Study for pathophysiological significance of growth hormone (GH) and insulin-like growth factor in metabolic disorders

本研究探讨了GH和IGF-I在代谢紊乱中的病理生理学意义。1）GH和IGF-I对3 T3-L1脂肪细胞11β-羟基类固醇脱氢酶（11β-hydroxysteroid dehydrogenase typel 1，11β-HSD 1）的影响在外周组织中，皮质类固醇的作用部分受11β-HSD的调节，11β-HSD可使皮质醇（F）和皮质醇（E）相互转化。11β-HSD 1主要作为还原酶将E转化为F，在肝脏和脂肪组织中表达。GH缺乏的患者具有内脏肥胖的临床特征，并且据报道这些患者增加了F/E代谢物比率。本研究探讨了生长激素（GH）和胰岛素样生长因子-I（IGF-I）对3 T3-L1脂肪细胞11β-HSD 1表达的影响。根据常规方法将3 T3-L1前脂肪细胞分化为脂肪细胞，并用各种浓度的GH或IGF-I处理脂肪细胞长达24小时。测定11β-HSD 1 mRNA水平和活性。 关于我们 在前脂肪细胞向脂肪细胞分化的过程中，11β-HSD 1 mRNA水平和活性增加，而GH和IGF-I则抑制分化的脂肪细胞11β-HSD 1 mRNA水平和活性。这些数据表明，低浓度GH和/或IGF-I时脂肪组织中的11β-HSD 1活性较高，导致诱导脂肪生成和/或脂肪生成的活性皮质醇增加。GH缺乏者内脏性肥胖可能与11β-HSD 1活性升高有关。2）成人GH缺乏者血清脂联素水平与代谢紊乱脂联素是一种脂肪细胞源性血浆蛋白，具有胰岛素增敏和抗动脉粥样硬化的特性，是胰岛素抵抗的负调节因子。成人生长激素缺乏症（GHD）患者体内脂肪增加，腹部占优势，早期动脉粥样硬化的发生率和心血管疾病的死亡率增加。胰岛素抵抗可能在这些发病机制中起一定作用。脂联素在血清中以两种形式存在，即低分子量（LMW）形式和高分子量（HMW）复合物。最近，有报道血清高分子量脂联素与糖耐量的相关性比血清总脂联素更好。本研究检测了GHD患者血清高分子量脂联素和总脂联素水平，并探讨了脂联素与胰岛素抵抗的关系。ELISA法测定血清高分子量和总脂联素水平。GHD患者的体重指数（BMI）和HOMA-R值均显著高于对照组。GHD患者血清HMW和总脂联素水平的中位数分别为4.5μg/ml和8.1μml。与对照组（5.7μg/ml、9.9μg/ml）相比，差异有显著性（P <0.05）。高分子量脂联素水平与HOMA-R、BMI呈负相关（Rs=-0.57，Rs =-0.35 ; P<0.01）。提示高分子量脂联素可能与GHD患者的胰岛素抵抗有关。少

In this study, we have investigated pathopysiological significance of GH and IGF-I in metabolic disorders as follows.1) Effect of GH and IGF-I on 11β-hydroxysteroid dehydrogenase typel (HSD1) in 3T3-L1 adipocytesIn peripheral tissues, corticosteroid action is partly regulated by 11β-hydroxysteroid dehydrogenase (11β-HSD) which interconverts hormonally active cortisol (F) and inactive cortisone (E) . The 11β-HSD1 that acts principally as reductase converting E to F, expresses in liver and adipose tissues. Patients with GH deficiency have a clinical feature of visceral adiposity and it has been reported that these patients increased the F/E metabolite ratio. In the present study, we investigated the effect of GH and IGF-I on 11β-HSD1 in 3T3-L1 adipocytes. 3T3-L1 preadipocytes were differentiated to adipocytes according to the conventional method and adipocytes were treated for up to 24 hours with various concentrations of GH or IGF-I. 11β-HSD1 mRNA levels and activity were measured. … More 11β-HSD1 mRNA levels and activity increased during differentiation from preadipocytes to adipocytes and the levels were suppressed by GH and IGF-I in differentiated adipocytes. These data suggest that 11β-HSD1 activity in adipose tissues is higher with low concentrations of GH and/or IGF-I, leading to an increase in active cortisol that induces adipogenesis and/or lipogenesis. Visceral adiposity in the patients with GH deficiency might be related to increased 11β-HSD1 activity.2) Serum adiponectin levels and metabolic disorders in the patients with adult GH deficinencyAdiponectin, an adipocyte-derived plasma protein with insulin-sensitizing and anti-atherosclerotic properties, has been found to be a negative regulator of insulin resistance. Patients with adult growth hormone deficiency (GHD) have been found to have increased body fat with abdominal preponderance, prev,alence of premature atherosclerosis, and mortality from cardiovascular disease. It has been suggested that insulin resistance might play some role in these pathogenesis. Adiponectin is found as two forms in serum, as a lower molecular weight (LMW) form and a high molecular weight (HMW) complex. Recently, it has been reported that serum HMW adiponectin correlates better with glucose tolerance than total serum adiponectin. In the present study, we measured serum HMW adiponectin as well as total adiponectin in patients with GHD and investigated the relationship between the adiponectin and insulin resistance in these patients. Serum HMW and total adiponectin levels were measured by ELISA, respectively. Body mass index (BMI) and HOMA-R values in GHD were significantly greater than those in control subjects The median values of serum HMW and total adiponectin levels in patients with GHD were 4.5μg/ml and 8.1μml, respectively. The values were significantly lower than those in controls (5.7μg/ml, 9.9μg/ml). The HMW adiponectin levels inversely correlated with HOMA-R and BMI (Rs=-0.57, Rs=-0.35 ; P<0.01). These data demonstrate that the HMW adiponectin might be related with insulin resistance in patients with GHD. Less