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

描述(申请人提供)：肥胖症和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水平。糖皮质激素(GC)过多的患者(库欣综合征)会出现反转性肥胖和胰岛素抵抗。然而，特发性肥胖和/或代谢综合征患者的循环GC水平并没有升高。代谢组织，如肝脏和脂肪组织，只表达112-羟基类固醇脱氢酶(112-HSD1)，在完整的细胞和器官中，它作为一种依赖NADPH的还原酶，从惰性循环中的皮质醇中产生活性皮质醇。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)转化葡萄糖-6-磷酸(G6P)和NADP生成NADPH。这个反应需要G6P转运体(G6PT)来维持其代谢底物G6P的可用性。这产生了被112-HSD1利用的NADPH，从而构成了H6PDH和112-HSD1在调节组织GC再生方面的联系。支持这一点的是，H6PDH基因敲除小鼠无法再生组织GC，并损害了112-HSD1的活性。我们最近报道，在高脂饮食肥胖模型中，H6PDH表达减少导致肝脏和脂肪112-HSD1活性受到抑制，这可能有助于胰岛素敏感性和体重减轻。我们新的初步数据显示，在2型糖尿病动物模型中，H6PDH表达的组织特异性激活导致112-HSD1活性上调，这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GCs的关键决定因素，而GCs是2型糖尿病和肥胖症的致病因素。在这项授权中，我们将利用siRNA技术，通过操纵H6PDH调节12-HSD1放大完整小鼠肝细胞和脂肪细胞中的GC再生，来研究H6PDH对胰岛素信号转导作用的影响。这些细胞培养研究将通过在病毒载体中用特定的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/肥胖症的新策略 公共卫生相关性：产生过多皮质醇的患者会患上肥胖症，在某些情况下还会患上2型糖尿病。我们推测，这部分归因于H6PDH诱导的112-HSD1放大组织糖皮质激素(GC)的再生。阻断H6PDH对112-HSD1的影响可能是一种有效治疗2型糖尿病和肥胖症的新策略，它可能通过减少组织GC的可获得性来调节胰岛素敏感性和葡萄糖稳态。

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.