Type 1 Diabetes
Conditions
Keywords
Diabetes, Insulin, Metformin, Vascular, Vessels, Type 1
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.
Interventions
DRUGMetformin
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.
DRUGPlacebo
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.
Sponsors
US Department of Veterans Affairs
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
25 Years to 59 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| 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. |
| 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: 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. |
| 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 |
| Heart Rate Variability | End of each 6 week intervention period | measure of autonomic function: ratio of fastest to slowest heart rate during valsalva maneuver |
| 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 |
| 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: Glucagon | End of each 6 week intervention period | Glucagon (pg/ml); baseline on AM of each phase final study visit. |
| 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 |
| 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 |
| 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 |
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mitochondrial Measures: Oxidant Generation | End of each 6 week intervention period | oxidant generation |
| Inflammatory Markers: Exploratory | End of each 6 week intervention period | IL6, TNF alpha |
| Mitochondrial Oxidant Generation | after each 6 week intervention | exploratory measure looking at H2O2 production. not performed due to equipment not available. |
| Vascular Markers: PAI-1 | End of each 6 week intervention period | PAI-1 exploratory thromobotic marker. |
| Oxidative Stress Markers | End of each 6 week intervention period | TBARs, GSSG:GSH ratio |
| Vascular Markers: Exploratory | End of each 6 week intervention period | ICAM |
Countries
United States
Participant flow
Pre-assignment details
3 participants screen failed before starting the study. 3 more participants withdrew after randomization, but before starting the study.
Participants by arm
| Arm | Count |
|---|---|
| Metformin, Then Placebo 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.
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. | 5 |
| Placebo, Then Metformin 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.
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. | 12 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Metformin, Then Placebo | Total | Placebo, Then Metformin |
|---|---|---|---|
| Age, Continuous | 43.0 years STANDARD_DEVIATION 14.4 | 43.2 years STANDARD_DEVIATION 12 | 43.3 years STANDARD_DEVIATION 11.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 15 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 17 Participants | 12 Participants |
| Region of Enrollment United States | 5 participants | 17 participants | 12 participants |
| Sex: Female, Male Female | 4 Participants | 9 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 8 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 17 |
| other Total, other adverse events | 0 / 16 | 0 / 17 |
| serious Total, serious adverse events | 0 / 16 | 0 / 17 |
Outcome results
Primary
Flow-mediated Brachial Artery Dilation
Measure of endothelial function by brachial ultrasound of the percent dilation after 5 minutes of occlusion.
Time frame: End of each 6 week intervention period
Population: Not completed on last subjects -futility, concern re reliability, and difficulty getting US images analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Flow-mediated Brachial Artery Dilation | 8.19 percent change in BA diameter | Standard Deviation 3.85 |
| Placebo | Flow-mediated Brachial Artery Dilation | 7.45 percent change in BA diameter | Standard Deviation 5.86 |
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.
Time frame: End of each 6 week intervention period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp | 3.27 mg/kg/min | Standard Deviation 1.51 |
| Placebo | Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp | 3.46 mg/kg/min | Standard Deviation 2.15 |
Secondary
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.
Time frame: End of each 6 week intervention period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Arterial Stiffness by AI@75 | 15.89 ratio | Standard Deviation 9.08 |
| Placebo | Arterial Stiffness by AI@75 | 14.96 ratio | Standard Deviation 12.48 |
Secondary
Arterial Stiffness by PWV
Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec.
Time frame: End of each 6 week intervention period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Arterial Stiffness by PWV | 8.64 m/sec | Standard Deviation 2.76 |
| Placebo | Arterial Stiffness by PWV | 8.56 m/sec | Standard Deviation 3.02 |
Secondary
Cardiac Function
Cardiac output
Time frame: End of each 6 week intervention period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Cardiac Function | 5.52 L/min | Standard Deviation 0.76 |
| Placebo | Cardiac Function | 4.92 L/min | Standard Deviation 0.62 |
Secondary
Continuous Glucose Monitor Measures of Hypoglycemia
Percent of time less than 70 mg/dL during the final week of each phase by Dexcom CGM.
