Adult patients with Laron syndrome tend to develop the metabolic syndrome.

BACKGROUND: The metabolic Syndrome is the name of a cluster of abnormal clinical and metabolic states, which constitute a risk factor for diabetes and cardiovascular disease. AIM: To determine whether adult patients with Laron Syndrome with excessive obesity develop the characteristics of the Metabolic Syndrome. SUBJECTS: Out of a cohort of adult patients with Laron Syndrome followed in our clinic, records of 23 patients (12 females, 11 males) were found to have sufficient data for analysis. METHODS: The degree of obesity was determined by the measurement of subscapular skinfold thickness (SSFT), BMI and total body DEXA. NAFLD was determined by liver ultrasonography, serum lipids including adiponectin leptin, insulin and glucose were assessed by radioimmunoassay. RESULTS: Both female and male patients were markedly obese with 59% and 39% fat of the total body mass respectively, as were total and LDL cholesterol, triglycerides and adiponectin. Some had developed NAFLD. They also suffered from insulin resistance and glucose intolerance. Eleven patients (3 females, 8 males) developed diabetes. All had varying degrees of hypertension. Eight subjects (3 females, 5 males) suffered from cardiovascular disease. One female died at aged 53 years, and two males died at ages 75 and 78 years. CONCLUSION: With advancing age and increasing obesity, adult patients with Laron Syndrome developed the characteristics of Metabolic Syndrome including diabetes and cardiovascular disease.

The COVID-19 Pandemic Increased the Incidence of New-Onset Type One Diabetes in Children.

Background: The impact of the COVID-19 pandemic on the incidence rate of childhood type 1 diabetes (T1D) is controversial. Our aim was to analyze the incidence of new-onset T1D among children aged 0-17 before and during the COVID-19 pandemic in Israel. Methods: Data obtained from the national T1D registry for children aged 0-17 were analyzed for the pre-pandemic (1997-2019) and pandemic (2020-2022) periods. In the pre-pandemic period, 7246 children with newly diagnosed T1D were compared with 1490 children diagnosed during the pandemic period. Results: T1D incidence significantly increased in the 0-17 age group from a mean of 12.9/105 (pre-pandemic) to 17.7/105 and 16.7/105 during the first two years of the pandemic (2020 and 2021, respectively) (p = 0.0001). Stratifying by age group (0-4, 5-9, 10-14, and 15-17) revealed a significant increase in the 5-9, 10-14, and 15-17 groups, both in 2020 (p = 0.0001) and in 2021 (p = 0.0001). The incidence rate in the 0-4 age group showed no change in the first year of the pandemic (2020) (p = 0.4). However, in the second year of the pandemic (2021), there was a significant increase from 6.3/105 in the pre-pandemic period to 9.1/105 (p = 0.001). Anti-COVID-19 vaccination in 2022 led to a significant decrease in the incidence rates in the 10-14 and 15-17 age groups (p = 0.03 and p = 0.02, respectively). Conclusion: The COVID-19 pandemic was associated with a significant increase in the incidence of new-onset T1D in prepubertal and pubertal children. Anti-COVID-19 vaccination decreased the incidence rate significantly only in pubertal children.

Challenges in Pediatric Endocrinology.

As the Section Editor-in-Chief, it is my pleasure to introduce the new section of Children devoted to pediatric endocrinology [...].

Insulin-like growth factors and aging: lessons from Laron syndrome.

The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway emerged in recent years as a key determinant of aging and longevity. Disruption of this network in different animal species, including flies, nematodes and mouse, was consistently associated with an extended lifespan. Epidemiological analyses have shown that patients with Laron syndrome (LS), the best-characterized disease under the umbrella of the congenital IGF1 deficiencies, seem to be protected from cancer. While aging and cancer, as a rule, are considered diametrically opposite processes, modern lines of evidence reinforce the notion that aging and cancer might, as a matter of fact, be regarded as divergent manifestations of identical biochemical and cellular underlying processes. While the effect of individual mutations on lifespan and health span is very difficult to assess, genome-wide screenings identified a number of differentially represented aging- and longevity-associated genes in patients with LS. The present review summarizes recent data that emerged from comprehensive analyses of LS patients and portrays a number of previously unrecognized targets for GH-IGF1 action. Our article sheds light on complex aging and longevity processes, with a particular emphasis on the role of the GH-IGF1 network in these mechanisms.

Growth hormone insensitivity and adipose tissue: tissue morphology and transcriptome analyses in pigs and humans.

