Johansen T, Laurino C, Barreca A, Malmlöf K
Department of Pharmacological Research, Discovery, Novo Nordisk, DK-2760 Måløv, Denmark.
Growth Horm IGF Res. 2005 Feb;15(1):55-63. doi: 10.1016/j.ghir.2004.11.006. Epub 2005 Jan 22.
Growth Hormone (GH) promotes loss of body fat and causes insulin resistance. It is debated whether reduction of body fat mass during long term growth hormone (GH) administration improves carbohydrate metabolism. To answer this question we assessed carbohydrate handling and tissue specific function of the insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) during prolonged GH treatment of obese rats.
Body fat % estimated by DEXA scanning, plasma IGF-I, glucose and insulin were studied in 17 months old dietary induced obese rats treated for 4, 21 or 41 days (GH: 4 mg/kg/d or saline total n=90). Adipose tissue, muscle and liver samples were obtained after 21 days and expression and tyrosine phosphorylation of IR and IRS-1 proteins and the degree of IRS-1-Janus Kinase-2 (JAK2) interaction were analyzed by immunoprecipitation and immunoblotting.
Forty-one days GH treatment caused the body fat to decline significantly to 20+/-3% (Mean+/-SEM), whereas it remained steady on 51+/-4% in the pair fed group. Insulin levels in response to OGTT were significantly elevated throughout the experiment. IR amount was elevated in adipose tissue but decreased in liver after GH treatment while IR phosphorylation was increased in muscle only. IRS-1 amount was elevated in adipose tissue and muscle while IRS-1 phosphorylation was increased only in liver. The association of IRS-1 with JAK-2 was increased in liver and muscle.
An extensive reduction of fat mass did not improved signs of insulin resistance in GH treated old obese rats. The molecular events associated with GH treatment included tissue specific changes in the function of IR and IRS-1 suggesting the liver to be the primary site of insulin resistance. Furthermore, the association of IRS-1with JAK-2 in the course of GH signaling could present a mechanism for GH to directly induce insulin resistance.
生长激素（GH）可促进体脂减少并导致胰岛素抵抗。长期应用生长激素（GH）期间体脂量的减少是否能改善碳水化合物代谢，目前仍存在争议。为回答这个问题，我们评估了肥胖大鼠长期接受GH治疗期间的碳水化合物处理情况以及胰岛素受体（IR）和胰岛素受体底物-1（IRS-1）的组织特异性功能。
对17月龄饮食诱导的肥胖大鼠进行4、21或41天的治疗（GH：4mg/kg/d或生理盐水，共n = 90只），通过双能X线吸收法扫描评估体脂百分比，研究血浆胰岛素样生长因子-I（IGF-I）、葡萄糖和胰岛素水平。21天后获取脂肪组织、肌肉和肝脏样本，通过免疫沉淀和免疫印迹分析IR和IRS-1蛋白的表达、酪氨酸磷酸化以及IRS-1与Janus激酶-2（JAK2）的相互作用程度。
41天的GH治疗使体脂显著下降至20±3%（均值±标准误），而配对喂养组则维持在51±4%。在整个实验过程中，口服葡萄糖耐量试验（OGTT）后的胰岛素水平显著升高。GH治疗后，脂肪组织中的IR含量升高，肝脏中的IR含量降低，而仅肌肉中的IR磷酸化增加。脂肪组织和肌肉中的IRS-1含量升高，仅肝脏中的IRS-1磷酸化增加。肝脏和肌肉中IRS-1与JAK-2的结合增加。
在接受GH治疗的老年肥胖大鼠中，大量体脂减少并未改善胰岛素抵抗迹象。与GH治疗相关的分子事件包括IR和IRS-1功能的组织特异性变化，提示肝脏是胰岛素抵抗的主要部位。此外，在GH信号传导过程中IRS-1与JAK-2的结合可能是GH直接诱导胰岛素抵抗的一种机制。
