The Role of 11beta-HSD1 in Type II Diabetes and Obesity

11β-HSD1 在 II 型糖尿病和肥胖中的作用

• 批准号: 7144557
• 负责人: YANJUN LIU
• 金额: $ 13.21万
• 依托单位: CHARLES R. DREW UNIVERSITY OF MED & SCI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144557
• 关键词: adipocytes; cortisol; cortisone; enzyme induction /repression; enzyme inhibitors; glucocorticoids; glucose transport; hormone regulation /control mechanism; hydroxysteroid dehydrogenases; insulin sensitivity /resistance; laboratory mouse; liver cells; metabolic syndrome; noninsulin dependent diabetes mellitus; obesity; small interfering RNA; steroid hormone metabolism; tissue /cell culture

DESCRIPTION (provided by applicant): It is well-known that patients with cortisol excess develop Cushing's syndrome with central obesity and insulin resistance. However, recent studies in humans and rodents suggest a role for tissue rather than plasma cortisol excess in the development of idiopathic obesity and the metabolic syndrome via intracellular steroid reactivation of inert circulating cortisone (11-dehydrocorticosterone in rodents) into active cortisol (corticosterone) by an enzyme called 11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). In support of this, mice with excess of this enzyme in their fat and liver cells develop insulin resistance and metabolic syndrome through increasing intracellular active cortisol levels. Similarly, we used an animal model of type 2 diabetes, called obese db/db mice and found that they have high liver and fat levels of 11 beta -HSD1, which positively correlated with their insulin resistance, hyperglycemia and obesity. We and others also reported that inhibition of this enzyme increased insulin sensitivity in obese mice as well as in humans. We hypothesized that the enzyme 11beta-HSD1 determines the availability of intracellular steroids and insulin sensitivity, and further that 11beta-HSD1 could be a new therapeutic target for type 2 diabetes and obesity. We are now interested in trying to understand why increased intracellular glucocorticoid availability may contribute to insulin resistance and obesity and if endogenous manipulation and exogenous drugs aimed at reducing the tissue levels of this enzyme will improve type 2 diabetes and obesity of obese rodents. In this grant application, we will examine the effects of intracellular glucocorticoid availability on insulin signaling and glucose transport in primary cultures of mouse hepatocytes and adipocytes through manipulation of 11 beta-HSD1 activity with its inhibitor and specific siRNA silence (direct against 11 beta- HSD1 expression). Animal studies will further define the benefits of decreasing tissue glucocorticoid availability in insulin sensitivity and body weight by endogenous modulation and specific inhibition of 11 beta- HSD1 with viral-mediated siRNA technology. Our experiments will help to comprehensively elucidate the potential beneficial mechanism for selective enzyme inhibition within liver and adipose tissues as a novel therapeutic strategy for metabolic syndromes, and thus, would provide a base for the development of a specific 11 beta-HSD1 inhibitor, which can be used to target type 2 diabetes and/or obesity in humans.

描述（由申请人提供）： 众所周知，皮质醇过量的患者患有中枢性肥胖和胰岛素抵抗的库欣综合症。然而，最近对人类和啮齿动物的研究表明，通过细胞内循环循环循环循环循环的皮质酮（11-脱水皮革皮质酮）在活性皮质醇（Cortisticoltery insy nhire）中，通过细胞内循环循环循环循环循环循环循环的循环循环循环（11-脱水皮质酮）通过细胞循环循环的循环循环循环（11-脱水皮质酮）通过11点蛋白酶酶（Cotortosol（Cortisticoltery）促成11-蛋白酶酶（11-），这表明了组织性肥胖和代谢综合征的作用，这是由活性皮质溶液（cortroxsosterone）通过11点蛋白酶酶（11-脱水皮质酮）的作用。 1（11Beta-HSD1）。为此，通过增加细胞内活性皮质醇水平，其脂肪和肝细胞中该酶过量的小鼠会产生胰岛素抵抗和代谢综合征。同样，我们使用了2型糖尿病的动物模型，称为肥胖的DB/db小鼠，发现它们具有高肝脏和脂肪水平为11β-HSD1，这与其胰岛素抵抗，高血糖和肥胖呈正相关。我们和其他人还报告说，抑制这种酶会提高肥胖小鼠以及人类的胰岛素敏感性。我们假设酶11BETA-HSD1决定了细胞内类固醇和胰岛素敏感性的可用性，进一步的11BETA-HSD1可能是2型型糖尿病和肥胖症的新治疗靶标。现在，我们有兴趣尝试了解为什么增加的细胞内糖皮质激素可利用性可能有助于胰岛素抵抗和肥胖，以及旨在降低该酶组织水平的内源性操纵和外源性药物是否会改善2型型糖尿病型糖尿病和肥胖。在此赠款应用中，我们将通过操纵11个β-HSD1活性的抑制剂和特定的siRNA静音（直接抗11 beta-hsd1表达），研究小鼠肝细胞的原代培养物和脂肪细胞的原发性培养物和脂肪细胞的胰岛素信号传导和葡萄糖转运的影响（直接）。动物研究将进一步定义通过内源性调节和通过病毒介导的siRNA技术对11个βHSD1的特异性抑制，降低组织糖皮质激素可用性在胰岛素敏感性和体重中的好处。我们的实验将有助于全面阐明肝脏和脂肪组织内选择性酶抑制的潜在有益机制，以作为代谢综合征的新型治疗策略，因此，将为特定的11β-HSD1抑制剂提供基础，该抑制剂可用于靶向2型2型糖尿病和/或肥胖症。