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P107 rhIGF-1 therapy for growth failure and IGF-1 deficiency in Congenital Disorder of Glycosylation Ia
Poster Presentations / Growth Hormone & IGF Research 20 (2010) S39–S81
In order to identify a potential IGFBP-3 receptor, we have employed the yeast two-hybrid screening using a cDNA construct encoding the mid region (amino acids 88–148) of the IGFBP-3 protein as bait against an Hs578T, human breast cancer cell cDNA library. This screen resulted in the identification of a cDNA, later designated IGFBP-3R, representing a novel gene comprised of 915 base pairs and encoding a 240 amino acid polypeptide. Further investigation has revealed that IGFBP-3R is a single-span membrane protein and binds specifically to IGFBP-3 but not other IGFBP species. Expression analysis of IGFBP-3 and IGFBP-3R indicates that the IGFBP-3/IGFBP-3R axis is impaired in breast and prostate cancer. We also provide evidence for anti-tumor effect of IGFBP-3R in vivo using prostate and breast cancer xenografts in athymic nude mice. Further in vitro studies demonstrate that IGFBP-3R mediates IGFBP-3-induced caspase-8-dependent apoptosis in various cancer cells. Knockdown of IGFBP-3R attenuated IGFBP-3-induced caspase activities and apoptosis, whereas overexpression of IGFBP-3R enhanced IGFBP-3 biological effects. IGFBP-3R physically interacts and activates caspase-8, and knockdown of caspase-8 expression or activity inhibited IGFBP-3/IGFBP-3R-induced apoptosis. Together, these data demonstrate that IGFBP-3R represents a novel cell death receptor and is essential for the IGFBP-3-induced apoptosis and tumor suppression. Thus, the IGFBP-3/IGFBP-3R axis may provide therapeutic and prognostic value for the treatment of cancer. P105 The IGF-I and IGFBP-3 response after two years of growth hormone treatment using recommended doses differs in children with growth hormone deficiency, small-for-gestational age status, Ullrich–Turner and Prader–Willi syndrome: implications for treatment? B.P. Hauffa1 , W.-S. Liu1 , A. Grabensee1 , C.A. Liebrand1 , K. Schaaf1 . 1 Pediatric Endocrinology & Diabetes, University Children’s Hospital, University Duisburg-Essen, Essen, Germany Introduction: Response to growth hormone (GH) therapy varies widely. Measurements of serum IGF-I and IGFBP-3 are used to monitor treatment compliance and safety. For some diseases, it is proposed to lower GH doses if IGF-I concentrations exceed +2 standard deviations (SD). At the same time, specific GH dosage levels must be maintained to achieve catch-up growth or keep up desired metabolic effects. We hypothesized that at recommended GH doses (RD), IGF-I and IGFBP-3 responses to treatment differ between children with growth hormone deficiency (GHD), smallfor-gestational age status (SGA), Ullrich–Turner syndrome (UTS) and Prader–Willi syndrome (PWS). That would include varying proportions of patients with elevated IGF-I and IGFBP-3 levels in these diagnostic groups. Patients and Methods: 88 consecutive patients on GH therapy with RD from a single center (Essen) who had completed 2 years of treatment, were analysed. (GHD n = 25, RD 0.025–0.035 mg/kg/d; SGA n = 28, RD 0.035 mg/kg/d; UTS n = 17, RD 0.045 mg/kg/d; PWS n = 18, RD 0.035 mg/kg/d). Height was measured, and IGF-I and IGFBP-3 concentrations were determined with commercial assays (Mediagnost, Germany) at baseline and after 1 and 2 years of treatment. Results: At start, GHD, SGA and UTS patients were shortest with mean height SDS ranging from −3.46 to −3.05, in contrast to PWS with −2.50 (P < 0.05). Mean IGF-I (IGFBP-3) SDS at start of therapy ranged from -1.96 to -1.32 (−0.76 to −0.16) in SGA, UTS and PWS and was lowest in GHD with −3.26 (−2.22) (P < 0.0001 for both hormones). After one year, overall IGF-I SDS had increased to −0.62 to −0.42 with no difference between groups. Similar increases were found for IGFBP-3, resulting in a significant difference between means for GHD (+0.13 SD) and PWS (+1.34 SD; P = 0.008). In year 2 further increases in IGF-I SDS were noted only for the PWS
