Role of Lipotoxicity in Insulin Resistance, Vascular, and Mitochondrial Dysfunction in Type 1 Diabetes
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- Insulin Sensitivity: M-value From Hyperinsulinemic Euglycemia Clamp Study
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 25 Years 至 59 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •Any comorbid condition associated with inflammation, insulin resistance, or dyslipidemia,
- •Tobacco use,
- •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.
研究组 & 干预措施
Acipimox
Drug: acipimox
干预措施: Acipimox (Drug)
Placebo
Drug: Placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Insulin Sensitivity: M-value From Hyperinsulinemic Euglycemia Clamp Study
时间窗: 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.
24 Hour Mean Fatty Acid Levels
时间窗: 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).
Percent Flow-mediated Brachial Artery Dilation
时间窗: 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.
State 3 Mitochondrial Oxygen Consumption
时间窗: 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.
次要结局
- Arterial Stiffness (AI)(day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment)
- Oxidative Stress and Inflammatory Markers: TNFalpha(day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment)
- Oxidative Stress and Inflammatory Markers: 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)(day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment)
- Heart Rate Variability(day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment)
- Arterial Stiffness (PWV)(day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment)
- Metabolic Markers: Continuous Glucose Monitoring Measures(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(day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment)
- Oxidative Stress and Inflammatory Markers: Interleukin 6 (IL6)(day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment)
- Metabolic Markers: Insulin(day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment)
- Metabolic Markers: Glycerol(day 6 to 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)(day 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment)
- Vascular Markers(day 6 to 7 of each of the 2 random order intervention phases; max 16 weeks post enrollment)