Molecular Mechanisms of Type 2 Diabetes Mellitus

NCT00816218 | Completed Phase 4

• 1 other identifier: 012-5014-401
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Type 2 Diabetes Mellitus

Outcome Measures

Primary Outcomes (1)

• Vascular Endothelial Function

  Brachial arterial dilation and blood flow

  at 3 , 6 and 9 months post-therapy

Secondary Outcomes (1)

• Insulin Resistance

  Basal and 9 months

Study Arms (1)

Pioglitazone

EXPERIMENTAL

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

Interventions

Pioglitazone DRUG

pioglitazone, 45 mg daily

Also known as: Actos

Pioglitazone

Eligibility Criteria

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

You may qualify if:

• male or female 18-65 years of age;
• type 2 diabetes based on the American Diabetes Association criteria;
• HbA1c = 6.5-9.0% while on diet alone or diet plus sulfonylurea (or meglitinides) therapy;
• no history of thiazolidinediones, insulin, ACE inhibitor or AII-receptor blockade therapy;
• taking no medications known to affect glycemic control or endothelial function, unless the medication has been stable for at least 3 months;
• blood pressure equal or below 140/90 mmHg;
• not pregnant and willing to take appropriate contraceptive measures if capable of becoming pregnant;
• serum creatinine below 1.7 mg/dl in female and 1.8 mg/dl in males;
• 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;
• hematocrit \> 34% in females and \>35% in males;
• normal thyroid function;
• 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);
• 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
• absence of any condition or situations which would preclude adherence and completion of the protocol;
• the ability to give voluntary informed consent.

You may not qualify if:

• Subjects were excluded from study if they had ever received insulin, metformin, TZDs, exenatide or DPP IV inhibitor.
• 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.

Sponsors & Collaborators

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

Study Sites (1)

The University of Texas Health Science Center at San Antonio

San Antonio, Texas, 78229, United States

Location

Related Publications (1)

• Coletta DK, Sriwijitkamol A, Wajcberg E, Tantiwong P, Li M, Prentki M, Madiraju M, Jenkinson CP, Cersosimo E, Musi N, Defronzo RA. Pioglitazone stimulates AMP-activated protein kinase signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation in human skeletal muscle in vivo: a randomised trial. Diabetologia. 2009 Apr;52(4):723-32. doi: 10.1007/s00125-008-1256-9. Epub 2009 Jan 24.

  PMID: 19169664 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Pioglitazone

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

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

Study Officials

• Eugene Cersosimo, MD

  The University of Texas Health Science Center at San Antonio

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 15, 2008
• First Posted: January 1, 2009
• Study Start: March 1, 2003
• Primary Completion: July 1, 2006
• Study Completion: November 1, 2008
• Last Updated: May 31, 2012

Record last verified: 2012-05

Locations

US (1)