Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice
Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice
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DOI：
10.1007/s00125-002-0959-6
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发表时间：
2002-11-01
期刊：
影响因子：
8.2
通讯作者：
Abrahmsén, L
中科院分区：
文献类型：
--
作者：
Alberts, P;Engblom, L;Abrahmsén, L
目的/假设。目前II型（非胰岛素依赖型）糖尿病的药物治疗存在各种局限性。需要新的治疗方法来降低糖尿病并发症和死亡率的长期风险：我们测试了一种降低血糖的新原理。糖皮质激素过量会导致糖耐量异常和胰岛素抵抗。酶11 β-羟基类固醇脱氢酶1型和2型相互转化非活性和活性糖皮质激素，从而在靶组织中激动剂浓度的局部调节和皮质激素受体的活化中发挥主要作用。据推测，选择性抑制1型11 β-羟基类固醇脱氢酶可减少高血糖症和糖尿病患者的过度肝葡萄糖生成。BVT. 2733是一种新的小分子非甾体异构体选择性小鼠11 β-羟基类固醇脱氢酶1型抑制剂。本研究的目的是检测选择性抑制1型11 β-羟基类固醇脱氢酶是否能降低高血糖和高胰岛素血症小鼠模型的血糖浓度。使用皮下渗透微型泵将BVT. 2733给予自发性高血压KKAy小鼠7天。BVT：2733降低肝脏PEPCK和葡萄糖-6-磷酸酶的mRNA，血糖和血清胰岛素浓度相比，车辆处理的大米。相反，肝11 β-羟基类固醇脱氢酶1型mRNA，肝功能标志酶表达天冬氨酸转氨酶，单独的氨基转移酶和碱性磷酸酶，每日食物摄入量和体重没有改变轮胎treatment.Conclusion/解释。这些结果表明，人类11 β-羟基类固醇脱氢酶1型的选择性抑制剂可以昏迷船员的方法，降低血糖浓度的II型糖尿病。
Aims/hypothesis. Current pharmacological treatments for Type II (non-insulin-dependent) diabetes mellitus brave various limitations. New treatments are needed to reduce long-term risks for diabetic complications and mortality: We tested a new principle for lowering blood glucose. It is well own that glucocorticoids in excess cause glucose intolerance and insulin resistance. The enzymes 11beta-hydroxysteroid dehydrogenase type 1 and type 2 inter-convert inactive and active glucocorticoid, thereby playing a major role i local modulation of agonist concentration and activation of corticostroid receptors in target tissues. It has been hypothesized that selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases excessive hepatic glucose production in hyperglycemia and diabetes. BVT.2733 is a new, small molecule, non-steroidal isoform-selective inhibitor of mouse 11beta-hydroxysteroid dehydrogenase type 1. The aim of the present study is to test if selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 lowers blood glucose concentrations in a hyperglycaemic and hyperinsulinaemc mouse modelsMethods. BVT.2733 was given to spontaneously hyperglycaemic KKAy mice for 7 days using subcutaneous osmotic mini-pumps.Results. BVT:2733 lowered hepatic PEPCK and glucose-6-phosphatase mRNA, blood glucose and serum insulin concentrations compared with vehicle treated rice. In contrast, hepatic 11beta-hydroxysteroid dehydrogenase type 1 mRNA, liver function marker enzyme expression aspartate anotransferase, alone aminotrasferase and alkaline phosphtes, daily food intake and body weight were not altered by tire treatment.Conclusion/interpretation. These results suggest that a selective inhibitor of human 11beta-hydroxysteroid dehydrogenase type 1 can coma crew approach for lowering blood glucose concentrations in Type II diabetes.