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

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.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.
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 Names: glucophage

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp	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.	End of each 6 week intervention period
Flow-mediated Brachial Artery Dilation	Measure of endothelial function by brachial ultrasound of the percent dilation after 5 minutes of occlusion.	End of each 6 week intervention period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial Stiffness by PWV	Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec.	End of each 6 week intervention period
Arterial Stiffness by AI@75	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.	End of each 6 week intervention period
Mitochondrial Measures: Oxygen Consumption	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.	End of each 6 week intervention period
Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes	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.	End of each 6 week intervention period
Inflammatory Marker: hsCRP	hsCRP (mg/L) by Beckman Coulter assay	End of each 6 week intervention period
Heart Rate Variability	measure of autonomic function: ratio of fastest to slowest heart rate during valsalva maneuver	End of each 6 week intervention period
Continuous Glucose Monitor Measures of Mean Glucose	Mean Glucose & Glucose Standard Deviation (Glycemic Variability) by Dexcom CGM	Last Week of each 6 Week Intervention Period (over 7 days)
Continuous Glucose Monitor Measures of Hypoglycemia	Percent of time less than 70 mg/dL during the final week of each phase by Dexcom CGM.	Last Week of each 6 Week Intervention Period (over 7 days)
Metabolic Markers: Glucagon	Glucagon (pg/ml); baseline on AM of each phase final study visit.	End of each 6 week intervention period
Metabolic Markers: Glucose, Triglycerides, Cholesterol	Glucose (mg/dL), triglycerides (mg/dL), cholesterol (mg/dL) at baseline after each phase	End of each 6 week intervention period
Metabolic Markers: Fatty Acids	fatty acids (microeq/L) at baseline after each phase in the AM of the final visit	End of each 6 week intervention period
Metabolic Markers: Glycerol	glycerol (micromol/L) at baseline after each phase in the AM of the final phase visit	End of each 6 week intervention period
Metabolic Markers: Insulin	insulin (microIU/ml) at baseline after each phase in the AM of the final phase visit	End of each 6 week intervention period
Metabolic Markers: Lactate	lactate (mmol/L) at baseline after each phase in the AM of the final phase visit	End of each 6 week intervention period
Metabolic Markers: Adiponection	adiponection (microg/ml) at baseline after each phase in the AM of the final phase visit	End of each 6 week intervention period
Vascular Markers: Endothelin-1 (pg/ml)	endothelin-1 at baseline after each phase in the AM of the final phase visit by peninsula labs radioimmunoassay	End of each 6 week intervention period
In Vivo Mitochondrial Function: Ratio of the Amount of ATP Generated Per Unit of Oxygen Consumed	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	End of each 6 week intervention period
In Vivo Mitochondrial Function: Time Constants	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.	End of each 6 week intervention period
In Vivo Mitochondrial Function: QMax, VPCr	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.	End of each 6 week intervention period
In Vivo Mitochondrial Function: Oxidative Phosphorylation	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)	End of each 6 week intervention period
In Vivo Mitochondrial Function:AnGly	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.	End of each 6 week intervention period
Cardiac Function	Cardiac output	End of each 6 week intervention period

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: US Department of Veterans Affairs
• Investigators: Principal Investigator: Irene Schauer, MD, PhD, University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): March 24, 2017
• Study Completion (Actual): March 24, 2017

Study Registration Dates

• First Submitted: September 28, 2012
• First Submitted That Met QC Criteria: March 14, 2013
• First Posted (Estimate): March 19, 2013

Study Record Updates

• Last Update Posted (Actual): January 21, 2022
• Last Update Submitted That Met QC Criteria: December 21, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Diabetes; Insulin; Metformin; Vascular; Type 1; Vessels
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 11-0693