Pilot Study of the Efficacy of Mifepristone in Males with Type 2 Diabetes Mellitu

米非司酮对男性 2 型糖尿病患者疗效的初步研究

• 批准号: 9566210
• 负责人: Stanley Hsia
• 金额: $ 10.76万
• 依托单位: CHARLES R. DREW UNIVERSITY OF MED & SCI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9566210
• 关键词: Adrenal Gland Hyperfunction; Adverse effects; Affect; Anti-Progestin; Beta Cell; Blood Pressure; Body Composition; Body Weight; Caucasians; Cell physiology; Clinical; Clinical Trials; Closure by clamp; Counseling; Development; Diabetes Mellitus; Diet; Dose; Double-Blind Method; Enrollment; Epidemic; Esterified Fatty Acids; Fatty Acids; Follow-Up Studies; Functional disorder; Funding; Glucocorticoid Receptor; Glucocorticoids; Glucose; Gynecology; Hepatic; Hydrocortisone; Hyperglycemia; Hypoglycemic Agents; Indirect Calorimetry; Individual; Insulin; Intravenous infusion procedures; Investigation; Lead; Life Style; Lipids; Low income; Measures; Mediating; Mifepristone; Minority Groups; Molecular; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Oral; Outcome Measure; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Pilot Projects; Pituitary-dependent Cushing' s disease; Placebos; Play; Population; Prevalence; Procedures; Productivity; Protocols documentation; Public Health; Randomized; Research; Role; Safety; Secondary to; Standardization; Steroids; Tablets; Termination of pregnancy; Whole Organism; Woman; blood glucose regulation; body system; career; common treatment; diabetic patient; dosage; efficacy study; glucose disposal; glucose output; glycemic control; improved; in vivo; insulin secretion; insulin sensitivity; male; men; oxidation; public health relevance; racial minority; response; treatment choice

 DESCRIPTION (provided by applicant): Type 2 diabetes mellitus affects a growing number of individuals worldwide, and U.S. racial minority groups in particular. States of excess cortisol secretion (Cushing's disease) are associated with hyperglycemia and diabetes mellitus. Mifepristone inhibits the action of glucocorticoids and is currently approved for the treatment of hyperglycemia in patients with Cushing's disease. We propose to study the efficacy of mifepristone in patients with "usual" type 2 diabetes mellitus not associated with Cushing's disease, wherein more subtle abnormalities of cortisol action may still play a role in adversely affecting glucose control. Because mifepristone may also have gynecological side effects due to anti-­‐progesterone effects and is also used clinically by women for pregnancy termination, we will restrict this initial pilot study to men only; if this project determines that it has favorabl actions on glucose lowering in men, it would then justify replicating this study in women to assess its glycemic benefits against those potential gynecological side effects. This pilot project will enroll 60 predominantly racial minority male subjects with type 2 diabetes mellitus inadequately controlled on combination oral agents. They will be randomized to receive either mifepristone 600 mg daily or matching placebo tablets, in a double blind fashion, for 3 months. All concurrent medication dosages will be kept constant, and consistent dietary and lifestyle counseling will be provided. Changes in glucose control, body weight and body composition, measures of insulin sensitivity and beta cell function from oral glucose tolerance testing, lipids, blood pressure, and clinical safety will be compared between groups. At baseline and at 3 months, a subset of 10 subjects will also undergo a euglycemic hyperinsulinemic clamp procedure to determine physiological responses to a standardized intravenous infusion of high-­‐dose insulin, measuring insulin-­‐mediated glucose uptke, insulin mediated suppression of hepatic glucose output, and suppression of non-­‐ esterified fatty acids. Indirect calorimetry will also be performed simultaneously to determine changes in rates of insulin-­‐stimulated glucose oxidation, non-­‐oxidative glucose disposal and suppression of lipid oxidation. If successful, our findings will 1) support further follow-�up studies to delineate a potential clinical role for mifepristone as a new pharmaceutical choice for the treatment of "common-­‐variety" type 2 diabetes; 2) support further molecular, cellular and in vivo investigations into the mechanisms of how usual physiological levels of glucocorticoids contribute to the pathophysiology of type 2 diabetes, both at the intracellular and whole organism levels; and 3) stimulate greater research productivity for the PI towards achieving independent funding for additional studies aimed at better understanding all of the above research aims.

 描述（由适用提供）：2型糖尿病会影响全球越来越多的个人，尤其是美国族裔少数群体。过度皮质醇分泌（库欣氏病）的状态与高血糖和糖尿病有关。米沙酮抑制了糖皮质激素的作用，目前已批准用于治疗库欣病患者的高血糖。我们建议研究米非酮在与库欣氏病无关的“常规” 2型糖尿病患者中的有效性，其中皮质醇作用的更微妙的异常可能仍可能在不利影响葡萄糖控制中发挥作用。由于米非生剂也可能由于抗孕酮作用而产生妇科副作用，并且在妇女临床上也用于妊娠终止，我们将仅将此初步的试点研究限制在男性中。如果该项目确定其对男性降低葡萄糖的最爱作用，那么它将证明在女性中复制这项研究以评估其血糖益处，以应对那些潜在的妇科副作用。这个试点项目 他们将招募60名主要是种族少数族裔男性受试者，其中2型糖尿病对口服剂的控制不足。他们将被随机接收每天600毫克的米非司酮或以双盲方式匹配的安慰剂片，持续3个月。所有并发药物剂量将保持恒定，并提供一致的饮食和生活方式咨询。葡萄糖控制，体重和体内组成的变化，胰岛素敏感性的度量以及口服葡萄糖耐受性测试，脂质，血压和临床安全性的β细胞功能将在组之间进行比较。 基线和3个月时，10个受试者的子集还将强调一种葡萄糖高胰岛素夹的程序，以确定对标准化的高剂量胰岛素静脉注入的物理反应，测量胰岛素介导的葡萄糖UPTKE，胰岛素介导的胰岛素介导的肝葡萄糖输出抑制非脂肪含量 - 抑制非脂肪酸化。还将简单地进行间接量热法，以确定胰岛素氧化，非氧化葡萄糖处置以及脂质氧化抑制的变化。如果成功的话，我们的发现将1）支持进一步的后续研究，以描述米非司酮的潜在临床作用，为新的药物选择 2型糖尿病的“常见 - 变化”治疗； 2）支持进一步的分子，细胞和 在体内研究糖皮质激素的通常生理水平如何在细胞内和整个生物体水平上有助于2型糖尿病的病理生理学的机制； 3）刺激PI的更大研究生产力，以获得独立的资金，以更好地理解上述所有研究目的。