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group, resulting in a mean of +1.5 vs. −0.73 to +0.07 for the other groups; P = 0.0002 vs. GHD, UTS). Similar changes were observed for IGFBP-3 (P = 0.0015; PWS vs. GHD). In 7 of 18 PWS patients IGF-I was above +2 SD, whereas only 1 of 25 GHD patients, 3 of 28 SGA patients and 3 of 17 UTS patients exceeded +2 SD. Conclusion: Our data shows that at 2 years of GH treatment with RD, children with PWS have increased IGF-I (IGFBP-3) to higher levels than children with GHD or UTS (GHD). Proposals to lower GH dose in response to elevated IGF-I (IGFBP-3) concentrations may conflict with the need to maintain GH doses required for metabolic effects. P106 Can IGFBP-1 level predict hepatic steatosis? R. Gupta1 , A. Bhangoo2 , S. Jain2 , E.J. Dickman2 , S. Ten2 . 1 Pediatric Endocrinology, Maimonides Medical Center, Brooklyn, NY, USA; 2 Pediatrics, Maimonides Medical Center, Brooklyn, NY, USA Background: IGFBP-1 (Insulin like growth factor binding protein-1) transcription in hepatocytes is inhibited by portal insulin, therefore serving as a liver-specific marker of insulin sensitivity. Additionally, IGFBP-1 levels were recently shown to be inversely correlated with liver fat content and were obesity-independent. Also leptin and TG(triglyceride) levels are presumed to correlate with the visceral adiposity and insulin resistance but their role is not established in terms of hepatic steatosis. Hepatic steatosis is observed frequently in hispanic boys and does not appear to necessarily be correlated with severity of overweight, therefore markers of this condition remain unknown. Hypothesis: IGFBP-1 can be used as a marker not only for insulin sensitivity but also for hepatic steatosis. Aim: To investigate the difference in IGFBP-1 level in obese boys with normal liver enzymes (LE) and in obese boys with abnormal LE suggestive of hepatic steatosis. Methodology: 21 obese boys were divided into 2 groups according to their LE and fasting insulin. Different causes of abnormal LE like hepatitis and metabolic liver disease were excluded by blood tests. Insulin resistance indices were calculated from fasting glucose and insulin and OGTT test. Along with IGFBP-1, Leptin and lipid profile were also compared. Results: Group 1 with normal LE (n = 13, age 12.6±2.2, 60% Hispanic, 20% AA, 20% others, ALT 22.6±5.3, AST 22.1±3.9), Group 2 with abnormal LE (n = 8, age 12.13±4.9, 100% Hispanic, ALT 136±118, AST 90.2±62.2). There were no differences between the groups BMI, lipid profile and insulin resistance indices HOMA, IRG and Quicki. IGFBP-1 was significantly lower in Group 2: 2.3±1.1 than in Group 1: 8.8±3.9, p < 0.01. Leptin was lower in Group 2: 17.9±7.9, Group 1: 24.1±4.9, but didn’t reach statistical significance, p = 0.1. HDL was lower and TG was higher in Group 2 but didn’t reach statistical significance. Conclusions: In addition to being a indicator of insulin resistance, IGFBP-1 may be marker for hepatic steatohepititis. However, further investigation is necessary to confirm whether elevated IGFBP-1 levels can predict hepatic steatosis. Further larger, prospective studies are required to establish definitely the role of IGFBP-1 in predicting hepatic steatosis and to evaluate its progression. P107 rhIGF-1 therapy for growth failure and IGF-1 deficiency in Congenital Disorder of Glycosylation Ia B.S. Miller1 , M.M. Duffy1 , K. Sarafoglou1 . 1 Pediatrics, University of Minnesota, Minneapolis, MN, USA Background: Congenital disorders of glycosylation (CDG) are a group of rare disorders in which glycosylation required for proper protein-protein interactions and protein stability is disrupted, manifesting clinically with multiple system involvement and
S80
Poster Presentations / Growth Hormone & IGF Research 20 (2010) S39–S81
