Effect of Pioglitazone on TIMP-3 and TACE in Type 2 Diabetes
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus, Type 2
Intervention: Pioglitazone; Placebo
Intervention description: This study will examine the effect of Pioglitazone on tissue inhibitor of metalloproteinases (TIMP-3) and on TNF-alfa converting enzyme in the skeletal muscle of type 2 diabetic subjects.; Inactive placebo for comparison to Pioglitazone on tissue inhibitor of metalloproteinases (TIMP-3) and on TNF-alfa converting enzyme in the skeletal muscle of type 2 diabetic subjects.
Intervention MeSH terms: Pioglitazone
Phase: Phase 4
Study type: Interventional
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 60.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Type 2 Diabetes, Thiazolidinediones, TIMP-3, TACE, TNF-a,; insulin resistance

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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

        Exclusion Criteria:

          -  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