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：
7903432
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/7903432
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 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 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.