growth failure [1]. The insulin-like growth factor (IGF) system plays an important role in childhood growth and has been shown to be dysfunctional with low IGF-1 levels in a previous study in children with CDG type Ia (PMM2 Deficiency) [2]. rhIGF-1 therapy has not been reported in patients with CDG-Ia. Case Report: A 3 year old Caucasian male with failure to thrive was diagnosed with CDG-Ia at 5 months of age. Initially, his height and weight were <−2 standard deviation score (SDS), IGF-1: <25 ng/mL (49–289), IGFBP-3: 1.0 mcg/mL (0.9–4.3), & ALS: 1.3 mg/L (0.7–7.9). Despite an aggressive feeding schedule, with overnight g-tube supplementation, he continued to show poor growth and weight gain. At 16 months, he underwent an IGF-1 generation test with growth hormone (0.1 mg/kg/day) for seven days. At baseline, the IGF-1 was 27 ng/mL (55–327) and stimulated only to 33 ng/mL. rhIGF-1 therapy was initiated at 21 months of age at 40 mcg/kg/dose twice daily and increased to 130 mcg/kg/dose. The child showed an excellent linear growth response with height increasing from −2.73 to −1.39 SDS over 22 months of rhIGF-1 therapy. IGF-1 and IGFBP-3 levels also increased.
Interestingly, the child’s protein losing enteropathy also improved while on rhIGF-1. Blood glucose levels have been monitored with only one episode of documented hypoglycemia (glucose 60 mg/dL) during a febrile illness. Conclusion: This is the first case report of rhIGF-1 therapy in a patient with CDG-Ia. The child had an excellent linear growth response. These results provide additional in vivo evidence for IGF dysfunction in CDG-Ia and suggest that rhIGF-1 may be a novel treatment for growth failure in CDG-Ia.
Methods: This was a pre-planned subanalysis of all 700 pediatric critically ill patients included in a prospective, randomized study on IIT. Patients were randomly assigned to target blood glucose levels of 50–80 mg/dL in infants (age <1 year, n = 317) and 70–100 mg/dL in children (age ≥1 year, n = 383) with insulin infusion throughout ICU stay (IIT), or to insulin infusion only to prevent blood glucose from exceeding 215 mg/dL (conventional insulin therapy, CIT). We analyzed blood samples taken upon PICU admission, day 3 and day 7 from patients who were still in PICU on these days. In addition, using a nested case-control design, samples taken before and after hypoglycemia were analyzed in 63 patients experiencing hypoglycemia and in 63 matched patients without hypoglycemia. Circulating insulin, C-peptide, GH, IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-3 and acid labile subunit (ALS) were determined by radio-immunoassays (RIA). Bio-available IGF-I was quantified using a kinase receptor activation assay. In the nested case-control study, we also quantified circulating cortisol and glucagon. Results: On day 3 and day 7, circulating insulin was somewhat higher (p = 0.026 and p = 0.004) whereas C-peptide was >10-fold lower (all p < 0.001) in the IIT group than in the CIT group. On day 3, IIT increased circulating GH (p = 0.041), while there was no difference on day 7. Total IGF-I was unaltered. In contrast, bioavailable IGF-I was lower on day 3 (p = 0.002), but not on day 7, in the IIT group. IIT also decreased IGFBP-3 and ALS levels on day 3 (p = 0.001 and p = 0.007) and day 7 (p = 0.003 and p = 0.038) as compared with CIT. In contrast, IGFBP-1 levels were increased by IIT on day 3 only (p = 0.044). Multivariate logistic regression analysis suggested that only the lowering of portal insulin, as reflected by C-peptide, may have mediated an important part of the mortality benefit. In the nested case-control study, after “hypoglycemia”, only IGFBP-1 remained high in the cases whereas it decreased in controls (p = 0.055). No changes in cortisol or glucagon occurred with hypoglycemia. Conclusion: While improving outcome of PICU patients, IIT further accentuated the illness-associated ‘catabolic’ response within the somatotropic axis, despite feeding. Too low blood glucose targets may have played a role. However, the elimination of the portal insulin effect by exogenous insulin, as reflected by C-peptide, may also explain the changes within the GH axis. This C-peptide effect appeared to statistically explain at least part of the survival benefit with IIT.
