Effects of Acipimox on Insulin Action, Vascular Function, and Muscle Function in Type 1 Diabetes

Study Overview
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Brief Summary
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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.

Official Title
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Role of Lipotoxicity in Insulin Resistance, Vascular, and Mitochondrial Dysfunction in Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Acipimox
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acipimox<br>Drug: acipimox | Drug: Acipimox<br>* 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.<br>* Other names: Olbetam;|
| Placebo Comparator: Placebo<br>Drug: Placebo | Drug: Placebo<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | day 8 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| 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). | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| 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. | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| 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. | muscle biopsy on day 7 of each weeklong intervention period; max 16 weeks post enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6) | Interleukin 6 (IL6) | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| Oxidative Stress and Inflammatory Markers: TNFalpha | TNFalpha | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| Oxidative Stress and Inflammatory Markers: High-sensitivity C-reactive Protein (hsCRP) | high-sensitivity C-reactive protein (hsCRP) | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| Oxidative Stress and Inflammatory Markers: Adiponectin | adiponectin | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| Oxidative Stress and Inflammatory Markers: Plasminogen Activator Inhibitor (PAI-1) | Plasminogen activator inhibitor (PAI-1) | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| Heart Rate Variability | Measure of autonomic function; ratio of fastest to slowest heart rate during valsalva maneuver. | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| Arterial Stiffness (PWV) | Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec. Higher values reflect a stiffer vasculature. | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| 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 | day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| Metabolic Markers: Continuous Glucose Monitoring Measures | Continuous glucose monitoring measures for 3 days before clamp. Collected for participants with T1 Diabetes only. | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| 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). | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| 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). | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| 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). | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 
| Vascular Markers | endothelin 1 measured as a marker of vascular damage | day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, insulin, blood vessel, type 1