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NCT Number: NCT04442451

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.

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Key information

Conditions

Pre-diabetes Diabetes Mellitus Diabetes Mellitus, Type 2 Endocrine System Diseases Glucose Intolerance Glucose Metabolism Disorders Hyperglycemia Metabolic Diseases Nutritional and Metabolic Diseases Type 2 Diabetes

Age range

30 year–85 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Control Exercise

Other

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.

blood flow restriction exercise

Other

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.

Primary outcomes

  1. Fatigability - Reduction in Power

    Time frame: One session before and then after 8 weeks of training

    Reduction in limb power and maximal force in response to a dynamic fatiguing contraction.

  2. Strength - 1 Repetition Maximum

    Time frame: One session before and then after 8 weeks of training

    Reduction in limb power and maximal force in response to a dynamic fatiguing contraction

  3. Strength - Maximal Voluntary Contraction (MVC)

    Time frame: 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.

  4. Leg Blood Flow

    Time frame: 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.

  5. Skeletal Muscle Oxygenation

    Time frame: 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.

  6. Vasodilation in Skeletal Muscle Arterioles

    Time frame: 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

  7. Muscle Metabolism - Phosphorus Nuclear Magnetic Resonance Spectroscopy (31P-MRS))

    Time frame: 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.

  8. Capillary density

    Time frame: 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.

Study contacts

Contact information is provided by the study sponsor or research team.

Sandra Hunter, PhD

CONTACT

[email protected]

(734) 647-9819

Sarah Lessila, MSc

CONTACT

[email protected]

Sponsors and collaborators

Lead sponsor

University of Michigan

Other

Collaborators

  • Marquette University
  • Medical College of Wisconsin
  • National Institute on Aging (NIA)
  • University of Illinois at Chicago
  • University of Wisconsin, Madison

Registry information

Official study title

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

Important dates

Study start
2022
Primary completion
2027
Study completion
2027
First posted
Jun 22, 2020
Registry last updated
Oct 8, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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