Genetic Information on Diabetes Made Available

   (NIH) - 10/15/2015 -Researchers funded by the National Institutes of Health and the Foundation for the NIH (FNIH) have expanded a recently launched online library, called a knowledge portal, which allows open-access searching of human genetic and clinical information on type 2 diabetes. Individual data will remain confidential. The portal includes information from several major international networks, collected from decades of research.
   A product of the Accelerating Medicines Partnership (AMP) for type 2 diabetes, the portal is aimed at advancing type 2 diabetes research and treatment, and will include data from over 100,000 genetic samples obtained from clinical consortia supported by the NIH and FNIH. AMP is an innovative project of government, industry and nonprofit organizations working together to speed research in type 2 diabetes, Alzheimer’s disease, rheumatoid arthritis and lupus.
   “Through AMP, we have an unprecedented opportunity to advance international research in type 2 diabetes,” said NIH Director Francis S. Collins, M.D., Ph.D. “Our hope is that this portal – and this partnership – will lead to better disease targets and a shorter, less expensive drug development process, enabling companies to get safe and effective medications to patients who need them faster.”
   The portal collects data from human genetic samples, since the animal and cellular models that are typically used in diabetes drug development before human testing do not always replicate human behavior. The portal provides a way to identify the most promising therapeutic targets for diabetes from troves of potentially relevant human data.
   “The knowledge portal will allow us to translate differences in an individual’s genome into an understanding of how those differences affect a person’s risk of developing type 2 diabetes. By harnessing the power of international data sets, we can also better account for differences in race, ethnicity and locality,” said Philip Smith, Ph.D., of the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases. Smith is co-chair of AMP’s Type 2 Diabetes Steering Committee.
   The knowledge portal makes genetic and clinical information searchable in myriad ways, while keeping individual data confidential, to help researchers identify and describe the effects of genes on disease. Searches can include genes, gene variants and genetic regions, and can be cross-referenced with associations between glucose and insulin measurements and other criteria. The data can be sorted to include relevant genetic studies and the kind of data collected, and allows researchers to test biological hypotheses, and conduct many other analyses.
   The portal is publicly searchable and can be used as a tool to learn about genetics and health. However, only approved researchers will be able to access detailed data, while the general public can access aggregate results. Creators of the research engine are eager to expand the network to include more national and international research networks. The international source samples of genetic and clinical data will be housed in their home networks to ensure use of each sample complies with each country’s health information confidentiality rules.
   The portal’s creation was led by David Altshuler, M.D., Ph.D., while at Broad Institute of Massachusetts Institute of Technology and Harvard University in Cambridge. Jose Florez, M.D., Ph.D., also from Broad Institute, and Michael Boehnke, Ph.D., and Goncalo Abecasis, Ph.D., from the University of Michigan, Ann Arbor, were awarded respective grants from NIDDK (U01 DK105554) and FNIH, to continue the portal’s development. The FNIH grant to the University of Michigan supports portal infrastructure and expanded development of analytical tools.
   The portal team will work closely with Broad Institute’s Daniel MacArthur, Ph.D., and Benjamin Neale, Ph.D., who will lead a Center for Genome Interpretation (U54 DK105566) to develop methods to analyze the genomic data collected in the portal.
   “Type 2 diabetes is among our country’s and the world’s greatest and most costly health problems. In the United States alone, the disease affects more than 29 million people, with an additional 79 million more at high risk,” said NIDDK Director Dr. Griffin P. Rodgers. “We need more targeted drug therapies to treat type 2 diabetes. While multiple drugs are available to stabilize the disease, people still progress to complications including heart and kidney diseases.”
   In addition to NIH, support for the AMP Type 2 Diabetes project includes pharmaceutical companies Eli Lilly and Company; Janssen Research and Development, LLC; Merck & Co.; Pfizer Inc.; and Sanofi US Services and the not-for-profit organizations FNIH, JDRF International and the American Diabetes Association. Support from these sources funds awards made by the FNIH directly to awardees institutions. Additional support to Broad Institute for the portal is provided by the Carlos Slim Foundation.
   The NIDDK, part of the NIH, conducts and supports basic and clinical research and research training on some of the most common, severe and disabling conditions affecting Americans. The Institute's research interests include: diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic and hematologic diseases. For more information, visit www.niddk.nih.gov.
   Source: National Institutes of Health

