Geffner M E, Bersch N, Golde D W
Department of Pediatrics, University of California Medical Center, Los Angeles 90024.
J Clin Endocrinol Metab. 1993 Apr;76(4):1039-47. doi: 10.1210/jcem.76.4.8473379.
GH is the hormone primarily responsible for regulating body size within the genetic program. While GH has pleiotropic actions on cellular growth and metabolism, most of its effects are believed to be mediated by a single GH receptor. This receptor is not functional in tissues from patients with Laron dwarfism. We used human T-cell leukemia virus-immortalized T-lymphoblast cell lines from Laron dwarfs and normal individuals to examine the mechanism of GH-induced insulin resistance at the cellular level. GH (5-500 micrograms/L) caused a profound decrease in the sensitivity of normal T-lymphoblasts in response to all insulin concentrations (P < 0.0001 vs. insulin alone); pretreatment with GH and GH receptor antibody significantly improved sensitivity to all concentrations of insulin (P = NS vs. insulin alone). Preincubation with GH and PRL receptor antibody was associated with partial improvement in insulin sensitivity (P = 0.004 vs. insulin alone). Thus, in normal T-cell lines, the major pathway of GH-induced insulin resistance appears to be directed by the GH receptor, with a smaller effect mediated through the PRL receptor. While T-cell lines from Laron dwarfs do not respond to GH in clonal proliferation assays, GH (50 and 100 micrograms/L) caused profound insulin resistance in these cells (P = 0.008 and P < 0.0001, respectively, vs. insulin alone). GH receptor antibody did not abrogate this effect at any insulin concentration (P = NS vs. insulin alone), but there was partial restoration of insulin sensitivity when GH and PRL receptor antibody were coincubated (P = 0.0069 vs. insulin alone). Thus, in Laron T-cell lines, PRL and perhaps other lactogenic receptors appear to mediate GH-induced insulin resistance. The kinetics of GH-induced insulin resistance in Laron T-cells were also distinct from the pattern seen in normal T-cells, and unlike in normal cells, GH had no effect on insulin-like growth factor-I-induced clonal expansion of Laron T-cell lines (P = NS vs. insulin-like growth factor-I alone). These results provide evidence for an alternative pathway of GH action revealed in cells lacking classical growth responses to GH.
生长激素（GH）是在遗传程序内主要负责调节身体大小的激素。虽然GH对细胞生长和代谢具有多效性作用，但大多数作用被认为是由单一的GH受体介导的。该受体在拉伦侏儒症患者的组织中无功能。我们使用来自拉伦侏儒症患者和正常个体的人T细胞白血病病毒永生化T淋巴母细胞系，在细胞水平上研究GH诱导胰岛素抵抗的机制。GH（5 - 500微克/升）导致正常T淋巴母细胞对所有胰岛素浓度的反应敏感性显著降低（与单独使用胰岛素相比，P < 0.0001）；用GH和GH受体抗体预处理可显著提高对所有浓度胰岛素的敏感性（与单独使用胰岛素相比，P = 无显著性差异）。用GH和催乳素（PRL）受体抗体预孵育与胰岛素敏感性部分改善相关（与单独使用胰岛素相比，P = 0.004）。因此，在正常T细胞系中，GH诱导胰岛素抵抗的主要途径似乎由GH受体介导，通过PRL受体介导的作用较小。虽然来自拉伦侏儒症患者的T细胞系在克隆增殖试验中对GH无反应，但GH（50和100微克/升）在这些细胞中引起显著的胰岛素抵抗（分别与单独使用胰岛素相比，P = 0.008和P < 0.0001）。在任何胰岛素浓度下，GH受体抗体均未消除这种作用（与单独使用胰岛素相比，P = 无显著性差异），但当GH和PRL受体抗体共同孵育时，胰岛素敏感性有部分恢复（与单独使用胰岛素相比，P = 0.0069）。因此，在拉伦T细胞系中，PRL以及可能的其他催乳素受体似乎介导了GH诱导的胰岛素抵抗。拉伦T细胞中GH诱导胰岛素抵抗的动力学也与正常T细胞中的模式不同，并且与正常细胞不同的是，GH对胰岛素样生长因子-I诱导的拉伦T细胞系克隆扩增无影响（与单独使用胰岛素样生长因子-I相比，P = 无显著性差异）。这些结果为在缺乏对GH经典生长反应的细胞中揭示的GH作用的替代途径提供了证据。
