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Background Diabetic nephropathy (DN) is a type of progressive kidney disease affecting approximately 40% of patients with diabetes. Current DN diagnostic criteria predominantly rely on albuminuria and serum creatinine (sCr) levels. However, the specificity and reliability of both markers are limited. Hence, reliable biomarkers are required for early diagnosis to effectively manage DN progression. Methods In this study, a cohort of 159 individuals were clinically evaluated and the plasma levels of NGAL, IGFBP-1, IGFBP-3, and IGFBP-4 were determined using Multiplexing Assays. Additionally, the association between the plasma levels of NGAL, IGFBP-1, IGFBP-3, and IGFBP-4 in patients with DN were compared to those in patients with T2D without kidney disease and control participants. Results Circulating level of NGAL were significantly higher in people with DN compared to people with T2D and non-diabetic groups (92.76 ± 7.5, 57.22 ± 8.7, and 52.47 ± 2.9 mg/L, respectively; p  <  0.0001). IGFBP-4 showed a similar pattern, where it was highest in people with DN (795.61 ng/ml ±130.7) compared to T2D and non-diabetic people (374.56 ng/ml ±86.8, 273.06 ng/ml ±27.8 respectively, ANOVA p  <  0.01). The data from this study shows a significant positive correlation between NGAL and IGFBP-4 in people with DN ( ρ  = .620, p  <  0.005). IGFBP-4 also correlated positively with creatinine level and negatively with eGFR, in people with DN supporting its involvement in DN. Conclusion The data from this study shows a parallel increase in the plasma levels of NGAL and IGFBP-4 in DN. This highlights the potential to use these markers for early diagnosis of DN.

Gestational diabetes mellitus (GDM) increases the risk of fetal overgrowth and macrosomia, yet the molecular mechanisms remain unclear. Emerging evidence implicates primate-specific placental microRNAs (miRNAs) from the C19MC cluster in modulating fetal growth via the insulin-like growth factor (IGF) axis. This study aimed to investigate the expression of circulating C19MC miRNAs in GDM pregnancies and their association with IGF axis biomarkers and birthweight outcomes. In this cross-sectional study, 158 pregnant women were stratified into normoglycemic pregnancies (n = 52), GDM with normal birthweight (n = 56), and GDM with large-for-gestational-age (LGA) newborns (n = 50). Plasma levels of 19 C19MC miRNAs and IGF-related proteins were measured. Associations between miRNAs, IGF axis components, and birthweight were analyzed using linear regression and correlation models adjusted for relevant covariates. Several miRNAs, including miR-516a-5p, miR-518d-3p, miR-521, and miR-525-3p, were differentially expressed in GDM, particularly in LGA cases. Strong correlations were observed, such as that of miR-516a-5p with IGFBP-5 (r = 0.705; p < 0.001). Inverse associations with birthweight were found for miR-519b-3p, miR-518d-5p, and miR-520a-5p. Circulating C19MC miRNAs are dysregulated in GDM and correlate with IGF signaling and fetal growth, supporting their potential as early biomarkers for macrosomia risk in GDM.

Regular physical activity not only improves the exercise capacity of the skeletal muscle performing the contractions, but it is beneficial for the whole body. An extensive search for “exercise factors” mediating these beneficial effects has been going on for decades. Particularly skeletal muscle tissue has been investigated as a source of circulating exercise factors, and several myokines have been identified. However, exercise also has an impact on other tissues. The liver is interposed between energy storing and energy utilising tissues and is highly active during exercise, maintaining energy homeostasis. Recently, a novel group of exercise factors—termed hepatokines—has emerged. These proteins (fibroblast growth factor 21, follistatin, angiopoietin-like protein 4, heat shock protein 72, insulin-like growth factor binding protein 1) are released from the liver and increased in the bloodstream during or in the recovery after an exercise bout. In this narrative review, we evaluate this new group of exercise factors focusing on the regulation and potential function in exercise metabolism and adaptations. These hepatokines may convey some of the beneficial whole-body effects of exercise that could ameliorate metabolic diseases, such as obesity or type 2 diabetes.