NIH, Others Work To Validate Disease Targets

   (NIH) - 2/16-2014 -The National Institutes of Health, 10 biopharmaceutical companies and several nonprofit organizations recently launched an unprecedented partnership to transform the current model for identifying and validating the most promising biological targets of disease for new diagnostics and drug development.
   The Accelerating Medicines Partnership (AMP) aims to distinguish biological targets of disease most likely to respond to new therapies and characterize biological indicators of disease, known as biomarkers. Through the Foundation for the NIH (FNIH), AMP partners will invest more than $230 million over five years in the first projects, which focus on Alzheimer’s disease, type 2 diabetes, and the autoimmune disorders rheumatoid arthritis and systemic lupus erythematosus (lupus).
   A critical and groundbreaking element of the partnership is the agreement that the data and analyses generated will be made publicly available to the broad biomedical community. The three- to five-year, milestone-driven pilot projects in these disease areas could set the stage for broadening AMP to other diseases and conditions.
   “Patients and their caregivers are relying on science to find better and faster ways to detect and treat disease and improve their quality of life,” NIH Director Francis S. Collins stated. “Currently, we are investing a great deal of money and time in avenues with high failure rates, while patients and their families wait. All sectors of the biomedical enterprise agree that new approaches are sorely needed.”
    As a result of technological revolutions in genomics, imaging, and more, researchers have been able to identify many changes in genes, proteins, and other molecules that predispose to disease and influence disease progression. While researchers have identified thousands of such biological changes that hold promise as biomarkers and drug targets, only a small number have been pursued. Choosing the wrong target can result in failures late in the development process, costing time, money, and ultimately, lives. Currently, developing a drug from early discovery through U.S. Food and Drug Administration approval takes well over a decade and has a failure rate of more than 95 percent. As a consequence, each success costs more than $1 billion.
   “The AMP rallies scientific key players of the innovation ecosystem in a more unified way to address one of the key challenges to Biopharma drug discovery and development,” said Mikael Dolsten, M.D., Ph.D., President of Worldwide Research and Development at Pfizer. “This type of novel collaboration will leverage the strengths of both industry and NIH to ensure we expedite translation of scientific knowledge into next generation therapies to address the urgent needs of Alzheimer’s, diabetes and RA/lupus patients.”
  AMP has been more than two years in the making, with intense interactions between scientists in the public and private sectors, progressive refinement of the goals, strategy development support from the Boston Consulting Group, and scientific project and partnership management by the FNIH. Through this effort, AMP partners have developed research plans and are sharing costs, expertise, and resources in an integrated governance structure that enables the best informed contributions to science from all participants.
   The research highlights for each disease area are:

Alzheimer’s disease

   Identify biomarkers that can predict clinical outcomes by incorporating an expanded set of biomarkers into four major NIH-funded clinical trials, which include industry support, designed to delay or prevent disease.
    Conduct large-scale, systems biology analyses of human patient brain tissue samples with Alzheimer’s disease to validate biological targets that play key roles in disease progression, and increase understanding of molecular networks involved in the disease, to identify new potential therapeutic targets.
  For more information about NIH Alzheimer’s disease research, see the 2012-2013 Alzheimer’s Disease Progress Report: Seeking the Earliest Interventions.

Type 2 diabetes

   Build a knowledge portal of DNA sequence, functional genomic and epigenomic information, and clinical data from studies on type 2 diabetes and its heart and kidney complications. The portal will include existing data and new data from studies involving 100,000–150,000 individuals. The rich collection of curated and collated information in this portal will provide an opportunity to identify the most promising therapeutic targets for diabetes from the growing mountain of potentially relevant data.
    Focus on DNA regions that might be critical for the development or progression of type 2 diabetes and search for natural variations in targeted populations that might predict the likelihood of success of drug development aimed at these targets.

