11β-羟类固醇脱氢酶1型对2型糖尿病影响及干预研究
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摘要
背景近年2型糖尿病患病率急剧升高,已严重地威胁着人类的健康,其发病机制主要是胰岛素抵抗(IR)和β细胞功能的损伤。胰岛素抵抗是指外周胰岛素敏感组织(主要是肝、脂肪、骨骼肌)对胰岛素诱导葡萄糖摄取利用下降和肝糖输出增加,导致需要超生理剂量的胰岛素才能发挥作用;β细胞功能损伤包括β细胞分泌胰岛素的功能和β细胞数量的下降。但损伤的具体机制仍然不清楚。人们发现严重的库欣综合征病人具有2型糖尿病的特征,其病理生理是过量的糖皮质激素(GCs)可引高胰岛素血症、脂代谢异常、糖耐量异常、高血压、腹型肥胖,最后可发展成糖尿病。然而循环中糖皮质激素水平不高成为研究的疑点。目前发现局部脂肪组织细胞糖皮质激素浓度升高可引起胰岛素抵抗,且独立于循环中糖皮质激素水平,这主要是具有组织特异性的11β类固醇脱氢酶1型(11β-HSD1)能将循环中无活性的糖皮质激素代谢产物(11-OXO-corticoid)转化为有活性的糖皮质激素(11-OH-corticoid),进行受体前调解,改变局部激素生物效应。11β-HSD1在组织广泛表达,包括肝脏、肌肉、脂肪、胰岛、大脑、心脏等。流行病学提示2型糖尿病存在慢性应急,推测过量的11-OXO-corticoid为11β-HSD1提供底物,造成局部组织糖皮质激素水平增高,扩大激素效应。糖皮质激素主要作用是对抗胰岛素外周作用,促进肝糖异生,直接抑制胰岛素分泌,并参与细胞分化、组织发育和器官成熟,调节细胞周期,促进细胞凋亡。因而假设在某种遗传和环境因素的影响下,胰岛及其外周组织11β-HSD1过表达,造成胰岛β细胞慢性损伤和胰岛素抵抗。目的1.探讨2型糖尿病中胰岛11β类固醇脱氢酶1型的表达及其对胰岛β细胞功能的影响,以及可能的途径。2. 11β类固醇脱氢酶1型在2型糖尿病外周组织的表达(肝脏、肌肉、脂肪)和胰岛素抵抗的关系。方法1体内实验①建立2型糖尿病动物模型。②腹腔葡萄糖耐量试验,并评价胰岛β细胞功能和胰岛素抵抗程度③检测空腹血脂、糖皮质激素,了解代谢和应急状态。④同时检测胰岛、肝脏、脂肪、骨骼肌组织11β-HSD1基因和蛋白表达,并分别分析其表达与胰岛功能和胰岛素抵抗的关系。⑤利用11β-HSD1抑制剂生胃酮(carbonoxlone,CBX)进行干预研究。2.体外试验用不同浓度的葡萄糖和游离脂肪酸(Free fat acid,FFA)及加或不加酶底物干预离体培养的原代胰岛β细胞,用MTT法分析细胞的生成活力,流式-PI分析细胞凋亡,葡萄糖刺激胰岛素释放试验(Glucose stimulating insulin secretion, GSIS),酸醇抽提法和放免法检测细胞内胰岛素含量,并检测胰岛β细胞11β-HSD1基因和蛋白的表达和Pdx1(Pancreatic and duodenal homeobox factor-1)基因表达。结果1. 2型糖尿病动物模型胰岛11β-HSD1高表达,与空腹血糖(FBG)正相关;与空腹胰岛素(FINS)、HOMA-β%和AUC-I/G负相关;与血浆皮质酮高低无相关性;与Pdx1表达负相关。2. 2型糖尿病动物模型外周组织肝脏、脂肪、骨骼肌高表达11β-HSD1,DM、FD和NC组11β-HSD1表达与GCs、FINS、IR、TG、TCh和(AUC-I/G)明显相关。CDM干预治疗后血脂、IR、胰岛β细胞胰岛素分泌反应改善,血糖皮质激素水平降低。3.①原代胰岛β细胞表达11β-HSD1,在有底物共孵育时,11β-HSD1表达明显增加,酶的活性增加。②11β-HSD1表达和活性与葡萄糖浓度和FFA浓度呈剂量依赖性。③胰岛β细胞11β-HSD1表达与β细胞生成能力负相关和细胞凋亡正相关,与β细胞胰岛素颗粒含量、对葡萄糖刺激反应性负相关。④胰岛β细胞11β-HSD1mRNA表达与Pdx1mRNA负相关。⑤11β-HSD1抑制剂CBX对胰岛β细胞有一定的保护作用。结论STZ和高脂饮食诱导的2型糖尿病大鼠胰岛β细胞高表达11β-HSD1,使胰岛局部糖皮质激素增加,扩大激素局部效应,抑制胰岛β细胞胰岛素分泌,诱导慢性胰岛β细胞凋亡。同时,外周组织高表达11β-HSD1,加重胰岛素抵抗和血脂紊乱。提示阻止11β-HSD1表达和活性可能是2型糖尿病的一个病因治疗。
Backgroud With rapidly increasing morbidity of type 2 diabetes mellitus recently, it has made a heavy threaten in human health. From a pathophysiologic standpoint, persons with type 2 diabetes consistently demonstrate three cardinal abnormalities: (1) resistance to the action of insulin in peripheral tissues, particularly muscle and fat but also liver; (2) defective insulin secretion, particularly in response to a glucose stimulus, and chronic mass lose of isletβcell; and (3) increased glucose production by the liver. But the detailed mechanisms are still unknown. From patients suffered from Cushing syndrome, it is known that glucocorticoids plays a crucial role in development of metabolic syndrome, including type 2 diabetes mellitus. Over glucocorticoids in circulation can cause hyperinsulineamia, hyperlipidaemia, glucose intolerance, hypertension and visceral obesity. However, a fact that a level of circulation glucocorticoids in type 2 diabets does not rise became an embarrassment. Today, because of better understanding of type 1 11beta-hydroxysteroid dehydrogenase (11β-HSD1), which activates functionally inert glucocorticoids precursors(cortisone in humans, 11-dehydro-corticosterone in roden) to active glucocorticoids(cortisol in humans) within insulin target tissue such as adipose tissue by oxoreductase activity, thereby regulating local glucocorticoid action independent curculation. 