Reference(s) [1] Miller BS and HH Freeze, Rev Endo Metab Dis 2003; 4:103. [2] Miller BS et al., Clin Endocrinol 2009; 70:892.
P109 Up-regulation of IGFBP-2 following a controlled cortical impact injury
Table 1: Growth data Chronologic Age Height Ht (cm) SDS 5 mo 9 mo 11 mo 1 yr 2 mo 1 yr 4 mo 1 yr 9 mo 2 yr 6 mo 3 yr 1 mo 3 yr 7 mo
57.6 63.2 67 68.4 72.8 75.8 84 89.2 94
−3.71 −3.32 −3.05 −3.45 −2.69 −2.73 −1.86 −1.72 −1.39
Growth Weight Weight IGF-1 IGFBP-3 velocity (kg) SDS (ng/mL) (mcg/mL) (cm/yr) 20.0 15.8 6.7 18.3 8.6 11.5 8.5 8.9
5.0 6.1 6.7 7.8 8.8 8.8 10.6 11.0 12.9
−3.37 −3.75 −3.86 −3.09 −2.52 −3.11 −2.27 −2.67 −1.69
<25 <25 31 27 64 39 53 346
1.1 1.0 1.5 1.0 1.0 1.2 1.9
P108 Effect of intensive insulin therapy on the somatotropic axis in critically ill children M. Gielen1 , D. Mesotten1 , M.P. Brugts2 , I. Vanhorebeek1 , S.W.J. Lamberts2 , J.A.M.J.L. Janssen2 , G. Van den Berghe1 . 1 Intensive Care Medicine, Katholieke Universiteit Leuven, Leuven, Belgium; 2 Internal Medicine, Erasmus MC, Rotterdam, Netherlands Introduction: Critical illness evokes a ‘catabolic’ response within the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. Despite improving patient outcome, intensive insulin therapy (IIT) in critically ill adults unexpectedly lowered IGF-I and increased GH, possibly explained by concomitant malnutrition. In the pediatric intensive care unit (PICU), targeting blood glucose levels to age-adjusted normal fasting values also reduced morbidity and mortality, despite increased incidence of (brief) hypoglycemia. Hormonal responses in children may differ from adults and higher amounts of feeding are administered in critically ill children. We therefore hypothesized that IIT in PICU patients could reactivate the somatotropic axis.