Rheumatoid arthritis and lupus

    Collect and analyze tissue and blood samples from people with rheumatoid arthritis and lupus to pinpoint biological changes at the single cell level, to allow comparisons across the diseases and provide insights into key aspects of the disease process.
Identify differences between rheumatoid arthritis patients who respond to current therapies and those who do not, and provide a better systems-level understanding of disease mechanisms in RA and lupus.
   Highly collaborative steering committees with representation from public- and private-sector partners will be established for each disease area to oversee the research plans. The steering committees will be managed by FNIH under the direction of an AMP executive committee comprised of leaders from NIH, industry, the FDA, and patient advocacy organizations.
   More information about the program and the disease research plans can be found here: www.nih.gov/amp.
   Source: The National Institutes of Health

Link identified between metabolism, breast cancer

   (NIH) - 2/6/2013 - A protein associated with conditions of metabolic imbalance, such as diabetes and obesity, may play a role in the development of aggressive forms of breast cancer, according to new findings by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and their colleagues. Metabolic imbalance is often caused by elevated carbohydrate intake, which can lead to over-activating a molecule called C-terminal binding protein (CtBP). This over-activation, in turn, can increase the risk of breast cancer. Results of their work appeared in Nature Communications, Feb. 5, 2013.
   “Modifying diet and maintaining a healthy diet, combined with developing pharmacological ways of lessening CtBP activity, may one day lead to a way to break the link between cancer and obesity,” said Kevin Gardner, M.D., Ph.D., head of NCI’s Transcription Regulation Section, Genetics Branch.
   It has been known, primarily through population based studies, that there is a strong link between obesity and cancer. But the mechanism behind this link has been uncertain. A previous study conceived and carried out in Gardner’s laboratory found that CtBP repressed expression of a gene associated with breast cancer (BRCA1) at an early age by sensing when the cell was in a high metabolic state that, in turn, led to processing large amounts of carbohydrates in the body.
    This early study suggested that obesity and weight gain may contribute to breast cancer by decreasing the level of the BRCA1 tumor suppressor gene expression in response to high carbohydrate intake. This explains, in part, why women who have hereditary mutations of BRCA1 also experience an increased risk of breast cancer if they gain weight.
   Gardner’s new study expands upon his past work. He analyzed prior gene expression studies to determine if gene pathways, repressed by CtBP, were diminished in breast cancer patients who suffered from more aggressive clinical outcomes. Gardner’s team began first with the human breast cancer cells in the laboratory. They measured the association of CtBP and the genes it bound to in order to regulate expression. The researchers combined this approach with genome sequencing to confirm how, and where, CtBP bound to genes associated with breast cancer. Next, they integrated analyses with gene expression studies in cells in which they observed decreased the levels of CtBP by RNA interference (a process that inhibits gene expression), or by decreasing carbohydrate feeding of the cells.
   The scientists found that, under conditions where they decreased the levels of CtBP, DNA repair increased and the cells developed stability and growth control. They determined that gene pathways targeted by CtBP were also disrupted in more aggressive breast cancers. Moreover, patients with high levels of CtBP in their tumors had shortened survival. And they showed that a small molecular inhibitor previously shown to bind to CtBP was able to reverse the gene-repressive effects of CtBP in breast cancer cells even under conditions of high carbohydrate feeding.
   “Our new work suggests that targeting CtBP may provide a way of treating breast cancer and possibly preventing breast cancer,” Gardner said. “Research should continue to focus on the link between obesity, CtBP and breast cancer. This will require more population-based studies and multi-disciplinary teams of scientist to investigate these links.”
   This project was funded by NCI project number 1Z01BC010847-01.
   Source: National Institutes of Health

