Mechanisms of Fatigability With Diabetes

Pre-diabetes (Pre-D) is a precursor to type 2 diabetes (T2D) and characterized by increased exercise fatigability of lower limb muscles, that can impede exercise performance. The cause for the increased fatigability in people with Pre-D is not known. Given the profound vascular disease present in people who have had uncontrolled diabetes for several years, we will determine whether dynamic, fatiguing contractions of the lower limb muscles in people with Pre-D are limited by vascular dysfunction at multiple levels along the vascular tree including the artery, arteriole, and/or capillary. This clinical trial involves a novel exercise training regime involving blood flow restriction to the exercising limb will be used as a probe to further understand the vascular mechanisms for increased fatigability in people with Pre-D and T2D. The long-term goal is to better understand what limits exercise and functional performance in people with diabetes to help develop targeted, more effective exercise programs.

The aim of the clinical trial is to determine the effectiveness of dynamic resistance exercise training coupled with blood flow restriction to improve fatigability and vascular function in people with Pre-D and T2D. People with Pre-D and T2D from Aim 1 will perform 8 weeks of dynamic unilateral resistance exercise training in which one leg is exercised with freely perfused conditions and the other leg with blood flow restriction. We will assess fatigability, skeletal muscle metabolism, capillary density, and vascular function in people with Pre-D and T2D before and after a novel training intervention that couples dynamic resistance training with blood flow restriction to the exercising limb. This novel intervention has been shown to improve vascular function in young and older adults but has not been investigated in people with Pre-D and T2D. Endothelial function in intact large conduit arteries and arterioles isolated from skeletal muscle biopsies will be measured before and after the training intervention to assess whether the novel training improves vascular function along multiple levels of the vascular tree in people with Pre-D and T2D. Skeletal muscle blood flow through the femoral artery will be quantified with Doppler ultrasonography and skeletal muscle oxygenation will be measured with near infrared spectroscopy (NIRS) during a dynamic fatiguing knee extension exercise. We will closely match participant groups for physical activity levels, age, sex, and body mass index (BMI), because these confounders are not typically controlled for in other human studies.

Diabetes, Pre-diabetes, Fatigability, Blood Flow Restriction Training, Vascular Function, Muscle Fatigue

Each participant will attend 3 sessions per week for 8 weeks. A training session will start with a 10-minute warm up on a bike ergometer. Each leg will then perform low-load resistance training (~20% of 1-RM) for 4 sets of contractions with 15 contractions per set of contractions with a 30 second rest between each set of contractions while seated in a knee extension weight machine. One leg will be randomized to always perform the training with blood flow restriction (BFR leg) while the contralateral leg performs the exercise training without blood flow occlusion (Control leg).

Low-load knee extension resistance training (20% of 1-RM) without blood flow restriction. A 10-cm wide inflatable cuff will be placed around the upper portion of the thigh but not inflated.

Low-load knee extension resistance training (20% of 1-RM) with blood flow restriction using a 10-cm wide inflatable cuff placed around the most proximal part of the exercising thigh. Blood flow will be restricted in the BFR leg at above the limb occlusion pressure of the and this will be determined prior to the exercise while the participant is seated in the knee extensor machine. The cuff pressure during the BFR protocol will be 10 mmHg above limb occlusion pressure.

Each participant will attend 3 sessions per week for 8 weeks. Participants will perform low-load knee extension resistance training (20% of 1-RM) without blood flow restriction on the designated leg for 4 sets of contractions with 15 contractions per set of contractions with a 30 second rest between each set of contractions.

Each participant will attend 3 sessions per week for 8 weeks. Participants will perform low-load knee extension resistance training (20% of 1-RM) with blood flow restriction on the designated leg for 4 sets of contractions with 15 contractions per set of contractions with a 30 second rest between each set of contractions.

Changes in MVC after 8 weeks resistance training. MVC is the greatest force generated during a brief isometric contraction.

Femoral artery mean blood velocity and femoral artery diameter will be measured using Doppler ultrasonography before and immediately after the fatiguing task in each leg.

Near-Infrared Spectroscopy recordings will be used to quantify blood flow kinetics of the knee extensor muscle tissue (rectus femoris and vastus lateralis) during the dynamic, fatiguing exercise in each leg.

Vessel diameters of arterioles that are extracted and isolated from Skeletal muscle biopsies of the vastus lateralis will be measured in response to vasodilators and constrictors

31P-MRS is used to noninvasively measure muscle metabolism by calculating intracellular ATP, ADP, phosphocreatine (PCr), inorganic phosphate (Pi), and pH in the quadriceps of participants. This measurement is conducted while participants perform fatiguing knee extensor exercise in the magnetic bore.

Immunohistochemical analysis will be performed on muscle biopsy samples to determine the number and density of capillaries for each fiber type.

Inclusion Criteria: Men and women adults 30 years to 85 years or less Pre-diabetes [glycosylated hemoglobin (HbA1c) of 5.7-6.4% and fasting plasma glucose 100-125 mg/dL at the time of initial screening] Controls [normoglycemic with a HbA1c level ≤5.6% and fasting blood glucose ≤ 99 mg/dL (5.5 mmol/L)] Type 2 Diabetes Mellitus [elevated glycosylated hemoglobin (HbA1c) >6.5% and <10%] Exclusion Criteria: Signs or symptoms of neuropathy Medications associated with advanced stages of T2D including insulin Poor glycemic control (HbA1c>10%) Peripheral edema Severe obesity (BMI, >45kg·m-2) Untreated hypothyroidism Smoking Hypertension Cardiovascular or musculoskeletal disease that preclude exercise testing Hormone replacement drugs or vasoactive medications