Neuromuscular Fatigue and Exercise Capacity in Patients With Type 2 Diabetes Mellitus and HFpEF

NCT06057623 | Completed

• 1 other identifier: Ics Maugeri CE 2756
• Study Type: observational
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

An important feature of patients with HFpEF is impaired exercise tolerance, resulting in worsening and reduced quality of life. Studies in the literature on patients with HFpEF suggest that the limited transport of oxygen to the muscles can be one factor leading to the early development of fatigue during physical activity and reduced effort tolerance. A recent study also shows that patients with HFpEF have an increased susceptibility to both central and peripheral fatigue, suggesting that neuromuscular fatigue may be one of the main mechanisms limiting exercise in this population. Type 2 diabetes mellitus (T2DM), which affects 90-95% of diabetic patients, is a comorbidity of particular interest in heart failure (HF). In T2DM, as in HF, some observed an altered energy metabolism of the muscle and a shift in the type of muscle fibers. Hyperglycemia influences neuromuscular function and appeared to be one of the major causes of oxidative stress by affecting the intrinsic properties of the muscle (mitochondrial activity and function, myofilaments) related to the expression of force. The impact of diabetes on neuromuscular function is also linked to long-term complications such as diabetic peripheral neuropathy involving impairment of motor nerve conduction and vascular complications. This opens up a rather complex picture suggesting that T2DM in patients with HF could contribute to a further decline in muscle strength by further reducing the aerobic capacity of these patients. It seems, there are currently no studies in the literature evaluating how much the coexistence of T2DM impacts neuromuscular fatigue and strength in patients with HF. Thus, the primary aim of this study will be to evaluate the differences in central and peripheral neuromuscular fatigue - determined by a submaximal exercise protocol with intermittent isometric contractions - in two groups of patients with heart failure with preserved ejection fraction with or without type 2 diabetes mellitus. Secondary outcomes will be related to the investigation of the differences in NO-mediated vascular function induced by a single passive movement of the leg, in the energy cost of walking, and in muscle oxygenation between the two groups.

Conditions

Diabetes Mellitus, Type 2; Heart Failure Preserved Ejection Fraction

Keywords

Heart failure preserved ejection fraction; Diabetes Mellitus, Type 2

Outcome Measures

Primary Outcomes (1)

• Change of the isometric force

  The change in maximal isometric force is a measure to estimate the central and peripheral fatigue. Assessment maximal isometric contractions (MVC) pre, at midway through the fatigue protocol, 10' post fatigue protocol and 30' after the fatigue protocol. Maximum force reduction expressed in Newtons will be analyzed. Subjects will be seated upright with back support. The hip and knee will be flexed to 90° and the force will be measured by a force transducer. Change in MCV will be calculated as the difference in percentage between the post-pre fatigue task, as follows: (MVCpost - MVCpre) / MVCpre \*100, and expressed as percentage.

  baseline and up to 1400 secs

Secondary Outcomes (9)

• Nitric oxide-mediated vasodilation

  Baseline

• Change in muscle oxygenation

  Up to 12 seconds

• Evaluation of the energy cost of walking

  Baseline

• Evaluation of Angle of the pennation of Vastus Lateralis

  Baseline

• Evaluation of the Volume of Quadriceps

  Baseline

Study Arms (2)

Group 1

\- Group 1: HFpEF patients with diabetes mellitus (HF-T2DM): patients with a diagnosis of diabetes mellitus in optimized drug therapy, documented by values of glycated hemoglobin (HbA1c) between 6% and 9%

Other: Evaluation of central and peripheral neuromuscular fatigue

Group 2

\- Group 2: HFpEF without diabetes mellitus (HF-NotT2DM): patients with HF in absence of diabetes evidenced by values of glycated hemoglobin (HbA1c) \< 6.0%

Other: Evaluation of central and peripheral neuromuscular fatigue

Interventions

Evaluation of central and peripheral neuromuscular fatigue OTHER

To define peripheral and central component of fatigue, the investigators will test, before, during and after the fatigue task, the force produced during a Maximal Voluntary Contraction (MVC) and the force produced by the electrically evoked Resting Twitch (RT) produced, at rest, 5 seconds after the MVC.

Group 1; Group 2

Eligibility Criteria

• Age: 65 Years - 80 Years
• Gender Eligibility Details: Because of the limited number of HFpEF females attending our Institute, we restricted the study to the male gender only.
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Old men, with diagnosis of HFpEF and in additional some of them with Diabetes Mellitus Type II

You may qualify if:

• Have a diagnosis of heart failure with preserved ejection fraction (\>50%, NYHA class II - III)
• Have an age between 65 and 80 years
• Be males
• Have at least one hospitalization for heart failure during the previous 10 years
• Have a diagnosis of diabetes for no more than 10 years at the time of cardiology examination

You may not qualify if:

• \. Unstable diabetes documented by HbA1c ≥ 9%
• \. Significant additional valvular heart diseases
• \. Unstable heart failure
• \. Presence of a pacemaker or implanted defibrillator (AICD)
• \. Changes in drug therapy in the previous three months because of clinical instability
• \. Body mass index (BMI) \> 35 and \< 20 kg/m2
• \. Orthopedic limitations that prevent the exercise
• \. Presence of diagnosis and signs and symptoms of diabetic neuropathy (intensified perception of pain, burning or cold sensation, tingling, pins, and needles, hypo-hypersensitivity to touch)
• \. Severe deconditioning (patient is confined to home) or vigorous physical activity (sports or similar activity, estimated as more than two hours/day of vigorous exercise)

Sponsors & Collaborators

• Istituti Clinici Scientifici Maugeri SpA: lead

Study Sites (1)

Istituti Clinici Scientifici Maugeri IRCCS

Lumezzane, Brescia, 25065, Italy

Location

Related Publications (2)

• Senefeld JW, Keenan KG, Ryan KS, D'Astice SE, Negro F, Hunter SK. Greater fatigability and motor unit discharge variability in human type 2 diabetes. Physiol Rep. 2020 Jul;8(13):e14503. doi: 10.14814/phy2.14503.

  PMID: 32633071 BACKGROUND

• Weavil JC, Thurston TS, Hureau TJ, Gifford JR, Kithas PA, Broxterman RM, Bledsoe AD, Nativi JN, Richardson RS, Amann M. Heart failure with preserved ejection fraction diminishes peripheral hemodynamics and accelerates exercise-induced neuromuscular fatigue. Am J Physiol Heart Circ Physiol. 2021 Jan 1;320(1):H338-H351. doi: 10.1152/ajpheart.00266.2020. Epub 2020 Nov 8.

  PMID: 33164549 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Heart Failure, Diastolic

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Heart Failure; Heart Diseases; Cardiovascular Diseases

Study Officials

• Mara Paneroni, PhD

  Istituti Clinici Scientifici Maugeri

  STUDY DIRECTOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Target Duration: 1 Day
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 21, 2023
• First Posted: September 28, 2023
• Study Start: June 15, 2023
• Primary Completion: December 31, 2024
• Study Completion: April 30, 2025
• Last Updated: July 30, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)