Acute in vivo regulation of 11β-hydroxysteroid dehydrogenase type 1 activity by insulin and intralipid infusions in humans
Acute in vivo regulation of 11β-hydroxysteroid dehydrogenase type 1 activity by insulin and intralipid infusions in humans
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DOI：
10.1210/jc.2006-0819
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发表时间：
2006-11-01
影响因子：
5.8
通讯作者：
Walker, Brian R.
中科院分区：
文献类型：
--
作者：
Wake, Deborah J.;Homer, Natalie Z. M.;Walker, Brian R.
背景：混合餐后11β-羟基类固醇脱氢酶1型(11HSD1)对皮质醇的肾上腺外再生增加。目前还不清楚是哪个组织负责，以及这是否反映了11HSD1的复杂转录控制，或者是由己糖-6-磷酸脱氢酶提供还原的烟酰胺腺嘌呤二核苷酸磷酸所施加的转录后控制。目的：本研究的目的是测试高胰岛素血症和/或血清游离脂肪酸增加是否增加全身和脂肪内11HSD1，以及脂肪11HSD1是否从脱氢酶切换到还原酶活性。我们测量了全身皮质醇的再生(静脉注射9，11，12，12-[H-2](4)-皮质醇)和脂肪内皮质醇和皮质醇的相互转化(通过sc微透析法在单独的管内注入[H-3](4)-皮质醇和[H-3](2)-皮质松)：1)高胰岛素正血糖钳夹；2)静脉注射脂肪乳剂(Intralipid 20%脂肪乳剂)；3)生理盐水注射，每次3.5h。结果：高胰岛素血症使9，12，12[H-2](3)-皮质醇的出现率增加(生理盐水组9.3+/-0.8vs.16.7+/-1.1nmol/min，P<；0.001)，表明全身11HSD1增加。在脂肪内，主要的反应是还原酶将皮质醇转化为皮质醇(3.5h后，每小时还原酶为11.0+/-2.7%，而脱氢酶为5.2+/-1.3，P<；0.02)，胰岛素增加了还原酶(达到15.8+/-3.0，P<；0.05)，并有增加脱氢酶活性的趋势。脂肪脂肪注射对全身去氢皮质醇代谢无影响，但可增加脂肪组织中脱氢酶和还原酶的活性(达到16.7+/-1.8，P<；0.01)。结论：高胰岛素血症和游离脂肪酸的增加导致脂肪组织11HSD1活性的急剧增加，这不是脱氢酶向还原酶的转换所致。高胰岛素血症还会增加全身皮质醇的再生。这些效应可能会增加餐后细胞内皮质醇的浓度。
Context: Extraadrenal regeneration of cortisol by 11 beta-hydroxysteroid dehydrogenase type 1 (11HSD1) is increased after a mixed meal. It is unknown which tissue is responsible and whether this reflects the complex transcriptional control of 11HSD1 or posttranscriptional control exerted by supply of reduced nicotinamide adenine dinucleotide phosphate from hexose-6-phosphate dehydrogenase.Objective: The objective of this study was to test whether hyperinsulinemia and/or increased serum free fatty acids increase wholebody and intraadipose 11HSD1, and whether adipose 11HSD1 switches from dehydrogenase to reductase activity.Methods: In nine healthy men, we measured whole-body cortisol regeneration (by iv infusion of 9,11,12,12-[H-2](4)-cortisol) and intraadipose interconversion of cortisol and cortisone (by sc microdialysis infusion of [H-3](4)-cortisol and [H-3](2)-cortisone in separate cannulae) during: 1) a hyperinsulinemic euglycemic clamp; 2) iv lipid infusion (Intralipid 20% fat emulsion); and 3) saline infusion, each for 3.5 h.Results: Hyperinsulinemia increased rate of appearance of 9,12,12[H-2](3)-cortisol (9.3 +/- 0.8 vs. 16.7 +/- 1.1 nmol/min with saline, P < 0.001), indicating increased whole-body 11HSD1. Within adipose, the predominant reaction was reductase conversion of cortisone to cortisol (after 3.5 h of saline infusion, reaching 11.0 +/- 2.7% per hour reductase vs. 5.2 +/- 1.3 dehydrogenase, P < 0.02); insulin increased reductase (reaching 15.8 +/- 3.0, P < 0.05) and tended to increase dehydrogenase activity. Intralipid infusion had no effects on wholebody deuterated cortisol metabolism, but increased both dehydrogenase and reductase (reaching 16.7 +/- 1.8, P < 0.01) activities in adipose.Conclusions: Hyperinsulinemia and increased free fatty acids induce acute increases in 11HSD1 activity in adipose tissue that are not attributable to a switch from dehydrogenase to reductase. Hyperinsulinemia also increases systemic cortisol regeneration. These effects may enhance intracellular cortisol concentrations after a meal.