Type 1 Diabetes
Conditions
Keywords
diabetes, insulin, blood vessel, type 1
Brief summary
Insulin resistance (IR) is an important contributor to increased cardiovascular disease risk in type 1 diabetes (T1D). Non-esterified fatty acid elevation is a significant contributor to IR in T1D and may be a target of intervention. The hypothesis of the study is that isolated fatty acid lowering with acipimox will improve insulin action and blood vessel function and have the benefit of reducing mitochondrial oxidant generation and improving mitochondrial function in T1D. Targeting IR through fatty acid lowering is a novel approach to T1D treatment that may significantly improve current management of TID and of cardiovascular disease (CVD) risk in this high risk population.
Interventions
DRUGAcipimox
Subjects will take acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day.
DRUGPlacebo
Subjects will take placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day
Sponsors
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
Yes
Inclusion criteria
1. Men and women, with and without type 1 diabetes between 25-59 years of age, 2. HbA1c 6.0-9.5 (T1D only), 3. Subjects who are willing to commit to: * 14 days of prescribed diet, * two 44 hour inpatient stays, and * two muscle biopsies.
Exclusion criteria
1. Any comorbid condition associated with inflammation, insulin resistance, or dyslipidemia, 2. Tobacco use, 3. Pregnancy, 4. Steroid use, 5. Scheduled physical activity \>3 days a week, 6. Angina or any other cardiovascular or pulmonary disease, 7. History of chronic obstructive pulmonary disease or asthma, 8. Systolic blood pressure \>190 at rest or \>250 with exercise, or 9. Diastolic pressure \>95 at rest, or \>105 with exercise, 10. Proteinuria (urine protein \>200 mg/dl), or 11. Creatinine \> 2 mg/dl, suggestive of severe renal disease, 12. Severe Proliferative retinopathy, 13. Niacin treatment, 14. History of peptic ulcers, 15. History of hereditary angioedema, and 16. C1 esterase deficiency.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 24 Hour Mean Fatty Acid Levels | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | Assesses whether fatty acid level is consistently lowered by acipimox. Mean of fatty acid levels measured 22 times over 24 hours (hourly except 0100 and 0300 hours). |
| Percent Flow-mediated Brachial Artery Dilation | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | To determine the effects of NEFA lowering and insulin sensitization on endothelial function. Measures percent change in brachial artery diameter with hyperemia after occlusion. |
| State 3 Mitochondrial Oxygen Consumption | muscle biopsy on day 7 of each weeklong intervention period; max 16 weeks post enrollment | Measures skeletal muscle mitochondrial function and effects of acipimox thereon, carbohydrate & lipid substrates. State 3 is fully active coupled oxygen flux using PMG or PMGS (pyruvate, malate, glutamate, +/- succinate) or OCMS (octanyl carnitine, malate, +/- succinate) as substrates. FCCP is added as an uncoupler to measure maximum possible O2 flux. Higher values reflect better mitochondrial function. |
| Insulin Sensitivity: M-value From Hyperinsulinemic Euglycemia Clamp Study | day 8 of each of the 2 random order intervention phases; max 16 weeks post enrollment | Evaluate the impact of Non esterified fatty acid (NEFA)-lowering on insulin sensitivity in T1D versus non-DM. Glucose infusion rate is reported normalized to lean body weight in kg and to final insulin concentration. The unit of measure reflects the rate at which glucose needs to be infused to maintain a normal blood sugar in the setting of a given serum insulin level from an insulin infusion. As such, a higher number means more glucose was needed and indicates greater sensitivity to insulin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Oxidative Stress and Inflammatory Markers: Adiponectin | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | adiponectin |
| Oxidative Stress and Inflammatory Markers: Plasminogen Activator Inhibitor (PAI-1) | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | Plasminogen activator inhibitor (PAI-1) |
| Heart Rate Variability | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | Measure of autonomic function; ratio of fastest to slowest heart rate during valsalva maneuver. |
| Arterial Stiffness (PWV) | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec. Higher values reflect a stiffer vasculature. |
| Metabolic Markers: Continuous Glucose Monitoring Measures | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | Continuous glucose monitoring measures for 3 days before clamp. Collected for participants with T1 Diabetes only. |
| Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | mean glucose and triglycerides for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300). |
| Metabolic Markers: Insulin | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | mean insulin for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300). |
| Metabolic Markers: Glycerol | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | mean glycerol for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300). |
| Vascular Markers | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | endothelin 1 measured as a marker of vascular damage |
| Arterial Stiffness (AI) | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 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. Higher values indicate stiffer vessels |
| Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6) | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | Interleukin 6 (IL6) |
| Oxidative Stress and Inflammatory Markers: TNFalpha | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | TNFalpha |
| Oxidative Stress and Inflammatory Markers: High-sensitivity C-reactive Protein (hsCRP) | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | high-sensitivity C-reactive protein (hsCRP) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Counterregulatory Hormones | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | Planned glucagon and cortisol as a markers of counteregulation, but not done due to financial limitations |
| Oxidative Stress and Inflammatory Markers: Exploratory (Not Collected) | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | thiobarbituric acid reactive substances (TBARs), glutathione disulfide (GSSG): reduced Glutathione (GSH) ratio; amplex red assay of hydrogen peroxide (H2O2) production, |
| Other Mitochondrial Measures: Mito Content and Electron Transport Chain Complexes | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | Mito content and electron transport chain complexes by western blot analysis. |
Countries
United States
Participant flow
Pre-assignment details
10 participants (7 withdrawals, 3 screen fails) were excluded from the study after enrollment, but prior to beginning the study. One T1D acipimox to placebo was withdrawn during the acipimox phase due to an SAE.
Participants by arm
| Arm | Count |
|---|---|
| All Participants With T1 Diabetes Acipimox, Then Placebo: Subjects will take acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day, followed by placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day.
Placebo, then Acipimox :Subjects will take placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day, followed by acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. | 10 |
| All Participants Without T1 Diabetes Placebo, then Acipimox :Subjects will take placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day, followed by acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day.
Acipimox, Then Placebo: Subjects will take acipimox 250mg by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day, followed by placebo by mouth four times a day for a total of seven days plus one dose the morning of the final study visit day. | 8 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants With T1 Diabetes | All Participants Without T1 Diabetes | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 8 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 8 Participants | 18 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 | 2 Participants | 2 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 | 10 Participants | 6 Participants | 16 Participants |
| Region of Enrollment United States | 10 participants | 8 participants | 18 participants |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 9 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 10 | 0 / 9 | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 1 / 10 | 0 / 9 | 0 / 8 | 0 / 8 |
Outcome results
Primary
24 Hour Mean Fatty Acid Levels
Assesses whether fatty acid level is consistently lowered by acipimox. Mean of fatty acid levels measured 22 times over 24 hours (hourly except 0100 and 0300 hours).
Time frame: day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1 Diabetes, Acipimox | 24 Hour Mean Fatty Acid Levels | 343 microEq/L | Standard Deviation 122 |
| T1 Diabetes, Placebo | 24 Hour Mean Fatty Acid Levels | 297 microEq/L | Standard Deviation 56 |
| No T1 Diabetes, Acipimox | 24 Hour Mean Fatty Acid Levels | 298 microEq/L | Standard Deviation 90 |
| No T1 Diabetes, Placebo | 24 Hour Mean Fatty Acid Levels | 335 microEq/L | Standard Deviation 65 |
Primary
Insulin Sensitivity: M-value From Hyperinsulinemic Euglycemia Clamp Study
Evaluate the impact of Non esterified fatty acid (NEFA)-lowering on insulin sensitivity in T1D versus non-DM. Glucose infusion rate is reported normalized to lean body weight in kg and to final insulin concentration. The unit of measure reflects the rate at which glucose needs to be infused to maintain a normal blood sugar in the setting of a given serum insulin level from an insulin infusion. As such, a higher number means more glucose was needed and indicates greater sensitivity to insulin.
Time frame: day 8 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1 Diabetes, Acipimox | Insulin Sensitivity: M-value From Hyperinsulinemic Euglycemia Clamp Study | 4.65 mg/kg*minute*microIU/mL*100 | Standard Deviation 1.52 |
| T1 Diabetes, Placebo | Insulin Sensitivity: M-value From Hyperinsulinemic Euglycemia Clamp Study | 3.67 mg/kg*minute*microIU/mL*100 | Standard Deviation 1.45 |
| No T1 Diabetes, Acipimox | Insulin Sensitivity: M-value From Hyperinsulinemic Euglycemia Clamp Study | 8.8 mg/kg*minute*microIU/mL*100 | Standard Deviation 3.04 |
| No T1 Diabetes, Placebo | Insulin Sensitivity: M-value From Hyperinsulinemic Euglycemia Clamp Study | 9.05 mg/kg*minute*microIU/mL*100 | Standard Deviation 2.88 |
Primary
Percent Flow-mediated Brachial Artery Dilation
To determine the effects of NEFA lowering and insulin sensitization on endothelial function. Measures percent change in brachial artery diameter with hyperemia after occlusion.
Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1 Diabetes, Acipimox | Percent Flow-mediated Brachial Artery Dilation | 8.21 Percent change in BA diameter | Standard Deviation 3.02 |
| T1 Diabetes, Placebo | Percent Flow-mediated Brachial Artery Dilation | 8.82 Percent change in BA diameter | Standard Deviation 4.4 |
| No T1 Diabetes, Acipimox | Percent Flow-mediated Brachial Artery Dilation | 5.88 Percent change in BA diameter | Standard Deviation 4.17 |
| No T1 Diabetes, Placebo | Percent Flow-mediated Brachial Artery Dilation | 7.32 Percent change in BA diameter | Standard Deviation 4.25 |
Primary
State 3 Mitochondrial Oxygen Consumption
Measures skeletal muscle mitochondrial function and effects of acipimox thereon, carbohydrate & lipid substrates. State 3 is fully active coupled oxygen flux using PMG or PMGS (pyruvate, malate, glutamate, +/- succinate) or OCMS (octanyl carnitine, malate, +/- succinate) as substrates. FCCP is added as an uncoupler to measure maximum possible O2 flux. Higher values reflect better mitochondrial function.
Time frame: muscle biopsy on day 7 of each weeklong intervention period; max 16 weeks post enrollment
Population: 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Another participant did not have a muscle biopsy collected (T1D, Acipimox).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| T1 Diabetes, Acipimox | State 3 Mitochondrial Oxygen Consumption | OCMS Uncoupled Max Oxygen Flux | 51.8 pmoles/mg/s | Standard Deviation 22.9 |
| T1 Diabetes, Acipimox | State 3 Mitochondrial Oxygen Consumption | OCM State 3 Oxygen Flux | 14.0 pmoles/mg/s | Standard Deviation 5.8 |
| T1 Diabetes, Acipimox | State 3 Mitochondrial Oxygen Consumption | PMGS State 3 Oxygen Flux | 38.0 pmoles/mg/s | Standard Deviation 11.8 |
| T1 Diabetes, Acipimox | State 3 Mitochondrial Oxygen Consumption | PMG State 3 Oxygen Flux | 26.1 pmoles/mg/s | Standard Deviation 8.3 |
| T1 Diabetes, Acipimox | State 3 Mitochondrial Oxygen Consumption | OCMS State 3 Oxygen Flux | 38.6 pmoles/mg/s | Standard Deviation 14.6 |
| T1 Diabetes, Acipimox | State 3 Mitochondrial Oxygen Consumption | PMGS Uncoupled Max Oxygen Flux | 65.2 pmoles/mg/s | Standard Deviation 18.4 |
| T1 Diabetes, Placebo | State 3 Mitochondrial Oxygen Consumption | OCMS State 3 Oxygen Flux | 38.5 pmoles/mg/s | Standard Deviation 11.2 |
| T1 Diabetes, Placebo | State 3 Mitochondrial Oxygen Consumption | OCMS Uncoupled Max Oxygen Flux | 56.4 pmoles/mg/s | Standard Deviation 20 |
| T1 Diabetes, Placebo | State 3 Mitochondrial Oxygen Consumption | PMG State 3 Oxygen Flux | 24.9 pmoles/mg/s | Standard Deviation 7.6 |
| T1 Diabetes, Placebo | State 3 Mitochondrial Oxygen Consumption | PMGS State 3 Oxygen Flux | 36.9 pmoles/mg/s | Standard Deviation 12.7 |
| T1 Diabetes, Placebo | State 3 Mitochondrial Oxygen Consumption | PMGS Uncoupled Max Oxygen Flux | 62.1 pmoles/mg/s | Standard Deviation 16.3 |
| T1 Diabetes, Placebo | State 3 Mitochondrial Oxygen Consumption | OCM State 3 Oxygen Flux | 15.0 pmoles/mg/s | Standard Deviation 5.6 |
| No T1 Diabetes, Acipimox | State 3 Mitochondrial Oxygen Consumption | OCMS Uncoupled Max Oxygen Flux | 80.1 pmoles/mg/s | Standard Deviation 24.8 |