11β-HSD1 makes a decided role in local glucocorticoid action as a prereceptor regulator, widely expressed in live, fat, skeletal muscle, brain and also islet and other organs. It is known Insulin antagonism of glucocorticoids impair insulin-dependent glucose uptake and increase lipolysis, enhance hepatic gluconeogenesis and provide substrates by promoting proteolysis, and directly inhibit insulin secretion from pancreaticβcells, moreover glucocorticoids regulate cell cycle and enhance cell apoptosis. Above all, a hypothesis is supposed that under some kind heredity and enviroment, chronically increased expression of 11β-HSD1 in pancreatic isletβcell and peripheral tissue including liver, visceral fat and skeletal muscle in type 2 diabetes enhance local glucocorticoid action, resulting in disfunction of pancreaticβcell and increasing mass lose ofβcell as well as insulin resistance. Objective 1. To assay the expression and effect of 11β-hydroxysteroid dehydrogenase type 1 onβ-cell function in the T2DM conditions and simplely regulating way. 2. To assay the effect of 11β-hydroxysteroid dehydrogenase type 1 of peripheral tissues on diabetic traits. Methods 1. In Vivo①Building STZ-and fat-diet-induced type 2 diabetes.②The expression of 11β-HSD1mRNA or protein in liver, visceral fat, skeletal muscle and pancreatic islet was observed by RT-PCR, or western blot and immunohistochemitry in every group respectively, after performed IPGTT. Fast plasma cortisone ,insulin was detected by RIA,TG and TCh were detected by GPO-PAP and COD-PAP respectively; Serial plasma glucose and insulin during IPGTT was detected. AUC-I/G HOMAβ% and IR were calculated. 2. In Vitro After isolated primary isletβ-cells were treated with different glucose and FFA concentration with or without enzymic substrate and cooperator NADPH, or enzyme inhibitor carbenoxolone (CBX). MTT and FACS-FCM PI were performed to analyze the viability and apoptosis ofβ-cell, in situ hybridization and semiquantitative RT-PCR and western blot were performed to evaluate the expression of 11β-HSD1, cortisone and insulin were measured by radioimmunoassay (RIA) using rat insulin and cortisone as standard to evaluateβ-cell function. 3. Intervention study of inhibitor of 11β-HSD1, carbonoxlone(CBX). Results 1. the expression of 11β-HSD1mRNA or protein was higher in pancreatic islet,liver visceral fat, and skeletal muscle in the diabetic rats than in control, and was correlated with fast plasma glucose, insulin ,HOMA-β% IR and AUC-I/G, respectively. 2. In vitro, the activity and expression of 11β-HSD1 increased in the higher glucose and FFA concentration with enzymic substrate and NADPH, andβ-cell viability decreased,the cellular numbers of apoptosis rose,β-cell insulin content and secretion declined, corresponding decreased expression of Pdx1. Conclusion the increased activity and expression of 11β-HSD1 caused by higher glucose and FFA concentration may damageβ-cell function due to amplifying effect of glucocorticoids on rat pancreaticβ-cell or in model diabetic rat, and enhanced insulin resistance in peripheral tissues. These data supported prevention from action of 11β-HSD1 is a causal treatment of type 2 diabetes.