M. Qin1 , Y. Jiang1 , B. Peng1 , T. Cominsk1 , S. Levison1 , J. Pintar1 . 1 Robert Wood Johnson Medical School and New Jersey Medical School, UMDNJ, Piscataway, NJ, USA We have previously documented up-regulation of several of the IGFBPs via puncture wound (Berry, Logan, Pintar) and sought to determine whether the more physiologically relevant compression model for TBI (controlled cortical impact) would lead to alterations in IGFBP expression following this type of injury. We found thar one specific IGFBP, IGFBP-2, was reproducibly up-regulated in the parenchyma adjacent to the injury site, with the results for the expression pattern similar at several time points following CCI. Low IGFBP-2 expression is un-injured mice is normally seen at the X-ray level only in the meninges and choroids plexus. However, even only one day following CCI, low levels of IGFBP-2 expression are detected near the lesion site while prominent up-regulation is apparent in the nearby meninges. The up-regulation of IGFBP-2 remains clear and more dramatic at both day 3 and day 7 following CCI. The higher levels of expression at day 3 are readily apparent with expression relatively evenly distributed through the brain parenchyma adjacent to the lesion site. By day 7 following lesion,
In order to identify a potential IGFBP-3 receptor, we have employed the yeast two-hybrid screening using a cDNA construct encoding the mid region (amino acids 88–148) of the IGFBP-3 protein as bait against an Hs578T, human breast cancer cell cDNA library. This screen resulted in the identification of a cDNA, later designated IGFBP-3R, representing a novel gene comprised of 915 base pairs and encoding a 240 amino acid polypeptide. Further investigation has revealed that IGFBP-3R is a single-span membrane protein and binds specifically to IGFBP-3 but not other IGFBP species. Expression analysis of IGFBP-3 and IGFBP-3R indicates that the IGFBP-3/IGFBP-3R axis is impaired in breast and prostate cancer. We also provide evidence for anti-tumor effect of IGFBP-3R in vivo using prostate and breast cancer xenografts in athymic nude mice. Further in vitro studies demonstrate that IGFBP-3R mediates IGFBP-3-induced caspase-8-dependent apoptosis in various cancer cells. Knockdown of IGFBP-3R attenuated IGFBP-3-induced caspase activities and apoptosis, whereas overexpression of IGFBP-3R enhanced IGFBP-3 biological effects. IGFBP-3R physically interacts and activates caspase-8, and knockdown of caspase-8 expression or activity inhibited IGFBP-3/IGFBP-3R-induced apoptosis. Together, these data demonstrate that IGFBP-3R represents a novel cell death receptor and is essential for the IGFBP-3-induced apoptosis and tumor suppression. Thus, the IGFBP-3/IGFBP-3R axis may provide therapeutic and prognostic value for the treatment of cancer. P105 The IGF-I and IGFBP-3 response after two years of growth hormone treatment using recommended doses differs in children with growth hormone deficiency, small-for-gestational age status, Ullrich–Turner and Prader–Willi syndrome: implications for treatment? B.P. Hauffa1 , W.-S. Liu1 , A. Grabensee1 , C.A. Liebrand1 , K. Schaaf1 . 1 Pediatric Endocrinology & Diabetes, University Children’s Hospital, University Duisburg-Essen, Essen, Germany Introduction: Response to growth hormone (GH) therapy varies widely. Measurements of serum IGF-I and IGFBP-3 are used to monitor treatment compliance and safety. For some diseases, it is proposed to lower GH doses if IGF-I concentrations exceed +2 standard deviations (SD). At the same time, specific GH dosage levels must be maintained to achieve catch-up growth or keep up desired metabolic effects. We hypothesized that at recommended GH doses (RD), IGF-I and IGFBP-3 responses to treatment differ between children with growth hormone deficiency (GHD), smallfor-gestational age status (SGA), Ullrich–Turner syndrome (UTS) and Prader–Willi syndrome (PWS). That would include varying proportions of patients with elevated IGF-I and IGFBP-3 levels in these diagnostic groups. Patients and Methods: 88 consecutive patients on GH therapy with RD from a single center (Essen) who had completed 2 years of treatment, were analysed. (GHD n = 25, RD 0.025–0.035 mg/kg/d; SGA n = 28, RD 0.035 mg/kg/d; UTS n = 17, RD 0.045 mg/kg/d; PWS n = 18, RD 0.035 mg/kg/d). Height was measured, and IGF-I and IGFBP-3 concentrations were determined with