| Outcome Measures: |
Primary: 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: 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: 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
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