Effect of Pioglitazone on TIMP-3 and TACE in Type 2 Diabetes (PIO-TACE)
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.
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
|Official Title:||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.|
- Whole Body Insulin Sensitivity During the Euglycemic Insulin Clamp [ Time Frame: 6 months ] [ Designated as safety issue: No ]
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)
- Effect of Pioglitazone on TNF (Tumor Necrosis Factor) Alpha Converting Enzyme (TACE) Activity in Skeletal Muscle. [ Time Frame: 6 months ] [ Designated as safety issue: No ]The activity of TACE is measured by detecting the release of a fluorogenic synthetic substrate of TACE and measuring in a fluorometer. It is expressed in Fluorescence Units (F.U.)
- Percentage (%) of Haemoglobin A1C [ Time Frame: 6 months ] [ Designated as safety issue: No ]HbA1c (Haemoglobin A1c) is glycosylated haemoglobin, measured as a % of total Hb in red blood cells by a standard biochemical method (HPLC).
|Study Start Date:||August 2009|
|Study Completion Date:||December 2011|
|Primary Completion Date:||December 2011 (Final data collection date for primary outcome measure)|
Placebo Comparator: Placebo
One arm of the study subjects will be treated with Placebo only, once a day, for 6 months
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.
Active Comparator: Pioglitazone
One arm of the study subjects will be treated with Pioglitazone, 15mg, once a day, for 6 months
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.
Other Name: ACTOS
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01223196
|United States, Texas|
|Bartter Research Unit , ALM VA Hospital|
|San Antonio, Texas, United States, 78229|
|Principal Investigator:||Franco Folli, MD||The University of Texas Health Science Center at San Antonio|