Hokken-Koelega A C S, De Waal W J, Sas T C J, Van Pareren Y, Arends N J T
Department of Pediatrics, Sophia Children's Hospital, Erasmus University Medical Center Rotterdam, The Netherlands.
J Pediatr Endocrinol Metab. 2004 Mar;17 Suppl 3:463-9.
Several studies have demonstrated an association between low birth weight and impaired insulin sensitivity or even type 2 diabetes mellitus (DM2) in later life. Growth hormone (GH) is known to increase fasting and postprandial insulin levels. For that reason concern has been expressed regarding possible detrimental effects of GH therapy in children born SGA. In a Dutch trial the possible side effects of GH therapy on carbohydrate metabolism were assessed in short children born SGA after 6 years and at 6 months after discontinuation of GH therapy. This study included 79 prepubertal short children born SGA, participating in a multicenter double-blind, randomized, dose-response GH trial. Inclusion criteria were: 1) birth length SDS below -1.88, 2) age 3-11 years in boys and 3-9 years in girls, 3) height SDS < -1.88, 4) no spontaneous catch-up growth, and 5) an uncomplicated neonatal period. Mean (SD) value for age was 7.3 (2.1) years, birth length SDS -3.6, height SDS -3.0 (0.7) and BMI SDS -1.2 (1.3). All children were randomly assigned to either group A (n = 41) using 1 mg GH/m2/day or group B (n = 38) using 2 mg/m2/ d/ay (approximately 0.1 or 0.2 IU/kg/d, respectively). Standard oral glucose tolerance tests (OGTTs) were performed before and during 6 years of GH therapy and 6 months after discontinuation of GH therapy. Before GH therapy 8% of the children had impaired glucose tolerance (IGT) according to criteria of the WHO. After 6 years of GH therapy, IGT was found in 4% and after stopping GH in 10%. Mean fasting glucose increased significantly with 0.5 mMol/l after 1 year of GH therapy, without a further increase thereafter. GH therapy induced considerably higher fasting and glucose-stimulated insulin levels. None of the observed changes were different between the GH dosage groups. Children who remained prepubertal had similar glucose and insulin levels compared to children who entered puberty. HbA1c levels were always in the normal range and none of the children developed diabetes mellitus. After discontinuation of GH therapy the mean serum glucose levels remained normal and the mean serum insulin levels decreased significantly, to normal age reference values. Before the start of GH the mean systolic blood pressure was significantly higher compared to age-matched peers, whereas during GH therapy a significant decline in mean systolic blood pressure occurred, which remained similar after discontinuation of GH treatment. In conclusion, continuous, long-term GH therapy in short children born SGA has no adverse effects on glucose levels, even with GH dosages up to 2 mg/m2/day. However, as has been reported in other patient groups, GH induced higher fasting and glucose-stimulated insulin levels, indicating insulin resistance. After discontinuation of GH, serum insulin levels declined to normal age-matched reference levels. Since impaired insulin sensitivity and DM2 have been demonstrated in relatively young patients born SGA, long-term follow-up of children born SGA is advised, also after discontinuation of GH therapy.
多项研究表明，低出生体重与日后胰岛素敏感性受损甚至2型糖尿病（DM2）之间存在关联。已知生长激素（GH）可提高空腹和餐后胰岛素水平。因此，有人担心GH治疗对小于胎龄儿（SGA）出生的儿童可能产生有害影响。在一项荷兰试验中，对SGA出生的矮小儿童在接受GH治疗6年后以及停止GH治疗6个月后，评估了GH治疗对碳水化合物代谢的可能副作用。该研究纳入了79名青春期前SGA出生的矮小儿童，他们参与了一项多中心双盲、随机、剂量反应性GH试验。纳入标准为：1）出生身长标准差评分（SDS）低于-1.88；2）男孩年龄3至11岁，女孩年龄3至9岁；3）身高SDS < -1.88；4）无自然追赶生长；5）新生儿期无并发症。年龄的平均（标准差）值为7.3（2.1）岁，出生身长SDS为-3.6，身高SDS为-3.0（0.7），体重指数SDS为-1.2（1.3）。所有儿童被随机分为A组（n = 41），使用1 mg GH/m²/天，或B组（n = 38），使用2 mg/m²/天（分别约为0.1或0.2 IU/kg/d）。在GH治疗的6年期间以及停止GH治疗6个月后，进行了标准口服葡萄糖耐量试验（OGTT）。根据世界卫生组织的标准，在GH治疗前，8%的儿童存在糖耐量受损（IGT）。GH治疗6年后，IGT发生率为4%，停止GH治疗后为10%。GH治疗1年后，空腹血糖平均显著升高0.5 mmol/L，此后未进一步升高。GH治疗导致空腹和葡萄糖刺激的胰岛素水平显著升高。在不同GH剂量组之间，观察到的变化无差异。与进入青春期的儿童相比，仍处于青春期前的儿童血糖和胰岛素水平相似。糖化血红蛋白（HbA1c）水平始终在正常范围内，且无儿童患糖尿病。停止GH治疗后，平均血清葡萄糖水平保持正常，平均血清胰岛素水平显著下降至正常年龄参考值。在开始GH治疗前，平均收缩压与年龄匹配的同龄人相比显著更高，而在GH治疗期间，平均收缩压显著下降，停止GH治疗后仍保持相似水平。总之，对SGA出生的矮小儿童进行持续、长期的GH治疗，即使GH剂量高达2 mg/m²/天，对血糖水平也无不良影响。然而，正如在其他患者群体中所报道的，GH会导致空腹和葡萄糖刺激的胰岛素水平升高，表明存在胰岛素抵抗。停止GH治疗后，血清胰岛素水平下降至与年龄匹配的正常参考水平。由于已证明SGA出生的相对年轻患者存在胰岛素敏感性受损和DM2，建议对SGA出生的儿童进行长期随访，即使在停止GH治疗后也是如此。
