Researchers Identify Epigenetic Roots of Insulin Resistance

Aiman is a sophomore at the University of Michigan studying biochemistry.

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Artistic representation of chromatin structure (photo source).

Researchers at the Beth Israel Deaconess Medical Center and Broad Institute at Harvard have identified previously unknown epigenetic pathways that may contribute to the development of insulin resistance. The team, whose paper was published in Nature Cell Biology in January, hopes its discovery may reveal the root causes of type-2 diabetes, a disease that afflicts nearly 30 million Americans.

Insulin resistance is a condition in which cells fail to respond to the hormone insulin and consequently absorb glucose from the blood much more slowly than normal. This decreased uptake leads to prolonged periods of high blood sugar and ultimately type-2 diabetes. Although there are many well established risk factors for insulin resistance, including obesity and sedentary lifestyle, scientists are still investigating the cellular and molecular causes of the disease.

Most research in past decades has focused on the molecular events occurring on the cell membrane, where insulin binds, and the resulting cascade of responses in the cytosol. However, an increasing amount of data has suggested that events in the nucleus, where genetic information is stored, may also play a critical role in the development of insulin resistance.

To explore this possibility, the researchers treated fat cells with two distinct chemical agents known to cause insulin resistance: dexamethasone (Dex), an anti-inflammatory corticosteroid, and tumor necrosis factor alpha (TNF), a cytokine known to cause inflammation.

“By their nature, these agents would be predicted to cause almost opposite effects in cells, and yet we know that both cause insulin resistance,” said Dr. Evan Rosen, a Professor of Medicine at Harvard Medical School and one of the authors of the recent paper. “This provided us with a unique opportunity to see how each agent was affecting the epigenome of cells. Then by focusing on changes that were shared by the two treatments, we could discern which epigenomic events might be at the core of insulin resistance.”

The epigenome refers to the collection of chemical modifications to DNA and its associated scaffolding proteins in the nucleus, which affects the chromatin structure of the genome. These changes can be inherited in subsequent generations and cause functional differences in gene expression. Unlike mutations, however, epigenetic alterations do not change the base sequence of the DNA blueprint.

The team found that both Dex and TNF cause epigenetic changes that allow two transcription factors, glucocorticoid receptor (GR) and vitamin D receptor, to induce the expression of genes implicated in the development of insulin resistance. These results surprised the researchers because vitamin D levels have previously been correlated with better insulin sensitivity, and Dex and GR are known to induce opposite inflammatory responses.  

“We have now identified events that take longer to develop and that involve previously unsuspected biological pathways,” said Dr. Rosen. “Perhaps most importantly, we found that these pathways work completely in the nucleus of the cell by regulating the expression of key target genes, a process that was felt by many to be irrelevant to the development of this widespread condition."

The research team’s identification of unsuspected pathways implicated in the onset of insulin resistance illustrates the need to better understand the cellular and molecular events at the root of many diseases. It may also pave the way for the development of new drug therapies for metabolic disorders that have become significant public health concerns in the United States and around the world.

This news brief was adapted from a BIDMC press release and developed under the guidance of Dr. Susan Swanberg.

 

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