An international team led by researchers at the Broad Institute and Massachusetts General Hospital (MGH), both Harvard affiliates, has identified mutations in a gene that can reduce the risk of individuals 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: If a drug can be developed that mimics the protective effect of these mutations, it could open up new ways of preventing this devastating disease.
Type 2 diabetes affects more than 300 million people worldwide and is rising rapidly in prevalence. Lifestyle changes and existing medicines slow the progression of the disease, but many patients are inadequately served by current treatments. The first step to developing a new therapy is discovering and validating a “drug target” — a human protein that, if activated or inhibited, results in prevention and treatment of the disease.
The current study breaks new ground in type 2 diabetes research and guides future therapeutic development in this disease. In the 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.
“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,” said co-senior author David Altshuler, deputy director and chief academic officer at the Broad Institute of Harvard and MIT and a Harvard Medical School professor at MGH.
The Nature Genetics study grew from a research partnership that started in 2009 involving the Broad Institute, MGH, Pfizer Inc., and Lund University Diabetes Centre in Sweden, which set out to find mutations that reduce a person’s risk of type 2 diabetes. The research team selected people with severe risk factors for diabetes, such as advanced age and obesity, who never developed the disease and in fact had normal blood sugar levels. They focused on a set of genes previously identified as playing a role in type 2 diabetes and used next-generation sequencing (then a new technology) to search for rare mutations.
The team identified a genetic mutation that appeared to abolish function of the SLC30A8 gene and that was enriched in nondiabetic individuals studied in Sweden and Finland. The protection was surprising, because studies in mice had suggested that mutations in SLC30A8 might have the opposite effect — increasing rather than decreasing risk of type 2 diabetes. However, because this particular genetic variation was exceedingly rare outside of Finland, it proved difficult to obtain additional evidence to corroborate the initial discovery by the Broad/MGH/Pfizer/Lund team.
Read more: harvard.edu
The results focus the search for developing novel therapeutic strategies for type 2 diabetes: If a drug can be developed that mimics the protective effect of these mutations, it could open up new ways of preventing this devastating disease.
Type 2 diabetes affects more than 300 million people worldwide and is rising rapidly in prevalence. Lifestyle changes and existing medicines slow the progression of the disease, but many patients are inadequately served by current treatments. The first step to developing a new therapy is discovering and validating a “drug target” — a human protein that, if activated or inhibited, results in prevention and treatment of the disease.
The current study breaks new ground in type 2 diabetes research and guides future therapeutic development in this disease. In the 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.
“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,” said co-senior author David Altshuler, deputy director and chief academic officer at the Broad Institute of Harvard and MIT and a Harvard Medical School professor at MGH.
The Nature Genetics study grew from a research partnership that started in 2009 involving the Broad Institute, MGH, Pfizer Inc., and Lund University Diabetes Centre in Sweden, which set out to find mutations that reduce a person’s risk of type 2 diabetes. The research team selected people with severe risk factors for diabetes, such as advanced age and obesity, who never developed the disease and in fact had normal blood sugar levels. They focused on a set of genes previously identified as playing a role in type 2 diabetes and used next-generation sequencing (then a new technology) to search for rare mutations.
The team identified a genetic mutation that appeared to abolish function of the SLC30A8 gene and that was enriched in nondiabetic individuals studied in Sweden and Finland. The protection was surprising, because studies in mice had suggested that mutations in SLC30A8 might have the opposite effect — increasing rather than decreasing risk of type 2 diabetes. However, because this particular genetic variation was exceedingly rare outside of Finland, it proved difficult to obtain additional evidence to corroborate the initial discovery by the Broad/MGH/Pfizer/Lund team.
Read more: harvard.edu
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