Mechanisms of Fatigability With Diabetes

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Mechanisms of Fatigability and the Protective Effects of Exercise in People With Diabetes

Conditions
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Pre-diabetes, Type 2 Diabetes

Intervention / Treatment
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* Other: Control Exercise
* Other: Blood Flow Restriction Exercise


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Control Exercise<br>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. | Other: Control Exercise<br>* 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.<br>|
| Experimental: Blood Flow Restriction Exercise<br>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. | Other: Blood Flow Restriction Exercise<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fatigability - Reduction in Power | Reduction in limb power and maximal force in response to a dynamic fatiguing contraction. | One session before and then after 8 weeks of training | 
| Strength - 1 Repetition Maximum | Reduction in limb power and maximal force in response to a dynamic fatiguing contraction | One session before and then after 8 weeks of training | 
| Strength - Maximal Voluntary Contraction (MVC) | Changes in MVC after 8 weeks resistance training. MVC is the greatest force generated during a brief isometric contraction. | One session before and then after 8 weeks of training | 
| Leg Blood Flow | 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. | One session before and then after 8 weeks of training | 
| Skeletal Muscle Oxygenation | 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. | One session before and then after 8 weeks of training | 
| Vasodilation in Skeletal Muscle Arterioles | 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 | One session before and then after 8 weeks of training | 
| Muscle Metabolism - Phosphorus Nuclear Magnetic Resonance Spectroscopy (31P-MRS)) | 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. | One session before and then after 8 weeks of training | 
| Capillary density | Immunohistochemical analysis will be performed on muscle biopsy samples to determine the number and density of capillaries for each fiber type. | One session before and after 8 weeks of training | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Pre-diabetes, Fatigability, Blood Flow Restriction Training, Vascular Function, Muscle Fatigue