Mechanisms of Fatigability and the Protective Effects of Exercise in People with Diabetes - ABSTRACT Pre-diabetes (Pre-D) is characterized by elevated glycated hemoglobin and plasma glucose and is a clinical precursor to type 2 diabetes mellitus (T2D). Pre-D currently affects ~90 million Americans. Both Pre-D and T2D are highly associated with cardiovascular disease and among the top five causes of mortality worldwide. Exercise is the cornerstone of management and is most efficacious during the Pre-D stage when glycemia is below the diabetic threshold. However, excessive fatigability during exercise (i.e., exercise induced reductions in force or power of the limb muscles) limits exercise performance in people with Pre-D. Our laboratory demonstrated that (1) across the diabetic spectrum, people with Pre-D and T2D have greater fatigability of limb muscles than controls due to mechanisms within the muscle, and (2) fatigability in people with T2D was associated with a reduced blood flow to the exercising muscle. It is unknown, however, if people with Pre-D have impaired vascular function and oxygen delivery that leads to an increased fatigability. Our central hypothesis is that impaired vascular function impedes blood flow and blunts subsequent oxygen delivery to skeletal muscle during exercise, resulting in excessive fatigability of limb muscles in people with Pre-D. A unique and translational aspect of this proposal is the quantification of the vascular responses (macro- and micro-vasculature) to fatiguing exercise and exercising training at different sites along the vascular tree, including, in feed arteries (doppler ultrasonography), isolated skeletal muscle arterioles (extracted from muscle biopsy), capillary perfusion (near infrared spectroscopy, NIRS) and capillary density (from muscle biopsies). Aim 1 will determine if vascular dysfunction is a mechanism for excessive fatigability in people with Pre-D. Aim 1.1 will compare leg blood flow and skeletal muscle oxygenation in response to dynamic fatiguing exercise between people with Pre-D, healthy controls and T2D. Groups will be matched for age, sex, body mass index and physical activity levels to determine disease- related vascular function and fatigability rather than inactivity-related changes across the diabetic spectrum. Skeletal muscle blood flow through the femoral artery will be quantified with ultrasonography and skeletal muscle oxygenation with NIRS during a dynamic fatiguing knee extension exercise. Aim 1.2 will determine endothelial vascular function at macro- and micro-vascular levels in people with Pre-D and T2D. Flow-mediated dilation will be assessed in vivo in the femoral artery using ultrasonography and in isolated arterioles extracted from the vastus lateralis muscle biopsies. Aim 2 is a clinical trial that will determine the effectiveness of resistance exercise training coupled with blood flow restriction to improve fatigability and vascular function in people with diabetes. People with Pre-D and T2D will perform 8 weeks of unilateral resistance training in which one leg is exercised with freely perfused conditions and the other leg with blood flow restriction. Thus, blood flow restriction and resistance training will be used as a probe to further understand the mechanisms of fatigability along the vascular tree in people with Pre-D and T2D, and test training strategies to improve fatigability in this population.
