R01AG068232

Intensive lifestyle intervention, metabolomics, and risk of frailty fracture in overweight or obese patients with type 2 diabetes - Weight loss is critical to overweight or obese patients with type 2 diabetes (T2D) for improving glycemic control, cardiovascular risk factors, and quality of life. However, weight loss has been found to be associated with increased bone loss and risk for fractures by many studies, including the Action for Health in Diabetes (Look AHEAD) trial. In this trial, an intensive lifestyle intervention (ILI) for weight loss was associated with a 39% increased risk for frailty fracture (hip, pelvis, upper arm, or shoulder fractures) compared with diabetes support and education (DSE) (control group) among overweight or obese patients with T2D. Frailty fractures are devastating and represent a part of osteoporotic fracture types.

We also observed that the ILI was associated with increased bone loss in a subgroup of Look AHEAD participants who also had dual-energy X-ray absorptiometry (DXA) scans. However, the mechanisms linking the ILI and increased risk of fracture are still largely unknown but very important for developing effective methods for protecting bone and preventing fracture during intentional weight loss.

The overall goal of this proposed study is to identify metabolomic changes which mediate the effect of ILI on the increased risk for frailty fracture in the Look AHEAD trial using a state-of-the-art liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approach. In this study, we will include 4,659 Look AHEAD participants (2,357 in ILI and 2,302 in DSE) who had blood samples collected at both baseline and the 1-year visit and had a median follow-up of 11.3 years for fracture outcomes. Among those, 1,274 participants (642 in ILI and 632 in DSE) also had DXA scans for bone mineral density (BMD) at both baseline and year 1.

In this study, we will further measure serum bone turnover markers (BTMs) and reanalyze DXA images to obtain the trabecular bone score (TBS) to evaluate bone metabolism and bone microarchitecture (an indicator of bone quality) in the DXA subgroup. A comprehensive two-stage metabolomics approach, including an untargeted/global metabolomics analysis with relative quantification followed by chemical structure validation and absolute quantification, will support the following specific aims:

Aim 1) To examine the effects of ILI on changes in metabolomic profiles from baseline to year 1;
Aim 2) To examine whether 1-year changes in metabolomic profiles are associated with and mediate the effect of ILI on the risk of frailty fracture;
Aim 3) To examine whether 1-year changes in metabolomic profiles are associated with changes in BTMs, BMD, and TBS; and
Aim 4) To examine whether baseline metabolomic profiles modify the effect of ILI on the risk of frailty fracture.

The proposed study will provide comprehensive insights into the biological mechanisms underlying the increased risk of frailty fracture caused by the ILI. These findings will help discover molecular targets for blocking the detrimental effect of intentional weight loss on bone health. The study will also provide novel biomarkers for predicting the risk of frailty fracture and directing the personalization and optimization of lifestyle intervention for weight loss among overweight and obese patients with T2D.

University Of Tennessee

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Memphis, Tennessee 381055102 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 379% from $641,226 to $3,069,231.