Molecular Mechanisms of Type 2 Diabetes Mellitus
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|ClinicalTrials.gov Identifier: NCT00816218|
Recruitment Status : Completed
First Posted : January 1, 2009
Last Update Posted : May 31, 2012
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 or disease||Intervention/treatment||Phase|
|Type 2 Diabetes Mellitus||Drug: Pioglitazone||Phase 4|
Show Detailed Description
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||39 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Molecular Mechanisms of Endothelial Dysfunction in Type 2 Diabetes Mellitus|
|Study Start Date :||March 2003|
|Actual Primary Completion Date :||July 2006|
|Actual Study Completion Date :||November 2008|
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.
pioglitazone, 45 mg daily
Other Name: Actos
- Vascular Endothelial Function [ Time Frame: at 3 , 6 and 9 months post-therapy ]Brachial arterial dilation and blood flow
- Insulin Resistance [ Time Frame: Basal and 9 months ]Inmsulin-mediated glucose disposal
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): NCT00816218
|United States, Texas|
|The University of Texas Health Science Center at San Antonio|
|San Antonio, Texas, United States, 78229|
|Principal Investigator:||Eugene Cersosimo, MD||The University of Texas Health Science Center at San Antonio|