Backgroud With rapidly increasing morbidity of type 2 diabetes mellitus recently, it has made a heavy threaten in human health. From a pathophysiologic standpoint, persons with type 2 diabetes consistently demonstrate three cardinal abnormalities: (1) resistance to the action of insulin in peripheral tissues, particularly muscle and fat but also liver; (2) defective insulin secretion, particularly in response to a glucose stimulus, and chronic mass lose of isletβcell; and (3) increased glucose production by the liver. But the detailed mechanisms are still unknown. From patients suffered from Cushing syndrome, it is known that glucocorticoids plays a crucial role in development of metabolic syndrome, including type 2 diabetes mellitus. Over glucocorticoids in circulation can cause hyperinsulineamia, hyperlipidaemia, glucose intolerance, hypertension and visceral obesity. However, a fact that a level of circulation glucocorticoids in type 2 diabets does not rise became an embarrassment. Today, because of better understanding of type 1 11beta-hydroxysteroid dehydrogenase (11β-HSD1), which activates functionally inert glucocorticoids precursors(cortisone in humans, 11-dehydro-corticosterone in roden) to active glucocorticoids(cortisol in humans) within insulin target tissue such as adipose tissue by oxoreductase activity, thereby regulating local glucocorticoid action independent curculation. 11β-HSD1 makes a decided role in local glucocorticoid action as a prereceptor regulator, widely expressed in live, fat, skeletal muscle, brain and also islet and other organs. It is known Insulin antagonism of glucocorticoids impair insulin-dependent glucose uptake and increase lipolysis, enhance hepatic gluconeogenesis and provide substrates by promoting proteolysis, and directly inhibit insulin secretion from pancreaticβcells, moreover glucocorticoids regulate cell cycle and enhance cell apoptosis. Above all, a hypothesis is supposed that under some kind heredity and enviroment, chronically increased expression of 11β-HSD1 in pancreatic isletβcell and peripheral tissue including liver, visceral fat and skeletal muscle in type 2 diabetes enhance local glucocorticoid action, resulting in disfunction of pancreaticβcell and increasing mass lose ofβcell as well as insulin resistance. Objective 1. To assay the expression and effect of 11β-hydroxysteroid dehydrogenase type 1 onβ-cell function in the T2DM conditions and simplely regulating way. 2. To assay the effect of 11β-hydroxysteroid dehydrogenase type 1 of peripheral tissues on diabetic traits. Methods 1. In Vivo①Building STZ-and fat-diet-induced type 2 diabetes.②The expression of 11β-HSD1mRNA or protein in liver, visceral fat, skeletal muscle and pancreatic islet was observed by RT-PCR, or western blot and immunohistochemitry in every group respectively, after performed IPGTT. Fast plasma cortisone ,insulin was detected by RIA,TG and TCh were detected by GPO-PAP and COD-PAP respectively; Serial plasma glucose and insulin during IPGTT was detected. AUC-I/G HOMAβ% and IR were calculated. 2. In Vitro After isolated primary isletβ-cells were treated with different glucose and FFA concentration with or without enzymic substrate and cooperator NADPH, or enzyme inhibitor carbenoxolone (CBX). MTT and FACS-FCM PI were performed to analyze the viability and apoptosis ofβ-cell, in situ hybridization and semiquantitative RT-PCR and western blot were performed to evaluate the expression of 11β-HSD1, cortisone and insulin were measured by radioimmunoassay (RIA) using rat insulin and cortisone as standard to evaluateβ-cell function. 3. Intervention study of inhibitor of 11β-HSD1, carbonoxlone(CBX). Results 1. the expression of 11β-HSD1mRNA or protein was higher in pancreatic islet,liver visceral fat, and skeletal muscle in the diabetic rats than in control, and was correlated with fast plasma glucose, insulin ,HOMA-β% IR and AUC-I/G, respectively. 2. In vitro, the activity and expression of 11β-HSD1 increased in the higher glucose and FFA concentration with enzymic substrate and NADPH, andβ-cell viability decreased,the cellular numbers of apoptosis rose,β-cell insulin content and secretion declined, corresponding decreased expression of Pdx1. Conclusion the increased activity and expression of 11β-HSD1 caused by higher glucose and FFA concentration may damageβ-cell function due to amplifying effect of glucocorticoids on rat pancreaticβ-cell or in model diabetic rat, and enhanced insulin resistance in peripheral tissues. These data supported prevention from action of 11β-HSD1 is a causal treatment of type 2 diabetes.
引文
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1. Fruehwald-Schultes B, Kern W, Born J, Fehm HL, Peters. AHyperinsulinemia causes activation of the hypothalamus-pituitary-adrenal axis in humans.Int J Obes Relat Metab Disord[J].2001;25 Suppl 1:S38-40
2. Takao T, Nishioka T, Hashimoto K,et al.Increased adrenocorticotropin responses to acute stress in Otsuka Long-Evans Tokushima Fatty (type 2 diabetic) rats[J]. Brain Res. 2000, 852(1):110-5.
3. Andrew R, Gale CR, Walker BR,et al. Glucocorticoid metabolism and the Metabolic Syndrome: associations in an elderly cohort[J]. Exp Clin Endocrinol Diabetes 2002,110(6):284-290.
4. JeffreyS.Flier ,Masuzaki H, Paterson J, et al. A transgenic model of visceral obesity and the metabolic syndrome.Science[J],2001,294:2166–170.
5. Behrous Davani, Neil Portwood, Galina Bryzgalova, Martina Kvist ReimerAged Transgenic Mice With Increased Glucocorticoid Sensitivity in Pancreatic β-Cells Develop Diabetes. Diabetes, 2004(53):S51- S 59
6. Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice.Diabetes. 2004 Apr;53(4):931-8
7. Morton NM, Holmes MC, Fievet C, et al. Improved lipid, lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem . 2001(276):41293–300.
