Muscular Deficits of Diabetic Myopathy

Study Overview
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Brief Summary
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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: Is chronic hyperglycemia in type 1 and 2 diabetes associated with functional and structural deficits of skeletal muscles unrelated to the presence of neuropathy? Is obesity associated with functional and structural impairments of skeletal muscles unrelated to the presence of type 2 diabetes ? 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.

Official Title
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Understanding Muscular Deficits of Diabetic Myopathy

Conditions
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Diabetes Mellitus, Obesity, Chronic Hyperglycaemia, Weight Loss, Diabetic Myopathy, Sarcopenia

Intervention / Treatment
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* Drug: 6-months of medically assisted glycemic improvement
* Procedure: Bariatric surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Study 1: Age: 18-60 years BMI: 18.5 - 27, minimum weight = 50kg Chronic hyperglycemia: HbA1c of ≥ 70 mmol/mol with a duration of ≥ 2 months 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 - 27, 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 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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

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

What is the study measuring?
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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 |