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

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ClinicalTrials.gov Identifier: NCT01223196
Recruitment Status : Completed
First Posted : October 18, 2010
Results First Posted : November 13, 2014
Last Update Posted : January 11, 2016
Sponsor:
Information provided by (Responsible Party):
Franco Folli, MD, The University of Texas Health Science Center at San Antonio

Brief 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.


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Drug: Pioglitazone Drug: Placebo Phase 4

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, 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.
Study Start Date : August 2009
Actual Primary Completion Date : December 2011
Actual Study Completion Date : December 2011

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebo
One arm of the study subjects will be treated with Placebo only, once a day, for 6 months
Drug: Placebo
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
Drug: Pioglitazone
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




Primary Outcome Measures :
  1. Whole Body Insulin Sensitivity During the Euglycemic Insulin Clamp [ Time Frame: 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)



Secondary Outcome Measures :
  1. Effect of Pioglitazone on TNF (Tumor Necrosis Factor) Alpha Converting Enzyme (TACE) Activity in Skeletal Muscle. [ Time Frame: 6 months ]
    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.)


Other Outcome Measures:
  1. Percentage (%) of Haemoglobin A1C [ Time Frame: 6 months ]
    HbA1c (Haemoglobin A1c) is glycosylated haemoglobin, measured as a % of total Hb in red blood cells by a standard biochemical method (HPLC).



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01223196


Locations
United States, Texas
Bartter Research Unit , ALM VA Hospital
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
The University of Texas Health Science Center at San Antonio
Investigators
Principal Investigator: Franco Folli, MD The University of Texas Health Science Center at San Antonio

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Franco Folli, MD, Professor of Medicine, The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT01223196     History of Changes
Other Study ID Numbers: HSC20080452
First Posted: October 18, 2010    Key Record Dates
Results First Posted: November 13, 2014
Last Update Posted: January 11, 2016
Last Verified: December 2015

Keywords provided by Franco Folli, MD, The University of Texas Health Science Center at San Antonio:
Type 2 Diabetes, Thiazolidinediones, TIMP-3, TACE, TNF-a,
insulin resistance

Additional relevant MeSH terms:
Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Pioglitazone
Tissue Inhibitor of Metalloproteinases
Tissue Inhibitor of Metalloproteinase-1
Matrix Metalloproteinase Inhibitors
Tissue Inhibitor of Metalloproteinase-3
TIMP1 protein, human
TIMP3 protein, human
Hypoglycemic Agents
Physiological Effects of Drugs
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action