8. Andrew R, Westerbacka J, Wahren J, Yki-Jarvinen H, Walker BR. The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans. Diabetes. 2005 May;54(5):1364-70.
9. Sandeep TC, Andrew R, Homer NZ, Andrews RC, Smith K, Walker BR.Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11beta-hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone.Diabetes. 2005 Mar;54(3):872-9
10. Rask E, Olsson T, Soderberg S, Andrew R, Livingstone DE, Johnson O, Walker BR. Tissue-specific dysregulation of cortisol metabolism in human obesity.J Clin Endocrinol Metab. 2001 Mar;86(3):1418-21.
11. Dawn E L, Brian R W. Is 11beta-hydroxysteroid dehydrogenase type 1 a therapeutic target? Effects of carbenoxolone in lean and obese Zucker rats[J]. J Pharmacol Exp Ther. 2003, 305(1):167-72
12. Berthiaume M,Sell H,Lalonde J,Gelinas Y,et al.Actions of PPARgamma agonism on adipose tissue remodeling, insulin sensitivity, and lipemia in absence of glucocorticoids[J]. 2004,287(5):R1116-23
13. Berger J, Tanen M, Elbrecht A, et al. Peroxisome proliferator-activated receptor- gamma ligands inhibit adipocyte 11beta -hydroxysteroid dehydrogenase type 1 expression and activity[J]. J Biol Chem. 2001, 276(16):12629-35.
1. Draper N, Walker EA, Bujalska IJ,et al. Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency[J]. Nat Genet, 2003, 34(4): 434-439
2. Alberts P, Nilsson C, Selen G, et al. Selective inhibition of 11{beta} -hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains[J]. Endocrinology 2003,144(11):4755-6269
3. Wang GM, Ge RS, Latif SA,et al. Expression of 11beta-hydroxylase in rat Leydig cells[J]. Endocrinology 2002,143(2):621-626.
4. Bujalska IJ, Walker EA, Hewison M, et al. A switch in dehydrogenase to reductase activity of 11 beta-hydroxysteroid dehydrogenase type 1 upon differentiation of human omental adipose stromal cells[J]. J Clin Endocrinol Metab 2002, 87(3): 1205-1210
5. Maser E, Friebertshauser J, Volker B. Purification, characterization and NNK carbonyl reductase activities of 11beta-hydroxysteroid dehydrogenase type 1 from human liver: enzyme cooperativity and significance in the detoxification of a tobacco-derived carcinogen[J]. Chem Biol Interact 2003,143-144(1):435-448
6. Bahr V, Pfeiffer AF, Diederich S. The metabolic syndrome X and peripheral cortisol synthesis[J]. Exp Clin Endocrinol Diabetes 2002,110(7):313–318.
7. Tomlinson JW, Moore J, Cooper MS et al. Regulation of expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines[J].Endocrinology 2001,142(5):1982–1989
8. Herzig S, Long F, Jhala US et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1[J].Nature 2001, 413(13):179–183
9. Livingstone DE, Jones GC, Smith K, et al. Understanding the role of glucocorticoids in obesity:tissue-specific alterations of corticosterone metabolism in obese Zucker rats[J].Endocrinology 2000,141(2):560-563
10.Eva R,Tommy O,Brian Rw,et al. Tissue-Specific Dysregulation Of Cortisol Metabolism In Human Obesity[J].J Clin Endocrinol Metab.2001,86(3):1418-1421.
11.Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome[J].Science 2001,294(5594):2166-2170
12.Christopher BW, Stephen JD, Daniel F, et al. Increased Glucocorticoid Receptor Expression in Human Skeletal Muscle Cells May Contribute to the Pathogenesis of the Metabolic Syndrome[J]. Diabetes,2002,51(4):1066-1075.
13.Andrews RC, Herlihy O, Walker BR et al. Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance[J].J Clin Endocrinol Metab 2002,87(12):5587–5593
14.Vestergaard H, Bratholm P, Christensen NJ. Increments in insulin sensitivity during intensive treatment are closely correlated with decrements in glucocorticoid receptor mRNA in skeletal muscle from patients with Type II diabetes[J]. Clin Sci (Lond) 2001,101(5):533–540
15.Davani B, Khan A, Hult M et al. Type 1 11beta-hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets[J]. J Biol Chem 2000,275(45):34841–34844
16.Mattsson C, Lai M, Noble J,et al. Obese zucker rats have reduced mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type 1 expression in hippocampusimplications for dysregulation of the hypothalamic- pituitary-adrenal axis in obesity[J]. Endocrinology 2003,144(7):2997-3003
17.Tian-Quan C, Birming W, Steven SM. Induction of 11 β -hydroxysteroid dehydrogenase type 1 but not -2 in human aortic smooth muscle cells byinflammatory stimuli[J]. Journal of Steroid Biochemistry & Molecular Biology 2001, 77(2-3):117–122
18.Janice MP, Nicholas M M, Catherine F,et al. Metabolic syndrome without obesity: Hepatic overexpression of 11_-hydroxysteroid dehydrogenase type 1 in transgenic mice[J]. PNAS 2004,101(18):7088-7093.