commercial assays (Mediagnost, Germany) at baseline and after 1 and 2 years of treatment. Results: At start, GHD, SGA and UTS patients were shortest with mean height SDS ranging from −3.46 to −3.05, in contrast to PWS with −2.50 (P < 0.05). Mean IGF-I (IGFBP-3) SDS at start of therapy ranged from -1.96 to -1.32 (−0.76 to −0.16) in SGA, UTS and PWS and was lowest in GHD with −3.26 (−2.22) (P < 0.0001 for both hormones). After one year, overall IGF-I SDS had increased to −0.62 to −0.42 with no difference between groups. Similar increases were found for IGFBP-3, resulting in a significant difference between means for GHD (+0.13 SD) and PWS (+1.34 SD; P = 0.008). In year 2 further increases in IGF-I SDS were noted only for the PWS
S79
group, resulting in a mean of +1.5 vs. −0.73 to +0.07 for the other groups; P = 0.0002 vs. GHD, UTS). Similar changes were observed for IGFBP-3 (P = 0.0015; PWS vs. GHD). In 7 of 18 PWS patients IGF-I was above +2 SD, whereas only 1 of 25 GHD patients, 3 of 28 SGA patients and 3 of 17 UTS patients exceeded +2 SD. Conclusion: Our data shows that at 2 years of GH treatment with RD, children with PWS have increased IGF-I (IGFBP-3) to higher levels than children with GHD or UTS (GHD). Proposals to lower GH dose in response to elevated IGF-I (IGFBP-3) concentrations may conflict with the need to maintain GH doses required for metabolic effects. P106 Can IGFBP-1 level predict hepatic steatosis? R. Gupta1 , A. Bhangoo2 , S. Jain2 , E.J. Dickman2 , S. Ten2 . 1 Pediatric Endocrinology, Maimonides Medical Center, Brooklyn, NY, USA; 2 Pediatrics, Maimonides Medical Center, Brooklyn, NY, USA Background: IGFBP-1 (Insulin like growth factor binding protein-1) transcription in hepatocytes is inhibited by portal insulin, therefore serving as a liver-specific marker of insulin sensitivity. Additionally, IGFBP-1 levels were recently shown to be inversely correlated with liver fat content and were obesity-independent. Also leptin and TG(triglyceride) levels are presumed to correlate with the visceral adiposity and insulin resistance but their role is not established in terms of hepatic steatosis. Hepatic steatosis is observed frequently in hispanic boys and does not appear to necessarily be correlated with severity of overweight, therefore markers of this condition remain unknown. Hypothesis: IGFBP-1 can be used as a marker not only for insulin sensitivity but also for hepatic steatosis. Aim: To investigate the difference in IGFBP-1 level in obese boys with normal liver enzymes (LE) and in obese boys with abnormal LE suggestive of hepatic steatosis. Methodology: 21 obese boys were divided into 2 groups according to their LE and fasting insulin. Different causes of abnormal LE like hepatitis and metabolic liver disease were excluded by blood tests. Insulin resistance indices were calculated from fasting glucose and insulin and OGTT test. Along with IGFBP-1, Leptin and lipid profile were also compared. Results: Group 1 with normal LE (n = 13, age 12.6±2.2, 60% Hispanic, 20% AA, 20% others, ALT 22.6±5.3, AST 22.1±3.9), Group 2 with abnormal LE (n = 8, age 12.13±4.9, 100% Hispanic, ALT 136±118, AST 90.2±62.2). There were no differences between the groups BMI, lipid profile and insulin resistance indices HOMA, IRG and Quicki. IGFBP-1 was significantly lower in Group 2: 2.3±1.1 than in Group 1: 8.8±3.9, p < 0.01. Leptin was lower in Group 2: 17.9±7.9, Group 1: 24.1±4.9, but didn’t reach statistical significance, p = 0.1. HDL was lower and TG was higher in Group 2 but didn’t reach statistical significance. Conclusions: In addition to being a indicator of insulin resistance, IGFBP-1 may be marker for hepatic steatohepititis. However, further investigation is necessary to confirm whether elevated IGFBP-1 levels can predict hepatic steatosis. Further larger, prospective studies are required to establish definitely the role of IGFBP-1 in predicting hepatic steatosis and to evaluate its progression. P107 rhIGF-1 therapy for growth failure and IGF-1 deficiency in Congenital Disorder of Glycosylation Ia B.S. Miller1 , M.M. Duffy1 , K. Sarafoglou1 . 1 Pediatrics, University of Minnesota, Minneapolis, MN, USA Background: Congenital disorders of glycosylation (CDG) are a group of rare disorders in which glycosylation required for proper protein-protein interactions and protein stability is disrupted, manifesting clinically with multiple system involvement and
