Molecular Mechanisms of Endothelial Dysfunction in Type 2 Diabetes Mellitus
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 39
- 试验地点
- 1
- 主要终点
- Vascular Endothelial Function
研究概览
简要总结
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.
详细描述
Specific Aims
To test the global hypothesis that increases in insulin signaling through either PI-3-kinase or MAP kinase pathways correlate with improvements in NO production or NOS expression in skeletal muscle following pioglitazone therapy, we will determine whether 6 months of Pioglitazone therapy:
i. Increases the activities of muscle NO synthase, IRS-1, PI-3 kinase, PI3-kinase associated with IRS-1 and/or MAP-kinase ii. Improves brachial arterial endothelial function In addition, we will determine whether 6 months of pioglitazone therapy improves abnormal cardiovascular disease risk factors in type 2 diabetic patients by documenting the effects of the drug on plasma lipoprotein profile and on circulating levels of markers of hypercoagulability, inflammatory and endothelial damage.
Experimental Plan Subjects. Adult type 2 diabetic individuals ranging from 18-65 yrs, with BMI between 24 and 37 kg/m2 and mean hemoglobin A1c levels equal to 6.5 and 9.0% will be studied. A total of 50 subjects will be recruited. There are over 8,000 type 2 diabetic patients under treatment at the TDI with a total of approximately 90,000 visits per year registered in the year 2000. As the main source of diabetes care and education to a population of predominantly Hispanic Americans, the TDI also is responsible for periodic screening in the community. Thus, we do not anticipate any problems in recruiting 50 subjects required for the present study. All patients will be normotensive, free of significant medical problems other than diabetes, and either on diet alone or diet plus sulfonylurea (or meglitinides) therapy. Subjects who have received or are receiving treatment with a thiazolidinedione (TZD) will be excluded. We previously have shown that sulfonyureas have no direct insulin sensitizing effect.
Research Design. General Approach. An open-label prospective clinical trial including 50 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Pioglitazone (Drug)
结局指标
主要结局
Vascular Endothelial Function
时间窗: at 3 , 6 and 9 months post-therapy
Brachial arterial dilation and blood flow
次要结局
- Insulin Resistance(Basal and 9 months)