IGF1, serum glucose, and retinopathy of prematurity in extremely preterm infants

Bertan Cakir, William Hellström, Yohei Tomita, Zhongjie Fu, Raffael Liegl, Anna Winberg, Ingrid Hansen-Pupp, David Ley, Ann Hellström, Chatarina Löfqvist, Lois Eh Smith, Bertan Cakir, William Hellström, Yohei Tomita, Zhongjie Fu, Raffael Liegl, Anna Winberg, Ingrid Hansen-Pupp, David Ley, Ann Hellström, Chatarina Löfqvist, Lois Eh Smith

Abstract

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.

Keywords: Glucose metabolism; Insulin signaling; Ophthalmology; Retinopathy.

Conflict of interest statement

Conflict of interest: IHP, DL, and AH hold stock/stock options in Premalux and have received consulting fees from Shire. LEHS has received consulting fees from Shire. CL holds stocks in Premalux.

Figures

Figure 1. Flow chart for the selection…
Figure 1. Flow chart for the selection of study participants.
A total of 64 patients participated in the Lund prospective longitudinal observation study, and a total of 90 patients were included in the randomized controlled Donna Mega trial. In each study 12 patients were lost to follow-up (drop out). In the Lund cohort a total of 12 infants were excluded from analysis due to advanced gestational age (GA ≥28 weeks). Only 1 patient was excluded from the Donna Mega randomized controlled trial due to loss of records. SOC, standard of care.
Figure 2. Hyperglycemia in the first week…
Figure 2. Hyperglycemia in the first week of life is associated with poor glucose control.
(A) Illustration of glucose tertiles constructed using mean plasma glucose levels during the first week of life. (B) Correlation between mean plasma glucose and parenteral glucose intake in the first week of life (n = 39 each group). Spearman’s correlation (r) for the relationship between glucose levels and glucose intake within the respective glucose tertiles were 0.46 for Tlow (P = 0.003), 0.16 for Tintermediate (P = 0.32), and 0.67 for Thigh (P < 0.0001).The colored lines indicate the slope of the linear regression (red, Thigh; orange, Tintermediate; purple, Tlow).
Figure 3. Plasma IGF1 levels from P1…
Figure 3. Plasma IGF1 levels from P1 to P28 and ROP frequency.
(A) Mean plasma IGF1 levels from P1 to P28. The high glucose tertile group showed lower mean IGF1 levels through P1–P28 compared with Tlow and Tintermediate, with a significant difference compared with Tlow and Tintermediate at P28 (P = 0.038 and P = 0.030, mixed model regression). (B) Relationship between glucose tertile and frequency of retinopathy of prematurity (ROP) stages. Severity and frequency of ROP was higher in the high glucose tertile group compared with the intermediate and low glucose tertile group (P < 0.0001). *P < 0.05, Mantel-Haenszel χ2 test. Error bars represent 95% CI.
Figure 4. The neonatal hyperglycemia/hypoinsulinemia oxygen-induced retinopathy…
Figure 4. The neonatal hyperglycemia/hypoinsulinemia oxygen-induced retinopathy model.
(A) Scheme of neonatal hyperglycemia oxygen-induced retinopathy model (hyperglycemia/hypoinsulinemia oxygen-induced retinopathy [H-OIR]) vs. OIR control: C57BL/6 mouse pups were exposed to 75% oxygen from P7 to P12 to induce central vaso-obliteration (VO) and returned to room air at P12–P17, which was characterized by vascular regrowth and later by neovascular tuft formation (NV). To induce hyperglycemia, streptozotocin or PBS was injected daily (25 μg per gram body weight) from P2 to P12. (B) Top: Representative retinal whole-mount images at P12 stained with lectin (OIR, left; H-OIR, right). Bottom: Images after fully automated deep-learning segmentation. The yellow outlines the VO area. Scale bar: 1 mm. (C) Serum insulin levels were decreased at P12 in H-OIR mice compared with OIR controls (n = 10 for both groups; P = 0.0007). (D) There was no difference in VO between H-OIR and OIR mice at P12 (P = 0.39; n = 18 eyes for OIR and n = 16 eyes for H-OIR). (E) There was a significant difference in VO between H-OIR and OIR mice at P17 (P = 0.001; n = 9 eyes for OIR and n = 12 eyes for H-OIR). (F) There was a significant difference in NV between H-OIR and OIR mice at P17 (P = 0.049; n = 9 eyes for OIR and n = 12 eyes for H-OIR). (G) Top: Representative lectin-stained retinal whole-mount images at P17 (OIR, left; H-OIR, right). Bottom: Images after fully automated deep-learning segmentation. The yellow outlines the VO, and the red the NV area. Error bars represent mean ± SD. Unpaired t test was used for statistical analysis.
Figure 5. IGF1 and glucose expression profile…
Figure 5. IGF1 and glucose expression profile in the neonatal hyperglycemia/hypoinsulinemia oxygen-induced retinopathy model.
(A) Plasma glucose levels at P12 were unchanged between oxygen-induced retinopathy (OIR) controls (PBS) and hyperglycemia OIR (H-OIR) mice (n = 5 for OIR and n = 8 for H-OIR). (B) Liver mRNA expression at P12: Igf1 and Igfbp3 was reduced more than 2-fold in the H-OIR group. Igfbp1 was unchanged. (n = 6 for OIR group and n = 5 for H-OIR). (C) ELISA measurements of plasma IGF1 protein at P12 were unchanged between groups (n = 6 in each group). (D) Plasma glucose levels at P17 were increased in H-OIR pups (n = 5 for OIR and n = 8 for H-OIR). (E) Liver mRNA expression at P17: Igf1 and Igfbp3 were reduced more than 2-fold in the H-OIR group. Igfbp1 was unchanged (n = 5 for OIR and n = 8 for H-OIR). (F) ELISA measurements of plasma IGF1 protein at P17 were decreased in H-OIR mice compared with OIR controls (n = 5 for OIR and n = 8 for H-OIR). ***P < 0.001, ****P < 0.0001. Error bars represent mean ± SD. Unpaired t test was used for statistical analysis.
Figure 6. IGF1 reduces neovascularization in the…
Figure 6. IGF1 reduces neovascularization in the neonatal hyperglycemia/hypoinsulinemia oxygen-induced retinopathy model.
(A) Scheme of neonatal hyperglycemia oxygen-induced retinopathy (OIR) model (H-OIR): C57BL/6 mouse pups were exposed to 75% oxygen from P7 to P12 to induce central vaso-obliteration (VO) and returned to room air at P12–P17, which was characterized by vascular regrowth and later by neovascular tuft formation (NV). To induce hyperglycemia, streptozotocin (STZ) was injected daily (25 μg per gram body weight) from P2 to P12. IGF1 or control PBS injections were performed twice daily s.c. (4 μg per gram body weight) from P12 to P16. (B) Scatter blot of VO at P17: There was a significant difference in VO between IGF1 and PBS at P17 (P = 0.027; n = 18 eyes for PBS and n = 23 eyes for IGF1 in H-OIR). (C) Scatter blot of NV at P17: There was a significant difference in NV between IGF1 and PBS at P17 (P < 0.0001; n = 15 eyes for PBS and n = 19 eyes for IGF1). (D) Top: Representative retinal whole-mount images at P17 (PBS, left; IGF1, right). Bottom: Images after fully automated deep-learning segmentation. Yellow outlines the VO, and red the NV area. Scale bar: 1 mm. Error bars represent mean ± SD. Unpaired t test was used for statistical analysis.

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