genetic factors is further complicated by the fact that numerous environmental factors interact with genes to produce this disorder. High calorie diets and reduced physical activity definitely contribute to the increasing prevalence of obesity and T2DM. An extreme of maternal age is also found to be a contributing factor to low birth weight. The protective effect of breastfeeding for childhood obesity and T2DM has also been observed. High prevalence of the disease in the offspring of gestational diabetic mothers or concordance rates of T2DM in identical twins further suggests intrauterine environmental influences. Predictive Adaptive Response hypothesis proposes that the fetus dynamically interacts and reads the environment which it will be born into and adapts to gain a future survival advantage. Environmental pollution and infectivity has also been proposed in certain studies to stimulate the fat cells to secrete molecules that promote insulin resistance, endothelial dysfunction, coagulation disturbances and a proinflammatory state, leading to type 2 diabetes and CHD. Role of stress and depression in the development of T2DM is being implicated. The successes of primary prevention trials in T2DM support the notion that environmental influences were a cause of their T2DM and encourage further to concentrate on earlier interventions.
Better understanding of aetio-pathological genetic and environmental factors are suggesting prevention should begin much before the stage of IGT, and interventions in high-risk subjects i.e. families of people living with diabetes alone will not be sufficient. It is necessary to initiate population based programs for primary prevention of T2DM and must include a range of activities targeted at different age groups from fetal life to old age.