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Rare Genetic Variants Protect Against Type 2 Diabetes by Promoting Insulin Processing and Secretion

Studying rare variations in the gene SLC30A8 that were previously found to protect against type 2 diabetes, researchers have now discovered that these promote release of insulin in response to a rise of blood glucose (sugar) levels, potentially by increasing the proportion of insulin that is ready for release relative to a precursor form of the hormone. A previous genetic study of thousands of people from several parts of the world showed that very rare variants of SLC30A8—found in about 1 in 5,000 people—significantly reduce the risk of type 2 diabetes. The gene encodes a protein called ZnT8 that helps package insulin in a form that is compact yet can be quickly released from insulin-producing β (beta) cells when blood glucose levels rise, such as after a meal. Thus, ZnT8 plays an apparently key role in controlling blood glucose levels.

Results from this new study may therefore seem surprising: people with the type 2 diabetes-protective gene variant have less ZnT8 protein in their cells than people with the more common form of the gene, yet their insulin response to rising glucose levels was both faster and more robust. This super-charged insulin response is likely to be responsible for the unusual resistance to type 2 diabetes resulting from the rare mutation, raising the possibility that a medical intervention to reduce the activity of ZnT8 in β cells might help prevent type 2 diabetes in people at risk, or be a useful method to treat the disease in those that have developed it. Experiments in isolated human β cells are consistent with that idea: the scientists utilized an experimental approach to lower the amount of ZnT8 protein produced in these cells and found that this resulted in a higher rate of insulin secretion even at normal glucose levels. Notably, the procedure shifted the ratio of mature insulin relative to a precursor form of the hormone: compared to normal β cells, those with less ZnT8 had a higher proportion of mature, ready-to-secrete insulin. This suggests that by helping β cells store large quantities of tightly packed insulin precursor protein, ZnT8 might simultaneously be slowing the production and release of the mature, active hormone in times of caloric excess, when its rapid release is a higher priority. If so, and if medications can be developed that safely lower ZnT8 activity in β cells, such medicines may one day be clinically valuable for treating or preventing type 2 diabetes.

Dwivedi OP, Lehtovirta M, Hastoy B,…Groop L. Loss of ZnT8 function protects against diabetes by enhanced insulin secretion. Nat Genet 51: 1596-1606, 2019.

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