19.Masuzaki H, Yamamoto H, Flier JS,et al. Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice[J]. J Clin Invest 2003,112(1):83-90
20.Sheppard KE, Autelitano DJ. 11Beta-hydroxysteroid dehydrogenase 1 transforms 11-dehydrocorticosterone into transcriptionally active glucocorticoid in neonatal rat heart[J]. Endocrinology 2002,143(1):198-204
2. Behrous Davani, Neil Portwood, Galina Bryzgalova, Martina Kvist ReimerAged Transgenic Mice With Increased Glucocorticoid Sensitivity in Pancreatic β-Cells Develop Diabetes. Diabetes, 2004(53):S51- S 59
3. Davani B, Khan A, Hult M, Martensson E, Okret S, Efendic S, Jornvall H, Oppermann UC Type 1 11beta -hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets. J Biol Chem 2000(275): 34841-34844
4. Morton NM, Holmes MC, Fievet C, et al. Improved lipid, lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem . 2001(276):41293–300.
5. Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001(294):2166–170.
6. Alberts P, Engblom L, Edling N, et al. Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia. 2002(45):1528–32.
7. Alberts P, Nilsson C, Selen G, et al. Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycaemic mice strains. Endocrinology. 2003(144):4755–62.
8. S. Nair Y. H. Lee1 R. S. Lindsay B. R.Walker P. A. Tataranni1 11β-Hydroxysteroid dehydrogenase Type 1: genetic polymorphisms are associated with Type 2 diabetes in Pima Indians independently of obesity and expression in adipocyte and muscle。Diabetologia 2004(47):1088–1095
9. Yasushi Oshima, Md, Yukiko Kuroda, Phd, Makoto Kunishige, Md, Oxidative stress–associated mitochondrial dysfunction in corticosteroid-treated muscle cells. Muscle Nerve . 2004(30):49-54.
10. Evans, J.L., I.D. Goldfine, B.A. Maddux & G.M. Grodsky. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 2003(52):1-8.
1. JeffreyS.Flier,Masuzaki H, Paterson J, et al. A transgenic model of visceral obesity and the metabolic syndrome.Science,2001,294:2166–170.
2. Hasselgren PO. Glucocorticoids and muscle catabolism.Curr Opin Clin Nutr Metab Care,1999,2:201–205
3. Brindley DN.Role of glucocorticoids and fatty acids in the impairment of lipid metabolism observed in the metabolic syndrome. Int J Obes Relat Metab Disord, 1995, 19 [Suppl1]:S69–S75
4. Lambillotte C, Gilon P, Henquin JC. Direct glucocorticoidinhibition of insulin secretion. An in vitro study of dexamethasone effects in mouse islets. J Clin Invest, 1997, 99: 414–423
5. Andrews RC, Walker BR. Glucocorticoids and insulin resistance: old hormones,new targets. Clin Sci (Lond),1999,96:513–523
6. Offield, T.L. Jetton, P. Labosky, et al. PDX-1 is required for pancreas outgrowth and differentiation of the rostral duodenum. Development, 1996, 122: 983-985.
7. Kaneto, H., J. Miyagawa, Y. Kajimoto, et al. Expression of heparin-binding epidermal growth factor-like growth factor during pancreas development: a potential role of PDX-1 in the transcriptional activation. J. Biol. Chem,1997,272: 29137-29143.
8. Bonner-Weir, S., M. Taneja, G.C. Weir, et al. In vitro cultivation of human islets from expanded ductal tissue. Proc. Natl. Acad. Sci. USA, 2000, 97:7999-8004.
9. Yoshida, S., Y. Kajimoto, T. Yasuda, et al. PDX-1 induces differentiation of intestinal epithelioid IEC-6 into insulin-producing cells. Diabetes,2002,51: 2505-2513.
10. Kojima, H., T. Nakamura, Y. Fujita, et al. Combined expression of pancreatic duodenal homeobox 1 and islet factor 1 induces immature enterocytes to produce insulin. Diabetes, 2002,51:1398-1408.
11. Ahlgren, U., J. Jonsson, L. Jonsson, et al. ?-Cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the ?-cell phenotype and maturity onset diabetes. Genes Dev, 1998,12:1763-1768.
12. Wang, H., P. Maechler, B. Ritz-Laser, et al. Pdx 1 level defines pancreatic gene expression pattern and cell lineage differentiation. J. Biol. Chem, 2001, 276: 25279-25286.
13. Watada, H., Y. Kajimoto, Y. Umayahara, et al. The human glucokinase gene ?-cell-type promoter: an essential role of insulin promoter factor 1 (IPF1)/PDX-1 in its activation in HIT-T15 cells.Diabetes,1996,45: 1478-1488
14. Engeli S, Bohnke J, Feldpausch M, et al. Regulation of 11β-HSD genes in humanadipose tissue: influence of central obesity and weight loss. Obes Res. 2004: 12: 9–17.
15. Finkel, T. & N.J. Holbrook. Oxidants, oxidative stress and the biology of ageing. Nature, 2000, 408: 239-247.
16. Tiedge, M., S. Lortz, J. Drinkgern & S. Lenzen.. Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes, 1997, 46: 1733-1742.
