Insulin-Like Growth Factor Binding Proteins in Kidney Disease

The seven members of the insulin-like growth factor (IGF) binding protein family (IGFBPs) were initially considered to be the regulatory proteins of IGFs in the blood circulation, mainly as the subsequent reserve for bidirectional regulation of IGF function during environmental changes. However, in recent years, IGFBPs has been found to have many functions independent of IGFs. The role of IGFBPs in regulating transcription, inducing cell migration and apoptosis is closely related to the occurrence and development of kidney disease. IGFBP-1, IGFBP-3, IGFBP-4 are closely associated with diabetes and diabetic nephropathy. IGFBP-3, IGFBP-4, IGFBP-5, IGFBP-6 are involved in different kidney disease such as diabetes, FSGS and CKD physiological process as apoptosis proteins, IGFBP-7 has been used in clinical practice as a biomarker for early diagnosis and prognosis of AKI. This review focuses on the differential expression and pathogenesis of IGFBPs in kidney disease.

Insulin/IGF-1 Signaling is Downregulated in Barrett’s Esophagus Patients Undergoing a Moderate Calorie and Protein Restriction Program: A Randomized 2-Year Trial

Obesity and associated insulin resistance (Ins-R) have been identified as important risk factors for esophageal adenocarcinoma development. Elevated calories and protein consumption are also associated with Ins-R and glucose intolerance. We investigated the effect of a 24-month moderate calorie and protein restriction program on overweight or obese patients affected by Barrett’s esophagus (BE), as no similar dietary approach has been attempted to date in this disease context. Anthropometric parameters, levels of serum analytes related to obesity and Ins-R, and the esophageal insulin/IGF-1 signaling pathway were analyzed. This study is registered with ClinicalTrials.gov, number NCT03813381. Insulin, C-peptide, IGF-1, IGF-binding protein 3 (IGFBP3), adipokines, and esophageal expression of the main proteins involved in insulin/IGF-1 signal transduction were quantified using Luminex-XMAP® technology in 46 patients who followed the restriction program (IA) and in 54 controls (CA). Body mass index and waist circumference significantly decreased in 76.1% of IA and 35.2% of CA. IGF-1 levels were reduced in 71.7% of IA and 51.8% of CA. The simultaneous reduction of glycaemia, IGF-1, the IGF-1/IGFBP3 ratio, and the improvement in weight loss-dependent insulin sensitivity, were associated with the downregulation of the insulin/IGF-1 signal on BE tissue. The proposed intervention program was an effective approach to counteract obesity-associated cancer risk factors. The improvement in metabolic condition resulted in a downregulation of the ERK-mediated mitogenic signal in 43.5% of patients, probably affecting the molecular mechanism driving adenocarcinoma development in BE lesions.

Pregnancy-associated plasma protein A mRNA expression as a marker for differentiated thyroid cancer: results from a “surgical” and a “cytological” series

Purpose Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase initially described for its role during pregnancy. PAPPA regulates IGF ligands 1 (IGF1) bioavailability through the degradation of IGF-binding protein 4 (IGFBP4). After the cleavage of IGFBP4, free IGF1 is able to bind IGF1 receptors (IGF1R) triggering the downstream signaling. Recently, PAPPA expression has been linked with development of several cancers. No data have been published on thyroid cancer, yet. Methods We evaluated PAPPA, insulin-like growth factor (IGF1), IGF1 receptors (IGF1R) and IGF-binding protein 4 (IGFBP4) mRNA expression levels in a “Surgical series” of 94 thyroid nodules (64 cancers, 16 follicular adenomas and 14 hyperplastic nodules) and in a “Cytological series” of 80 nodules from 74 patients underwent to fine-needle aspiration cytology (FNAC). In tissues, PAPPA was also evaluated by western blot. Results We found that PAPPA expression was increased in thyroid cancer specimen at mRNA and protein levels and that, adenomas and hyperplastic nodules had an expression similar to normal tissues. When applied on thyroid cytologies, PAPPA expression was able to discriminate benign from malignant nodules contributing to pre-surgical classification of the nodules. We calculated a cut-off with a good specificity (91%) which reached 100% when combined with molecular biology. Conclusion These results show that PAPPA could represent a promising diagnostic marker for differentiated thyroid cancer.

Soluble alpha klotho in acromegaly: Comparison to traditional markers of disease activity

Context Soluble alpha klotho (sαKL) has been linked to growth hormone (GH) action, but systematic evaluation and comparison to traditional biomarkers in acromegaly are lacking. Objective To evaluate the potential of sαKL to aid classification of disease activity. Design and setting Retrospective study at two academic centers. Patients Patients with acromegaly before surgery (A, n=29), after surgery controlled, discordant or uncontrolled without (B1, B2, B3, n=28, 11, 8) or with somatostatin analogue treatment (C1, C2, C3, n=17,11, 5), non-functioning pituitary adenomas (n=20) and healthy controls (n=31). Interventions sαKL was measured by immunoassay and compared to traditional biomarkers (random and nadir GH, insulin-like growth-factor I (IGF-I), IGF binding-protein 3. Associations with disease activity were assessed. Results sαKL was correlated to traditional biomarkers, but particularly to IGF-I (rs=0.80, p<0.0001). High concentrations before treatment (A, median, IQR: 4.04 xULN (2.26-8.08)) dropped to normal after treatment in controlled, and in most discordant patients. A cut-off of 1548 pg/mL for sαKL discriminated controlled (B1, C1) and uncontrolled (B3, C3) patients with 97.8% (88.4-99.9) sensitivity and 100% (77.1-100) specificity. sαKL was below the cut-off in 84% of the discordant subjects. In the remaining 16%, sαKL and IGF-I persisted elevated, despite normal random GH. Sex, age, BMI and markers of bone and calcium metabolism did not significantly affect sαKL concentrations. Conclusions Our data support sαKL as a biomarker to assess disease activity in acromegaly. It exhibits close association with GH secretory status, large dynamic range and robustness towards biological confounders. Its measurement could be helpful particularly when GH and IGF-I provide discrepant information

Extremfrühgeborene: Schützt die rhIGF-1/rhIGFBP-Substitution vor Hirnschäden?

