Effects of Acipimox on Insulin Action, Vascular Function, and Muscle Function in Type 1 Diabetes (AcT1)

Role of Lipotoxicity in Insulin Resistance, Vascular, and Mitochondrial Dysfunction 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.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: Acipimox; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 59 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Drug: Placebo	Drug: Placebo; 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
Experimental: Acipimox; Drug: acipimox	Drug: Acipimox; 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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other Mitochondrial Measures: Mito Content and Electron Transport Chain Complexes	Mito content and electron transport chain complexes by western blot analysis.	day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
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,	day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment
Counterregulatory Hormones	Planned glucagon and cortisol as a markers of counteregulation, but not done due to financial limitations	day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: Irene Schauer, MD, PhD, University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): June 24, 2015
• Study Completion (Actual): June 24, 2015

Study Registration Dates

• First Submitted: June 13, 2012
• First Submitted That Met QC Criteria: March 18, 2013
• First Posted (Estimate): March 22, 2013

Study Record Updates

• Last Update Posted (Actual): January 21, 2022
• Last Update Submitted That Met QC Criteria: December 21, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: diabetes; insulin; blood vessel; type 1
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Acipimox
• Other Study ID Numbers: 11-0649; 6181 (Other Identifier: CTRC)