Genetic cause found for loss of beta cells during diabetes development

Genetic cause found for loss of beta cells during diabetes development

Diabetes is a hidden killer. One out of every 11 adults is suffering from the disease, yet half of them have not even been diagnosed. Diabetes is caused by the inability of the body to lower blood glucose, a process normally driven by insulin. In patients with type 1 diabetes (T1D), this is caused by the immune system killing off the beta cells that produce insulin. In patients with type 2 diabetes (T2D), a metabolic dysfunction prevents insulin from working on the liver. In both cases, left untreated the extra glucose in the blood can cause blindness, cardiovascular disease, diabetic nephropathy, diabetic neuropathy and death.

In this study published in the journal Nature Genetics researchers investigated how genetic variation controls the development of diabetes. While most previous work has focused on the effect of genetics in altering the immune system (in T1D) and metabolic dysfunction of the liver (in T2D), this research found that genetics also affected the beta cells that produce insulin.

Mice with fragile beta cells that were poor at repairing DNA damage would rapidly develop diabetes when those beta cells were challenged by cellular stress. Other mice, with robust beta cells that were good at repairing DNA damage, were able to stay non-diabetic for life, even when those islets were placed under severe cellular stress.

Genetic variation in Xrcc4 and Glis3 alters the response of non-obese diabetic (NOD) beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. Same pathways for beta cell survival and DNA damage repair were also found to be altered in diabetic patient samples, indicating that a genetic predisposition for fragile beta cells may underlie who develops diabetes.

Current treatments for T2D rely on improving the metabolic response of the liver to insulin. These antidiabetic drugs, in conjunction with lifestyle interventions, can control the early stages of T2D by allowing insulin to function on the liver again. However during the late stages of T2D, the death of beta cells means that there is no longer any insulin being produced. At this stage, antidiabetic drugs and lifestyle interventions have poor efficacy, and medical complications arise.