17. Evans, J.L., I.D. Goldfine, B.A. Maddux & G.M. Grodsky. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes,2003,52:1-8.
18. Kaneto, H., G. Xu, K.-H. Song, et al. Activation of the hexosamine pathway leads to deterioration of pancreatic ?-cell function by provoking oxidative stress. J.Biol.Chem, 2001,276:31099-31104.
19. Tanaka,Y.,P.O.Tran,J.Harmon & R.P.Robertson. A role of glutathione peroxidase in protecting pancreatic ? cells against oxidative stress in a model of glucose toxicity. Proc. Natl.Acad.Sci.USA, 2002,99: 12363-12368.
20. Sakai,K.,K.Matsumoto,T.Nishikawa,et al. Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic ?-cells. Biochem. Biophys. Res. Commun, 2003, 300:216-222.
21. Robertson,R.P.,J.Harmon, P.O. Tran, et al. Glucose toxicity in ?-cells: type2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes, 2003, 52: 581-587.
1. W. Aldhahi, E. Mun, A B. Goldfine. Portal and peripheral cortisol levels in obese humans. Diabetologia, 2004,47:833–836
2. Ruth Andrew, Jukka Westerbacka, John Wahren. The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans. (OBESITY STUDIES) Diabetes, 2005 ,54:1364-1367
3. Davani B, Khan A, Hult M, Martensson E, Okret S, Efendic S, Jornvall H, Oppermann UC Type 1 11beta -hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets. J Biol Chem, 2000, 275: 34841-34844
4. Hasselgren PO. Glucocorticoids and muscle catabolism.Curr Opin Clin Nutr Metab Care,1999,2:201–205
5. Brindley DN.Role of glucocorticoids and fatty acids in the impairment of lipid metabolism observed in the metabolic syndrome. Int J Obes Relat Metab Disord, 1995, 19 [Suppl1]:S69–S75
6. Lambillotte C, Gilon P, Henquin JC .Direct glucocorticoidinhibition of insulin secretion. An in vitro study of dexamethasone effects in mouse islets. J Clin Invest, 1997, 99: 414–423
7. Andrews RC, Walker BR . Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci (Lond),1999,96:513–523
8. Yasushi Oshima, Md, Yukiko Kuroda, Phd, Makoto Kunishige, Md. Oxidativestress–associated mitochondrial dysfunction in corticosteroid-treated muscle cells. Muscle Nerve. 2004, 30: 49–54.
9. Chia-Ning SHEN, Jonathan R. SECKL, Jonathan M. W. SLACK and David TOSH. Glucocorticoids suppress β-cell development and induce hepatic metaplasia in embryonic pancreas, Biochem. J. 2003, 375:41–50.
10. Offield, T.L. Jetton, P. Labosky, et al. PDX-1 is required for pancreas outgrowth and differentiation of the rostral duodenum. Development, 1996, 122: 983-985.
11. Kaneto, H., J. Miyagawa, Y. Kajimoto, et al. Expression of heparin-binding epidermal growth factor-like growth factor during pancreas development: a potential role of PDX-1 in the transcriptional activation. J. Biol. Chem,1997,272: 29137-29143.
12. Bonner-Weir, S., M. Taneja, G.C. Weir, et al. In vitro cultivation of human islets from expanded ductal tissue. Proc. Natl. Acad. Sci. USA, 2000, 97:7999-8004.
13. Yoshida, S., Y. Kajimoto, T. Yasuda, et al. PDX-1 induces differentiation of intestinal epithelioid IEC-6 into insulin-producing cells. Diabetes,2002,51: 2505-2513.
14. Kojima, H., T. Nakamura, Y. Fujita, et al. Combined expression of pancreatic duodenal homeobox 1 and islet factor 1 induces immature enterocytes to produce insulin. Diabetes,2002,51:1398-1408.
15. Ahlgren, U., J. Jonsson, L. Jonsson, et al. ?-Cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the ?-cell phenotype and maturity onset diabetes. Genes Dev,1998,12:1763-1768.
16. Wang, H., P. Maechler, B. Ritz-Laser, et al. Pdx 1 level defines pancreatic gene expression pattern and cell lineage differentiation. J. Biol. Chem, 2001, 276: 25279-25286.
17. Watada, H., Y. Kajimoto, Y. Umayahara, et al. The human glucokinase gene ?-cell-type promoter: an essential role of insulin promoter factor 1 (IPF1)/PDX-1 in its activation in HIT-T15 cells. Diabetes. 1996, 45: 1478-1488
18. Franck Delaunay,Akhtar Khan,Antonio Cintra and Sam Okret et al. Pancreatic ? Cells Are Important Targets for the Diabetogenic Effects of Glucocorticoids.J. Clin. Invest. 1997, 100:2094–2098.
19. Gremlich, S., R. Roduit, and B. Thorens. Dexamethasone induces posttranslational degradation of GLUT2 and inhibition of insulin secretion in isolated pancreatic b cells. J. Biol. Chem. 1997, 272:3216–3222.
