Type 1 Diabetes, Endothelin, and Skeletal Muscle Mitochondrial Dysfunction: The Role of Sirtuin-1

Study Overview
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Brief Summary
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The proposed study is designed to test the hypothesis that treatment of resveratrol for 12 weeks will improve both endothelin-B receptor (aim 1) and skeletal muscle mitochondrial function (aim 2) in people with type 1 diabetes.

Detailed Description
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Preliminary data from the investigators' laboratory demonstrate a negative relationship between hemoglobin A1c (HbA1c) and ETBR function, supporting ETBR may be dysfunctional in the presence of T1D. Using near infrared spectroscopy (NIRS) to non-invasively assess muscle function, the investigators have also observed reduced skeletal muscle mitochondrial function in people with T1D compared to healthy controls. In addition, reduced circulating Sirt1 is associated with both ETBR and skeletal muscle mitochondrial dysfunction in the general population. For the current application, the investigators propose to utilize intradermal microdialysis and NIRS as unique, novel, and minimally invasive methods to investigate ETBR and skeletal muscle mitochondrial function, respectively, in people with T1D. Accordingly, the central hypothesis is that increasing circulating Sirt1 with oral supplementation of resveratrol will improve both ETBR function and mitochondrial skeletal muscle function, reducing overall CVD risk (Figure 1). The investigators will test this hypothesis with the following specific aims: Aim 1: To test the hypothesis that an increase in Sirt1 will improve ETBR function in people with T1D. The investigators will evaluate ETBR function and circulating Sirt1 at baseline and after a 12-week treatment of resveratrol or placebo. Based on preliminary data, the investigators predict that people with T1D will have ETBR dysfunction compared to controls. In addition, the investigators predict that increasing Sirt1 following resveratrol treatment will improve ETBR function, whereas no change will occur with placebo. Aim 2: To test the hypothesis that an increase in Sirt1 will improve skeletal muscle mitochondrial function and lower HbA1c in people with T1D. A non-invasive assessment of skeletal muscle function will be performed on people with T1D before and after 12-weeks of treatment with resveratrol or placebo. Compared to controls, the investigators predict that people with T1D will have skeletal muscle dysfunction. Following 12 weeks of resveratrol, the investigators predict that the increase in circulating Sirt1 will improve skeletal muscle function. Additionally, the investigators predict the improved skeletal muscle function will contribute to a subsequent decrease in HbA1c in people with T1D.

Official Title
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Type 1 Diabetes, Endothelin, and Skeletal Muscle Mitochondrial Dysfunction: The Role of Sirtuin-1

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Resveratrol
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and premenopausal women All races Clinical diagnosis of insulin-dependent type 1 diabetes (patients only) Exclusion Criteria: Clinical diagnosis of hepatic, cardiovascular, or renal disease Uncontrolled diabetes (HbA1C >12%) Diabetic complications (i.e. neuropathy) Uncontrolled hypertension (>140/90 mm Hg on therapy) Pregnancy Use of vasoactive medications

Ages Eligible for Study
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Minimum Age: 18 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Individuals with type 1 diabetes<br>Individuals with type 1 diabetes will be randomly assigned to 1 of the 2 interventions (Resveratrol or placebo) | Drug: Resveratrol<br>* 500 mg of oral trans-resveratrol twice daily (in the morning and evening) for 12-weeks<br>Other: Placebo<br>* placebo for 12 weeks<br>|
| No Intervention: Healthy Controls<br>Healthy individuals who participate will receive no intervention and serve as controls. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in AUC for ET-1 + BQ-123 | Change in Area Under the Curve (AUC) for Cutaneous Vascular Conductance (CVC) in response to co-perfusion of ET-1 + BQ-123 at 12 weeks. Measured using intradermal microdialysis technique in conjunction with Laser Speckle Contrast Imaging (Moor FLPI-2) and beat-by-beat blood pressure monitoring (Finapres NOVA). | Measure taken at Baseline and post 12 weeks | 
| Skeletal Muscle Mitochondrial Function | Change in Skeletal Muscle Mitochondrial Function at 12 weeks. Measured using Near Infrared Spectroscopy (NIRS). Values are an index of phosphocreatine recovery expressed as a rate constant (min-1) | Measure taken at Baseline and post 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Percentage Flow-Mediated Dilation (FMD) | Change in Percentage FMD at 12 weeks. Measured via ultrasound in conjunction with edge detection software. Expressed as % | Measure taken at Baseline and post 12 weeks | 
| Change in Pulse Wave Velocity (PWV) | Change in PWV at 12 weeks. Measured by Shygmocor Xcel in m/s. | Measure taken at Baseline and post 12 weeks | 
| Change in Post Occlusive Reactive Hyperemia (PORH) | Change in PORH at 12 weeks. Measured by Laser Speckle Contrast Imager (Moor FLPI-2) in perfusion units (PU). Represents the maximal dilatory response in the microcirculation post 5 minute occlusion. | Baseline and post 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, heart disease, muscle function, blood vessels