Extrem unreife Frühgeborene haben postnatal unphysiologisch niedrige IGF-1-Spiegel (IGF-1: insulin-like growth factor-1). Eine internationale Phase-II-Studie untersuchte, ob die Behandlung mit einem Komplex aus rekombinantem humanem (rh)IGF-1 und IGF-Binding-Protein-3 (rhIGF-1/rhIGFBP-3) im Vergleich zur Standardbehandlung Frühgeburtskomplikationen reduziert. Nun berichtet das Forscherteam, ob die Therapie verschiedenen zerebralen Schäden vorbeugt.

Chorionic somatomammotropin RNA interference alters fetal liver glucose utilization

Chorionic somatomammotropin (CSH) is a placenta-specific hormone associated with fetal growth, and fetal and maternal metabolism in both humans and sheep. We hypothesized that CSH deficiency could impact sheep fetal liver glucose utilization. To generate CSH-deficient pregnancies, day 9 hatched blastocysts were infected with lentiviral particles expressing CSH-specific shRNA (RNAi) or scramble control shRNA (SC) and transferred to synchronized recipients. CSH RNAi generated two distinct phenotypes at 135 days of gestational age (dGA); pregnancies with IUGR (RNAi-IUGR) or with normal fetal weight (RNAi-NW). Fetal body, fetal liver and placental weights were reduced (P < 0.05) only in RNAi-IUGR pregnancies compared to SC. Umbilical artery plasma insulin and insulin-like growth factor 1 (IGF1) concentrations were decreased, whereas insulin receptor beta (INSR) concentration in fetal liver was increased (P < 0.05) in both RNAi phenotypes. The mRNA concentrations of IGF1, IGF2, IGF binding protein 2 (IGFBP2) and IGFBP3 were decreased (P < 0.05) in fetal livers from both RNAi phenotypes. Fetal liver glycogen concentration and glycogen synthase 1 (GYS1) concentration were increased (P < 0.05), whereas fetal liver phosphorylated-GYS (inactive GYS) concentration was reduced (P < 0.05) in both RNAi phenotypes. Lactate dehydrogenase B (LDHB) concentration was increased (P < 0.05) and IGF2 concentration was decreased (P < 0.05) in RNAi-IUGR fetal livers only. Our findings suggest that fetal liver glucose utilization is impacted by CSH RNAi, independent of IUGR, and is likely tied to enhanced fetal liver insulin sensitivity in both RNAi phenotypes. Determining the physiological ramifications of both phenotypes, may help to differentiate direct effect of CSH deficiency or its indirect effect through IUGR.

Hyperphosphorylation of fetal liver IGFBP-1 precedes slowing of fetal growth in nutrient-restricted baboons and may be a mechanism underlying IUGR

In cultured fetal liver cells, insulin-like growth factor (IGF) binding protein (IGFBP)-1 hyperphosphorylation in response to hypoxia and amino acid deprivation is mediated by inhibition of mechanistic target of rapamycin (mTOR) and activation of amino acid response (AAR) signaling and casein kinase (CK)2. We hypothesized that fetal liver mTOR inhibition, activation of AAR and CK2, and IGFBP-1 hyperphosphorylation occur before development of intrauterine growth restriction (IUGR). Pregnant baboons were fed a control (C) or a maternal nutrient restriction (MNR; 70% calories of control) diet starting at gestational day (GD) 30 (term GD 185). Umbilical blood and fetal liver tissue were obtained at GD 120 (C, n = 7; MNR, n = 10) and 165 (C, n = 7; MNR, n = 8). Fetal weights were unchanged at GD 120 but decreased at GD 165 in the MNR group (−13%, P = 0.03). IGFBP-1 phosphorylation, as determined by parallel reaction monitoring mass spectrometry (PRM-MS), immunohistochemistry, and/or Western blot, was enhanced in MNR fetal liver and umbilical plasma at GD 120 and 165. IGF-I receptor autophosphorylationTyr1135 (−64%, P = 0.05) was reduced in MNR fetal liver at GD 120. Furthermore, fetal liver CK2 (α/α′/β) expression, CK2β colocalization, proximity with IGFBP-1, and CK2 autophosphorylationTyr182 were greater at GD 120 and 165 in MNR vs. C. Additionally, mTOR complex (mTORC)1 (p-P70S6KThr389, −52%, P = 0.05) and mTORC2 (p-AktSer473, −56%, P < 0.001) activity were decreased and AAR was activated (p-GCN2Thr898, +117%, P = 0.02; p-eIF2αSer51, +294%, P = 0.002; p-ERKThr202, +111%, P = 0.03) in MNR liver at GD 120. Our data suggest that fetal liver IGFBP-1 hyperphosphorylation, mediated by mTOR inhibition and both AAR and CK2 activation, is a key link between restricted nutrient and oxygen availability and the development of IUGR.