Obesity Induces Genetic Changes in Diabetes

An experimental epigenetic analysis of obesity has unmasked 4 functional genes that have roles in insulin resistance, and the findings may lead to early tests of susceptibility to diabetes mellitus (DM), according to a new study.

“It’s well known that most common diseases like diabetes result from a combination of genetic and environmental risk factors. What we haven’t been able to do is figure out how, exactly, the 2 are connected,” said Andrew Feinberg, MD, MPH, Director of the Center for Epigenetics in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine in Baltimore. “This study takes a step in that direction.”

Dr Feinberg and colleagues found that obesity can cause epigenetic changes that modify how genes behave and can alter the production of proteins necessary for proper metabolism and secretion of insulin.

“Diet-induced obesity in mice induces widespread changes in DNA methylation. Differentially methylated regions are conserved in obesity and reversed by gastric bypass,” the researchers stated. These regions “map to diabetes single nucleotide polymorphisms and adipocyte enhancers.”

Beginning with dietary manipulation of genetically homogeneous mice, the investigators identified differentially DNA-methylated genomic regions. Some sites that bore methyl groups, which prevent genes from making proteins, in the lean mice were missing in the obese mice, and vice versa. The researchers found that the mice placed on a high-fat diet grew obese and diabetic, while the mice on a regular diet stayed lean and healthy.

They then replicated these results in adipose samples from lean and obese patients pre- and post–Roux-en-Y gastric bypass, “identifying regions where both the location and direction of methylation change are conserved,” they stated. These regions overlap with 27 genetic type 2 DM risk loci.

In effect, the researchers found nearly the exact same pattern of epigenetic changes at key sites in DNA isolated from the human fat cells.

Dr Feinberg said, “Mice and humans are separated by 50 million years of evolution, so it’s interesting that obesity causes similar epigenetic changes to similar genes in both species.”

Some of the epigenetic changes were associated with genes already known to raise DM risk, in addition to changes in other genes linked to metabolism in general.

At least some of these genes regulate insulin action on sugar uptake and offer insights into new potential targets for treating type 2 DM.

“Functional analysis of genes associated with these regions revealed 4 genes with roles in insulin resistance, demonstrating the potential general utility of this approach for complementing conventional human genetic studies by integrating cross-species epigenomics and clinical genetic risk,” the researchers stated.

The new study suggests that the epigenome in obese patients becomes more like the epigenome in lean persons after gastric bypass surgery.

“In addition to providing leads for drug development, the results also suggest that an epigenetic test could be developed to identify people much earlier on the path to type 2 DM, giving more hope for preventing the disease,” Dr Feinberg said.

The researchers published their results on January 6, 2015 in Cell Metabolism.