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: 9073698
• 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/9073698
• 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; 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; Hepatic; Hydrocortisone; Hyperglycemia; 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; Staging; Steroids; Tablets; Termination of pregnancy; Whole Organism; Woman; blood glucose regulation; body system; career; common treatment; diabetic patient; dosage; follow-up; 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（由申请人提供）：2型糖尿病影响全球越来越多的个体，特别是美国少数民族。皮质醇分泌过多（库欣病）与高血糖症和糖尿病有关。米非司酮抑制糖皮质激素的作用，目前已被批准用于治疗库欣病患者的高血糖症。我们建议研究米非司酮在“普通”2型糖尿病患者中的疗效，这些患者与库欣病无关，其中皮质醇作用的更微妙的异常可能仍然在不利地影响血糖控制中发挥作用。由于米非司酮也可能因抗孕酮作用而具有妇科副作用，并且临床上也被女性用于终止妊娠，因此我们将仅将该初步初步研究限制在男性中;如果该项目确定其对男性的降糖作用是可行的，则证明在女性中复制该研究是合理的，以评估其对这些潜在妇科副作用的血糖益处。这一试点项目 将入组60例主要为少数种族的2型糖尿病男性受试者，这些受试者接受复方口服降糖药后血糖控制不佳 剂.他们将随机接受米非司酮600毫克，每天或匹配的安慰剂片剂，在一个双盲的方式，为3个月。所有并发药物剂量将保持不变，并提供一致的饮食和生活方式咨询。血糖控制、体重和身体成分、胰岛素敏感性和口服葡萄糖耐量试验的β细胞功能、血脂、血压和临床安全性的变化将被纳入研究。 组间比较。 在 在基线和3个月时，10名受试者的亚组还将接受正常血糖高胰岛素钳夹程序，以确定对标准化高剂量胰岛素静脉输注的生理反应， 测量胰岛素-β介导的葡萄糖升高，胰岛素介导的肝脏抑制 葡萄糖输出和非酯化脂肪酸的抑制。还将同时进行间接量热法，以确定胰岛素β刺激的葡萄糖氧化、非氧化性葡萄糖处置和脂质氧化抑制速率的变化。如果成功，我们的研究结果将支持进一步的后续研究，以描述米非司酮作为一种新的药物选择的潜在临床作用。 治疗“常见-非常见”2型糖尿病; 2）支持进一步的分子，细胞和 在细胞内和整个生物体水平上，对糖皮质激素的正常生理水平如何促进2型糖尿病病理生理学的机制进行体内研究; 3）刺激PI提高研究生产力，以实现对其他研究的独立资助， 更好地理解上述所有研究目标。