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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Franco Folli, MD, The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier:
NCT01223196
First received: July 21, 2010
Last updated: December 9, 2015
Last verified: December 2015
  Purpose

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 Intervention Phase
Type 2 Diabetes
Drug: Pioglitazone
Drug: Placebo
Phase 4

Study Type: Interventional
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.

Resource links provided by NLM:


Further study details as provided by The University of Texas Health Science Center at San Antonio:

Primary Outcome Measures:
  • 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)



Secondary Outcome Measures:
  • 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.)


Other Outcome Measures:
  • 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).


Enrollment: 60
Study Start Date: August 2009
Study Completion Date: December 2011
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Genders Eligible for Study:   Both
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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
  More Information

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 
Study First Received: July 21, 2010
Results First Received: February 19, 2013
Last Updated: December 9, 2015
Health Authority: United States: Institutional Review Board

Keywords provided by 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

ClinicalTrials.gov processed this record on August 23, 2016