Mechanisms of Fatigability With Diabetes

Not Applicable

Recruiting

• Conditions: Pre-diabetes; Type 2 Diabetes
• Interventions: Other: Blood Flow Restriction Exercise; Other: Control Exercise

• Registration Number: NCT04442451
• Lead Sponsor: Marquette University

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2020-06-18
• Study First Submitted QC: 2020-06-18
• Study First Posted: 2020-06-22
• Study Start: 2022-09-01
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-16
• Last Update Posted: 2024-10-18
• Primary Completion: 2027-01-01
• Study Completion: 2027-04-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 80

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%]

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Blood Flow Restriction Exercise	Blood Flow Restriction Exercise	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.
Control Exercise	Control Exercise	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.

Primary Outcome Measures

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

Trial Locations

Locations (1)

Marquette University; 🇺🇸 Milwaukee, Wisconsin, United States