S80
Poster Presentations / Growth Hormone & IGF Research 20 (2010) S39–S81
growth failure [1]. The insulin-like growth factor (IGF) system plays an important role in childhood growth and has been shown to be dysfunctional with low IGF-1 levels in a previous study in children with CDG type Ia (PMM2 Deficiency) [2]. rhIGF-1 therapy has not been reported in patients with CDG-Ia. Case Report: A 3 year old Caucasian male with failure to thrive was diagnosed with CDG-Ia at 5 months of age. Initially, his height and weight were <−2 standard deviation score (SDS), IGF-1: <25 ng/mL (49–289), IGFBP-3: 1.0 mcg/mL (0.9–4.3), & ALS: 1.3 mg/L (0.7–7.9). Despite an aggressive feeding schedule, with overnight g-tube supplementation, he continued to show poor growth and weight gain. At 16 months, he underwent an IGF-1 generation test with growth hormone (0.1 mg/kg/day) for seven days. At baseline, the IGF-1 was 27 ng/mL (55–327) and stimulated only to 33 ng/mL. rhIGF-1 therapy was initiated at 21 months of age at 40 mcg/kg/dose twice daily and increased to 130 mcg/kg/dose. The child showed an excellent linear growth response with height increasing from −2.73 to −1.39 SDS over 22 months of rhIGF-1 therapy. IGF-1 and IGFBP-3 levels also increased.
Interestingly, the child’s protein losing enteropathy also improved while on rhIGF-1. Blood glucose levels have been monitored with only one episode of documented hypoglycemia (glucose 60 mg/dL) during a febrile illness. Conclusion: This is the first case report of rhIGF-1 therapy in a patient with CDG-Ia. The child had an excellent linear growth response. These results provide additional in vivo evidence for IGF dysfunction in CDG-Ia and suggest that rhIGF-1 may be a novel treatment for growth failure in CDG-Ia.
Methods: This was a pre-planned subanalysis of all 700 pediatric critically ill patients included in a prospective, randomized study on IIT. Patients were randomly assigned to target blood glucose levels of 50–80 mg/dL in infants (age <1 year, n = 317) and 70–100 mg/dL in children (age ≥1 year, n = 383) with insulin infusion throughout ICU stay (IIT), or to insulin infusion only to prevent blood glucose from exceeding 215 mg/dL (conventional insulin therapy, CIT). We analyzed blood samples taken upon PICU admission, day 3 and day 7 from patients who were still in PICU on these days. In addition, using a nested case-control design, samples taken before and after hypoglycemia were analyzed in 63 patients experiencing hypoglycemia and in 63 matched patients without hypoglycemia. Circulating insulin, C-peptide, GH, IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-3 and acid labile subunit (ALS) were determined by radio-immunoassays (RIA). Bio-available IGF-I was quantified using a kinase receptor activation assay. In the nested case-control study, we also quantified circulating cortisol and glucagon. Results: On day 3 and day 7, circulating insulin was somewhat higher (p = 0.026 and p = 0.004) whereas C-peptide was >10-fold lower (all p < 0.001) in the IIT group than in the CIT group. On day 3, IIT increased circulating GH (p = 0.041), while there was no difference on day 7. Total IGF-I was unaltered. In contrast, bioavailable IGF-I was lower on day 3 (p = 0.002), but not on day 7, in the IIT group. IIT also decreased IGFBP-3 and ALS levels on day 3 (p = 0.001 and p = 0.007) and day 7 (p = 0.003 and p = 0.038) as compared with CIT. In contrast, IGFBP-1 levels were increased by IIT on day 3 only (p = 0.044). Multivariate logistic regression analysis suggested that only the lowering of portal insulin, as reflected by C-peptide, may have mediated an important part of the mortality benefit. In the nested case-control study, after “hypoglycemia”, only IGFBP-1 remained high in the cases whereas it decreased in controls (p = 0.055). No changes in cortisol or glucagon occurred with hypoglycemia. Conclusion: While improving outcome of PICU patients, IIT further accentuated the illness-associated ‘catabolic’ response within the somatotropic axis, despite feeding. Too low blood glucose targets may have played a role. However, the elimination of the portal insulin effect by exogenous insulin, as reflected by C-peptide, may also explain the changes within the GH axis. This C-peptide effect appeared to statistically explain at least part of the survival benefit with IIT.
