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Molecular Mechanisms of Type 2 Diabetes Mellitus

This study has been completed.
Sponsor:
Collaborator:
Takeda Global Research & Development Center, Inc.
Information provided by (Responsible Party):
The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier:
NCT00816218
First received: December 15, 2008
Last updated: May 30, 2012
Last verified: May 2012
History of Changes
  Purpose

This project is designed to evaluate the molecular mechanisms involved in the early development of endothelial dysfunction in type 2 diabetic patients. The investigators intend to correlate increases in insulin signaling pathway activity following pioglitazone therapy with improvements in nitric oxide synthase expression in skeletal muscle. In addition, the investigators will evaluate vascular responses and in vivo nitric oxide release during administration of acetylcholine and nitroprusside in patients with type 2 diabetes. Enhanced knowledge of the molecular mechanisms responsible for endothelial dysfunction, an early abnormality in the pathogenesis of atherosclerosis, is critical before novel therapies to arrest or delay the appearance of cardiovascular complications in diabetes can be developed.

The investigators intend to recruit fifty type 2 diabetic patients treated with diet alone or diet plus sulfonylureas or meglitinides and add Pioglitazone (45 mg), an insulin sensitizer, for 6 months. In addition to assessment of clinical and metabolic parameters, insulin sensitivity and brachial artery and skin microcirculatory responses to acetylcholine and nitroprusside in combination with simultaneous determination of nitric oxide release will be documented before, 3 and 6 months after Pioglitazone therapy is initiated. Circulating levels of markers of endothelial damage (VCAM, ICAM, selectins), inflammation (C-reactive protein and interleukins), increased coagulability (PAI-1) as well as lipids and apolipoproteins will measured during the study. Skeletal muscle biopsies will be performed during the euglycemic insulin clamp before and 6 months after therapy for measurements of NO synthase activity and key elements of the insulin signal transduction pathway involved in the regulation of glucose metabolism (IRS-1, PI-3 kinase, PI-3 kinase associated with IRS-1 and the mitogenesis MAP-kinase.

Type 2 diabetes confers a substantial increase in the risk of cardiovascular disease. This is believed to be due, in part, to endothelial dysfunction, which correlates closely with impaired vascular responsiveness. Our study will clarify further the extent to which resistance to insulin action and impaired nitric oxide release from endothelial cells are interrelated. We also expect to demonstrate that insulin sensitizers (pioglitazone) can help to restore normal endothelial function, and ultimately prevent/delay the appearance of vascular disease in patients with type 2 diabetes.


Condition Intervention Phase
Type 2 Diabetes Mellitus
 Drug: Pioglitazone
 Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Molecular Mechanisms of Endothelial Dysfunction in Type 2 Diabetes Mellitus

Resource links provided by NLM:

U.S. FDA Resources

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

Primary Outcome Measures:
  • Vascular Endothelial Function [ Time Frame: at 3 , 6 and 9 months post-therapy ] [ Designated as safety issue: No ]
    Brachial arterial dilation and blood flow


Secondary Outcome Measures:
  • Insulin Resistance [ Time Frame: Basal and 9 months ] [ Designated as safety issue: No ]
    Inmsulin-mediated glucose disposal


Enrollment: 39
Study Start Date: March 2003
Study Completion Date: November 2008
Primary Completion Date: July 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pioglitazone
Fifty type 2 diabetic patients (25 diet-treated and 25 treated with diet plus sulfonylurea) will have pioglitazone, 45 mg daily; added to their therapeutic regimen. All patients will be closely monitored and, in addition to periodic contacts and clinical visits, metabolic and vascular parameters will be assessed at the beginning and after 3 and 6 months of therapy. Euglycemic hyperinsulinemic clamp with muscle biopsies will be performed at the beginning and after 6 months of treatment.
 Drug: Pioglitazone
pioglitazone, 45 mg daily
Other Name: Actos

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. male or female 18-65 years of age;
  2. type 2 diabetes based on the American Diabetes Association criteria;
  3. HbA1c = 6.5-9.0% while on diet alone or diet plus sulfonylurea (or meglitinides) therapy;
  4. no history of thiazolidinediones, insulin, ACE inhibitor or AII-receptor blockade therapy;
  5. taking no medications known to affect glycemic control or endothelial function, unless the medication has been stable for at least 3 months;
  6. blood pressure equal or below 140/90 mmHg;
  7. not pregnant and willing to take appropriate contraceptive measures if capable of becoming pregnant;
  8. serum creatinine below 1.7 mg/dl in female and 1.8 mg/dl in males;
  9. ALT (SGTP) or AST (SGOT) less than 2 times the upper limit of normal for the laboratory and absence of clinical signs or symptoms of liver disease;
  10. hematocrit > 34% in females and >35% in males;
  11. normal thyroid function;
  12. no evidence of coronary heart disease (by history or EKG) or moderate to severe congestive heart failure (NY Heart Association Cardiac Class III or IV);
  13. no history or the presence of any clinically significant or unstable medical condition that makes the subject unlikely to complete the study in the opinion of the PI; and
  14. absence of any condition or situations which would preclude adherence and completion of the protocol;
  15. the ability to give voluntary informed consent.

Exclusion Criteria:

  1. Subjects were excluded from study if they had ever received insulin, metformin, TZDs, exenatide or DPP IV inhibitor.
  2. All subjects were free of cardiovascular, renal or major organ disease, as determined by medical history, physical examination, screening blood chemistries, complete blood cell count, and electrocardiogram.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00816218

Locations
United States, Texas
The University of Texas Health Science Center at San Antonio
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
The University of Texas Health Science Center at San Antonio
Takeda Global Research & Development Center, Inc.
Investigators
Principal Investigator: Eugene Cersosimo, MD The University of Texas Health Science Center at San Antonio
  More Information

No publications provided by The University of Texas Health Science Center at San Antonio

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT00816218     History of Changes
Other Study ID Numbers: 012-5014-401
Study First Received: December 15, 2008
Last Updated: May 30, 2012
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
 Pioglitazone
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 22, 2013