Time frame: Last Week of each 6 Week Intervention Period (over 7 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Continuous Glucose Monitor Measures of Hypoglycemia | 8.4 percentage of time | Standard Deviation 10.7 |
| Placebo | Continuous Glucose Monitor Measures of Hypoglycemia | 7.9 percentage of time | Standard Deviation 6.9 |
Secondary
Continuous Glucose Monitor Measures of Mean Glucose
Mean Glucose & Glucose Standard Deviation (Glycemic Variability) by Dexcom CGM
Time frame: Last Week of each 6 Week Intervention Period (over 7 days)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin | Continuous Glucose Monitor Measures of Mean Glucose | Mean 7 Day Glucose | 162 mg/dL | Standard Deviation 35 |
| Metformin | Continuous Glucose Monitor Measures of Mean Glucose | Glucose Standard Deviation (variability in glucoses throughout the 7 day period) | 64 mg/dL | Standard Deviation 14 |
| Placebo | Continuous Glucose Monitor Measures of Mean Glucose | Mean 7 Day Glucose | 163 mg/dL | Standard Deviation 26 |
| Placebo | Continuous Glucose Monitor Measures of Mean Glucose | Glucose Standard Deviation (variability in glucoses throughout the 7 day period) | 68 mg/dL | Standard Deviation 21 |
Secondary
Heart Rate Variability
measure of autonomic function: ratio of fastest to slowest heart rate during valsalva maneuver
Time frame: End of each 6 week intervention period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Heart Rate Variability | 1.55 ratio | Standard Deviation 0.34 |
| Placebo | Heart Rate Variability | 1.42 ratio | Standard Deviation 0.18 |
Secondary
Inflammatory Marker: hsCRP
hsCRP (mg/L) by Beckman Coulter assay
Time frame: End of each 6 week intervention period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Inflammatory Marker: hsCRP | 2.13 mg/L | Standard Deviation 2.29 |
| Placebo | Inflammatory Marker: hsCRP | 2.95 mg/L | Standard Deviation 2.75 |
Secondary
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.
Time frame: End of each 6 week intervention period
Population: One placebo subject out of range for AnGly
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | In Vivo Mitochondrial Function:AnGly | 0.22 mmol/L/s | Standard Deviation 0.15 |
| Placebo | In Vivo Mitochondrial Function:AnGly | 0.29 mmol/L/s | Standard Deviation 0.21 |
Secondary
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)
Time frame: End of each 6 week intervention period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | In Vivo Mitochondrial Function: Oxidative Phosphorylation | 0.19 mmol/L/s | Standard Deviation 0.07 |
| Placebo | In Vivo Mitochondrial Function: Oxidative Phosphorylation | 0.13 mmol/L/s | Standard Deviation 0.06 |
Secondary
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.
Time frame: End of each 6 week intervention period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin | In Vivo Mitochondrial Function: QMax, VPCr | QMax | 0.42 mmoles/sec | Standard Deviation 0.14 |
| Metformin | In Vivo Mitochondrial Function: QMax, VPCr | VPCr | 0.24 mmoles/sec | Standard Deviation 0.07 |
| Placebo | In Vivo Mitochondrial Function: QMax, VPCr | QMax | 0.38 mmoles/sec | Standard Deviation 0.13 |
| Placebo | In Vivo Mitochondrial Function: QMax, VPCr | VPCr | 0.19 mmoles/sec | Standard Deviation 0.08 |
Secondary
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
Time frame: End of each 6 week intervention period
Population: 2 subjects complete data for metformin, but not placebo. (images not good) ME not reported for one placebo subject due to AnGly out of range.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | In Vivo Mitochondrial Function: Ratio of the Amount of ATP Generated Per Unit of Oxygen Consumed | 0.152 ratio | Standard Deviation 0.067 |
| Placebo | In Vivo Mitochondrial Function: Ratio of the Amount of ATP Generated Per Unit of Oxygen Consumed | 0.116 ratio | Standard Deviation 0.044 |
Secondary
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.
