Investigating Muscle Failure in Diabetic Myopathy

Understanding Muscular Deficits of Diabetic Myopathy

The goal of this observational study is to assess if diabetes and obesity are independently related to functional and structural muscle deficits, and how muscular deficits relate to metabolic properties of diabetes and obesity. All studies will include clinical muscle strength and contractile examinations, functional tests, and MR imaging and spectroscopy techniques.

The main questions this project aims to answer are:

1. Is chronic hyperglycemia in type 1 and 2 diabetes associated with functional and structural deficits of skeletal muscles unrelated to the presence of neuropathy?
2. Is obesity associated with functional and structural impairments of skeletal muscles unrelated to the presence of type 2 diabetes ?
3. Does weight loss improve muscle metabolic flexibility and economy and modify skeletal muscle function and structure in obese subjects with and without type 2 diabetes?

The project will include three studies, intended to answer the hypotheses listed above:

Study 1: Evaluation of functional and structural muscular deficits of diabetic myopathy in relation to prolonged hyperglycemia prior to and 6 months following glycemic improvement in patients with type 1 and 2 diabetes

Study 2: Functional and structural muscular deficits in severely obese subjects with and without type 2 diabetes prior to assisted weight loss.

Study 3: Changes in functional and structural muscle properties following assisted weight loss in severely obese subjects with and without type 2 diabetes - a 1-year follow-up study.

Study Overview

• Status: Active, not recruiting
• Conditions: Obesity; Diabetes Mellitus; Weight Loss; Sarcopenia; Chronic Hyperglycaemia; Diabetic Myopathy
• Intervention / Treatment: Drug: 6-months of medically assisted glycemic improvement; Procedure: Bariatric surgery

• Study Type: Observational
• Enrollment (Estimated): 108

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8000
    • Aarhus University Hospital, Denmark

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The study population consist of participants with type 1 diabetes (study 1) and participants with obesity and/or type 2 diabetes (study 1 and 2). Participants will be included at the Dept. of Endocrinology and Steno Diabetes Center Aarhus, Aarhus University Hospital, Denmark. Healthy control participants will be recruited by advertising in local media and at dedicated participant recruitment homepages.

Description

Inclusion Criteria:

Study 1:

• Age: 18-60 years
• BMI: 18.5 - 39, minimum weight = 50kg
• Chronic hyperglycemia: HbA1c of ≥ 70 mmol/mol with a duration of ≥ 2 months prior to enrollment
• Physical activity: Less than 3 x 60 min of structured physical activity per week

Study 2 & 3:

• Age: 25-60 years
• BMI: ≥ 35
• Physical activity: Less than 3 x 60 min of structured physical activity per week

Healthy Control Participants:

• Age: 18-60 years
• BMI: 18.5 - 30, minimum weight = 50kg
• Physical activity: Less than 3 x 60 min of structured physical activity per week

Exclusion Criteria:

Study 1, 2, 3 and healthy controls:

• Diabetic neuropathy with expected motor deficits
• Uncontrolled cardiovascular or pulmonary disease, peripheral vascular disease, osteoarthropathy of the lower extremity, or any neurological og rheumatological disease which may affect muscle function, as well as any other disease that may effect ones ability to perform physical activity.
• Any Magnetic Resonance contraindications
• Any condition that by the principal investigator is expected to affect the participants ability to execute the study elements

Specifically for healthy control participants:

• The presence of diabetes or pre-diabetes (HbA1c ≥42 mmol/mol)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Non-obese participants with dysregulated type 1 diabetes	Drug: 6-months of medically assisted glycemic improvement; Administrated by the clinic at Steno Diabetes Center, Aarhus, Denmark
Non-obese participants with dysregulated type 2 diabetes	Drug: 6-months of medically assisted glycemic improvement; Administrated by the clinic at Steno Diabetes Center, Aarhus, Denmark
Obese participants with type 2 diabetes	Procedure: Bariatric surgery; Participants are examined prior to and 1 year following bariatric surgery in the Central Region, Denmark
Obese participants without type 2 diabetes	Procedure: Bariatric surgery; Participants are examined prior to and 1 year following bariatric surgery in the Central Region, Denmark
Healthy control participants