Weight Loss, Type 2 Diabetes Risk Questioned

   (NIH) - 10/21/2012 - An intensive diet and exercise program resulting in weight loss does not reduce cardiovascular events such as heart attack and stroke in people with longstanding type 2 diabetes, according to a study supported by the National Institutes of Health.
   The Look AHEAD (Action for Health in Diabetes) study tested whether a lifestyle intervention resulting in weight loss would reduce rates of heart disease, stroke, and cardiovascular-related deaths in overweight and obese people with type 2 diabetes, a group at increased risk for these events.
   Researchers at 16 centers across the United States worked with 5,145 people, with half randomly assigned to receive an intensive lifestyle intervention and the other half to a general program of diabetes support and education. Both groups received routine medical care from their own health care providers.
   Although the intervention did not reduce cardiovascular events, Look AHEAD has shown other important health benefits of the lifestyle intervention, including decreasing sleep apnea, reducing the need for diabetes medications, helping to maintain physical mobility, and improving quality of life. Previous Look AHEAD findings are available at www.lookaheadtrial.org.
   "Look AHEAD found that people who are obese and have type 2 diabetes can lose weight and maintain their weight loss with a lifestyle intervention," said Dr. Rena Wing, chair of the Look AHEAD study and professor of psychiatry and human behavior at Brown University. "Although the study found weight loss had many positive health benefits for people with type 2 diabetes, the weight loss did not reduce the number of cardiovascular events."
   Data are currently being analyzed to fully understand the cardiovascular disease results. Investigators are preparing a report of the findings for a peer-reviewed publication.
   Few, if any, studies of this size and duration have had comparable success in achieving and maintaining weight loss. Participants in the intervention group lost an average of more than 8 percent of their initial body weight after one year of intervention. They maintained an average weight loss of nearly 5 percent at four years, an amount of weight loss that experts recommend to improve health. Participants in the diabetes support and education group lost about 1 percent of their initial weight after one and four years.
   In September, the NIH stopped the intervention arm, acting on the recommendation of the study’s data and safety monitoring board. The independent advisory board, charged with monitoring the study data and safety of participants, found that the intensive lifestyle did no harm but did not decrease occurrence of cardiovascular events, the primary study goal. At the time, participants had been in the intervention for up to 11 years.
   Because there was little chance of finding a difference in cardiovascular events between the groups with further intervention, the board recommended stopping the intensive lifestyle intervention, but encouraged the study to continue following all Look AHEAD participants to identify longer-term effects of the intervention.
  "The intervention group did not have fewer cardiovascular events than the group receiving general diabetes support and education, but one positive factor we saw was that both groups had a low number of cardiovascular events compared to previous studies of people with diabetes," said Dr. Mary Evans, director of Special Projects in Nutrition, Obesity, and Digestive Diseases within the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the study's primary sponsor.
   Type 2 diabetes — affecting nearly 24 million people in the United States alone — has increased in prevalence along with the country's epidemic of overweight and obesity. Cardiovascular diseases are the most common cause of death among people with type 2 diabetes. Look AHEAD is the first study to examine the long-term effects of a lifestyle intervention on major cardiovascular disease events and death in adults with type 2 diabetes.
   "Look AHEAD provides important, definitive information about the long-term health effects of weight loss in people with type 2 diabetes," NIDDK Director Dr. Griffin Rodgers said. "Beyond cardiovascular disease, this study and others have shown many other health benefits of weight loss through improved diet and increased physical activity. For example, for overweight and obese adults at high risk for diabetes, modest weight loss has been shown to prevent or delay developing type 2 diabetes."
   Participants were 45 to 76 years old when they enrolled in the study. Sixty percent of enrollees were women. More than 37 percent were from racial and ethnic minority groups. Researchers are now analyzing data to measure effects of the lifestyle intervention on subgroups, including racial and ethnic groups and people with a history of cardiovascular disease.
  Find more information about the Look AHEAD trial (NCT00017953), including a list of current publications, at www.lookaheadtrial.org. For a list of centers enrolling patients for diabetes or obesity trials, search for keywords "diabetes" or "obesity" at www.clinicaltrials.gov.

   Source: National Institutes of Health release.