Effect of Pioglitazone on TIMP-3 and TACE in Type 2 Diabetes

• Status: Completed
• Trial end date: 2011-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: The University of Texas Health Science Center at San Antonio
• Treatments: Matrix Metalloproteinase Inhibitors; Pioglitazone; TIMP1 protein, human; TIMP3 protein, human; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-3; Tissue Inhibitor of Metalloproteinases

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