Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes
- Registration Number
- NCT01813929
- Lead Sponsor
- University of Colorado, Denver
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 23
- 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.
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Any comorbid condition associated with:
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inflammation,
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insulin Resistance, or
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dyslipidemia including:
- cancer,
- heart failure,
- active or end stage liver disease,
- kidney disease, or
- rheumatological disease;
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Tobacco use;
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Pregnancy or women who are breastfeeding;
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Steroid use;
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Scheduled strenuous physical activity >3 days a week;
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Angina, known CAD, or any other cardiovascular or pulmonary disease;
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A history of COPD or asthma;
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Presence of systolic blood pressure >190 at rest or >250 with exercise, or diastolic pressure >95 at rest or >105 with exercise;
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Untreated thyroid disease;
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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;
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Severe Proliferative retinopathy;
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Niacin treatment;
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Administration of experimental agent for T1D within 30 days prior to screening;
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Recent (prior 6 months) or current metformin or thiazolidenedione use;
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Hypoglycemia unawareness or recurrent severe hypoglycemia (no symptoms of hypoglycemia with FSBS<40 and episodes of this severity >1 per week);
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Weight instability (weight change >5% in last 6 months);
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History of any organ transplant, including islet cell transplant;
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Current or prior infection with HIV, hepatitis B or hepatitis C or hepatic -insufficiency (AST or ALT > 2x the upper limits of normal);
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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;
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History of substance abuse within the 12 months prior to screening.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Metformin Metformin - Placebo Placebo -
- Primary Outcome Measures
Name Time Method Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp 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.
Flow-mediated Brachial Artery Dilation 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
Name Time Method Arterial Stiffness by PWV End of each 6 week intervention period Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec.
Continuous Glucose Monitor Measures of Hypoglycemia 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.
Metabolic Markers: Glucose, Triglycerides, Cholesterol End of each 6 week intervention period Glucose (mg/dL), triglycerides (mg/dL), cholesterol (mg/dL) at baseline after each phase
Metabolic Markers: Lactate End of each 6 week intervention period lactate (mmol/L) at baseline after each phase in the AM of the final phase visit
Heart Rate Variability End of each 6 week intervention period measure of autonomic function: ratio of fastest to slowest heart rate during valsalva maneuver
Arterial Stiffness by AI@75 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.
Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes 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.
Inflammatory Marker: hsCRP End of each 6 week intervention period hsCRP (mg/L) by Beckman Coulter assay
Metabolic Markers: Fatty Acids End of each 6 week intervention period fatty acids (microeq/L) at baseline after each phase in the AM of the final visit
Metabolic Markers: Glycerol End of each 6 week intervention period glycerol (micromol/L) at baseline after each phase in the AM of the final phase visit
Metabolic Markers: Insulin End of each 6 week intervention period insulin (microIU/ml) at baseline after each phase in the AM of the final phase visit
Vascular Markers: Endothelin-1 (pg/ml) 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
In Vivo Mitochondrial Function: Ratio of the Amount of ATP Generated Per Unit of Oxygen Consumed 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
Mitochondrial Measures: Oxygen Consumption 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.Continuous Glucose Monitor Measures of Mean Glucose Last Week of each 6 Week Intervention Period (over 7 days) Mean Glucose \& Glucose Standard Deviation (Glycemic Variability) by Dexcom CGM
Metabolic Markers: Glucagon End of each 6 week intervention period Glucagon (pg/ml); baseline on AM of each phase final study visit.
Metabolic Markers: Adiponection End of each 6 week intervention period adiponection (microg/ml) at baseline after each phase in the AM of the final phase visit
In Vivo Mitochondrial Function: Time Constants 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.
In Vivo Mitochondrial Function: QMax, VPCr 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.In Vivo Mitochondrial Function: Oxidative Phosphorylation 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)
In Vivo Mitochondrial Function:AnGly 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.
Cardiac Function End of each 6 week intervention period Cardiac output
Trial Locations
- Locations (1)
University of Colorado Denver
🇺🇸Aurora, Colorado, United States