PURPOSE: Growth hormone receptor knockout (GHR-KO) pigs have recently been developed, which serve as a large animal model of Laron syndrome (LS). GHR-KO pigs, like individuals with LS, are obese but lack some comorbidities of obesity. The purpose of this study was to examine the histological and transcriptomic phenotype of adipose tissue (AT) in GHR-KO pigs and humans with LS. METHODS: Intraabdominal (IA) and subcutaneous (SubQ) AT was collected from GHR-KO pigs and examined histologically for adipocyte size and collagen content. RNA was isolated and cDNA sequenced, and the results were analyzed to determine differentially expressed genes that were used for enrichment and pathway analysis in pig samples. For comparison, we also performed limited analyses on human AT collected from a single individual with and without LS. RESULTS: GHR-KO pigs have increased adipocyte size, while the LS AT had a trend towards an increase. Transcriptome analysis revealed 55 differentially expressed genes present in both depots of pig GHR-KO AT. Many significant terms in the enrichment analysis of the SubQ depot were associated with metabolism, while in the IA depot, IGF and longevity pathways were negatively enriched. In pathway analysis, multiple expected and novel pathways were significantly affected by genotype, i.e. KO vs. controls. When GH related gene expression was analyzed, SOCS3 and CISH showed species-specific changes. CONCLUSION: AT of GHR-KO pigs has several similarities to that of humans with LS in terms of adipocyte size and gene expression profile that help describe the depot-specific adipose phenotype of both groups.

Administration of insulin like growth factor I (IGFI) lowers serum lipoprotein(a)-impact on atherosclerotic cardiovascular disease.

Insulin like growth factor I (IGFI) secreted by the liver upon stimulation by pituitary growth hormone (GH) acts as the most important growth stimulating hormone in children. The present review presents evidence that among its additional metabolic effects, IGF-I suppresses the synthesis of lipoprotein(a) [Lp(a)], an independent risk factor for atherosclerotic cardiovascular disease. In view of this property, it is suggested that the addition of IGF-I to the armamentarium of hyperlipoproteinemia treatment should be considered.

Congenital IGF-1 deficiency protects from cancer: lessons from Laron syndrome.

Many clinical and experimental studies have implicated the growth hormone (GH)-insulin-like growth factor (IGF-1) axis with the progression of cancer. The epidemiological finding that patients with Laron syndrome (LS), the best-characterized disease under the spectrum of congenital IGF-1 deficiencies, do not develop cancer is of major scientific and translational relevance. The evasion of LS patients from cancer emphasizes the central role of the GH-IGF-1 system in cancer biology. To identify genes that are differentially expressed in LS and that might provide a biological foundation for cancer protection, we have recently conducted genome-wide profiling of LS patients and normal controls. Analyses were performed on immortalized lymphoblastoid cell lines derived from individual patients. Bioinformatic analyses identified a series of genes that are either over- or under-represented in LS. Differential expression was demonstrated in a number of gene families, including cell cycle, metabolic control, cytokine-cytokine receptor interaction, Jak-STAT and PI3K-AKT signaling, etc. Major differences between LS and controls were also noticed in pathways associated with cell cycle distribution, apoptosis, and autophagy. The identification of novel downstream targets of the GH-IGF-1 network highlights the biological complexity of this hormonal system and sheds light on previously unrecognized mechanistic aspects associated with GH-IGF-1 action in the cancer cell.

Hypothesis: Viral infections of pregnant women may be early triggers of childhood type 1 diabetes and other autoimmune disease.

Children and adolescents with early onset autoimmune diseases have a different seasonality of month of birth than the general population. This pattern is consistent with an infection during pregnancy affecting the fetus or an infection immediately after birth that act as early triggers of the autoimmune diseases. We present data supporting the use of Rotavirus vaccinations in the reduction of incidence of childhood T1D and propose further investigations into whether other anti-virus vaccinations may reduce the burden of other autoimmune diseases such as multiple sclerosis, atopic dermatitis, psoriasis and subtypes of rheumatoid arthritis, Hashimoto thyroiditis.

Comparison of Commonly Used Methods to Predict the Final Height in Constitutional Tall Stature

Objective: To determine the accuracy of adult height prediction in children with constitutional tall stature. Methods: The medical records of 138 non-syndromatic prepubertal and early pubertal children (52 male, 86 female) with a height of ≥90th percentile born between the years 1975 and 1988 were included in this study. Using the Bayley-Pinneau (BP) and Tanner-Whitehouse I (TWI) prediction methods, their height standard deviation score (SDS) at referral was compared with their height SDS at age 17 years when measured at the IDF conscription center. Results: While remaining tall, the height SDS at age 17 years was lower than that at referral decreasing from 2.13±1 to 1.65±1.21 in boys and from 2.48±1 to 2.15±1 in girls. Conclusion: The prediction by the BP and TWI methods can be useful for estimating adult height in constitutional tall stature even in the prepubertal and early pubertal period. However, the fallibility of these methods should be kept in mind during clinical practice. We think that this study will shed light on these issues.

