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

描述（由申请人提供）： 众所周知，皮质醇过量的患者会发展为伴有向心性肥胖和胰岛素抵抗的库欣综合征。然而，最近在人类和啮齿动物中的研究表明，组织而不是血浆皮质醇过量在特发性肥胖和代谢综合征的发展中起作用，其通过称为11 β-羟基类固醇脱氢酶1（11 β-HSD 1）的酶将惰性循环可的松（啮齿动物中的11-脱氢皮质酮）细胞内类固醇再活化为活性皮质醇（皮质酮）。为了支持这一点，在脂肪和肝细胞中具有过量这种酶的小鼠通过增加细胞内活性皮质醇水平而产生胰岛素抵抗和代谢综合征。同样，我们使用了一种2型糖尿病的动物模型，称为肥胖db/db小鼠，发现它们的肝脏和脂肪中11 β-HSD 1水平很高，这与它们的胰岛素抵抗、高血糖和肥胖呈正相关。我们和其他人还报道，抑制这种酶会增加肥胖小鼠和人类的胰岛素敏感性。我们假设，酶11 β-HSD 1决定了细胞内类固醇和胰岛素敏感性的可用性，并进一步认为11 β-HSD 1可能是2型糖尿病和肥胖症的新治疗靶点。我们现在有兴趣试图了解为什么增加细胞内糖皮质激素的可用性可能有助于胰岛素抵抗和肥胖，如果内源性操纵和外源性药物，旨在减少这种酶的组织水平将改善2型糖尿病和肥胖的肥胖啮齿动物。在这项资助申请中，我们将通过用其抑制剂和特异性siRNA沉默（直接针对11 β-HSD 1表达）操纵11 β-HSD 1活性，研究细胞内糖皮质激素可用性对小鼠肝细胞和脂肪细胞原代培养物中胰岛素信号传导和葡萄糖转运的影响。动物研究将进一步确定通过内源性调节和用病毒介导的siRNA技术特异性抑制11 β-HSD 1来降低组织糖皮质激素可用性在胰岛素敏感性和体重方面的益处。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作为代谢综合征的新治疗策略的潜在有益机制，因此，将为开发特异性11 β-HSD 1抑制剂提供基础，该抑制剂可用于靶向人类2型糖尿病和/或肥胖。

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.