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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
28
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.
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
University of Colorado Denver
Aurora, Colorado, United States
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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