Maria Angela Ziveri

Relationships between serum IGF-1, IGFBP-2, interleukin-1beta and interleukin-6 in inflammatory bowel disease.

Aims: To study the relationships between serum IGF-1, IGFBP-3 and IGFBP-2 and interleukin (IL)-1β and IL-6 in inflammatory bowel disease (IBD). Methods: Thirty-seven patients (18 males, 19 females, aged 8.8–26.1 years) with IBD (Crohn’s disease, CD, n = 17, and ulcerative colitis, UC, n = 20) were studied. Patients were in relapse or remission according to established criteria. Serum IGF-1, IGFBP-3, IGFBP-2, IL-1β and IL-6 levels were determined in patients and 15 healthy controls (aged 8.2–19.0 years). Results: IGF-1 levels were lower in patients with CD in relapse compared with controls (p < 0.05). IGFBP-2 levels were higher in CD in relapse compared with other groups (all p < 0.05). In CD and UC patients (n = 37), IGF-1 levels were inversely correlated with the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). IGFBP-2 levels correlated positively with ESR and IL-1β. IL-6 levels correlated positively with ESR and CRP. IL-1β levels were elevated in CD in relapse compared to controls (p < 0.05) and were higher in UC in relapse than in other groups (all p < 0.05). In combined CD/UC patients in relapse (n = 20), IL-1β levels were higher (p < 0.05) in patients with recto-sigmoiditis (n = 5) than in other patients. Conclusions: IGF-1, IGFBP-2 levels were related to IL levels, disease activity and anatomical distribution, consistent with active inflammation modifying the IGF-IGFBP system, possibly relevant to disturbance of growth.

Effects of Cord Serum Insulin, IGF-II, IGFBP-2, IL-6 and Cortisol Concentrations on Human Birth Weight and Length: Pilot Study

Background The IGF system is recognised to be important for fetal growth. We previously described increased Insulin-like growth factor binding protein (IGFBP)-2 cord serum concentrations in intra-uterine growth retardation (IUGR) compared with appropriate for gestational age (AGA) newborns, and a positive relationship of IGFBP-2 with Interleukin (IL)-6. The role of cortisol in the fetus at birth is largely unknown, and interactions among peptides are their real effect on birth size is unknown. Furthermore, almost all studies have previously assayed peptides in serum several years after birth, and follow-up data from pregnancy are always lacking. This study aimed at establishing and clarifying the effect of cord serum insulin, IGF-II, IGFBP-2, cortisol and IL-6 concentrations on birth length and weight. Methods 23 IUGR and 37 AGA subjects were followed up from the beginning of pregnancy, and were of comparable gestational age. Insulin, IGF-II, IGFBP-2, cortisol and IL-6 concentrations were assayed in cord serum at birth, and a multiple regression model was designed and applied to assess which were the significant biochemical determinants of birth size. Results Insulin, cortisol, and IL-6, showed similar concentrations in IUGR and AGA as previously described, whereas IGF-II was lower, and IGFBP-2 increased in IUGR compared with AGA. IGF-II serum concentration was found to have a significant positive effect on both birth length (r::0.546; p: 0.001) and weight (r:0.679; p: 0.0001). IGFBP-2 had a near significant negative effect on both birth weight (r:−0.342; p: 0.05) and length (r:−0.372; p:0.03). Conclusion IGF-II cord serum concentration was shown to have a significant positive effect on both birth length and weight, whereas IGFBP-2 had a significant negative effect. Insulin, cortisol, and IL-6 cord serum concentrations had no significant effect on birth size.

Impairment of insulin receptor signal transduction in placentas of intra-uterine growth-restricted newborns and its relationship with fetal growth

OBJECTIVE Intra-uterine growth restriction (IUGR) is related to a higher incidence of type 2 diabetes mellitus. We previously reported reduced adiponectin and increased interleukin 6 (IL6) concentrations in IUGR placentas, which are features of insulin resistance. We aimed to investigate placental insulin receptor (IR) function and activation in human placenta and subsequently the relationships of insulin signalling peptides with placental protein content in IL6, insulin, resistin and adiponectin, and with parameters of fetal growth. DESIGN AND METHODS Whole villous tissue was collected from 18 IUGR and 24 appropriate for gestational age (AGA) placentas of comparable gestational age. Insulin signalling peptides, suppressors of cytokine signalling-2 (SOCS2), insulin, adiponectin, resistin, and IL6 concentrations were determined by using western immunoblotting or specific research kits. RESULTS The amount of total IR was similar in both groups but activated IR significantly higher in IUGR. Total IR substrate-1 (IRS1) was increased in IUGR, whereas total IRS2 and activated IRS1 were similar. AKT content was reduced and activated AKT was undetectable in IUGR placentas. c-Jun N-terminal kinase content was reduced in IUGR. Total and activated ERK1/2 was similar in IUGR and AGA groups, and total SOCS2 was increased in IUGR. IL6 lysate concentrations correlated with AKT content and activated IR. Correlations were found also with adiponectin and resistin. SOCS2 correlated negatively with all growth parameters at birth. CONCLUSIONS IR was more activated in placentas of IUGR compared with AGA; however, signal transduction downstream of the receptor was impaired. The increase in activated IR could be in favour of a compensatory mechanism to increase insulin sensitivity. Close relationships of insulin action in placenta with fetal growth were shown.

