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Research Team Awarded $3 Million to Study Weight Loss, Bone Frailty Link in Diabetics

Qi Zhao, MD, PhD

Two researchers in the Department of Preventive Medicine at the University of Tennessee Health Science Center have received a $3 million award from the National Institute on Aging to study why bones become more frail and prone to fracture in diabetics who achieve long-term weight loss. Qi Zhao, MD, PhD, associate professor of Epidemiology, and Karen Johnson, MD, MPH, department chair and the Endowed Professor of Women's Health, are the principal investigators on the study.

Weight loss is critical to overweight and obese patients with type 2 diabetes for improving cardiovascular health and quality of life. But it also puts them at increased risk of bone loss and fracture. The link between the two is still largely unknown, but may be key to protecting bone health during intentional weight loss.

Karen Johnson, MD, MPH

The goal of Dr. Zhao and Dr. Johnson is to identify the metabolomic changes occurring during intentional weight loss in type 2 diabetics that might cause increased fracture risk. They are building on findings from the Look AHEAD (Action for Health in Diabetes) Study, a multicenter, randomized clinical trial examining the effects of sustained weight loss through reduced calorie consumption and increased physical activity in volunteers with type 2 diabetes. Dr. Johnson was the principal investigator for the Memphis site, and has continuously followed participants of the original trial through an observational study, and through an extension study.

Findings from the Look AHEAD trial showed an intensive lifestyle intervention for weight loss was associated with 39% increased frailty fracture risk. Bone mineral density scans in a subgroup showed participants were also at increased risk for bone loss.

This new study will use a state-of-the-art liquid chromatography mass spectrometry-based metabolomics approach to examine blood samples from 4,659 Look AHEAD participants. These participants had blood samples collected at both baseline and one-year visits and had a median follow-up of 11.3 years for fracture outcomes. Among those, 1,274 participants also had bone mineral density scans at both baseline and year one.

The team will examine the effects of intensive lifestyle intervention on changes in metabolomic profiles from baseline to year one. Once these metabolomic changes are identified, they will examine whether increased fracture risk is associated with these changes, and whether changes in bone density, quality, and strength are co-occurring. They will also work to discover whether baseline metabolomic profiles modify the effect of intensive lifestyle intervention on fracture risk.

"We are looking forward to identifying potential mechanisms for why the Look AHEAD participants lost bone when they lost weight to see if we can identify ways to prevent this loss and prevent fractures," Dr. Johnson said.

The study will yield comprehensive insights into the biological mechanisms underlying the increased bone frailty caused by intensive lifestyle intervention. These findings will fuel future discoveries of molecular targets for blocking the detrimental effects of intentional weight loss on bone health. It will also provide new biomarkers for predicting fracture risk and for personalizing/optimizing lifestyle intervention for reducing weight in overweight diabetics.

"The completion of the project will be a collaborative effort of a multidisciplinary team with expertise in clinical trials, molecular and genetic epidemiology, biostatistics, bioinformatics, analytical and synthetic chemistry," Dr. Zhao said. "We are very excited about this award and hope our study will contribute to the precision prevention of fracture among overweight or obese patients with type 2 diabetes when they try to lose weight."

The project, titled "Intensive Lifestyle Intervention, Metabolomics, and Risk of Frailty Fracture in Overweight or Obese Patients with Type 2 Diabetes," is being funded for five years.


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