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

H6PDH 和 11beta-HSD1 在 2 型糖尿病和肥胖中的作用

基本信息

批准号：
8305688
负责人：
YANJUN LIU
金额：
$ 31.73万
依托单位：
CHARLES R. DREW UNIVERSITY OF MED & SCI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8305688
关键词：
11-beta-Hydroxysteroid Dehydrogenase Type 1 Adipocytes Adipose tissue Affect American Animal Experiments Animal Model Animals Applications Grants Attenuated Award Biochemistry Biomedical Research Blood Glucose Body Composition Body Weight Body Weight decreased Cardiovascular Diseases Cell Culture Techniques Cells Central obesity Chlorogenic Acid Collaborations Corticosterone Cortisone Cushing Syndrome Data Developed Countries Developing Countries Development Diabetes Mellitus Diabetic mouse Diet Disease Eating Educational process of instructing Effectiveness Eligibility Determination Endocrine Endocrinology Endoplasmic Reticulum Epidemic Faculty Fatty acid glycerol esters Foundations Functional disorder Funding Gene Expression Generations Glucocorticoids Glucose-6-Phosphate Grant Hepatic Hepatocyte Hexoses Human Hydrocortisone Hydroxysteroid Dehydrogenases Hypertension Incidence Insulin Insulin Resistance Insulin Signaling Pathway International Journals Kidney Knockout Mice Laboratories Lead Link Liver Manuscripts Measurement Mediating Medical Medicine Metabolic Metabolic syndrome Metabolism Modeling Molecular Molecular Biology Mus NADP Natural regeneration Neurosciences Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Oxidoreductase Paper Pathogenesis Patients Peer Review Play Prevalence Principal Investigator Production Publications Publishing Reaction Regulation Reporting Research Research Personnel Rodent Rodent Model Role Science Secure Small Interfering RNA Societies Steroids Streptozocin Syndrome System Techniques Technology Therapeutic Time Tissues United States National Institutes of Health Universities Up-Regulation Update Viral Vector Weight Western World base blood glucose regulation career cofactor db/db mouse diabetic effective therapy experience glucose 6-phosphate(transporter)glucose transport glucose uptake improved inhibitor/antagonist inorganic phosphate insight insulin sensitivity insulin signaling medical schools meetings member new therapeutic target novel therapeutics professor programs public health relevance skills steroid metabolism therapeutic target

项目摘要

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.

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达到了全球流行病。糖皮质激素（GC）过量（库欣综合征）患者会产生逆转肥胖和胰岛素抵抗。但是，特发性肥胖症和/或代谢综合征的患者的循环GC水平升高。代谢组织（例如肝脏和脂肪组织）仅表达112-羟基甾体脱氢酶（112-HSD1），其中它在完整的细胞和器官中作用于NADPH依赖性还原酶，从而从惰性的循环cortisone中产生活性皮质醇。因此，112-HSD1在局部类固醇重新激活中起着至关重要的作用。在内质网（ER）腔中，己糖-6-磷酸脱氢酶（H6PDH）转换葡萄糖-6-磷酸（G6P）和NADP以产生NADPH。该反应要求G6P转运蛋白（G6PT）维持其代谢子战斗6P的可用性。这会产生由112-HSD1使用的NADPH，因此在组织GC再生调节时构成了H6PDH和112-HSD1的连接。为此，H6PDH敲除小鼠无法再生组织GC并受损112-HSD1活性。我们最近报道，H6PDH表达的降低会导致肝脏和脂肪112-HSD1活性受到抑制，这可能有助于肥胖的高脂饮食模型中胰岛素敏感性和体重减轻。我们的新初步数据表明，H6PDH表达的组织特异性激活导致对112-HSD1活性的加强，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H6PDH是112-HSD1是否可以再生GC的关键决定因素，该GC有助于2型糖尿病和肥胖症的发病机理。在这笔赠款中，我们将通过操纵H6PDH对胰岛素信号传导作用的影响，通过操纵H6PDH对12-HSD1的调节，通过在完整的小鼠肝细胞和脂肪细胞中使用siRNA技术来调节GC再生。这些细胞培养研究将通过病毒载体中用特定的H6PDH或G6PT siRNA处理动物来加强这些细胞培养研究，以确定抑制H6PDH可以为糖尿病和肥胖提供治疗益处。我们认为，阻止H6PDH对112-HSD1的影响可能是有效治疗糖尿病/或肥胖的新策略公共卫生相关性：生产过多皮质醇的患者会产生肥胖症，在某些情况下是2型糖尿病。我们认为这部分归因于H6PDH诱导的112-HSD1扩增组织糖皮质激素（GC）再生。通过降低介导胰岛素敏感性和葡萄糖稳态的组织GC可用性，阻止H6PDH对112-HSD1的影响可能代表有效治疗2型糖尿病和肥胖的新策略。