Diabetes epigenetics: Fact or fiction
Article Outline
Diabetes mellitus, especially type 2, is a disorder characterized by complex genetic components influenced by environmental perturbations. The field of epigenetics has emerged to bridge the gap between nature and nurture. It is defined as the development and maintenance of an organism orchestrated by a set of chemical reactions that switch parts of the genome on and off at strategic times and locations. Epigenetics is the study of these reactions, and the factors that influence them. In the beginning of this millennium, epigenetics is defined as the study of heritable changes in genome function that occur without a change in DNA sequence.
To be more specific, the epigenetics of type 2 diabetes is the interaction between gene activation and epidemiology, where gene activation can be in the form of DNA methylation, histone modification or RNA activation. This could be affected by different epidemiological factors, namely age, obesity, nutrition, physical activity and intrauterine environment. Environmental factors that contribute to the development of type 2 diabetes can lead to a disease phenotype by affecting gene expression through epigenetic modifications. Epigenetic modifications of the genome provide a mechanism that allows the stable propagation of gene expression from one generation of cell to the next [1].
The environmental role in epigenetic regulation was demonstrated in offsprings of Agouti mice when retrovirus-like transposon was inserted, leading to demethylation and resulting in epigenetic agouti expression of a yellow coat color [2]. When feeding pregnant females with diet supplemented with methyl donors, a larger proportion of the offspring had a brown coat color when compared with the offspring of mothers fed with standard diets [3]. This study has proved that maternal nutrition can affect gene expression in-utero through epigenetic modifications.
This proves that whether using virus or diet, gene expression will be affected. Another example is exposure to an abnormal intrauterine milieu that could subject infants to the genetic expression of certain diseases, like the type 2 diabetes of infants born with low birth weight secondary to women’s exposure to hunger, where daily caloric intake is limited. This was seen during the Dutch Hunger Winter in late World War II, during which daily caloric intake was limited to 400–800
kcal. Offspring had impaired glucose tolerance by the age of 50, compared to offspring who were born either one year before or after the famine [4].
Many studies have linked type 2 diabetes with low birth weight, as shown by Hales et al. who found that men with a birth weight of less than 2.5kg were seven times more likely to have glucose intolerance or type 2 diabetes than those who were heavier in their body weight [5].
The environmental role in regulating epigenetic phenomena may be explained by methylation, and it has been suggested that DNA methyl transferase might act on chromatin, which is methylated at H3K9Ac. Epigenetic modifications might be reversible, which provide a therapeutic tool that can be used to prevent common diseases like type 2 diabetes [1], [5].
The real challenge is to prove epigenetic inheritance that is not associated with genetic mutation. At the same time, direct exposure should be ruled out, to prove the epigenetic effect passage through enough generations. In pregnancy, exposure to any environmental factors (i.e., diet, toxins, hormones, etc.) has an effect on three generations, including the mother and fetus. This environmental factor may have an effect on a third generation, which is the gem cells of the fetal reproductive organ [6].
Epigenetic changes are transient, and move more rapidly than the relatively fixed DNA code. Epigenetic changes are triggered by environmental conditions and may be reversed if environmental conditions change again. The rheostat model suggests that both genetic and epigenetic variants can contribute to an integrated mixed Mendelian and non-Mendelian inheritance, and suggests the possibility that the majority of variants are not intrinsically eleterious but, depending on the environment, are each potentially advantageous. Moreover, his would be a reversible form of evolution, with the ability not only to protect a silent allele from selection for many generations, but to reactivate and expand it quickly in the population [7]. Random mutation in the genome occurs slowly, and it takes many generations for a genetic trait to be expressed in a population.
Epigenetic inheritance may allow an organism to continually adjust its gene expression to fit its environment without changing its DNA code [8].
References
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PII: S1877-5934(10)00037-8
doi:10.1016/j.ijdm.2010.06.001
© 2010 International Journal of Diabetes Mellitus. Published by Elsevier Inc. All rights reserved.
