Study pinpoints protective genetic mutations for Type 2 diabetes
CAMBRIDGE, Mass. — An international team led by researchers at the Broad Institute and Massachusetts General Hospital has identified mutations in a gene that can reduce the risk of developing Type 2 diabetes, even in people who have such risk factors as obesity and old age, the group announced Sunday. 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.
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 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 and a Harvard Medical School professor at Massachusetts General Hospital.
The new Type 2 diabetes study, which appears this week in Nature Genetics, suggests that CCR5 and PCSK9 are likely just the beginning, but that it will take large numbers of samples and careful sleuthing to find additional genes with similar protective properties.
The Nature Genetics study grew out of a research partnership that started in 2009 involving the Broad Institute, Massachusetts General Hospital, Pfizer 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 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 non-diabetic 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.
Then, in 2012, these unpublished results were shared with deCODE genetics, who uncovered a second mutation in an Icelandic population that also appeared to abolish function of the gene SLC30A8. That mutation independently reduced risk for Type 2 diabetes and also lowered blood sugar in non-diabetics without any evident negative consequences.
Finally, 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 10 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% reduction in risk of diabetes.
"Through this partnership, we have been able to identify genetic mutations related to loss of gene function, which are protective against Type 2 diabetes," said Tim Rolph, VP and chief scientific officer of cardiovascular, metabolic and endocrine disease research at Pfizer. "Such genetic associations provide important new insights into the pathogenesis of diabetes, potentially leading to the discovery of drug targets, which may result in a novel medicine."
GPhA addresses Congress on economic impact of FDA’s proposed rule on prescription labeling
WASHINGTON — The Generic Pharmaceutical Association on Friday hosted a Congressional briefing highlighting the economic impact the Food and Drug Administration’s proposed rule on prescription labeling that would allow for label changes without prior FDA approval.
“By allowing label changes without prior FDA review and approval, the proposal will expose generic drug manufacturers to new liability that will drive up costs of generic drugs by at least $4 billion annually and, furthermore, may create confusion in the marketplace for patients, pharmacists and physicians," said Alex Brill, CEO Matrix Global Advisors. "The resulting cost increase will be borne by both consumers in the form of higher insurance premiums and the government in the form of higher Medicare and Medicaid costs.”
A recent report by Matrix Global Advisors estimated that U.S. healthcare costs would rise $4 billion annually if the proposed rule is enacted. Medicare and other government programs will incur $1.5 billion in annual new spending, while private insurers and patients will pay $2.5 billion per year.
“This proposal directly undermines the ‘sameness’ of generics and their brand counterparts — a fundamental scientific principle that is the very cornerstone of the success of generic medicines in the last thirty years,” stated Gordon Johnston, former deputy director, FDA Office of Generic Drugs. “The proposed rule paves the way for different versions of safety information for the same products, undermining the important principle of consistency. Disregarding decades of regulatory stability in this way will create unwarranted confusion, raises patient safety concerns and threatens the system that created thousands of affordable options for consumers. ”
Pharma industry calls on Congress to do more in the fight against counterfeit medicines
WASHINGTON — "The problem [of counterfeit medicines] is so big, disperse and complex that it requires a sweeping coordinated global response," wrote Scott LaGanga, executive director of the Partnership for Safe Medicines and SVP public affairs and advocacy for PhRMA in a blog published by The Hill on Saturday.
"According to the National Association of Boards of Pharmacy, 97% of all internet pharmacies do not meet the most basic criteria for accreditation," LaGanga wrote. "The reality is that all those emails clogging our inboxes from purported ‘Canadian’ pharmacies are often selling unapproved, counterfeit and potentially lethal medicines with no guarantees of the drugs being produced in Canada or other so-called ‘Tier One’ countries."
The blog follows a Congressional hearing on counterfeit medicines, held Thursday by the House Energy and Commerce Committee’s Subcommittee on Oversight and Investigations.
According to the Partnership for Safe Medicines, as many as 36 million Americans have purchased prescription medicines online without a prescription. Coupled with the fact that only 3-in-10 online pharmacies are legitimate, "that is, put very simply, a recipe for disaster," said Marv Shepherd, PSM president. "The bottom line is that criminal enterprises have been evolving and innovating at a faster pace than our government’s efforts to stop them, and that must change soon," he said. "As the worldwide prevalence of counterfeit drugs continues to increase, it is imperative that we work together to ensure that the prescription drug supply chain in the United States remains the safest in the world.”
"However, there [is] much more to be done, and that requires decision-makers at all levels of our government to work in public/private partnership with industry, patients and providers," LaGanga concluded in his blog. "With the rise of counterfeit medicines as a booming global industry, there is simply too much at stake for patient health to ignore the issue any longer."