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

NCT01223196 | Completed Phase 4 Results

• 1 other identifier: HSC20080452
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Type 2 Diabetes

Keywords

Type 2 Diabetes, Thiazolidinediones, TIMP-3, TACE, TNF-a,; insulin resistance

Outcome Measures

Primary Outcomes (1)

• Whole Body Insulin Sensitivity During the Euglycemic Insulin Clamp

  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)

  6 months

Secondary Outcomes (1)

• Effect of Pioglitazone on TNF (Tumor Necrosis Factor) Alpha Converting Enzyme (TACE) Activity in Skeletal Muscle.

  6 months

Other Outcomes (1)

• Percentage (%) of Haemoglobin A1C

  6 months

Study Arms (2)

Placebo

PLACEBO COMPARATOR

One arm of the study subjects will be treated with Placebo only, once a day, for 6 months

Drug: Placebo

Pioglitazone

ACTIVE COMPARATOR

One arm of the study subjects will be treated with Pioglitazone, 15mg, once a day, for 6 months

Drug: Pioglitazone

Interventions

Pioglitazone DRUG

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.

Also known as: ACTOS

Pioglitazone

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• The University of Texas Health Science Center at San Antonio: lead

Study Sites (1)

Bartter Research Unit , ALM VA Hospital

San Antonio, Texas, 78229, United States

Location

Related Publications (1)

• Tripathy D, Daniele G, Fiorentino TV, Perez-Cadena Z, Chavez-Velasquez A, Kamath S, Fanti P, Jenkinson C, Andreozzi F, Federici M, Gastaldelli A, Defronzo RA, Folli F. Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3-TACE dyad in type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled, mechanistic study. Diabetologia. 2013 Oct;56(10):2153-63. doi: 10.1007/s00125-013-2976-z. Epub 2013 Jun 30.

  PMID: 23811853 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Insulin Resistance

Interventions

Pioglitazone

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Franco Folli, MD PhD/Professor
• Organization: UT Health Science Center San Antonio

FOLLI@uthscsa.edu

210-567-4826

Study Officials

• Franco Folli, MD

  The University of Texas Health Science Center at San Antonio

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: July 21, 2010
• First Posted: October 18, 2010
• Study Start: August 1, 2009
• Primary Completion: December 1, 2011
• Study Completion: December 1, 2011
• Last Updated: January 11, 2016
• Results First Posted: November 13, 2014

Record last verified: 2015-12

Locations

US (1)