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Clues On How Type 2 Diabetes Develops Revealed Through Research Using Twins

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Clues On How Type 2 Diabetes Develops Revealed Through Research Using Twins
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type 2 diabetes and twinsA new study, entitled “Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes” published in the journal Diabetes by Dr. Emma Nilsson, part of Dr. Charlotte Ling’s research group from the Department of Clinical Sciences at the Lund University Diabetes Centre in Sweden, is offering scientists a better understanding of molecular mechanisms that can induce the development of Type 2 Diabetes (T2D).

In the new research, the authors investigated the molecular mechanisms essential for T2D using genome-wide expression and DNA methylation approaches in adipose tissue from 14 pairs of identical, monozygotic (MZ) twins in Sweden and Denmark who were discordant for T2D (i.e. where one twin had type 2 diabetes and the other was healthy) and from independent case-control cohorts.

Type 2 diabetes mellitus is multifactorial disease and is caused by a complex interplay between genetic predisposition and the environment, with prevalence of the disease increasing significantly throughout the world. Age, unhealthy lifestyle characterized by physical inactivity, and obesity together with genetic predisposition are risks factors for developing type 2 diabetes. Adipose tissue plays a major role in the regulation of nutrient and energy homeostasis, but is also involved in the modulation of the immune response, reproductive function, hemostasis, mechanical support, bone mass growth, and thermogenesis. In individuals with T2D, the regulation of nutrient and energy homeostasis function is normally perturbed by an impaired response of the adipocytes, the main cells that compose the adipose tissue, to insulin, resulting in elevated lipid levels in circulation and storage in alternative tissues such as liver, muscle, and pancreas.

The researchers decided to assess if epigenetic changes in the DNA, a link that has been suggested to exist between environment and T2D, could lead to changes in gene expression in the adipose tissue and consequently induce the development of type 2 diabetes. For this, they investigated DNA methylation at 480,000 points on the DNA. The authors found in diabetic twins a decreased expression of genes involved in oxidative phosphorylation; carbohydrate, amino acid, and lipid metabolism; and increased expression of genes involved in inflammation and glycan degradation. The genes most significantly expressed included ELOVL6, GYS2, FADS1, SPP1 (OPN), CCL18, and IL1RN. Notably, these results were consistent in adipose tissue from an independent case-control cohort, showing the relevance of these data for the general population. Several candidate genes for obesity and T2D (e.g., IRS1 and VEGFA) were differentially expressed in discordant twins. Importantly, the authors found a heritable contribution to the genome-wide DNA methylation variability in twins.

“This means that they are not able to process fat as well, which leads to raised levels of fat in the blood and uptake of fat by other organs instead, such as the muscles, liver or pancreas. This causes insulin resistance, which leads to type 2 diabetes,” said Dr. Emma Nilsson. “Twins are a good model for finding mechanisms, but the results are applicable to all,” added Dr. Emma Nilsson, in the Lund University press release.

“Non-identical twins generally share 50 per cent of their DNA and it is usually said that identical twins share 100 per cent of theirs. Despite this, we found 1,400 places on the identical twins’ DNA where there was a difference in DNA methylation between the diabetic and the non-diabetic. It is believed that these differences are due to differences in lifestyle and this confirms the theory that type 2 diabetes is strongly linked to lifestyle,” said Dr. Nilsson, in the Lund University press release.

“We found six cases where one of the set of twins had more or fewer of these copies in his or her DNA, and we suspect that this could be another cause of the disease,” said Emma Nilsson. “This is interesting because it is usually taken for granted that identical twins are genetically 100 per cent alike. However, there are in fact differences and it is not known whether or how, these affect the development of type 2 diabetes. More studies are needed to investigate their impact,” concluded Dr. Nilsson.


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