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 型糖尿病影响着全世界越来越多的人，尤其是美国少数族裔群体。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症。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，其中更微妙的皮质醇作用异常可能仍然对血糖控制产生不利影响。由于米非司酮还可能因抗黄体酮作用而产生妇科副作用，并且临床上也被女性用于终止妊娠，因此我们将这项初步试点研究仅限于男性；如果该项目确定它对男性降低血糖具有有利作用，那么就有理由在女性中重复这项研究，以评估其对潜在妇科副作用的血糖益处。本次试点项目 将招募 60 名以少数族裔为主的男性受试者，这些受试者患有 2 型糖尿病，但联合口服药物未得到充分控制。他们将以双盲方式随机接受每日 600 毫克米非司酮或匹配的安慰剂片剂，为期 3 个月。所有同时服用的药物剂量将保持恒定，并将提供一致的饮食和生活方式咨询。将比较各组之间的血糖控制、体重和身体成分的变化、胰岛素敏感性和口服葡萄糖耐量测试的β细胞功能的测量、血脂、血压和临床安全性。 在 基线和 3 个月时，10 名受试者的子集还将接受血糖正常的高胰岛素钳夹手术，以确定对标准化静脉输注高剂量胰岛素的生理反应，测量胰岛素介导的葡萄糖上升、胰岛素介导的肝葡萄糖输出抑制和非酯化脂肪酸抑制。还将同时进行间接量热法，以确定胰岛素刺激的葡萄糖氧化、非氧化葡萄糖处理和脂质氧化抑制的速率变化。如果成功，我们的研究结果将 1) 支持进一步的后续研究，以描绘米非司酮作为新药物选择的潜在临床作用 “普通型”2 型糖尿病的治疗； 2) 支持进一步的分子、细胞和 体内研究糖皮质激素的正常生理水平如何在细胞内和整个有机体水平上促进 2 型糖尿病的病理生理学机制； 3) 激发 PI 更高的研究生产力，以实现旨在更好地理解所有上述研究目标的额外研究的独立资助。