Ader M, Agajanian T, Finegood D T, Bergman R N
Endocrinology. 1987 Feb;120(2):725-31. doi: 10.1210/endo-120-2-725.
Chronic administration of human GH (mol wt, 22,000; 22K-hGH) is known to generate insulin resistance in dogs. However, recent hypotheses claim that diabetogenicity may be attributable to smaller weight contaminants or fragments not found in purified lower weight hGH (mol wt, 20,000; 20K-hGH) also secreted by the pituitary. In this study, we examined the effects of chronic (12-day) low dose (0.02 mg/kg X day) infusion of recombinant DNA-derived methionyl 22K- and 20K-hGH on glucose tolerance in conscious dogs. Minimal model analysis of the frequently sampled iv glucose tolerance tests quantified insulin sensitivity and glucose effectiveness, the ability of glucose per se to normalize its own concentration. Infusion of 22K-hGH, raising plasma hGH levels to 3.8 +/- 0.6 ng/ml, resulted in an elevation in fasting glucose levels after 2 days of infusion (104 +/- 1 vs. pre-hGH 97 +/- 2 mg/dl; P less than 0.01), but the effect was transient. No change was noted during 20K-hGH treatment (P greater than 0.2). Mildly elevated fasting insulin levels were observed in both 22K- and 20K-hGH-treated dogs (P less than 0.04 and 0.03, respectively). However, despite maintenance of adequate glucose tolerance during both infusions (P greater than 0.07), marked insulin resistance was apparent; insulin sensitivity dropped from 9.7 +/- 2.4 and 11.2 +/- 2.1 X 10(-4) min-1/(microU/ml) in 22K- and 20K-hGH-treated dogs, to 2.5 and 2.8 X 10(-4) min-1/(microU/ml), a drop of 75% (P less than 0.01 and 0.001). Insulin resistance persisted throughout the infusion period, slowly returning to pre-hGH treatment levels in 22K-hGH-treated dogs during recovery. Insulin resistance persisted 3 days after cessation of 20K-hGH treatment (day 15), but returned to pre-hGH levels by day 25. Integrated glucose-stimulated insulin release was enhanced after 2 days of 22K- or 20K-hGH treatment (P less than 0.03 and less than 0.05), but the effect was transient. Maintenance of normal glucose tolerance in the face of severe insulin resistance and only transiently elevated insulin response was possible because glucose effectiveness remained unchanged. In conclusion, despite minimal effects of low dose hGH infusion on glucose tolerance and fasting glucose and insulin levels, 22K- and 20K-hGH are equipotent in generating severe insulin resistance and potentiating glucose-stimulated insulin release.
已知长期给予人生长激素（分子量22,000；22K-hGH）会使犬产生胰岛素抵抗。然而，最近的假说认为，致糖尿病性可能归因于垂体分泌的纯化低分子量hGH（分子量20,000；20K-hGH）中未发现的较小分子量污染物或片段。在本研究中，我们检测了重组DNA衍生的甲硫氨酰22K-和20K-hGH以低剂量（0.02 mg/kg×天）连续输注12天对清醒犬葡萄糖耐量的影响。对频繁采样的静脉注射葡萄糖耐量试验进行最小模型分析，以量化胰岛素敏感性和葡萄糖效能，即葡萄糖自身使自身浓度正常化的能力。输注22K-hGH使血浆hGH水平升至3.8±0.6 ng/ml，输注2天后空腹血糖水平升高（104±1 vs. 输注hGH前97±2 mg/dl；P<0.01），但该效应是短暂的。20K-hGH治疗期间未观察到变化（P>0.2）。在接受22K-和20K-hGH治疗的犬中均观察到空腹胰岛素水平轻度升高（分别为P<0.04和0.03）。然而，尽管在两种输注期间均维持了足够的葡萄糖耐量（P>0.07），但明显存在显著的胰岛素抵抗；胰岛素敏感性从接受22K-和20K-hGH治疗的犬中的9.7±2.4和11.2±2.1×10⁻⁴ min⁻¹/(μU/ml)降至2.5和2.8×10⁻⁴ min⁻¹/(μU/ml)，下降了75%（P<0.01和0.001）。胰岛素抵抗在整个输注期间持续存在，在接受22K-hGH治疗的犬恢复过程中缓慢恢复至输注hGH前水平。20K-hGH治疗停止后3天（第15天）胰岛素抵抗持续存在，但在第25天恢复至输注hGH前水平。22K-或20K-hGH治疗2天后，葡萄糖刺激的胰岛素释放积分增加（P<0.03和<0.05），但该效应是短暂的。由于葡萄糖效能保持不变，因此在存在严重胰岛素抵抗且仅胰岛素反应短暂升高的情况下仍能维持正常葡萄糖耐量。总之，尽管低剂量hGH输注对葡萄糖耐量、空腹血糖和胰岛素水平影响极小，但22K-和20K-hGH在产生严重胰岛素抵抗和增强葡萄糖刺激的胰岛素释放方面具有同等效力。
