Back to resultsEffects of Acipimox on Insulin Action, Vascular Function, and Muscle Function in Type 1 Diabetes (AcT1)
Primary Purpose
Type 1 Diabetes
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Acipimox
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Type 1 Diabetes focused on measuring diabetes, insulin, blood vessel, type 1
Eligibility Criteria
Inclusion Criteria:
- Men and women, with and without type 1 diabetes between 25-59 years of age,
- HbA1c 6.0-9.5 (T1D only),
Subjects who are willing to commit to:
- 14 days of prescribed diet,
- two 44 hour inpatient stays, and
- two muscle biopsies.
Exclusion Criteria:
- Any comorbid condition associated with inflammation, insulin resistance, or dyslipidemia,
- Tobacco use,
- Pregnancy,
- Steroid use,
- Scheduled physical activity >3 days a week,
- Angina or any other cardiovascular or pulmonary disease,
- History of chronic obstructive pulmonary disease or asthma,
- Systolic blood pressure >190 at rest or >250 with exercise, or
- Diastolic pressure >95 at rest, or >105 with exercise,
- Proteinuria (urine protein >200 mg/dl), or
- Creatinine > 2 mg/dl, suggestive of severe renal disease,
- Severe Proliferative retinopathy,
- Niacin treatment,
- History of peptic ulcers,
- History of hereditary angioedema, and
- C1 esterase deficiency.
Sites / Locations
- University of Colorado Denver
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Acipimox
Placebo
Arm Description
Drug: acipimox
Drug: Placebo
Outcomes
Primary Outcome Measures
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.
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).
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.
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.
Secondary Outcome Measures
Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6)
Interleukin 6 (IL6)
Oxidative Stress and Inflammatory Markers: TNFalpha
TNFalpha
Oxidative Stress and Inflammatory Markers: High-sensitivity C-reactive Protein (hsCRP)
high-sensitivity C-reactive protein (hsCRP)
Oxidative Stress and Inflammatory Markers: Adiponectin
adiponectin
Oxidative Stress and Inflammatory Markers: Plasminogen Activator Inhibitor (PAI-1)
Plasminogen activator inhibitor (PAI-1)
Heart Rate Variability
Measure of autonomic function; ratio of fastest to slowest heart rate during valsalva maneuver.
Arterial Stiffness (PWV)
Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec. Higher values reflect a stiffer vasculature.
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
Metabolic Markers: Continuous Glucose Monitoring Measures
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
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
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
mean glycerol for the 24 hours before the 2nd overnight stay from 22 hourly measurements over 24 hours (except 0100 and 0300).
Vascular Markers
endothelin 1 measured as a marker of vascular damage
Full Information
NCT ID
NCT01816165
First Posted
June 13, 2012
Last Updated
December 21, 2021
Sponsor
University of Colorado, Denver
1. Study Identification
Unique Protocol Identification Number
NCT01816165
Brief Title
Effects of Acipimox on Insulin Action, Vascular Function, and Muscle Function in Type 1 Diabetes
Acronym
AcT1
Official Title
Role of Lipotoxicity in Insulin Resistance, Vascular, and Mitochondrial Dysfunction in Type 1 Diabetes
Study Type
Interventional
2. Study Status
Record Verification Date
December 2021
Overall Recruitment Status
Completed
Study Start Date
June 2011 (undefined)
Primary Completion Date
June 24, 2015 (Actual)
Study Completion Date
June 24, 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Colorado, Denver
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes
Keywords
diabetes, insulin, blood vessel, type 1
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
28 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Acipimox
Arm Type
Experimental
Arm Description
Drug: acipimox
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Drug: Placebo
Intervention Type
Drug
Intervention Name(s)
Acipimox
Other Intervention Name(s)
Olbetam
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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
Primary Outcome Measure Information:
Title
Insulin Sensitivity: M-value From Hyperinsulinemic Euglycemia Clamp Study
Description
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
Title
24 Hour Mean Fatty Acid Levels
Description
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
Title
Percent Flow-mediated Brachial Artery Dilation
Description
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
Title
State 3 Mitochondrial Oxygen Consumption
Description
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
Secondary Outcome Measure Information:
Title
Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6)
Description
Interleukin 6 (IL6)
Time Frame
day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Title
Oxidative Stress and Inflammatory Markers: TNFalpha
Description
TNFalpha
Time Frame
day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Title
Oxidative Stress and Inflammatory Markers: High-sensitivity C-reactive Protein (hsCRP)
Description
high-sensitivity C-reactive protein (hsCRP)
Time Frame
day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Title
Oxidative Stress and Inflammatory Markers: Adiponectin
Description
adiponectin
Time Frame
day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Title
Oxidative Stress and Inflammatory Markers: Plasminogen Activator Inhibitor (PAI-1)
Description
Plasminogen activator inhibitor (PAI-1)
Time Frame
day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Title
Heart Rate Variability
Description
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
Title
Arterial Stiffness (PWV)
Description
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
Title
Arterial Stiffness (AI)
Description
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
Title
Metabolic Markers: Continuous Glucose Monitoring Measures
Description
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
Title
Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels
Description
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
Title
Metabolic Markers: Insulin
Description
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
Title
Metabolic Markers: Glycerol
Description
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
Title
Vascular Markers
Description
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
Other Pre-specified Outcome Measures:
Title
Other Mitochondrial Measures: Mito Content and Electron Transport Chain Complexes
Description
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
Title
Oxidative Stress and Inflammatory Markers: Exploratory (Not Collected)
Description
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
Title
Counterregulatory Hormones
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
59 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Men and women, with and without type 1 diabetes between 25-59 years of age,
HbA1c 6.0-9.5 (T1D only),
Subjects who are willing to commit to:
14 days of prescribed diet,
two 44 hour inpatient stays, and
two muscle biopsies.
Exclusion Criteria:
Any comorbid condition associated with inflammation, insulin resistance, or dyslipidemia,
Tobacco use,
Pregnancy,
Steroid use,
Scheduled physical activity >3 days a week,
Angina or any other cardiovascular or pulmonary disease,
History of chronic obstructive pulmonary disease or asthma,
Systolic blood pressure >190 at rest or >250 with exercise, or
Diastolic pressure >95 at rest, or >105 with exercise,
Proteinuria (urine protein >200 mg/dl), or
Creatinine > 2 mg/dl, suggestive of severe renal disease,
Severe Proliferative retinopathy,
Niacin treatment,
History of peptic ulcers,
History of hereditary angioedema, and
C1 esterase deficiency.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Irene Schauer, MD, PhD
Organizational Affiliation
University of Colorado, Denver
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Colorado Denver
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Effects of Acipimox on Insulin Action, Vascular Function, and Muscle Function in Type 1 Diabetes
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