The Role of H6PDH and 11beta-HSD1 in Type 2 Diabetes and Obesity

描述（由申请人提供）：肥胖和2型糖尿病的发病率在发达国家和发展中国家都已达到全球流行。糖皮质激素（GC）过量（库欣综合征）的患者会发生逆转性肥胖和胰岛素抵抗。然而，特发性肥胖和/或代谢综合征患者没有循环GC水平升高。代谢组织如肝脏和脂肪组织仅表达112-羟基类固醇脱氢酶（112- hsd1），它在完整的细胞和器官中作为nadph依赖性还原酶起作用，从惰性循环皮质醇中生成活性皮质醇。因此112-HSD1在局部类固醇再激活中起着至关重要的作用。在内质网（ER）腔内，己糖-6-磷酸脱氢酶（H6PDH）将葡萄糖-6-磷酸（G6P）和NADP转化为NADPH。该反应需要G6P转运蛋白（G6PT）维持其代谢子strateg6p的可用性。生成NADPH，被112-HSD1利用，从而构成H6PDH和112-HSD1调控组织GC再生的纽带。H6PDH敲除小鼠不能再生组织GCs， 112- HSD1活性受损。我们最近报道了H6PDH表达的降低导致肝脏和脂肪112-HSD1活性的抑制，这可能有助于高脂肪饮食肥胖模型的胰岛素敏感性和体重减轻。我们新的初步数据表明，在2型糖尿病动物模型中，组织特异性激活H6PDH表达可导致112-HSD1活性上调，该活性与胰岛素抵抗和肥胖相关。因此，我们假设H6PDH是112-HSD1能否再生参与2型糖尿病和肥胖发病机制的GCs的关键决定因素。在本次资助中，我们将通过使用siRNA技术在完整的小鼠肝细胞和脂肪细胞中通过操纵H6PDH来调节12-HSD1扩增GC再生，来研究H6PDH对胰岛素信号传导作用的影响。这些细胞培养研究将通过在病毒载体中使用特定的H6PDH或G6PT siRNA治疗动物来加强，以确定抑制H6PDH可以为糖尿病和肥胖症提供治疗益处。我们认为阻断H6PDH对112-HSD1的影响可能是有效治疗糖尿病或肥胖的新策略

DESCRIPTION (provided by applicant): The incidence of obesity and type 2 diabetes has reached global epidemic prevalence in both the developed and developing countries. Patients with glucocorticoid (GC) excess (Cushing's syndrome) develop reversal obesity and insulin resistance. However, patients with idiopathic obesity and/or metabolic syndrome do not have elevated circulating GC levels. Metabolic tissues such as liver and adipose tissue solely express 112- hydroxysteroid dehydrogenase (112-HSD1) where it acts in intact cells and organs as a NADPH-dependent reductase to generate active cortisol from inert circulating cortisone. 112-HSD1 therefore plays a crucial role in local steroid reactivation. In the endoplasmic reticulum (ER) lumen, hexose-6-phosphate dehydrogenase (H6PDH) converts glucose-6-phosphate (G6P) and NADP to generate NADPH. This reaction requires the G6P transporter (G6PT) to maintain its metabolic substrateG6P availability. This generates NADPH which is utilized by 112-HSD1, thus constituting a connection of H6PDH and 112-HSD1 in regulation of tissue GC regeneration. In support of this, H6PDH knockout mice are unable to regenerate tissue GCs and impaired 112- HSD1 activity. We recently reported that reduction of H6PDH expression leads to suppressed hepatic and adipose 112-HSD1 activity that may contribution to insulin sensitivity and weight loss in a high- fat diet model of obesity. Our new preliminary data show that tissue-specific activation of H6PDH expression leads to up- regulation of 112-HSD1 activity that correlated with insulin resistance and obesity in type 2 diabetic animal models. We therefore hypothesize that H6PDH is the critical determinant of whether 112-HSD1 can regenerate GCs that contributes to the pathogenesis of type 2 diabetes and obesity. In this grant, we will examine the impact of H6PDH on insulin signaling action through manipulation of H6PDH to regulation of 12-HSD1 amplifying GC regeneration by using siRNA technology in intact mouse hepatocytes and adipocytes. These cell culture studies will be reinforced by treatment of animals with specific H6PDH or G6PT siRNA in a viral vector to define that inhibition of H6PDH could provide therapeutic benefits for diabetes and obesity. We believe that blocking the effects of H6PDH on 112-HSD1 may be a new strategy in the effective treatment of diabetes/or obesity Public Health Relevance: Patients who produce too much cortisol develop obesity and in some cases, type 2 diabetes. We posit this is due, in part, to the H6PDH-induced 112-HSD1 amplifying tissue glucocorticoid (GC) regeneration. Blocking the effects of H6PDH on 112-HSD1 may represent a new strategy in the effective treatment of type 2 diabetes and obesity through reduction of tissue GC availability mediating insulin sensitivity and glucose homeostasis.