Summary The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3,GCKR,TNS3, GHSR,FOXO3, ASXL2, NUBP2/IGFALS,SORCS2,and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

Background Insulin‐like growth factor‐I (IGF‐I) is used to screen for acromegaly in diabetic cats. In humans, most circulating IGF‐I forms ternary complexes (TC) with IGF‐binding protein (IGFBP‐3) and an acid‐labile subunit. Compared to humans, the amount of TC in cats is more variable. Insulin‐like growth factor‐I concentrations are reported to increase during insulin treatment, more rapidly in cats achieving remission. Objectives To investigate (i) factors associated with circulating IGF‐I concentrations, including IGFBP‐profiles (ii) effect of insulin treatment on IGF‐I concentrations and (iii) IGF‐I as prognostic marker of diabetes mellitus remission. Animals Thirty‐one privately owned diabetic cats of which 24 were followed 1 year, and 13 healthy cats. Methods Prospective study. Serum insulin, IGF‐I, glucose, and fructosamine concentrations were measured. IGF‐binding forms were determined by chromatography in 14 diabetic and 13 healthy cats; and IGF‐I, IGF‐II, IGFBP‐3, and IGFBP‐5 by mass spectrometry in 3 cats achieving remission. Results Insulin‐like growth factor‐I median (interquartile range) before start of insulin treatment was 300 (160‐556) ng/mL. Insulin‐like growth factor‐I was positively associated with TC (P < .0001) and endogenous insulin (P = .005) and negatively associated with fructosamine (P < .0001). Median IGF‐I was higher 2‐4 weeks after start of insulin treatment compared with baseline (300 versus 670 ng/mL, P = .0001) and predicted future remission (P = .046). In cats that went into remission, the amount of TC and IGFBP‐3 increased, suggesting increase in IGF‐I is dependent on TC formation. Conclusions Insulin treatment should be accounted for when interpreting IGF‐I in diabetic cats. Insulin‐like growth factor‐I 2‐4 weeks after initiation of insulin treatment shows promise as prognostic marker for remission in diabetic cats.

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.

The corneal epithelium, comprising three layers of cells, represents the outermost portion of the eye and functions as a vital protective barrier while concurrently serving as a critical refractive structure. Maintaining its homeostasis involves a complex regenerative process facilitated by the functions of the lacrimal gland, tear film, and corneal nerves. Crucially, limbal epithelial stem cells located in the limbus (transitional zone between the cornea and the conjunctiva) are instrumental for the corneal epithelium integrity by replenishing and renewing cells. Re-epithelialization failure results in persistent defects, often associated with various ocular conditions including diabetic keratopathy. The insulin-like growth factor (IGF) system is a sophisticated network of insulin and other proteins essential for numerous physiological processes. This review examines its role in maintaining the corneal epithelium homeostasis, with a special focus on the interplay with corneal limbal stem cells and the potential therapeutic applications of the system components.

