Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes (MeT1)

• ClinicalTrials.gov Identifier: NCT01813929
• Recruitment Status: Completed
• First Posted: March 19, 2013
• Results First Posted: January 21, 2022
• Last Update Posted: January 21, 2022
• Sponsor: University of Colorado, Denver
• Collaborator: US Department of Veterans Affairs
• Information provided by (Responsible Party): University of Colorado, Denver

Study Description

Brief Summary:

Insulin resistance (IR) is an important contributor to increased cardiovascular disease risk in type 1 diabetes (T1D). The purpose of this study is to measure the effect of metformin on insulin sensitivity, vascular function and compliance, and mitochondrial function in T1D. The long term goal is to identify novel non-glycemic approaches to managing cardiovascular disease risk in T1D. The results of this study may validate a novel approach to T1D treatment that could significantly improve current management of cardiovascular disease risk in this high risk population.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes	Drug: Metformin; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes
• Study Start Date: June 2011
• Actual Primary Completion Date: March 24, 2017
• Actual Study Completion Date: March 24, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Metformin	Drug: Metformin; Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.; Other Name: glucophage
Placebo Comparator: Placebo	Drug: Placebo; Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.

Outcome Measures

Primary Outcome Measures :

1. Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp [ Time Frame: End of each 6 week intervention period ]
   Determine the effect of metformin on insulin sensitivity in T1D. Reported measure is glucose infusion rate during hyperinsulinemic euglycemic clamp normalized to total body weight. For this measure, insulin was infused at 40 mU/m2 surface area. Blood sugar wass checked every 5 minutes and glucose infusion adjusted to maintain glucose level at 90 mg/dL for 2 hours. The glucose infusion rate for the final 30 minutes is reported as GIR (aka M-value or glucose disposal rate) in mg glucose/kg*min. A higher value corresponds to greater sensitivity to insulin. There is no strictly defined normal range.
2. Flow-mediated Brachial Artery Dilation [ Time Frame: End of each 6 week intervention period ]
   Measure of endothelial function by brachial ultrasound of the percent dilation after 5 minutes of occlusion.

Secondary Outcome Measures :

1. Arterial Stiffness by PWV [ Time Frame: End of each 6 week intervention period ]
   Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec.
2. Arterial Stiffness by AI@75 [ Time Frame: End of each 6 week intervention period ]
   Augmentation index by Sphygmacor is a measure of aortic arterial stiffness. AI@75 is the ratio of augmented pressure/pulse pressure adjusted to a heart rate of 75.
3. Mitochondrial Measures: Oxygen Consumption [ Time Frame: End of each 6 week intervention period ]

   Oxygen consumption rate with various substrates and max uncoupled O2 consumption.

   Measure is performed on permeabilized muscle fibers from biopsy tissue from the vastus lateralis using the Oroboros OxygraphO2k high resolution respirometer. State 3 is full coupled oxygen flux using PMG or PMGS (pyruvate, malate, glutamate, +/- succinate) or OCMS (octanyl carnitine, malate, +/- succinate) as substrates. state 4 is after addition of oligomycin to inhibit the ATP synthase and thus corresponds to the maximum leak state where O2 consumption is limited by the buildup of the proton gradient and can only proceed as fast as the protons can leak back across the membrane. FCCP is added as an uncoupler, allowing free leakage of protons across the inner membrane, and thus measures maximum possible O2 flux. There are no defined normal ranges, but higher state 3 and uncoupled flux indicate better mitochondrial function, while state 4 is needed to correct state 3 to the fully coupled flux.

4. Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes [ Time Frame: End of each 6 week intervention period ]
   Mito content by Western Blotting of electron transport chain complexes I, II, III, and V. complex 1 utilizes NADH from pyruvate/malate/glutamate while complex II utilizes FADH from succinate. complex III is the cytochrome c reductase while complex V is the ATP synthase.
5. Inflammatory Marker: hsCRP [ Time Frame: End of each 6 week intervention period ]
   hsCRP (mg/L) by Beckman Coulter assay
6. Heart Rate Variability [ Time Frame: End of each 6 week intervention period ]
   measure of autonomic function: ratio of fastest to slowest heart rate during valsalva maneuver
7. Continuous Glucose Monitor Measures of Mean Glucose [ Time Frame: Last Week of each 6 Week Intervention Period (over 7 days) ]
   Mean Glucose & Glucose Standard Deviation (Glycemic Variability) by Dexcom CGM
8. Continuous Glucose Monitor Measures of Hypoglycemia [ Time Frame: Last Week of each 6 Week Intervention Period (over 7 days) ]
   Percent of time less than 70 mg/dL during the final week of each phase by Dexcom CGM.
9. Metabolic Markers: Glucagon [ Time Frame: End of each 6 week intervention period ]
   Glucagon (pg/ml); baseline on AM of each phase final study visit.
10. Metabolic Markers: Glucose, Triglycerides, Cholesterol [ Time Frame: End of each 6 week intervention period ]
    Glucose (mg/dL), triglycerides (mg/dL), cholesterol (mg/dL) at baseline after each phase
11. Metabolic Markers: Fatty Acids [ Time Frame: End of each 6 week intervention period ]
    fatty acids (microeq/L) at baseline after each phase in the AM of the final visit
12. Metabolic Markers: Glycerol [ Time Frame: End of each 6 week intervention period ]
    glycerol (micromol/L) at baseline after each phase in the AM of the final phase visit
13. Metabolic Markers: Insulin [ Time Frame: End of each 6 week intervention period ]
    insulin (microIU/ml) at baseline after each phase in the AM of the final phase visit
14. Metabolic Markers: Lactate [ Time Frame: End of each 6 week intervention period ]
    lactate (mmol/L) at baseline after each phase in the AM of the final phase visit
15. Metabolic Markers: Adiponection [ Time Frame: End of each 6 week intervention period ]
    adiponection (microg/ml) at baseline after each phase in the AM of the final phase visit
16. Vascular Markers: Endothelin-1 (pg/ml) [ Time Frame: End of each 6 week intervention period ]
    endothelin-1 at baseline after each phase in the AM of the final phase visit by peninsula labs radioimmunoassay
17. In Vivo Mitochondrial Function: Ratio of the Amount of ATP Generated Per Unit of Oxygen Consumed [ Time Frame: End of each 6 week intervention period ]
    Measured by 31P-mass spec. This ratio measures mitochondrial efficiency. The higher the ratio, the more efficiently the individual converts metabolic substrates into ATP, with the ATP then available for energy-demanding cellular processes such as protein synthesis and biomass production
18. In Vivo Mitochondrial Function: Time Constants [ Time Frame: End of each 6 week intervention period ]
    Measured by 31P-mass spec. ADP time constant and phosphocreatine time constant. ADP time constant is a measure of the time required to convert ADP → ATP and is a measure of muscle mitochondrial health (energy metabolism). A faster recovery is a better outcome; a slower recovery is a worse outcome. Similarly for phosphocreatine.
19. In Vivo Mitochondrial Function: QMax, VPCr [ Time Frame: End of each 6 week intervention period ]

    Measured by 31P-mass spec. For each measure, a higher value indicates better mitochondrial function. All re calculated from multiple measures from the MRS spectra. These are relatively new research measures and normal values are not known or generally accepted.

    • QMax is theoretical maximum activity.
    • VPCr measures the rate at which PCr is regenerated.
20. In Vivo Mitochondrial Function: Oxidative Phosphorylation [ Time Frame: End of each 6 week intervention period ]
    Measured by 31P-mass spec. A higher value indicates better mitochondrial function. All re calculated from multiple measures from the MRS spectra. These are relatively new research measures and normal values are not known or generally accepted. Oxidative Phosphorylation measures the rate at which electron transport activity generates phosphorylated energy sources (ATP and PCr)
21. In Vivo Mitochondrial Function:AnGly [ Time Frame: End of each 6 week intervention period ]
    Measured by 31P-mass spec. Anaerobic glycolysis measures the amount of anaerobic ATP generation for energy. It is generally felt that a higher value here reflects impaired mitochondrial function necessitating greater reliance on anaerobic metabolism.
22. Cardiac Function [ Time Frame: End of each 6 week intervention period ]
    Cardiac output

