Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Pediatrics, Institute of Clinical Sciences, and.
JCI Insight. 2020 Oct 2;5(19):140363. doi: 10.1172/jci.insight.140363.
BACKGROUNDHyperglycemia, insulin insensitivity, and low IGF1 levels in extremely preterm infants are associated with an increased risk of retinopathy of prematurity (ROP), but the interactions are incompletely understood.METHODSIn 117 extremely preterm infants, serum glucose levels and parenteral glucose intake were recoded daily in the first postnatal week. Serum IGF1 levels were measured weekly. Mice with oxygen-induced retinopathy alone versus oxygen-induced retinopathy plus streptozotocin-induced hyperglycemia/hypoinsulinemia were assessed for glucose, insulin, IGF1, IGFBP1, and IGFBP3 in blood and liver. Recombinant human IGF1 was injected to assess the effect on glucose and retinopathy.RESULTSThe highest mean plasma glucose tertile of infants positively correlated with parenteral glucose intake [r(39) = 0.67, P < 0.0001]. IGF1 plasma levels were lower in the high tertile compared with those in low and intermediate tertiles at day 28 (P = 0.038 and P = 0.03). In high versus lower glucose tertiles, ROP was more prevalent (34 of 39 versus 19 of 39) and more severe (ROP stage 3 or higher; 71% versus 32%). In oxygen-induced retinopathy, hyperglycemia/hypoinsulinemia decreased liver IGF1 expression (P < 0.0001); rh-IGF1 treatment improved normal vascular regrowth (P = 0.027) and reduced neovascularization (P < 0.0001).CONCLUSIONIn extremely preterm infants, high early postnatal plasma glucose levels and signs of insulin insensitivity were associated with lower IGF1 levels and increased ROP severity. In a hyperglycemia retinopathy mouse model, decreased insulin signaling suppressed liver IGF1 production, lowered serum IGF1 levels, and increased neovascularization. IGF1 supplementation improved retinal revascularization and decreased pathological neovascularization. The data support IGF1 as a potential treatment for prevention of ROP.TRIAL REGISTRATIONClinicalTrials.gov NCT02760472 (Donna Mega).FUNDINGThis study has been supported by the Swedish Medical Research Council (14940, 4732, 20144-01-3, and 21144-01-3), a Swedish government grant (ALFGB2770), Lund medical faculty grants (ALFL, 11615 and 11601), the Skåne Council Foundation for Research and Development, the Linnéa and Josef Carlsson Foundation, the Knut and Alice Wallenberg Foundation, the NIH/National Eye Institute (EY022275, EY017017, EY017017-13S1, and P01 HD18655), European Commission FP7 project 305485 PREVENT-ROP, Deutsche Forschungsgemeinschaft (CA-1940/1-1), and Stiftelsen De Blindas Vänner.
极高早产儿的高血糖、胰岛素不敏感和 IGF1 水平低与早产儿视网膜病变（ROP）的风险增加有关，但相互作用尚不完全清楚。
在 117 名极高早产儿中，在出生后的第一周内每天记录血清葡萄糖水平和肠外葡萄糖摄入量。每周测量 IGF1 水平。单独氧诱导视网膜病变的小鼠与氧诱导视网膜病变加链脲佐菌素诱导的高血糖/胰岛素血症的小鼠的血液和肝脏中的葡萄糖、胰岛素、IGF1、IGFBP1 和 IGFBP3 进行评估。注射重组人 IGF1 以评估其对葡萄糖和视网膜病变的影响。
婴儿的最高平均血浆葡萄糖 tertile 与肠外葡萄糖摄入呈正相关 [r(39) = 0.67，P < 0.0001]。与低和中 tertile 相比，第 28 天的 IGF1 血浆水平在高 tertile 中较低（P = 0.038 和 P = 0.03）。与较低的葡萄糖 tertile 相比，高 tertile 的 ROP 更为普遍（39 例中有 34 例，39 例中有 19 例）且更为严重（ROP 3 期或更高；71%比 32%）。在氧诱导的视网膜病变中，高血糖/胰岛素血症降低了肝脏 IGF1 表达（P < 0.0001）；rh-IGF1 治疗改善了正常血管再生（P = 0.027）并减少了新生血管形成（P < 0.0001）。
在极高早产儿中，早期高血糖水平和胰岛素不敏感的迹象与较低的 IGF1 水平和 ROP 严重程度增加有关。在高血糖性视网膜病变小鼠模型中，胰岛素信号的降低抑制了肝脏 IGF1 的产生，降低了血清 IGF1 水平，并增加了新生血管形成。IGF1 补充改善了视网膜再血管化并减少了病理性新生血管形成。这些数据支持 IGF1 作为预防 ROP 的潜在治疗方法。
ClinicalTrials.gov NCT02760472（Donna Mega）。
本研究得到了瑞典医学研究委员会（14940、4732、20144-01-3 和 21144-01-3）、瑞典政府拨款（ALFGB2770）、伦德医学学院拨款（ALFL、11615 和 11601）、斯科讷委员会基金会研究与发展、林奈和约瑟夫·卡尔森基金会、科特和爱丽丝·瓦伦堡基金会、美国国立卫生研究院/国家眼科研究所（EY022275、EY017017、EY017017-13S1 和 P01 HD18655）、欧盟委员会 FP7 项目 305485 PREVENT-ROP、德国研究基金会（CA-1940/1-1）和盲人之友基金会的支持。