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline: Evaluating the presence of sarcopenia in relation to the presence of hyperglycemia and/or obesity	The presence of sarcopenia is assessed based on recommended methods including measures of muscle strength (Biodex Dynamometer), muscle quantity and quality (MRI), and physical performance tests.	The prevalence of sarcopenia in participants with diabetes and hyperglycemia (study 1) or obesity (study 2) as compared to healthy control participants at baseline
Baseline: Skeletal muscle Force-velocity assessment in relation to the presence of hyperglycemia and/or obesity	Assessed by isokinetic knee-extension and dorsal flexion on a Biodex Dynamometer at increasing angular-velocities	The force-velocity relationship in participants with diabetes and hyperglycemia (study 1) or obesity (study 2) as compared to healthy control participants at baseline
Baseline: Assessment of skeletal muscle fatigue in relation to the presence of hyperglycemia and/or obesity	Assessed by a fatiguing isotonic protocol for knee-extension and dorsal flexion on a Biodex Dynamometer including twitch-parameters of knee-extensors	Fatigue in participants with diabetes and hyperglycemia (study 1) or obesity (study 2) as compared to healthy control participants at baseline
Changes in skeletal muscle force-velocity relationship with weight-loss or glycemic improvement		Change from baseline to follow-up at an average of 6 months for study 1 and 12 months for study 3
Changes in skeletal muscle fatigue in relation to weight-loss or glycemic improvement		Change from baseline to follow-up at an average of 6 months for study 1 and 12 months for study 3
Changes in parameters defining sarcopenia in relation to weight-loss or glycemic improvement		Change from baseline to follow-up at an average of 6 months for study 1 and 12 months for study 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
31P MRS: Skeletal muscle bioenergetics and metabolic economy	Assessed by phosphorus magnetic resonance spectroscopy (31P MRS) performed during an isotonic fatiguing exercise in a 3T MR-scanner	Bioenergetics and metabolic economy in participants with diabetes and hyperglycemia (study 1) or obesity (study 2) as compared to healthy control participants at baseline
31P MRS: Changes of skeletal muscle bioenergetics and metabolic economy in relation to weight-loss or glycemic improvement	Assessed by phosphorus magnetic resonance spectroscopy (31P MRS) performed during an isotonic fatiguing exercise in a 3T MR-scanner	Change from baseline to follow-up at an average of 6 months for study 1 and 12 months for study 3
ENG assessment of neuropathic changes	ENG is assessed in the Sural, Tibial and Peroneal nerve	Change from baseline to follow-up at an average of 6 months for study 1 and 12 months for study 3
Correlation analyses of primary measures with metabolic parameters including insulin resistance, HbA1c, metabolic economy, bioenergetics, and low-grade systemic inflammation (hs-CRP)		Change from baseline to follow-up at an average of 6 months for study 1 and 12 months for study 3

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
EMG assessment of myopathic changes	Will be assessed in knee extensors and/or dorsal flexors on a subgroup of participants demonstrating significant fatigue during primary measures	Change from baseline to follow-up at an average of 6 months for study 1 and 12 months for study 3

Collaborators and Investigators

• Sponsor: University of Aarhus
• Investigators: Principal Investigator: Anders Stouge, MD, PhD-student, Aarhus University, Aarhus University Hospital, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2022
• Primary Completion (Estimated): September 30, 2025
• Study Completion (Estimated): December 30, 2025

Study Registration Dates

• First Submitted: January 3, 2023
• First Submitted That Met QC Criteria: January 5, 2023
• First Posted (Actual): January 17, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 26, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Neuromuscular Diseases; Metabolic Diseases; Body Weight; Body Weight Changes; Glucose Metabolism Disorders; Muscular Atrophy; Atrophy; Weight Loss; Muscular Diseases; Hyperglycemia; Sarcopenia
• Other Study ID Numbers: DM2021AS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD data that underlies results in a publication
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No