20. Khan, A., C. Hong-Lie, and B.R. Landau. Glucose-6-phosphatase activity in islets from ob/ob and lean mice and the effect of dexamethasone. Endocrinology. 1995, 136: 1934–1938.
21. Khan, A., C.-G. ?stenson, P.-O. Berggren, and S. Efendic. Glucocorticoid increases glucose cycling and inhibits insulin release in pancreatic islets of ob/ob mice. Am. J. Physiol. 1992, 263:E663–E666.
22. Hamamdzic, D., E. Duzic, J.D. Sherlock, and S.M. Lanier. Regulation of a2-adrenergic receptor expression and signaling in pancreatic b-cells. Am. J. Physiol. 1995,269:E162–E171.
23. Wissal El-Assaad, Jean Buteau, Marie-Line Peyot, Christopher Nolan,Raphael Roduit, Serge Hardy, Erik Joly, Ghassan Dbaibo, Lawrence Rosenberg, And Marc Prentki .Saturated Fatty Acids Synergize with Elevated Glucose to Cause Pancreatic _-Cell Death. Endocrinology, 2003, 144(9):4154–4163
1. Laurence D, Young L,Roger HU,et al.Increased expression and activity of 11beta-HSD-1 in diabetic islets and prevention with troglitazone[J]. Biochem Biophys Res Commun. 2004,313(3):594-9.
2. Janice M P, Nicholas M M, John JM,et al. Metabolic syndrome without obesity: Hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice[J].Proc Natl Acad Sci. 2004,101(18):7088-93.
3. Berthiaume M,Sell H,Lalonde J,Gelinas Y,et al.Actions of PPARgamma agonism on adipose tissue remodeling, insulin sensitivity, and lipemia in absence of glucocorticoids[J]. 2004,287(5):R1116-23.
4. Berger J,Tanen M,Elbrecht A, et al.Peroxisome proliferator-activated receptor-gamma ligands inhibit adipocyte 11beta -hydroxysteroid dehydrogenase type 1 expression and activity[J]. J Biol Chem. 2001, 276(16):12629-35.
5. Takao T, Nishioka T, Hashimoto K,et al.Increased adrenocorticotropin responses to acute stress in Otsuka Long-Evans Tokushima Fatty (type 2 diabetic) rats[J]. Brain Res. 2000, 852(1):110-5.
6. Andrew R, Gale CR, Walker BR,et al. Glucocorticoid metabolism and the Metabolic Syndrome: associations in an elderly cohort[J]. Exp Clin Endocrinol Diabetes 2002,110(6):284-290.
7. Valsamakis G, Anwar A, Tomlinson JW, et al.11β-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus[J]. J Clin Endocrinol Metab.2004, 89(9):4755-4761
8. Basu R, Singh R J,Rizza R A, et al. Splanchnic cortisol production occurs in humans evidence for conversion of cortisone to cortisol via the11β- hydroxysteroid dehydrogenase Type 1 Pathway[J]. Diabetes.2004,53(8):2051-9
9. Laurence D,Young L, Roger H U,et al. Increased expression and activity of 11beta-HSD-1 in diabetic islets and prevention with troglitazone[J]. Biochem Biophys Res Commun. 2004, 313(3):594-9
10. Dawn E L, Brian R W. Is 11beta-hydroxysteroid dehydrogenase type 1 a therapeutic target? Effects of carbenoxolone in lean and obese Zucker rats[J]. J Pharmacol Exp Ther. 2003, 305(1):167-72
1. Fruehwald-Schultes B, Kern W, Born J, Fehm HL, Peters. AHyperinsulinemia causes activation of the hypothalamus-pituitary-adrenal axis in humans.Int J Obes Relat Metab Disord[J].2001;25 Suppl 1:S38-40
2. Takao T, Nishioka T, Hashimoto K,et al.Increased adrenocorticotropin responses to acute stress in Otsuka Long-Evans Tokushima Fatty (type 2 diabetic) rats[J]. Brain Res. 2000, 852(1):110-5.
3. Andrew R, Gale CR, Walker BR,et al. Glucocorticoid metabolism and the Metabolic Syndrome: associations in an elderly cohort[J]. Exp Clin Endocrinol Diabetes 2002,110(6):284-290.
4. JeffreyS.Flier ,Masuzaki H, Paterson J, et al. A transgenic model of visceral obesity and the metabolic syndrome.Science[J],2001,294:2166–170.
5. Behrous Davani, Neil Portwood, Galina Bryzgalova, Martina Kvist ReimerAged Transgenic Mice With Increased Glucocorticoid Sensitivity in Pancreatic β-Cells Develop Diabetes. Diabetes, 2004(53):S51- S 59
6. Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice.Diabetes. 2004 Apr;53(4):931-8
7. Morton NM, Holmes MC, Fievet C, et al. Improved lipid, lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem . 2001(276):41293–300.
8. Andrew R, Westerbacka J, Wahren J, Yki-Jarvinen H, Walker BR. The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans. Diabetes. 2005 May;54(5):1364-70.
