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Completed

NCT Number: NCT01816165

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

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.

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Key information

Conditions

Type 1 Diabetes Autoimmune Diseases Diabetes Mellitus Diabetes Mellitus, Type 1 Endocrine System Diseases Glucose Metabolism Disorders Hyperinsulinism Immune System Diseases Insulin Resistance Metabolic Diseases Nutritional and Metabolic Diseases

Age range

25 year–59 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

University of Colorado Denver

Aurora, Colorado, 80045, United States

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Acipimox

Drug

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.

Other names: Olbetam

Placebo

Drug

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 outcomes

  1. Insulin Sensitivity: M-value From Hyperinsulinemic Euglycemia Clamp Study

    Time frame: 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.

  2. 24 Hour Mean Fatty Acid Levels

    Time frame: 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).

  3. Percent Flow-mediated Brachial Artery Dilation

    Time frame: 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.

  4. State 3 Mitochondrial Oxygen Consumption

    Time frame: 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.

Secondary outcomes

  1. Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6)

    Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment

    Interleukin 6 (IL6)

  2. Oxidative Stress and Inflammatory Markers: TNFalpha

    Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment

    TNFalpha

  3. Oxidative Stress and Inflammatory Markers: High-sensitivity C-reactive Protein (hsCRP)

    Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment

    high-sensitivity C-reactive protein (hsCRP)

  4. Oxidative Stress and Inflammatory Markers: Adiponectin

    Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment

    adiponectin

  5. Oxidative Stress and Inflammatory Markers: Plasminogen Activator Inhibitor (PAI-1)

    Time frame: day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment

    Plasminogen activator inhibitor (PAI-1)

  6. Heart Rate Variability

    Time frame: 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.

  7. Arterial Stiffness (PWV)

    Time frame: 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.

  8. Arterial Stiffness (AI)

    Time frame: 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

  9. Metabolic Markers: Continuous Glucose Monitoring Measures

    Time frame: 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.

  10. Metabolic Markers: Mean 24 Hour Triglyceride and Glucose Levels

    Time frame: 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).

  11. Metabolic Markers: Insulin

    Time frame: 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).

  12. Metabolic Markers: Glycerol

    Time frame: 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).

  13. Vascular Markers

    Time frame: 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

Other outcomes

  1. Other Mitochondrial Measures: Mito Content and Electron Transport Chain Complexes

    Time frame: 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.

  2. Oxidative Stress and Inflammatory Markers: Exploratory (Not Collected)

    Time frame: 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,

  3. Counterregulatory Hormones

    Time frame: 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

Sponsors and collaborators

Lead sponsor

University of Colorado, Denver

Other

Registry information

Official study title

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

Acronym: AcT1

Important dates

Study start
2011
Primary completion
2015
Study completion
2015
First posted
Mar 22, 2013
Registry last updated
Jan 21, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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