Genetics Influence Diabetes Development

People with difficulty repairing damaged DNA develop diabetes more rapidly when beta cells are met with cellular stress.

A recent study found genetics affect beta cells that produce insulin in patients with type 1 and 2 diabetes.

Patients with type 1 diabetes (T1D) have an immune system that kills off beta cells responsible for producing insulin. Those with type 2 diabetes (T2D) have a metabolic dysfunction that prevents insulin from working on the liver.

Researchers sought to discover how genetic variation controls the development of diabetes, which revealed that genetics also have an effect on insulin-producing beta cells.

The results of the study, published in the online version of the Proceedings of the National Academy of Sciences, showed mice with fragile beta cells that had difficulty repairing damaged DNA would develop diabetes more rapidly when the beta cells were met with cellular stress.

Mice with stronger beta cells that were able to repair damaged DNA stayed non-diabetic for life, even when islets were placed under severe cellular stress.

The study suggested that because the same pathways for DNA damage repair and beta cell survival were altered in diabetic patient samples, there may be a genetic predisposition for fragile beta cells and who might develop diabetes.

“While genetics are really the most important factor for developing diabetes, our food environment can also play a deciding role,” said researcher Adrian Liston, of the Flanders Institute for Biotechnology. “Even mice with genetically superior beta cells ended up as diabetic when we increased the fat in their diet.”

Treatment options for patients with T2D look to improve the metabolic response of the liver to insulin. Individuals make lifestyle changes and are given antidiabetic drugs that allows insulin to function in the liver again, therefore controlling early stages of T2D.

Unfortunately, in late stage T2D insulin is no longer being produced in the pancreas because of beta cell death. Furthermore, lifestyle interventions and antidiabetic drugs have poor efficacy, resulting in medical complications, the study noted.

“The health cost for diabetes currently exceeds $600 billion, 12% of the global health budget, and will only increase as diabetes becomes more common,” said Lydia Makaroff of the International Diabetes Federation. “Much of this health care burden is caused by late-stage type 2 diabetes, where we do not have effective treatments, so we desperately need new research into novel therapeutic approaches. This discovery dramatically improves our understanding of type 2 diabetes, which will enable the design of better strategies and medications for diabetes in the future.”

Developing drugs for patients with late stage T2D has created challenges for researchers because of the lack of availability of animal models at the beta cell death stage.

“Previously, animal models were all based on the early stage of metabolic dysfunction in the liver, which has allowed the development of good drugs for treating early-stage T2D,” Liston said. “This new mouse model will allow us, for the first time, to test new antidiabetic drugs that focus on preserving beta cells.”

Powered by the new model for drug testing, researchers hope to develop compounds that may lead to new treatments for late-stage diabetes.

“There are many promising drugs under development at life sciences companies that have just been waiting for a usable animal model,” Liston added. “Who knows, there may even be useful compounds hidden away in alternative or traditional medicines that could be found through a good testing program. If a drug is found that stops late-stage diabetes, it would really be a major breakthrough."