An international team led by researchers at the Broad Institute and Massachusetts General Hospital (MGH) has 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 results focus the search for developing novel therapeutic strategies for type 2 diabetes.
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%. 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.
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.
“This work underscores that human genetics is not just a tool for understanding biology: it can also powerfully inform drug discovery by addressing one of the most challenging and important questions—knowing which targets to go after,” says co-senior author David Altshuler, MD, PhD.
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 plays a protective role remains unknown.