Time frame: End of each 6 week intervention period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin | In Vivo Mitochondrial Function: Time Constants | ADP time constant | 18.4 seconds | Standard Deviation 5.4 |
| Metformin | In Vivo Mitochondrial Function: Time Constants | Phosphocreatine time constant | 32.9 seconds | Standard Deviation 9.2 |
| Placebo | In Vivo Mitochondrial Function: Time Constants | ADP time constant | 23.3 seconds | Standard Deviation 10.3 |
| Placebo | In Vivo Mitochondrial Function: Time Constants | Phosphocreatine time constant | 32.8 seconds | Standard Deviation 12.5 |
Secondary
Metabolic Markers: Adiponection
adiponection (microg/ml) at baseline after each phase in the AM of the final phase visit
Time frame: End of each 6 week intervention period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Metabolic Markers: Adiponection | 13.5 microg/mL | Standard Deviation 8.1 |
| Placebo | Metabolic Markers: Adiponection | 15.1 microg/mL | Standard Deviation 9.4 |
Secondary
Metabolic Markers: Fatty Acids
fatty acids (microeq/L) at baseline after each phase in the AM of the final visit
Time frame: End of each 6 week intervention period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Metabolic Markers: Fatty Acids | 531 microEq/L | Standard Deviation 174 |
| Placebo | Metabolic Markers: Fatty Acids | 446 microEq/L | Standard Deviation 185 |
Secondary
Metabolic Markers: Glucagon
Glucagon (pg/ml); baseline on AM of each phase final study visit.
Time frame: End of each 6 week intervention period
Population: NS by paired t-test
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Metabolic Markers: Glucagon | 95.5 pg/ml | Standard Deviation 27.8 |
| Placebo | Metabolic Markers: Glucagon | 90.2 pg/ml | Standard Deviation 45.6 |
Secondary
Metabolic Markers: Glucose, Triglycerides, Cholesterol
Glucose (mg/dL), triglycerides (mg/dL), cholesterol (mg/dL) at baseline after each phase
Time frame: End of each 6 week intervention period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin | Metabolic Markers: Glucose, Triglycerides, Cholesterol | Glucose | 135 mg/dL | Standard Deviation 45 |
| Metformin | Metabolic Markers: Glucose, Triglycerides, Cholesterol | Triglycerides | 98 mg/dL | Standard Deviation 50 |
| Metformin | Metabolic Markers: Glucose, Triglycerides, Cholesterol | total cholesterol | 156 mg/dL | Standard Deviation 38 |
| Placebo | Metabolic Markers: Glucose, Triglycerides, Cholesterol | Glucose | 124 mg/dL | Standard Deviation 46 |
| Placebo | Metabolic Markers: Glucose, Triglycerides, Cholesterol | Triglycerides | 78 mg/dL | Standard Deviation 41 |
| Placebo | Metabolic Markers: Glucose, Triglycerides, Cholesterol | total cholesterol | 154 mg/dL | Standard Deviation 48 |
Secondary
Metabolic Markers: Glycerol
glycerol (micromol/L) at baseline after each phase in the AM of the final phase visit
Time frame: End of each 6 week intervention period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Metabolic Markers: Glycerol | 95 microM/L | Standard Deviation 33 |
| Placebo | Metabolic Markers: Glycerol | 87 microM/L | Standard Deviation 31 |
Secondary
Metabolic Markers: Insulin
insulin (microIU/ml) at baseline after each phase in the AM of the final phase visit
Time frame: End of each 6 week intervention period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Metabolic Markers: Insulin | 33.9 microIU/ml | Standard Deviation 34.3 |
| Placebo | Metabolic Markers: Insulin | 49.1 microIU/ml | Standard Deviation 56.8 |
Secondary
Metabolic Markers: Lactate
lactate (mmol/L) at baseline after each phase in the AM of the final phase visit
Time frame: End of each 6 week intervention period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Metabolic Markers: Lactate | 0.79 mmoles/L | Standard Deviation 0.26 |
| Placebo | Metabolic Markers: Lactate | 0.75 mmoles/L | Standard Deviation 0.2 |
Secondary
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.
