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(申请人提供)：2型糖尿病影响着全球越来越多的人，特别是美国的少数族裔群体。皮质醇分泌过多的状态(库欣病)与高血糖和糖尿病有关。米非司酮抑制糖皮质激素的作用，目前被批准用于治疗库欣病患者的高血糖。我们建议研究米非司酮对与库欣病无关的“普通”2型糖尿病患者的疗效，在这些患者中，皮质醇作用的更微妙的异常可能仍然在不利影响血糖控制方面发挥作用。由于米非司酮也可能由于抗孕酮作用而产生妇科副作用，而且也被女性用于临床终止妊娠，我们将把这项初步的初步研究仅限于男性；如果该项目确定它对男性降糖有有利作用，那么它将有理由在女性身上重复这项研究，以评估其针对这些潜在的妇科副作用的血糖益处。这一试点项目 将招募60名服用联合口服药物控制不佳的2型糖尿病男性受试者，这些受试者以少数族裔为主。他们将随机接受米非司酮600毫克的每日治疗，或以双盲方式服用与之匹配的安慰剂片，为期3个月。所有同时服药的剂量将保持不变，并将提供一致的饮食和生活方式咨询。将比较两组在血糖控制、体重和身体成分、口服葡萄糖耐量试验中的胰岛素敏感性和β细胞功能、血脂、血压和临床安全性方面的变化。在… 在基线和3个月后，10名受试者的子组还将接受正常血糖高胰岛素钳夹程序，以确定对标准化静脉输注大剂量胰岛素的生理反应，测量胰岛素介导的血糖升高，胰岛素介导的抑制肝脏葡萄糖输出，以及抑制非酯化脂肪酸。间接量热法也将同时进行，以确定胰岛素刺激的葡萄糖氧化、非氧化性葡萄糖处置和抑制脂质氧化的速率的变化。如果成功，我们的发现将1)支持进一步的�随访研究，以描绘米非司酮作为治疗 治疗“常见的”2型糖尿病；2)进一步支持分子、细胞和 在体内研究糖皮质激素通常的生理水平如何在细胞内和整个生物体水平上促进2型糖尿病的病理生理机制；以及3)刺激PI提高研究生产力，以实现旨在更好地理解所有上述研究目的的额外研究的独立资金。