Long-Term IGF1 Stimulation Leads to Cellular Senescence via Functional Interaction with the Thioredoxin-Interacting Protein, TXNIP.

The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway plays a major role in orchestrating cellular interactions, metabolism, growth and aging. Studies from worms to mice showed that downregulated activity of the GH/IGF1 pathway could be beneficial for the extension of lifespan. Laron syndrome (LS) is an inherited autosomal recessive disorder caused by molecular defects of the GH receptor (GHR) gene, leading to congenital IGF1 deficiency. Life-long exposure to minute endogenous IGF1 levels in LS is associated with low stature as well as other endocrine and metabolic deficits. Epidemiological surveys reported that patients with LS have a reduced risk of developing cancer. Studies conducted on LS-derived lymphoblastoid cells led to the identification of a novel link between IGF1 and thioredoxin-interacting protein (TXNIP), a multifunctional mitochondrial protein. TXNIP is highly expressed in LS patients and plays a critical role in cellular redox regulation by thioredoxin. Given that IGF1 affects the levels of TXNIP under various stress conditions, including high glucose and oxidative stress, we hypothesized that the IGF1-TXNIP axis plays an essential role in helping maintain a physiological balance in cellular homeostasis. In this study, we show that TXNIP is vital for the cell fate choice when cells are challenged by various stress signals. Furthermore, prolonged IGF1 treatment leads to the establishment of a premature senescence phenotype characterized by a unique senescence network signature. Combined IGF1/TXNIP-induced premature senescence can be associated with a typical secretory inflammatory phenotype that is mediated by STAT3/IL-1A signaling. Finally, these mechanistic insights might help with the understanding of basic aspects of IGF1-related pathologies in the clinical setting.

Increase of serum lipoprotein (a), an adverse effect of growth hormone treatment.

A number of reports show that high endogenous, or therapeutic administration of human growth hormone (hGH) cause an increase of serum lipoprotein a, Lp(a). Being thrombogenic Lp(a) is an independent risk factor of atherosclerotic cardiovascular disease (ASCVD). Hence, it is hypothesized that the recently reported association between childhood hGH treatment and cardiovascular morbidity is probably due to the GH effect on Lp(a) synthesis. It is therefore suggested to determine serum Lp(a) levels before and during hGH treatment in children and adults.

Prolactin response to growth hormone stimulation tests.

BACKGROUND: Despite many similarities between the structure, receptors, proliferative and growth promoting actions, the relationship between Prolactin (PRL) and Growth Hormone (GH) in clinical conditions has received little attention. OBJECTIVE: To determine the PRL response to GH stimulation tests. SUBJECTS: Prepubertal and early pubertal boys (n = 581) and girls (n = 502) with idiopathic, non-syndromatic short stature. DESIGN: Data was retrieved from the computerized records of the Endocrine Laboratory, Schneider Children's Medical Center. Peak GH and PRL levels during GH stimulation tests with glucagon (Gluc), Clonidine (Clon) and Clonidine with arginine (Clon+Arg), were compared. Both PRL and GH were determined by radioimmunoassay. RESULTS: Whereas Gluc stimulated both GH and PRL to similar levels, Clon alone or combined with Arg suppressed the PRL secretion (p < 0.0001). It is also evident that in both boys and girls Clon alone and Clon±Arg are superior to Gluc in GH stimulation. The higher GH levels during Clon+Arg than with Clon alone are attributed to the pubertal stage. CONCLUSION: This study provides further information on the Prolactin-Growth hormone relationship in children.

Identification of UDP-Glucuronosyltransferase 2B15 (UGT2B15) as a Target for IGF1 and Insulin Action.