| No T1 Diabetes, Acipimox | State 3 Mitochondrial Oxygen Consumption | OCMS State 3 Oxygen Flux | 43.8 pmoles/mg/s | Standard Deviation 13.3 |
| No T1 Diabetes, Acipimox | State 3 Mitochondrial Oxygen Consumption | OCM State 3 Oxygen Flux | 18.8 pmoles/mg/s | Standard Deviation 8.6 |
| No T1 Diabetes, Acipimox | State 3 Mitochondrial Oxygen Consumption | PMGS Uncoupled Max Oxygen Flux | 77.8 pmoles/mg/s | Standard Deviation 26.3 |
| No T1 Diabetes, Acipimox | State 3 Mitochondrial Oxygen Consumption | PMG State 3 Oxygen Flux | 30.2 pmoles/mg/s | Standard Deviation 9.8 |
| No T1 Diabetes, Acipimox | State 3 Mitochondrial Oxygen Consumption | PMGS State 3 Oxygen Flux | 42.5 pmoles/mg/s | Standard Deviation 15 |
| No T1 Diabetes, Placebo | State 3 Mitochondrial Oxygen Consumption | OCMS Uncoupled Max Oxygen Flux | 73.1 pmoles/mg/s | Standard Deviation 18.8 |
| No T1 Diabetes, Placebo | State 3 Mitochondrial Oxygen Consumption | PMGS Uncoupled Max Oxygen Flux | 80.2 pmoles/mg/s | Standard Deviation 28.9 |
| No T1 Diabetes, Placebo | State 3 Mitochondrial Oxygen Consumption | PMG State 3 Oxygen Flux | 29.7 pmoles/mg/s | Standard Deviation 10 |
| No T1 Diabetes, Placebo | State 3 Mitochondrial Oxygen Consumption | PMGS State 3 Oxygen Flux | 42.5 pmoles/mg/s | Standard Deviation 11.8 |
| No T1 Diabetes, Placebo | State 3 Mitochondrial Oxygen Consumption | OCM State 3 Oxygen Flux | 17.3 pmoles/mg/s | Standard Deviation 4.4 |
| No T1 Diabetes, Placebo | State 3 Mitochondrial Oxygen Consumption | OCMS State 3 Oxygen Flux | 41.7 pmoles/mg/s | Standard Deviation 9.9 |
Secondary
Arterial Stiffness (AI)
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. Higher values indicate stiffer vessels
Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Additionally, one participant in each of the T1D study phases did not have data collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1 Diabetes, Acipimox | Arterial Stiffness (AI) | 21.4 ratio | Standard Deviation 8.4 |
| T1 Diabetes, Placebo | Arterial Stiffness (AI) | 19.7 ratio | Standard Deviation 10 |
| No T1 Diabetes, Acipimox | Arterial Stiffness (AI) | 11.1 ratio | Standard Deviation 13 |
| No T1 Diabetes, Placebo | Arterial Stiffness (AI) | 12.4 ratio | Standard Deviation 12.7 |
Secondary
Arterial Stiffness (PWV)
Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec. Higher values reflect a stiffer vasculature.
Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Additionally, one participant in each of the T1D study phases did not have data collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1 Diabetes, Acipimox | Arterial Stiffness (PWV) | 9.24 m/sec | Standard Deviation 2.46 |
| T1 Diabetes, Placebo | Arterial Stiffness (PWV) | 9.91 m/sec | Standard Deviation 3.3 |
| No T1 Diabetes, Acipimox | Arterial Stiffness (PWV) | 6.97 m/sec | Standard Deviation 1.71 |
| No T1 Diabetes, Placebo | Arterial Stiffness (PWV) | 7.4 m/sec | Standard Deviation 1 |
Secondary
Heart Rate Variability
Measure of autonomic function; ratio of fastest to slowest heart rate during valsalva maneuver.
Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1 Diabetes, Acipimox | Heart Rate Variability | 1.37 ratio | Standard Deviation 0.17 |
| T1 Diabetes, Placebo | Heart Rate Variability | 1.43 ratio | Standard Deviation 0.14 |
| No T1 Diabetes, Acipimox | Heart Rate Variability | 1.59 ratio | Standard Deviation 0.19 |
| No T1 Diabetes, Placebo | Heart Rate Variability | 1.69 ratio | Standard Deviation 0.3 |
Secondary
Metabolic Markers: Continuous Glucose Monitoring Measures
Continuous glucose monitoring measures for 3 days before clamp. Collected for participants with T1 Diabetes only.
Time frame: day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: 1 participant was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| T1 Diabetes, Acipimox | Metabolic Markers: Continuous Glucose Monitoring Measures | Average Glucose | 8.82 mmol/L | Standard Deviation 1.2 |
| T1 Diabetes, Acipimox | Metabolic Markers: Continuous Glucose Monitoring Measures | Glycemic Variability | 3.64 mmol/L | Standard Deviation 0.92 |
| T1 Diabetes, Placebo | Metabolic Markers: Continuous Glucose Monitoring Measures | Average Glucose | 9.09 mmol/L | Standard Deviation 0.72 |
| T1 Diabetes, Placebo | Metabolic Markers: Continuous Glucose Monitoring Measures | Glycemic Variability | 3.64 mmol/L | Standard Deviation 0.66 |
Secondary
Metabolic Markers: Glycerol
mean glycerol for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300).
Time frame: day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1 Diabetes, Acipimox | Metabolic Markers: Glycerol | 86 micromoles/L | Standard Deviation 25 |
| T1 Diabetes, Placebo | Metabolic Markers: Glycerol | 75 micromoles/L | Standard Deviation 20 |
| No T1 Diabetes, Acipimox | Metabolic Markers: Glycerol | 63 micromoles/L | Standard Deviation 12 |
| No T1 Diabetes, Placebo | Metabolic Markers: Glycerol | 69 micromoles/L | Standard Deviation 14 |
Secondary
Metabolic Markers: Insulin
mean insulin for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300).
Time frame: day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1 Diabetes, Acipimox | Metabolic Markers: Insulin | 48 microIU/mL | Standard Deviation 25 |
| T1 Diabetes, Placebo | Metabolic Markers: Insulin | 47 microIU/mL | Standard Deviation 26 |
| No T1 Diabetes, Acipimox | Metabolic Markers: Insulin | 20 microIU/mL | Standard Deviation 6 |
| No T1 Diabetes, Placebo | Metabolic Markers: Insulin | 21 microIU/mL | Standard Deviation 10 |
Secondary
Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels
mean glucose and triglycerides for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300).
Time frame: day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| T1 Diabetes, Acipimox | Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels | glucose | 135 mg/dL | Standard Deviation 28 |
| T1 Diabetes, Acipimox | Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels | triglycerides | 59 mg/dL | Standard Deviation 29 |
| T1 Diabetes, Placebo | Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels | triglycerides | 68 mg/dL | Standard Deviation 33 |
| T1 Diabetes, Placebo | Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels | glucose | 131 mg/dL | Standard Deviation 31 |
| No T1 Diabetes, Acipimox | Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels | glucose | 87 mg/dL | Standard Deviation 10 |
| No T1 Diabetes, Acipimox | Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels | triglycerides | 67 mg/dL | Standard Deviation 20 |
| No T1 Diabetes, Placebo | Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels | glucose | 89 mg/dL | Standard Deviation 8 |
| No T1 Diabetes, Placebo | Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels | triglycerides | 83 mg/dL | Standard Deviation 27 |
Secondary
Oxidative Stress and Inflammatory Markers: Adiponectin
adiponectin
Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Two participants (one in each of the Non-T1D study phases) did not have data collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1 Diabetes, Acipimox | Oxidative Stress and Inflammatory Markers: Adiponectin | 11.6 micrograms/mL | Standard Deviation 7.7 |
| T1 Diabetes, Placebo | Oxidative Stress and Inflammatory Markers: Adiponectin | 14.9 micrograms/mL | Standard Deviation 10.8 |
| No T1 Diabetes, Acipimox | Oxidative Stress and Inflammatory Markers: Adiponectin | 7.3 micrograms/mL | Standard Deviation 5 |
| No T1 Diabetes, Placebo | Oxidative Stress and Inflammatory Markers: Adiponectin | 5.8 micrograms/mL | Standard Deviation 2.1 |
Secondary
