Mechanisms of Fatigability With Diabetes

NCT04442451 | Recruiting DMC

• 2 other identifiers: HUM002553755R01AG077688-03
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

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.

Conditions

Pre-diabetes; Type 2 Diabetes

Keywords

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

Outcome Measures

Primary Outcomes (8)

• 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

Study Arms (2)

Control Exercise

EXPERIMENTAL

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

Blood Flow Restriction Exercise

EXPERIMENTAL

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

Interventions

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.

Control Exercise

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.

Blood Flow Restriction Exercise

Eligibility Criteria

• Age: 30 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 \[elevated glycosylated hemoglobin (HbA1c) \>6.5% and \<10%\]

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (1)

University of Michigan

Ann Arbor, Michigan, 48109, United States

RECRUITING

MeSH Terms

Conditions

Glucose Intolerance; Diabetes Mellitus, Type 2; Diabetes Mellitus

Interventions

Blood Flow Restriction Therapy

Condition Hierarchy (Ancestors)

Hyperglycemia; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Exercise Therapy; Rehabilitation; Aftercare; Continuity of Patient Care; Patient Care; Therapeutics; Physical Therapy Modalities

Central Study Contacts

Sandra Hunter, PhD

CONTACT

(734) 647-9819; sandrahu@umich.edu

Sarah Lessila, MSc

CONTACT

slessila@umich.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Francie Kraker Goodridge Collegiate Professor of Kinesiology and Professor of Kinesiology, School of Kinesiology

Model Details: 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).

Study Record Dates

• First Submitted: June 18, 2020
• First Posted: June 22, 2020
• Study Start: September 1, 2022
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): August 31, 2027
• Last Updated: October 8, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)