Reference(s) [1] Miller BS and HH Freeze, Rev Endo Metab Dis 2003; 4:103. [2] Miller BS et al., Clin Endocrinol 2009; 70:892.
P109 Up-regulation of IGFBP-2 following a controlled cortical impact injury
Table 1: Growth data Chronologic Age Height Ht (cm) SDS 5 mo 9 mo 11 mo 1 yr 2 mo 1 yr 4 mo 1 yr 9 mo 2 yr 6 mo 3 yr 1 mo 3 yr 7 mo
57.6 63.2 67 68.4 72.8 75.8 84 89.2 94
−3.71 −3.32 −3.05 −3.45 −2.69 −2.73 −1.86 −1.72 −1.39
Growth Weight Weight IGF-1 IGFBP-3 velocity (kg) SDS (ng/mL) (mcg/mL) (cm/yr) 20.0 15.8 6.7 18.3 8.6 11.5 8.5 8.9
5.0 6.1 6.7 7.8 8.8 8.8 10.6 11.0 12.9
−3.37 −3.75 −3.86 −3.09 −2.52 −3.11 −2.27 −2.67 −1.69
<25 <25 31 27 64 39 53 346
1.1 1.0 1.5 1.0 1.0 1.2 1.9
P108 Effect of intensive insulin therapy on the somatotropic axis in critically ill children M. Gielen1 , D. Mesotten1 , M.P. Brugts2 , I. Vanhorebeek1 , S.W.J. Lamberts2 , J.A.M.J.L. Janssen2 , G. Van den Berghe1 . 1 Intensive Care Medicine, Katholieke Universiteit Leuven, Leuven, Belgium; 2 Internal Medicine, Erasmus MC, Rotterdam, Netherlands Introduction: Critical illness evokes a ‘catabolic’ response within the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. Despite improving patient outcome, intensive insulin therapy (IIT) in critically ill adults unexpectedly lowered IGF-I and increased GH, possibly explained by concomitant malnutrition. In the pediatric intensive care unit (PICU), targeting blood glucose levels to age-adjusted normal fasting values also reduced morbidity and mortality, despite increased incidence of (brief) hypoglycemia. Hormonal responses in children may differ from adults and higher amounts of feeding are administered in critically ill children. We therefore hypothesized that IIT in PICU patients could reactivate the somatotropic axis.
M. Qin1 , Y. Jiang1 , B. Peng1 , T. Cominsk1 , S. Levison1 , J. Pintar1 . 1 Robert Wood Johnson Medical School and New Jersey Medical School, UMDNJ, Piscataway, NJ, USA We have previously documented up-regulation of several of the IGFBPs via puncture wound (Berry, Logan, Pintar) and sought to determine whether the more physiologically relevant compression model for TBI (controlled cortical impact) would lead to alterations in IGFBP expression following this type of injury. We found thar one specific IGFBP, IGFBP-2, was reproducibly up-regulated in the parenchyma adjacent to the injury site, with the results for the expression pattern similar at several time points following CCI. Low IGFBP-2 expression is un-injured mice is normally seen at the X-ray level only in the meninges and choroids plexus. However, even only one day following CCI, low levels of IGFBP-2 expression are detected near the lesion site while prominent up-regulation is apparent in the nearby meninges. The up-regulation of IGFBP-2 remains clear and more dramatic at both day 3 and day 7 following CCI. The higher levels of expression at day 3 are readily apparent with expression relatively evenly distributed through the brain parenchyma adjacent to the lesion site. By day 7 following lesion,