Other Outcome Measures:

1. Vascular Markers: PAI-1 [ Time Frame: End of each 6 week intervention period ]
   PAI-1 exploratory thromobotic marker.
2. Vascular Markers: Exploratory [ Time Frame: End of each 6 week intervention period ]
   ICAM
3. Oxidative Stress Markers [ Time Frame: End of each 6 week intervention period ]
   TBARs, GSSG:GSH ratio
4. Mitochondrial Measures: Oxidant Generation [ Time Frame: End of each 6 week intervention period ]
   oxidant generation
5. Inflammatory Markers: Exploratory [ Time Frame: End of each 6 week intervention period ]
   IL6, TNF alpha
6. Mitochondrial Oxidant Generation [ Time Frame: after each 6 week intervention ]
   exploratory measure looking at H2O2 production. not performed due to equipment not available.

Eligibility Criteria

• Ages Eligible for Study: 25 Years to 59 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age 20-59 years of age,
• Type 1 diabetes based on antibody-positivity, rapid persistent conversion to insulin requirement after diagnosis, absent C-peptide, or DKA at diagnosis, or a clinical course consistent with T1D,
• HbA1c 6.0 - 9.5, and
• Willing and able to commit to two 6 week-long periods of blinded medication followed by hyperinsulinemic euglycemic clamp, vascular testing, and muscle biopsies.

Exclusion Criteria:

• Any comorbid condition associated with:

  • inflammation,
  • insulin Resistance, or

  • dyslipidemia including:

    1. cancer,
    2. heart failure,
    3. active or end stage liver disease,
    4. kidney disease, or
    5. rheumatological disease;
• Tobacco use;
• Pregnancy or women who are breastfeeding;
• Steroid use;
• Scheduled strenuous physical activity >3 days a week;
• Angina, known CAD, or any other cardiovascular or pulmonary disease;
• A history of COPD or asthma;
• Presence of systolic blood pressure >190 at rest or >250 with exercise, or diastolic pressure >95 at rest or >105 with exercise;
• Untreated thyroid disease;
• Proteinuria (urine protein >200 mg/dl) or a creatinine > 1.5 mg/dl (males) or 1.4 mg/dL (females), suggestive of severe renal disease;
• Severe Proliferative retinopathy;
• Niacin treatment;
• Administration of experimental agent for T1D within 30 days prior to screening;
• Recent (prior 6 months) or current metformin or thiazolidenedione use;
• Hypoglycemia unawareness or recurrent severe hypoglycemia (no symptoms of hypoglycemia with FSBS<40 and episodes of this severity >1 per week);
• Weight instability (weight change >5% in last 6 months);
• History of any organ transplant, including islet cell transplant;
• Current or prior infection with HIV, hepatitis B or hepatitis C or hepatic -insufficiency (AST or ALT > 2x the upper limits of normal);
• Any condition, medical or otherwise that would, in the opinion of the investigator, prevent complete participation in the study, or that would pose a significant hazard to the subject;
• History of substance abuse within the 12 months prior to screening.

Contacts and Locations

Locations

United States, Colorado

University of Colorado Denver

Aurora, Colorado, United States, 80045

Sponsors and Collaborators

University of Colorado, Denver

US Department of Veterans Affairs

Investigators

• Principal Investigator: Irene Schauer, MD, PhD; University of Colorado, Denver

  Study Documents (Full-Text)

Documents provided by University of Colorado, Denver:

Study Protocol and Statistical Analysis Plan  [PDF] June 10, 2015

More Information

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01813929
• Other Study ID Numbers: 11-0693
• First Posted: March 19, 2013
• Results First Posted: January 21, 2022
• Last Update Posted: January 21, 2022
• Last Verified: December 2021

Keywords provided by University of Colorado, Denver:

Diabetes; Insulin; Metformin; Vascular; Vessels; Type 1

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Metformin; Hypoglycemic Agents; Physiological Effects of Drugs