Time frame: End of each 6 week intervention period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin | Mitochondrial Measures: Oxygen Consumption | PMG State 3 Oxygen Flux | 28.3 pmoles/mg/s | Standard Deviation 6.8 |
| Metformin | Mitochondrial Measures: Oxygen Consumption | PMGS State 3 Oxygen Flux | 44.3 pmoles/mg/s | Standard Deviation 16.5 |
| Metformin | Mitochondrial Measures: Oxygen Consumption | PMGS State 4 Oxygen Flux | 14.6 pmoles/mg/s | Standard Deviation 8 |
| Metformin | Mitochondrial Measures: Oxygen Consumption | PMGS Uncoupled Max Oxygen Flux | 76.0 pmoles/mg/s | Standard Deviation 26.3 |
| Metformin | Mitochondrial Measures: Oxygen Consumption | OCM State 3 Oxygen Flux | 16.8 pmoles/mg/s | Standard Deviation 7 |
| Metformin | Mitochondrial Measures: Oxygen Consumption | OCMS State 3 Oxygen Flux | 43.8 pmoles/mg/s | Standard Deviation 16.9 |
| Metformin | Mitochondrial Measures: Oxygen Consumption | OCMS State 4 Oxygen Flux | 14.6 pmoles/mg/s | Standard Deviation 7.4 |
| Metformin | Mitochondrial Measures: Oxygen Consumption | OCMS Uncoupled Max Oxygen Flux | 67.1 pmoles/mg/s | Standard Deviation 23.3 |
| Placebo | Mitochondrial Measures: Oxygen Consumption | OCMS Uncoupled Max Oxygen Flux | 71.3 pmoles/mg/s | Standard Deviation 18.8 |
| Placebo | Mitochondrial Measures: Oxygen Consumption | PMG State 3 Oxygen Flux | 29.7 pmoles/mg/s | Standard Deviation 11 |
| Placebo | Mitochondrial Measures: Oxygen Consumption | OCM State 3 Oxygen Flux | 18.0 pmoles/mg/s | Standard Deviation 5.6 |
| Placebo | Mitochondrial Measures: Oxygen Consumption | PMGS State 3 Oxygen Flux | 41.5 pmoles/mg/s | Standard Deviation 16.1 |
| Placebo | Mitochondrial Measures: Oxygen Consumption | OCMS State 4 Oxygen Flux | 15.1 pmoles/mg/s | Standard Deviation 5.9 |
| Placebo | Mitochondrial Measures: Oxygen Consumption | PMGS State 4 Oxygen Flux | 14.0 pmoles/mg/s | Standard Deviation 6.3 |
| Placebo | Mitochondrial Measures: Oxygen Consumption | OCMS State 3 Oxygen Flux | 42.8 pmoles/mg/s | Standard Deviation 13.1 |
| Placebo | Mitochondrial Measures: Oxygen Consumption | PMGS Uncoupled Max Oxygen Flux | 76.4 pmoles/mg/s | Standard Deviation 21.2 |
Secondary
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.
Time frame: End of each 6 week intervention period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin | Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes | complex I | 1436 Arbitrary units | Standard Deviation 981 |
| Metformin | Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes | complex II | 4375 Arbitrary units | Standard Deviation 2022 |
| Metformin | Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes | complex III | 10361 Arbitrary units | Standard Deviation 5131 |
| Metformin | Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes | complex V | 23118 Arbitrary units | Standard Deviation 9281 |
| Placebo | Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes | complex V | 23254 Arbitrary units | Standard Deviation 8368 |
| Placebo | Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes | complex I | 1084 Arbitrary units | Standard Deviation 718 |
| Placebo | Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes | complex III | 9001 Arbitrary units | Standard Deviation 5451 |
| Placebo | Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes | complex II | 4201 Arbitrary units | Standard Deviation 1541 |
Secondary
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
Time frame: End of each 6 week intervention period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Vascular Markers: Endothelin-1 (pg/ml) | 6.3 pg/mL | Standard Deviation 4.8 |
| Placebo | Vascular Markers: Endothelin-1 (pg/ml) | 5.8 pg/mL | Standard Deviation 2.1 |
Other Pre-specified
Inflammatory Markers: Exploratory
IL6, TNF alpha
Time frame: End of each 6 week intervention period
Population: No data was collected for this exploratory outcome due to insufficient funds
Other Pre-specified
Mitochondrial Measures: Oxidant Generation
oxidant generation
Time frame: End of each 6 week intervention period
Population: This exploratory outcome measure was not collected.
Other Pre-specified
Mitochondrial Oxidant Generation
exploratory measure looking at H2O2 production. not performed due to equipment not available.
Time frame: after each 6 week intervention
Other Pre-specified
Oxidative Stress Markers
TBARs, GSSG:GSH ratio
Time frame: End of each 6 week intervention period
Population: This exploratory outcome measure was not collected
Other Pre-specified
Vascular Markers: Exploratory
ICAM
Time frame: End of each 6 week intervention period
Population: No outcome measure data was collected for this exploratory outcome measure due to insufficient funds.
Other Pre-specified
Vascular Markers: PAI-1
PAI-1 exploratory thromobotic marker.
Time frame: End of each 6 week intervention period
Population: this outcome not done-cost and assay issues