Researchers have identified mutations in a gene that can reduce the risk of developing type 2 diabetes, even in people who have risk factors such as obesity and old age.

The current study breaks new ground in type 2 diabetes research and guides future therapeutic development in this disease. In the new study, researchers describe the genetic analysis of 150,000 patients showing that rare mutations in a gene called SLC30A8 reduce risk of type 2 diabetes by 65 percent.

The results were seen in patients from multiple ethnic groups, suggesting that a drug that mimics the effect of these mutations might have broad utility around the globe.

The protein encoded by SLC30A8 had previously been shown to play an important role in the insulin-secreting beta cells of the pancreas, and a common variant in that gene was known to slightly influence the risk of type 2 diabetes.

However, it was previously unclear whether inhibiting or activating the protein would be the best strategy for reducing disease risk - and how large an effect could be expected.

The team set out to ask if the effects of SLC30A8 protective mutations were limited to the two mutations found in populations in Finland and Iceland. As part of the NIH-funded T2D-GENES Project, chaired by Mike Boehnke at the University of Michigan, the Broad Institute had performed sequencing of 13,000 samples drawn from multiple ethnicities.

The T2D-GENES Project joined the collaboration, found ten more mutations in the same gene, and again saw a protective effect. Combining all the results confirmed that inheriting one copy of a defective version of SLC30A8 led to a 65 percent reduction in risk of diabetes.

In laboratory experiments, members of Altshuler's team showed that the protective mutations disrupt the normal function of the protein encoded by SLC30A8, known as ZnT8. The ZnT8 protein transports zinc into insulin-producing beta cells, where zinc plays a key role in the crystallization of insulin. Exactly how the reduction in ZnT8 functions plays a protective role remains unknown.

THE study has been published in the journal Nature Genetics.