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Hannah Kanety, Avraham Karasik, Beatrice Klinger, Aviva Silbergeld and Zvi Laron

Insulin-like growth factor binding protein-3 (IGFBP-3) is the major carrier of insulin-like growth factor I (IGF-1) in serum, and its production is growth hormone (GH) dependent. It is unclear whether in humans IGFBP-3 production is directly regulated by GH or mediated via IGF-I. We addressed this question in six patients with Laron-type dwarfism, a syndrome characterized by the absence of GH receptor activity (LTD), who were chronically treated with recombinant IGF-I. Analysis of the electrophoretic profiles of serum IGFBPs in these patients by Western ligand blotting revealed an extremely low IGFBP-3 level. A striking progressive increase in serum IGFBP-3 was observed with continuous treatment, despite the absence of GH action. In LTD children, serum IGFBP-3 increased up to 19-fold after six months of therapy and equalled levels observed in controls, whereas in adult LTD patients the increase was smaller. A rise in serum levels of 34, 30 and 24 kDa BPs (presumably IGFBP-2, -1 and -4, respectively was also noted with chronic IGF-I therapy. This proof of GH-independent induction of IGFBP-3 by IGF-1 may be a major advantage in the therapeutic use of biosynthetic IGF-I in several types of short stature children.

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Hannah Kanety, Rina Hemi, Shira Ginsberg, Clara Pariente, Eleanor Yissachar, Ehud Barhod, Tohru Funahashi and Zvi Laron

Objective

Patients with Laron syndrome (LS; primary GH insensitivity) caused by molecular defects of the GH receptor gene, are characterized by dwarfism, profound obesity, and hyperlipidemia. The aim of the current study was to evaluate adiponectin levels in LS, as obesity is known to be associated with low adiponectin.

Design and methods

We studied nine untreated LS adult patients (5 males, 4 females) and six girls with LS receiving once-daily treatment by IGF1. Total and high molecular weight (HMW) adiponectin levels, adiponectin multimers distribution, and metabolic indices were analyzed in serum samples obtained during several years of follow-up.

Results

Adiponectin levels in the severely obese adult LS patients (percent body fat; females 61.0±2.5%, males 40.6±8.1%) were two- to three-fold higher than those reported for subjects of corresponding age, gender and degree of adiposity. Total adiponectin was significantly higher in females compared with males (21.4±3.5 vs 10.2±4.6 μg/ml, P<0.001). The elevated adiponectin in LS subjects was associated with an increased abundance of the HMW isoform, and positively correlated with body fat percentage (r=0.65, P=0.017) and leptin (r=0.65, P=0.012). There was no correlation between adiponectin levels (total and HMW) and the degree of insulin resistance in LS subjects or their blood lipids levels. Adiponectin was also high in young girls with LS (22.9±7.4 μg/ml) and did not change during long-term IGF1 replacement therapy.

Conclusion

Adiponectin hypersecretion in LS, despite profound obesity, suggests that GH activity may negatively impact adiponectin secretion from adipocytes.

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Liron Yoffe, Avital Polsky, Avital Gilam, Chen Raff, Federico Mecacci, Agostino Ognibene, Fatima Crispi, Eduard Gratacós, Hannah Kanety, Shali Mazaki-Tovi, Noam Shomron and Moshe Hod

Design

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications and its prevalence is constantly rising worldwide. Diagnosis is commonly in the late second or early third trimester of pregnancy, though the development of GDM starts early; hence, first-trimester diagnosis is feasible.

Objective

Our objective was to identify microRNAs that best distinguish GDM samples from those of healthy pregnant women and to evaluate the predictive value of microRNAs for GDM detection in the first trimester.

Methods

We investigated the abundance of circulating microRNAs in the plasma of pregnant women in their first trimester. Two populations were included in the study to enable population-specific as well as cross-population inspection of expression profiles. Each microRNA was tested for differential expression in GDM vs control samples, and their efficiency for GDM detection was evaluated using machine-learning models.

Results

Two upregulated microRNAs (miR-223 and miR-23a) were identified in GDM vs the control set, and validated on a new cohort of women. Using both microRNAs in a logistic-regression model, we achieved an AUC value of 0.91. We further demonstrated the overall predictive value of microRNAs using several types of multivariable machine-learning models that included the entire set of expressed microRNAs. All models achieved high accuracy when applied on the dataset (mean AUC = 0.77). The significance of the classification results was established via permutation tests.

Conclusions

Our findings suggest that circulating microRNAs are potential biomarkers for GDM in the first trimester. This warrants further examination and lays the foundation for producing a novel early non-invasive diagnostic tool for GDM.