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

Type 1 Diabetes Clinical Trial

— T-St1M  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04449198
• Other study ID #: 1595933
• Status: Recruiting
• Phase: Early Phase 1
• Start date: October 14, 2020
• Est. completion date: July 1, 2025

Study information

• Verified date: July 2023
• Source: Augusta University
• Contact: Ryan A Harris, PhD, CEP
• Phone: 7067215998
• Email: ryharris[@]augusta.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: July 1, 2025
• Est. primary completion date: January 1, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Type 1 Diabetes

Intervention

Drug:
• Resveratrol
500 mg of oral trans-resveratrol twice daily (in the morning and evening) for 12-weeks

Other:
• Placebo
placebo for 12 weeks

Locations

Country	Name	City	State
United States	Augusta University/Georgia Prevention Institute/ Laboratory of Integrative and Exercise Physiology	Augusta	Georgia

Sponsors (1)

Lead Sponsor	Collaborator
Augusta University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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