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均已达到全球流行病水平。糖皮质激素（GC）过量（库欣综合征）患者发生逆转性肥胖和胰岛素抵抗。然而，患有特发性肥胖和/或代谢综合征的患者不具有升高的循环GC水平。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-HSD 1），其中它在完整细胞和器官中作为NADPH依赖性还原酶起作用，以从惰性循环可的松产生活性皮质醇。因此，112-HSD 1在局部类固醇再活化中起关键作用。在内质网（ER）腔中，己糖-6-磷酸脱氢酶（H6 PDH）转化葡萄糖-6-磷酸（G6 P）和NADP以产生NADPH。该反应需要G6 P转运蛋白（G6 PT）来维持其代谢底物G6 P的可用性。这产生NADPH，其被112-HSD 1利用，从而构成H6 PDH和112-HSD 1在组织GC再生调节中的连接。为了支持这一点，H6 PDH敲除小鼠不能再生组织GC和受损的112-HSD 1活性。我们最近报道了H6 PDH表达的减少导致肝脏和脂肪112-HSD 1活性的抑制，这可能有助于肥胖症的高脂饮食模型中的胰岛素敏感性和体重减轻。我们的新的初步数据表明，H6 PDH表达的组织特异性激活导致112-HSD 1活性的上调，这与2型糖尿病动物模型中的胰岛素抵抗和肥胖相关。因此，我们假设H6 PDH是112-HSD 1是否可以再生GC的关键决定因素，而GC是2型糖尿病和肥胖症发病机制的重要因素。在这项研究中，我们将研究H6 PDH对胰岛素信号传导作用的影响，通过操纵H6 PDH调节12-HSD 1放大GC再生，通过使用siRNA技术在完整的小鼠肝细胞和脂肪细胞。这些细胞培养研究将通过用病毒载体中的特异性H6 PDH或G6 PT siRNA治疗动物来加强，以确定H6 PDH的抑制可以为糖尿病和肥胖症提供治疗益处。我们认为阻断H6 PDH对112-HSD 1的作用可能是有效治疗糖尿病/肥胖的新策略 公共卫生相关性：产生过多皮质醇的患者会患肥胖症，在某些情况下会患2型糖尿病。我们认为这部分是由于H6 PDH诱导的112-HSD 1放大组织糖皮质激素（GC）再生。阻断H6 PDH对112-HSD 1的作用可能代表了通过降低组织GC可用性介导胰岛素敏感性和葡萄糖稳态来有效治疗2型糖尿病和肥胖的新策略。

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.