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Obesity, type 2 diabetes and epigenetics in the islets of Langerhans – from genome-wide analysis to functional validation

Hjelt Grant Holder 2021, Karl Bacos
Karl Bacos.
Karl Bacos,
Hjelt grant holder 2021,
Lund University.

Epigenetic modifications regulate gene activity in our cells. For example, they help make sure that the gene for insulin is active in insulin producing cells, but inactive in cells where insulin is not needed. This is a dynamic system and changes to it can be induced by both internal and external factors, such as our age and sex, or our diet and exercise habits. We have shown that different risk factors for Type 2 diabetes (T2D) influence epigenetic patterns in the so-called islets of Langerhans, small cell clusters in the pancreas which contain insulin producing cells. These epigenetic changes in turn impair insulin secretion and can thereby contribute to the development of T2D. Obesity, perhaps the strongest T2D risk factor of them all, is associated with increased nutrient levels in blood. Exposing islets of Langerhans to increased nutrient levels in culture dishes for only 48h leads to detrimental epigenetic changes. In real life obesity often persist for years, or even decades, but the effect of obesity on epigenetics in the islets of Langerhans has not been studied. Based on these findings we hypothesized that obesity leads to epigenetic changes that in turn increase the risk for T2D.

Our current data supports this hypothesis. We have identified epigenetic changes that occur in islets of Langerhans from obese individuals and mimicking these changes in cultured insulin producing cells leads to impaired insulin secretion. The funds from the Hjelt foundation will be used for two main research tracks. The first is to identify the mechanism by which these epigenetic changes alter insulin secretion. The second is to use cutting-edge techniques for epigenetic editing to reverse the detrimental epigenetic changes in “sick” cells to improve cellular function. And vice versa, we want to induce the detrimental changes in “healthy” cells to impair cell function. This will provide direct evidence that the epigenetic changes we identify are causing cellular dysfunction and disease.

This project may reveal cellular targets for novel T2D therapeutics. As the changes we identify occur in individuals that are non-diabetic, but at high risk for disease, these targets could potentially be hit even to prevent development of the disease.

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