Effect of Pioglitazone on Tissue Inhibitor of Metalloproteinases 3 (TIMP-3) and TNF (Tumor Necrosis Factor)-α Converting Enzyme (TACE) in Skeletal Muscle and Their Circulating Substrates.
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Whole Body Insulin Sensitivity During the Euglycemic Insulin Clamp
研究概览
简要总结
Background: Pioglitazone has been shown to have potent anti-inflammatory as well anti-atherosclerotic effects. However, the mechanisms by which pioglitazone exerts these effects are not clear. The investigators propose that Tissue Inhibitor of MetalloProteinase-3 (TIMP-3) and TNF-alfa converting enzyme (TACE) play a major role in pioglitazone mediated improvement in insulin sensitivity and endothelial function. In animal models, low dose pioglitazone inhibits lesion progression and matrix metalloproteinase expression in advanced atherosclerotic plaques. The investigators believe that a lower dose of Pioglitazone will also have anti-inflammatory effects.
Aim: To examine the effect of low dose Pioglitazone (15mg/day) on TIMP and TACE in Pioglitazone mediated improvements in insulin sensitivity.
Methods: Thirty subjects with T2DM will participate in following studies: (i) oral glucose tolerance test (OGTT); (ii) Dual energy absorptiometry(DXA) for body fat content, (iv) skeletal muscle biopsy. Subjects will be randomized to receive either placebo or pioglitazone for 24 weeks. The investigators will study the effect of Pioglitazone on (1) TIMP and TACE substrate activity in skeletal muscle, adipose tissue, mononuclear cells, and their relationship to insulin sensitivity and vascular reactivity, other adipocytokines- resistin, TNF-α and Visfatin; (2) markers of inflammation and atherosclerosis- C-reactive protein, VCAM-1 (vascular cell adhesion molecule 1), ICAM-1 (Intercellular Adhesion Molecule 1), endothelin 1, E-selectin, P-selectin, TNFrecI (Tumor Necrosis Factor Receptor I), TNFrecII (Tumor Necrosis Factor Receptor II), IL-6 (Interleukin 6) receptor.
详细描述
Pioglitazone has been shown to have potent anti-inflammatory as well anti-atherosclerotic effects. However, the mechanisms by which pioglitazone exerts these effects are not clear. We propose that tissue inhibitor of metalloproteinase-3 (TIMP-3) and TNF-alfa converting enzyme (TACE) play a major role in pioglitazone mediated improvement in insulin sensitivity and endothelial function. In animal models, low dose pioglitazone inhibits lesion progression and matrix metalloproteinase expression in advanced atherosclerotic plaques. We believe that a lower dose of Pioglitazone will also have anti-inflammatory effects without the potential adverse effects of weight gain.
In order to examine the effect of low dose Pioglitazone (15mg/day) on TIMP-3 and TACE in Pioglitazone mediated improvements in insulin sensitivity and endothelial function, we propose to study subjects with type 2 diabetes mellitus (T2DM) will participate in following studies: (i) OGTT; (ii) DXA for body fat content, (iii) euglycemic hyperinsulinemic clamp, (iv) skeletal muscle biopsy.
This study will examine the effect of Pioglitazone on (1) TIMP and TACE substrate activity in skeletal muscle and their relationship to insulin sensitivity and adipocytokines- resistin, TNF-α and Visfatin; (2) markers of inflammation and atherosclerosis- C-reactive protein, VCAM-1, ICAM-1, endothelin 1, E-selectin, P-selectin, TNFrecI, TNFrecII, IL-6 rec. Fifteen subjects will receive placebo and 15 will receive pioglitazone.
Study Design.
Double blind placebo controlled parallel design.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Fasting plasma Glucose- 126-270
- •HbA1c <10%
- •Hematocrit >34%
- •Serum creatinine <1.8mg/dl
- •AST (aspartate aminotransferase) < 2 times upper limit of normal
- •ALT (Alanine aminotransferase) < 2 time upper limit of normal
- •Alkaline phosphatase <2 times upper limit of normal
排除标准
- •Type 1 DM
- •Fasting plasma glucose >270 mg/dl
- •Thiazolidinedione therapy
- •Insulin therapy in last 3 months
- •Congestive heart failure > NYHA (New York Heart Association) class II
- •History of dyspnoea on exertion
- •Abnormal breath sounds
- •EKG changes other than non-specific ST-T changes in the ECG (Electro-CardioGram) or LVH (Left Ventricular Hypertrophy)
- •H/O Claudication
研究组 & 干预措施
Placebo
One arm of the study subjects will be treated with Placebo only, once a day, for 6 months
干预措施: Placebo (Drug)
Pioglitazone
One arm of the study subjects will be treated with Pioglitazone, 15mg, once a day, for 6 months
干预措施: Pioglitazone (Drug)
结局指标
主要结局
Whole Body Insulin Sensitivity During the Euglycemic Insulin Clamp
时间窗: 6 months
Insulin sensitivity was measured by the euglycemic clamp before and 6 months after PIO (PIOGLITAZONE) or PLAC (PLACEBO) treatment. The outcome measure is Insulin sensitivity obtained from euglycemic insulin clamp and it is called M/I, where M = whole body glucose uptake during the euglycemic insulin clamp and I = circulating insulin levels during the euglycemic insulin clamp. It is expressed as Mg. of glucose/kg body weight/mU (milli Unit)x l (liter).of insulin (Ins)
次要结局
- Effect of Pioglitazone on TNF (Tumor Necrosis Factor) Alpha Converting Enzyme (TACE) Activity in Skeletal Muscle.(6 months)
研究者
Franco Folli, MD
Professor of Medicine
The University of Texas Health Science Center at San Antonio