Insulin Resistance Is Associated With Increased Serum Concentration of IGF-Binding Protein–Related Protein 1 (IGFBP-rP1/MAC25) Abel López-Bermejo 1 2 , Javad Khosravi 3 , José Manuel Fernández-Real 1 2 , Vivian Hwa 4 , Katherine L. Pratt 4 , Roser Casamitjana 5 , Maria M. Garcia-Gil 2 , Ron G. Rosenfeld 4 6 and Wifredo Ricart 1 2 1 Diabetes, Endocrinology and Nutrition Unit, Dr. Josep Trueta Hospital, Girona, Spain 2 Girona Institute for Biomedical Research, Girona, Spain 3 Diagnostic System Laboratories, Toronto, Canada 4 Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon 5 Endocrine Laboratory, University Clinical Hospital, Barcelona, Spain 6 Lucile Packard Foundation for Children’s Health, Palo Alto, California Address correspondence and reprint requests to Abel López-Bermejo, MD, Unit of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta Hospital, Av. Francia s/n, 17007 Girona, Spain. E-mail: uden.alopez{at}htrueta.scs.es Abstract IGF-binding protein (IGFBP)-related protein 1 (IGFBP-rP1) has been shown to bind both IGFs and insulin, albeit with low affinity, and to inhibit insulin signaling. We hypothesized that IGFBP-rP1 is associated with insulin resistance and components of the IGF system in humans. To this aim, a cross-sectional study was conducted in 113 nondiabetic and 43 type 2 diabetic men. Insulin sensitivity (insulin sensitivity index [ S i ] from intravenous glucose tolerance tests in nondiabetic subjects, or the rate constant for disappearance of glucose [ K ITT ] from insulin tolerance tests in type 2 diabetic subjects), circulating IGFBP-rP1 (from enzyme-linked immunosorbent assay), adiponectin (from radioimmunoassay), C-reactive protein (CRP; from immunoturbidimetry), soluble tumor necrosis factor receptor 2 (sTNFR2; from enzyme-amplified sensitivity immunoassay), and IGF system parameters (IGF-I, free IGF-I, and IGFBP-1 from immunoradiometric assay) were assessed in all subjects. Among nondiabetic men, those in the highest quartile for circulating IGFBP-rP1 exhibited decreased S i and adiponectin (both P < 0.01) as well as increased CRP and sTNFR2 (both P < 0.05). Circulating IGFBP-rP1 was also found to be increased in previously undiagnosed type 2 diabetic patients ( P = 0.01) but not in known type 2 diabetic patients receiving pharmacological therapy. Although no changes in IGF system components were evident by IGFBP-rP1 quartiles in nondiabetic subjects, independent positive associations of IGFBP-rP1 with circulating fasting IGFBP-1 were evident after adjustment for insulin resistance parameters in both nondiabetic and type 2 diabetic subjects, with IGFBP-rP1 explaining 2 and 11% of IGFBP-1 variance, respectively. In additional multivariate analyses, S i , sTNFR2, and age stood as independent predictive variables of IGFBP-rP1 (together explaining 18% of its variance) in nondiabetic subjects, and BMI became the only independent predictive variable of IGFBP-rP1 (explaining 26% of its variance) in type 2 diabetic men. These findings show for the first time that circulating IGFBP-rP1 is increased with insulin resistance, and they also suggest novel interactions between IGFBP-rP1 and the IGF system in humans. CRP, C-reactive protein IGFBP, IGF-binding protein IGFBP-rP, IGFBP-related protein sTNFR, soluble tumor necrosis factor receptor TNF, tumor necrosis factor Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 2, 2006. Received December 16, 2005. DIABETES

Insulin-like growth factors (IGFs) and insulin-like growth-factor-binding proteins (IGFBPs) regulate cell proliferation and differentiation and may be of importance in obesity development. The aim of the study was to analyze the expression of chosen IGF-axis genes and the concentration of their protein products in 28 obese children (OB) and 34 healthy control (HC), and their correlation with essential parameters associated with childhood obesity. The gene expression of IGFBP7 was higher, and the expression of IGF2 and IGFBP1 genes was lower in the OB. The expression of IGFBP6 tended to be lower in OB. IGFBP4 concentration was significantly higher, and IGFBP3 tended to be higher in the OB compared to the HC, while IGFBP1, IGFBP2, and IGFBP6 were significantly lower, and IGFBP7 tended to be lower in OB. We found numerous correlations between IGFs and IGFBP concentration and obesity metabolic parameters. IGFBP6 correlated positively with apelin, cholecystokinin, glucagone-like peptide-1, and leptin receptor. These peptides were also significantly lower in obese children in our study. The biological role of decreased levels of IGFBP6 in obese children needs further investigation.

Psychiatric disorders (PDs), including schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder (BD), autism spectrum disorder (ASD), among other disorders, represent a significant global health burden. Despite advancements in understanding their biological mechanisms, there is still no reliable objective and reliable biomarker; therefore, diagnosis remains largely reliant on subjective clinical assessments. Peripheral biomarkers in plasma or serum are interesting due to their accessibility, low cost, and potential to reflect central nervous system processes. Among these, the insulin-like growth factor (IGF) family, IGF-1, IGF-2, and IGF-binding proteins (IGFBPs), has gained attention for its roles in neuroplasticity, cognition, and neuroprotection, as well as for their capability to cross the blood–brain barrier. This review evaluates the evidence for IGF family alterations in PDs, with special focus on SZ, MDD, and BD, while also addressing other PDs covering almost 40 years of history. In SZ patients, IGF-1 alterations have been linked to metabolic dysregulation, treatment response, and hypothalamic–pituitary–adrenal axis dysfunction. In MDD patients, IGF-1 appears to compensate for impaired neurogenesis, although findings are inconsistent. Emerging studies on IGF-2 and IGFBPs suggest potential roles across PDs. While promising, heterogeneity among studies and methodological limitations highlights the need for further research to validate IGFs as reliable psychiatric biomarkers.