Study: obesity dramatically shortens lifespan

   (NIH) - 7/11/2014 - Adults with extreme obesity have increased risks of dying at a young age from cancer and many other causes including heart disease, stroke, diabetes, and kidney and liver diseases, according to results of an analysis of data pooled from 20 large studies of people from three countries. The study, led by researchers from the National Cancer Institute (NCI), part of the National Institutes of Health, found that people with class III (or extreme) obesity had a dramatic reduction in life expectancy compared with people of normal weight. The findings appeared July 8, 2014, in PLOS Medicine.
   “While once a relatively uncommon condition, the prevalence of class III, or extreme, obesity is on the rise. In the United States, for example, six percent of adults are now classified as extremely obese, which, for a person of average height, is more than 100 pounds over the recommended range for normal weight,” said Cari Kitahara, Ph.D., Division of Cancer Epidemiology and Genetics, NCI, and lead author of the study. “Prior to our study, little had been known about the risk of premature death associated with extreme obesity.”
   In the study, researchers classified participants according to their body mass index (BMI), which is a measure of total body fat and is calculated by dividing a person’s weight in kilograms by their height in meters squared. BMI classifications (kilogram/meter-squared) are:

• Normal weight: 18.5-24.9
• Overweight: 25.0- 29.9
• Class I obesity: 30.0-34.9
• Class II obesity: 35.0-39.9
• Class III obesity: 40.0 or higher

   The 20 studies that were analyzed included adults from the United States, Sweden and Australia. These groups form a major part of the NCI Cohort Consortium, which is a large-scale partnership that identifies risk factors for cancer death. After excluding individuals who had ever smoked or had a history of certain diseases, the researchers evaluated the risk of premature death overall and the risk of premature death from specific causes in more than 9,500 individuals who were class III obese and 304,000 others who were classified as normal weight.
   The researchers found that the risk of dying overall and from most major health causes rose continuously with increasing BMI within the class III obesity group. Statistical analyses of the pooled data indicated that the excess numbers of deaths in the class III obesity group were mostly due to heart disease, cancer and diabetes. Years of life lost ranged from 6.5 years for participants with a BMI of 40-44.9 to 13.7 years for a BMI of 55-59.9. To provide context, the researchers found that the number of years of life lost for class III obesity was equal or higher than that of current (versus never) cigarette smokers among normal-weight participants in the same study.
   The accuracy of the study findings is limited by the use of mostly self-reported height and weight measurements and by the use of BMI as the sole measure of obesity. Nevertheless, the researchers noted, the results highlight the need to develop more effective interventions to combat the growing public health problem of extreme obesity.
   “Given our findings, it appears that class III obesity is increasing and may soon emerge as a major cause of early death in this and other countries worldwide,” said Patricia Hartge, Sc.D., Division of Cancer Epidemiology and Genetics, and senior author of the study.
   Source: 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.