# Molecular Mechanisms of Exercise Benefits to Insulin Resistant People > **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2024 · $675,213 ## Abstract PROJECT SUMMARY This renewal application continues to focus on older people with insulin resistance (IR) and aims to understand the mechanisms of exercise benefits. The original grant focused on the mechanisms of resistance exercise training (RT) related enhancement of peripheral (muscle) insulin sensitivity (IS) and muscle hypertrophy. The premise of the current proposal is built on substantial preliminary data obtained with a supplement to our current grant which was focused on the effect of RT on brain metabolism and cognition. We will address the neuronal benefits of six months of either high-intensity aerobic interval training (HIIT) or RT in 60–85-year-old people with IR compared to sedentary controls (n=24 per group). We hypothesize that enhancement of IS in response to six months of HIIT or RT will improve cognition, measured by NIH Toolbox, concurrent to enhanced brain regional connectivity, measured by resting-state functional MRI, and greater glucose uptake in brain regions rich in insulin receptors, measured by PET scanning (F-18 FDG). We also will determine whether HIIT and RT increase cortical and hippocampal volumes measured by volumetric MRI. Although exercise benefits in central neuronal regulation are postulated, based mostly on pre-clinical experimental data, the benefits of exercise training on brain metabolism and cognition remains incompletely defined in humans. Furthermore, in addition to our postulation that exercise training enhances neuronal connections within the brain, we also propose that exercise can enhance neuronal connection between the brain and skeletal muscle. We will utilize transcranial magnetic stimulation combined with electromyography (TMS-EMG) to test a hypothesis that RT and HIIT increase neuronal connections from the central nervous system to muscle, as indicated by lower threshold of cortical stimulation needed to activate muscle, prior to structural and morphological changes accompanying long-term exercise training. We will compare TMS-EMG data at baseline, 2 weeks, 3 months, and 6 months after the initiation of exercise training with changes in muscle mass, histology, and metabolites. The results from these studies will determine if there are central neural adaptations to exercise training that drive muscle mass and strength changes. To ensure the successful completion of the study, we have assembled a group of highly experienced investigators with strong collaborative track records. The results from the proposed studies are likely to substantially advance our understanding of exercise benefits to neuronal and cognitive function in people with IR, who are at 2- to 4-fold greater risk for developing dementia compared to people without IR. We submit that these results can potentially form the basis of targeted exercise therapies and lay the groundwork for developing novel therapeutic approaches benefitting people who are unable to perform exercise training. ## Key facts - **NIH application ID:** 10977567 - **Project number:** 2R01AG062859-06 - **Recipient organization:** MAYO CLINIC ROCHESTER - **Principal Investigator:** K Sreekumaran Nair - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $675,213 - **Award type:** 2 - **Project period:** 2019-09-30 → 2029-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10977567 ## Citation > US National Institutes of Health, RePORTER application 10977567, Molecular Mechanisms of Exercise Benefits to Insulin Resistant People (2R01AG062859-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10977567. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*