9. Sandeep TC, Andrew R, Homer NZ, Andrews RC, Smith K, Walker BR.Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11beta-hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone.Diabetes. 2005 Mar;54(3):872-9
10. Rask E, Olsson T, Soderberg S, Andrew R, Livingstone DE, Johnson O, Walker BR. Tissue-specific dysregulation of cortisol metabolism in human obesity.J Clin Endocrinol Metab. 2001 Mar;86(3):1418-21.
11. Dawn E L, Brian R W. Is 11beta-hydroxysteroid dehydrogenase type 1 a therapeutic target? Effects of carbenoxolone in lean and obese Zucker rats[J]. J Pharmacol Exp Ther. 2003, 305(1):167-72
12. Berthiaume M,Sell H,Lalonde J,Gelinas Y,et al.Actions of PPARgamma agonism on adipose tissue remodeling, insulin sensitivity, and lipemia in absence of glucocorticoids[J]. 2004,287(5):R1116-23
13. Berger J, Tanen M, Elbrecht A, et al. Peroxisome proliferator-activated receptor- gamma ligands inhibit adipocyte 11beta -hydroxysteroid dehydrogenase type 1 expression and activity[J]. J Biol Chem. 2001, 276(16):12629-35.
1. Draper N, Walker EA, Bujalska IJ,et al. Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency[J]. Nat Genet, 2003, 34(4): 434-439
2. Alberts P, Nilsson C, Selen G, et al. Selective inhibition of 11{beta} -hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains[J]. Endocrinology 2003,144(11):4755-6269
3. Wang GM, Ge RS, Latif SA,et al. Expression of 11beta-hydroxylase in rat Leydig cells[J]. Endocrinology 2002,143(2):621-626.
4. Bujalska IJ, Walker EA, Hewison M, et al. A switch in dehydrogenase to reductase activity of 11 beta-hydroxysteroid dehydrogenase type 1 upon differentiation of human omental adipose stromal cells[J]. J Clin Endocrinol Metab 2002, 87(3): 1205-1210
5. Maser E, Friebertshauser J, Volker B. Purification, characterization and NNK carbonyl reductase activities of 11beta-hydroxysteroid dehydrogenase type 1 from human liver: enzyme cooperativity and significance in the detoxification of a tobacco-derived carcinogen[J]. Chem Biol Interact 2003,143-144(1):435-448
6. Bahr V, Pfeiffer AF, Diederich S. The metabolic syndrome X and peripheral cortisol synthesis[J]. Exp Clin Endocrinol Diabetes 2002,110(7):313–318.
7. Tomlinson JW, Moore J, Cooper MS et al. Regulation of expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines[J].Endocrinology 2001,142(5):1982–1989
8. Herzig S, Long F, Jhala US et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1[J].Nature 2001, 413(13):179–183
9. Livingstone DE, Jones GC, Smith K, et al. Understanding the role of glucocorticoids in obesity:tissue-specific alterations of corticosterone metabolism in obese Zucker rats[J].Endocrinology 2000,141(2):560-563
10.Eva R,Tommy O,Brian Rw,et al. Tissue-Specific Dysregulation Of Cortisol Metabolism In Human Obesity[J].J Clin Endocrinol Metab.2001,86(3):1418-1421.
11.Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome[J].Science 2001,294(5594):2166-2170
12.Christopher BW, Stephen JD, Daniel F, et al. Increased Glucocorticoid Receptor Expression in Human Skeletal Muscle Cells May Contribute to the Pathogenesis of the Metabolic Syndrome[J]. Diabetes,2002,51(4):1066-1075.
13.Andrews RC, Herlihy O, Walker BR et al. Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance[J].J Clin Endocrinol Metab 2002,87(12):5587–5593
14.Vestergaard H, Bratholm P, Christensen NJ. Increments in insulin sensitivity during intensive treatment are closely correlated with decrements in glucocorticoid receptor mRNA in skeletal muscle from patients with Type II diabetes[J]. Clin Sci (Lond) 2001,101(5):533–540
15.Davani B, Khan A, Hult M et al. Type 1 11beta-hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets[J]. J Biol Chem 2000,275(45):34841–34844
16.Mattsson C, Lai M, Noble J,et al. Obese zucker rats have reduced mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type 1 expression in hippocampusimplications for dysregulation of the hypothalamic- pituitary-adrenal axis in obesity[J]. Endocrinology 2003,144(7):2997-3003
17.Tian-Quan C, Birming W, Steven SM. Induction of 11 β -hydroxysteroid dehydrogenase type 1 but not -2 in human aortic smooth muscle cells byinflammatory stimuli[J]. Journal of Steroid Biochemistry & Molecular Biology 2001, 77(2-3):117–122
18.Janice MP, Nicholas M M, Catherine F,et al. Metabolic syndrome without obesity: Hepatic overexpression of 11_-hydroxysteroid dehydrogenase type 1 in transgenic mice[J]. PNAS 2004,101(18):7088-7093.
19.Masuzaki H, Yamamoto H, Flier JS,et al. Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice[J]. J Clin Invest 2003,112(1):83-90
20.Sheppard KE, Autelitano DJ. 11Beta-hydroxysteroid dehydrogenase 1 transforms 11-dehydrocorticosterone into transcriptionally active glucocorticoid in neonatal rat heart[J]. Endocrinology 2002,143(1):198-204