rhGH替代治疗对生长激素缺乏儿童糖代谢的影响

Effect of recombinant human growth hormone on glucose metabolism in children with growth hormone deficiency

目的探讨重组人生长激素(rhGH)替代治疗对生长激素缺乏症(GHD)儿童糖和胰岛素代谢的影响以及 GH 与糖代谢平衡之间的关系。方法对44例(男28例,女16例)4.5～16.5(10.4±2.6)岁 GHD 患儿在接受 rhGH 治疗前及治疗后每3个月检测体重指数、胰岛素样生长因子-1(IGF-1)、行口服葡萄糖耐量试验,计算稳态模型胰岛素抵抗指数。结果 (1)空腹血糖和 IGF-1在治疗3个月时即显著提高,一直持续较高水平,每个随访时间点与治疗前比较,差异均有统计学意义(F=6.81,7.31,P 均<0.01);稳态模型胰岛素抵抗指数和空腹胰岛素分别在治疗3和9个月时提高(P<0.01和 P<0.05),1年后下降,治疗1年半时与治疗前比较,差异已无统计学意义(均 P>0.05)。(2)相关分析发现,稳态模型胰岛素抵抗指数与体重指数、IGF-1和治疗持续时间显著相关(r=0.251,0.437,0.281,P 均<0.001)。二次方程曲线回归分析发现,稳态模型胰岛素抵抗指数与治疗持续时间呈近似抛物线量变关系。(3)发现2例暂时性高血糖,分别在停用 rhGH 治疗后1个月和5d 血糖恢复正常,再注射 rh GH 后,行口服葡萄糖耐量试验正常。结论 GHD 儿童接受 rhGH 治疗(尤第1年内)可增加胰岛素抵抗,极少数引起短暂糖代谢紊乱。循环 IGF-1可能参与控制胰岛素的敏感性,在 GH 与胰岛素平衡间起重要作用。有必要对所有接受 rhGH 治疗者定期监测糖代谢指标和 IGF-1水平。

Objective Numerous studies in children with growth hormone deficiency （GHD） show that recombinant human growth hormone （rhGH） treatment results in significant catch-up growth, but some papers reported that the children who underwent rhGH therapy might be at increased risk of diabetes. The aim of this study was to investigate the effects of rhGH treatment on blood glucose and insulin metabolism in children with GHD and the relationship between growth hormone （GH） and glucose homeostasis. Methods In this study, 44 children with GHD treated with rhGH [0. 1 U/（ kg · d）] and age- and sex-matched 20 healthy children were enrolled. The GHD group included 28 males and 16 females aged from 4. 5 to 16. 5 years （mean 10.4 ± 2.6 years）, including 18 cases of complete GHD and 26 cases of partial GHD. The sexual development stage of all subjects was in Tanner I. Oral glucose tolerance tests （OGTY） were done, and body mass index （BMI） , serum insulin-like growth factor-1 （IGF-1） level and insulin resistance by homeostasis model （HOMA-IR） were measured at the time of diagnosis and every 3 months after rhGH therapy. Continuous glucose monitoring system （ CGMS ） was applied for two cases with hyperglycemia. Results （ 1 ） Fasting glucose and IGF-1 levels increased since 3 months of treatment and did not decrease since then. The levels of fasting glucose and IGF-1 at every time points of rhGH therapy were higher than the levels at the time of diagnosis （F = 6. 81, P 〈 0.01; F = 7.31, P 〈 0.01, respectively）. HOMA-IR and fasting insulin levels were increased since 3 and 9 months of treatment （P = 0. 001 and P =0. 021, respectively）. They decreased after 12 months of therapy and the levels at 18 months of therapy were similar to that at diagnosis. （2） Pearson correlation analysis showed that HOMA-IR was positively correlated with BMI, IGF-1 and the duration of treatment （r =0. 251, 0. 437, 0. 281, P 〈0. 01, respectively）. The curve between HOMA-IR and duration of therapy was similar with parabola and the quadratic equation obtained was as follows： HOMA-IR = 1. 5048 ＋ 0. 2177 x duration of therapy （months） - 0. 0103 × duration of therapy （months） 2 （ r^2 = 0. 147, F = 14. 16, P 〈 0.01 ）. （3） Two cases had transitory hyperglycemia. Their fasting glucose levels were all higher than 7. 1 mmol/L. The glucose levels returned to normal after 1 month and 5 days respectively. OGTT and CGMS showed that their plasma glucose levels were normal after rhGH therapy was applied again. Conclusion The children who underwent rhGH therapy may be at increased risk of insulin resistance （ especially during the first year） and the therapy may even induce transitory glucose metabolic disorder in a very small proportion of patients. Circulating IGF-1 may participate in the control of insulin sensitivity and play an important role in the hormonal balance between GH and insulin. It may be necessary to monitor glucose metabolism and IGF-1 for all children who are treated with rhGH therapy.