Changes and relationships of IGFS and IGFBPS and cytokines in coeliac disease at diagnosis and on gluten-free diet

Objective  To evaluate changes and relationships of IGFs and IGFBPs, serum interleukin 6 (IL‐6) and tumour necrosis factor (TNF)‐α, and auxological parameters at diagnosis of coeliac disease (CD) and at 6 months and 12 months after starting a gluten‐free diet (GFD), compared with a control population.

Markers of insulin sensitivity in placentas and cord serum of intrauterine growth-restricted newborns.

Objective  Intrauterine growth restriction (IUGR) has been related to a higher incidence of insulin resistance in adult life, which is associated with low adiponectin and high resistin, insulin and interleukin (IL)‐6 serum concentrations. This study assessed cortisol, insulin, total insulin receptor, resistin, adiponectin and IL‐6 concentrations, as markers of insulin sensitivity, in placental lysates and cord serum of IUGR and appropriate for gestational age (AGA) newborns, to establish relationships among peptides and with growth parameters at birth.

The IGF system and cytokine interactions and relationships with longitudinal growth in prepubertal patients with cystic fibrosis

Objective  Growth delay is a feature of patients with cystic fibrosis (CF). CF is a condition characterized by chronic inflammation that has been shown to modify the IGF system, which is essential for normal growth, and is related to pulmonary function in CF patients. We aimed to verify whether circulating levels of tumour necrosis factor (TNF)‐α, interleukin (IL)‐6, insulin and the IGF system were related and/or had relationships with linear growth in children with CF.

Analysis of Bone Mineral Density and Turnover in Patients with Cystic Fibrosis: Associations between the IGF System and Inflammatory Cytokines

Background: Cystic fibrosis (CF) patients present an increased risk of osteoporosis, and increased fracture rate. Several factors have been identified as modulators of bone metabolism and bone mineral density (BMD). Aims: To evaluate BMD and serum markers of bone turnover and establish their relationships with serum concentrations of interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α, IGF-I, IGF-II, IGF binding protein (IGFBP)-2, IGFBP-3, and parathyroid hormone (PTH) in young adult CF patients. Methods: Seventeen young adult CF patients (4 M, 13 F; mean age: 26.6 ± 1.1 years) were enrolled in the study and analysed as a whole and as two subgroups according to the Shwachman-Kulczycki score. BMD was assessed at the lumbar spine (L1–L4) by dual energy X-ray absorptiometry (DXA Hologic QDR 2000). Bone turnover was assessed by measuring serum levels of osteocalcin (OC) and serum carboxyterminal propeptide of type I collagen (PICP) as markers of bone formation, and serum cross-linked carboxyterminal telopeptide of type I collagen (ICTP) as a marker of bone resorption. Serum IGFs, IGFBPs, and cytokines were assayed using special commercial kits. Daily calcium intake and weekly physical activity were estimated by questionnaires. Forced expiratory volume in one second was used to assess pulmonary function. Results: Lumbar BMD was normal, although there was a tendency to be lower in the patients with a lower clinical score. Both OC and PICP were increased, whereas ICTP was normal. Lumbar BMD was positively correlated with pulmonary function. IL-6 and C-reactive protein (markers of inflammation) were inversely correlated with PICP. Serum ICTP levels were correlated with serum IGF-I levels.No significant relationship was detected among lumbar BMD, markers of bone turnover and PTH, IGF-I, IGF-II, IGFBP-2, IGFBP-3, TNF-α, IL-1β, and body mass index Z-score. Conclusions: Bone turnover is abnormal in CF patients. Young adult CF patients with satisfying clinical status and nutritional conditions have normal BMD and increased serum OC and PICP levels.

Thyroid function, cytokine and IGF-IGFBP interactions in cystic fibrosis patients.

Background/Aims: Thyroid function impairment has been sporadically described in cystic fibrosis (CF) and ascribed to iodine overload or selenite deficiency. In this study we evaluated thyroid function in CF in order to verify these data and to evaluate if the modifications were related to serum levels of markers of inflammation and growth factors that we have previously shown to be altered in CF. Methods: Seventeen young adult CF patients and 18 age-matched controls were enrolled in this study. The diagnosis of CF was confirmed by genetic analysis. None was treated with pulmonary expectorants. Serum IL-1β, IL-6, TNF-α, IGF-I, IGF-II, IGFBP-2, IGFBP-3, TSH, fT3 and fT4 were measured using standard commercial kits. Results: TSH, fT3 and fT4 serum levels were similar in CF patients and controls. Within the patient group, thyroid function did not vary in relation to C-reactive protein serum levels, respiratory function and clinical conditions (Shwachman score). No correlation was found with any growth factor or cytokine analyzed. Conclusions: At variance with the few previously published data, we did not detect any difference in thyroid function in patients with CF compared with normal healthy subjects. This could be due to the fact that no iodine overload or selenite deficiency was present in our patients. Thyroid function seemed independent of markers of inflammation and IGF-IGFBP serum levels.