Oxidative Stress and Inflammatory Markers: High-sensitivity C-reactive Protein (hsCRP)
high-sensitivity C-reactive protein (hsCRP)
Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Another participant from the Non T1D Placebo group did not have data collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1 Diabetes, Acipimox | Oxidative Stress and Inflammatory Markers: High-sensitivity C-reactive Protein (hsCRP) | 3.19 mg/L | Standard Deviation 3.84 |
| T1 Diabetes, Placebo | Oxidative Stress and Inflammatory Markers: High-sensitivity C-reactive Protein (hsCRP) | 1.98 mg/L | Standard Deviation 1.64 |
| No T1 Diabetes, Acipimox | Oxidative Stress and Inflammatory Markers: High-sensitivity C-reactive Protein (hsCRP) | 1.43 mg/L | Standard Deviation 1.11 |
| No T1 Diabetes, Placebo | Oxidative Stress and Inflammatory Markers: High-sensitivity C-reactive Protein (hsCRP) | 1.44 mg/L | Standard Deviation 1.42 |
Secondary
Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6)
Interleukin 6 (IL6)
Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1 Diabetes, Acipimox | Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6) | 2.8 picograms/mL | Standard Deviation 1.6 |
| T1 Diabetes, Placebo | Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6) | 4.2 picograms/mL | Standard Deviation 3.2 |
| No T1 Diabetes, Acipimox | Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6) | 2.6 picograms/mL | Standard Deviation 2.4 |
| No T1 Diabetes, Placebo | Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6) | 3.5 picograms/mL | Standard Deviation 1.3 |
Secondary
Oxidative Stress and Inflammatory Markers: Plasminogen Activator Inhibitor (PAI-1)
Plasminogen activator inhibitor (PAI-1)
Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: Measure was not collected due to funding limitations.
Secondary
Oxidative Stress and Inflammatory Markers: TNFalpha
TNFalpha
Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Two other participants (T1D, Acipimox; No T1D Acipimox) did not have data collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1 Diabetes, Acipimox | Oxidative Stress and Inflammatory Markers: TNFalpha | 1.76 picograms/mL | Standard Deviation 1.08 |
| T1 Diabetes, Placebo | Oxidative Stress and Inflammatory Markers: TNFalpha | 1.71 picograms/mL | Standard Deviation 0.8 |
| No T1 Diabetes, Acipimox | Oxidative Stress and Inflammatory Markers: TNFalpha | 1.56 picograms/mL | Standard Deviation 0.95 |
| No T1 Diabetes, Placebo | Oxidative Stress and Inflammatory Markers: TNFalpha | .91 picograms/mL | Standard Deviation 0.46 |
Secondary
Vascular Markers
endothelin 1 measured as a marker of vascular damage
Time frame: day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. in addition, the last nonDM subjects did not have this collected due to funding limitations and futility based on prior results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T1 Diabetes, Acipimox | Vascular Markers | 4.92 pg/mL | Standard Deviation 1.56 |
| T1 Diabetes, Placebo | Vascular Markers | 4.9 pg/mL | Standard Deviation 0.91 |
| No T1 Diabetes, Acipimox | Vascular Markers | 4.83 pg/mL | Standard Deviation 0.92 |
| No T1 Diabetes, Placebo | Vascular Markers | 4.12 pg/mL | Standard Deviation 1 |
Other Pre-specified
Counterregulatory Hormones
Planned glucagon and cortisol as a markers of counteregulation, but not done due to financial limitations
Time frame: day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: 1 participant in the T1 Diabetes groups was excluded from the analysis because data was only collected in the Acipimox phase and matching Placebo data would have been required for comparison. Incorrectly listed as secondary outcome. This was an exploratory outcome.
Other Pre-specified
Other Mitochondrial Measures: Mito Content and Electron Transport Chain Complexes
Mito content and electron transport chain complexes by western blot analysis.
Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: Originally described as secondary but were actually exploratory. Not done due to funding and tissue limitations.
Other Pre-specified
Oxidative Stress and Inflammatory Markers: Exploratory (Not Collected)
thiobarbituric acid reactive substances (TBARs), glutathione disulfide (GSSG): reduced Glutathione (GSH) ratio; amplex red assay of hydrogen peroxide (H2O2) production,
Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Population: These oxidative stress and inflammatory markers were collected, but assays were found to be unreliable. These measurements were originally erroneously described as secondary outcome measures, but are exploratory.