Normal growth and development in mammals are tightly controlled by numerous genetic factors and metabolic conditions. The growth hormone (GH)-insulin-like growth factor-1 (IGF1) hormonal axis is a key player in the regulation of these processes. Dysregulation of the GH-IGF1 endocrine system is linked to a number of pathologies, ranging from growth deficits to cancer. Laron syndrome (LS) is a type of dwarfism that results from mutation of the GH receptor (GHR) gene, leading to GH resistance and short stature as well as a number of metabolic abnormalities. Of major clinical relevance, epidemiological studies have shown that LS patients do not develop cancer. While the mechanisms associated with cancer protection in LS have not yet been elucidated, genomic analyses have identified a series of metabolic genes that are over-represented in LS patients. We hypothesized that these genes might constitute novel targets for IGF1 action. With a fold-change of 11.09, UDP-glucuronosyltransferase 2B15 (UGT2B15) was the top up-regulated gene in LS. The UGT2B15 gene codes for an enzyme that converts xenobiotic substances into lipophilic compounds and thereby facilitates their clearance from the body. We investigated the regulation of UGT2B15 gene expression by IGF1 and insulin. Both hormones inhibited UGT2B15 mRNA levels in endometrial and breast cancer cell lines. Regulation of UGT2B15 protein levels by IGF1/insulin, however, was more complex and not always correlated with mRNA levels. Furthermore, UGT2B15 expression was dependent on p53 status. Thus, UGT2B15 mRNA levels were higher in cell lines expressing a wild-type p53 compared to cells containing a mutated p53. Animal studies confirmed an inverse correlation between UGT2B15 and p53 levels. In summary, increased UGT2B15 levels in LS might confer upon patient's protection from genotoxic damage.

Focal Epilepsy in Individuals with Laron Syndrome.

OBJECTIVE: The aim of the study was to describe focal epilepsy in patients with Laron syndrome (LS). METHODS: Data were retrieved from medical records of a single-center cohort of 75 patients with LS. RESULTS: We describe for the first time 4 patients with concomitant focal epilepsy and LS. Two of them experienced episodes of status epilepticus. Electroencephalogram examination in all 4 patients showed interictal epileptiform discharges in the temporal regions. Three achieved long-term seizure freedom on antiseizure medications. CONCLUSION: Patients with LS may be at risk of developing focal epilepsy, which seems to be unrelated to hypoglycemic episodes in childhood.

MicroRNA 132-3p Is Upregulated in Laron Syndrome Patients and Controls Longevity Gene Expression.

The growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis is a central player in normal growth and metabolism as well as in a number of pathologies, including cancer. The GH-IGF1 hormonal system, in addition, has emerged as a major determinant of lifespan and healthspan. Laron syndrome (LS), the best characterized entity under the spectrum of the congenital IGF1 deficiencies, results from mutation of the GH receptor (GHR) gene, leading to dwarfism, obesity and other defects. Consistent with the key role of IGF1 in cellular proliferation, epidemiological studies have shown that LS patients are protected from cancer development. While reduced expression of components of the GH-IGF1 axis is associated with enhanced longevity in animal models, it is still unknown whether LS is associated with an increased lifespan. MicroRNAs (miRs) are endogenous short non-coding RNAs that regulate the expression of complementary mRNAs. While a number of miRs involved in the regulation of IGF components have been identified, no previous studies have investigated the differential expression of miRs in congenital IGF1 deficiencies. The present study was aimed at identifying miRs that are differentially expressed in LS and that might account for the phenotypic features of LS patients, including longevity. Our genomic analyses provide evidence that miR-132-3p was highly expressed in LS. In addition, we identified SIRT1, a member of the sirtuin family of histone deacetylases, as a target for negative regulation by miR-132-3p. The data was consistent with the notion that low concentrations of IGF1 in LS lead to elevated miR-132-3p levels, with ensuing reduction in SIRT1 gene expression. The impact of the IGF1-miR-132-3p-SIRT1 loop on aging merits further investigation.

ZYG11A Is Expressed in Epithelial Ovarian Cancer and Correlates With Low Grade Disease.

The insulin-like growth factors (IGF) are important players in the development of gynecological malignancies, including epithelial ovarian cancer (EOC). The identification of biomarkers that can help in the diagnosis and scoring of EOC patients is of fundamental importance in clinical oncology. We have recently identified the ZYG11A gene as a new candidate target of IGF1 action. The aim of the present study was to evaluate the expression of ZYG11A in EOC patients and to correlate its pattern of expression with histological grade and pathological stage. Furthermore, and in view of previous analyses showing an interplay between ZYG11A, p53 and the IGF1 receptor (IGF1R), we assessed a potential coordinated expression of these proteins in EOC. In addition, zyg11a expression was assessed in ovaries and uteri of growth hormone receptor (GHR) knock-out mice. Tissue microarray analysis was conducted on 36 patients with EOC and expression of ZYG11A, IGF1R and p53 was assessed by immunohistochemistry. Expression levels were correlated with clinical parameters. qPCR was employed to assess zyg11a mRNA levels in mice tissues. Our analyses provide evidence of reduced ZYG11A expression in high grade tumors, consistent with a putative tumor suppressor role. In addition, an inverse correlation between ZYG11A and p53 levels in individual tumors was noticed. Taken together, our data justify further exploration of the role of ZYG11A as a novel biomarker in EOC.

Use of the Whole Country Insulin Consumption Data in Israel to Determine the Prevalence of Type 1 Diabetes in Children <5 Years of Age Before and During Rotavirus Vaccination.

BACKGROUND: Recent studies showed that rotavirus vaccination may affect the prevalence of type 1 diabetes (T1D). The aim of the study was to determine the prevalence of early childhood (<5 years) T1D before and during the introduction of rotavirus vaccination in Israel by syndromic surveillance. METHODS: Data on insulin purchases reported by Israel's four Health Maintenance Organizations (HMOs) were retrieved from the National Program for Quality Indicators in Community Healthcare. RESULTS: During the prevaccination years (2002-2007), a steady increase in insulin purchases was reported in the young (<5 years). The period percent change (PC) of children <5 years old diagnosed with T1D inferred from purchased insulin prescriptions increased by 50.0%, and the annual percent change (APC) increased by 10.0% (p = 0.01). During the period of free, universal Rotavirus vaccination (2011-2018), the PC for T1D diagnoses among children <5 years of age decreased by 3.8% with an APC of -2.5% (p = 0.14). There was a significant difference (p = 0.002) between the increasing trend in insulin use before vaccination versus the decreasing trend after vaccination. CONCLUSION: Rotavirus vaccination correlated with attenuation of the increasing rate in the prevalence of T1D in <5-year-old children in Israel.

The Olfactory Receptor Gene Product, OR5H2, Modulates Endometrial Cancer Cells Proliferation via Interaction with the IGF1 Signaling Pathway.

Endometrial cancer is the most common gynecologic malignancy in Western countries. The insulin-like growth factor-1 (IGF1) axis has an important role in endometrial cancer biology and emerged as a promising therapeutic target in oncology. However, there is an urgent need to identify biomarkers that may help in patient stratification and prognosis. Laron syndrome (LS) is a type of dwarfism that results from the mutation of the growth hormone receptor (GHR) gene, leading to congenital IGF1 deficiency. While high circulating IGF1 is regarded as a risk factor in cancer, epidemiological studies have shown that LS patients are protected from cancer development. Recent genome-wide profilings conducted on LS-derived lymphoblastoid cells led to the identification of a series of genes whose over- or under-representation in this condition might be mechanistically linked to cancer protection. The olfactory receptor 5 subfamily H member 2 (OR5H2) was the top downregulated gene in LS, its expression level being 5.8-fold lower than in the control cells. In addition to their typical role in the olfactory epithelium, olfactory receptors (ORs) are expressed in multiple tissues and play non-classical roles in various pathologies, including cancer. The aim of our study was to investigate the regulation of OR5H2 gene expression by IGF1 in endometrial cancer. Data showed that IGF1 and insulin stimulate OR5H2 mRNA and the protein levels in uterine cancer cell lines expressing either a wild-type or a mutant p53. OR5H2 silencing led to IGF1R downregulation, with ensuing reductions in the downstream cytoplasmic mediators. In addition, OR5H2 knockdown reduced the proliferation rate and cell cycle progression. Analyses of olfr196 (the mouse orthologue of OR5H2) mRNA expression in animal models of GHR deficiency or GH overexpression corroborated the human data. In summary, OR5H2 emerged as a novel target for positive regulation by IGF1, with potential relevance in endometrial cancer.

The Role of Nuclear Insulin and IGF1 Receptors in Metabolism and Cancer.

Insulin (InsR) and insulin-like growth factor-1 (IGF1R) receptors mediate the metabolic and growth-promoting actions of insulin and IGF1/IGF2, respectively. Evidence accumulated in recent years indicates that, in addition to their typical cell-surface localization pattern and ligand-activated mechanism of action, InsR and IGF1R are present in the cell nucleus of both normal and transformed cells. Nuclear translocation seems to involve interaction with a small, ubiquitin-like modifier protein (SUMO-1), although this modification is not always a prerequisite. Nuclear InsR and IGF1R exhibit a number of biological activities that classically fit within the definition of transcription factors. These nuclear activities include, among others, sequence-specific DNA binding and transcriptional control. Of particular interest, nuclear IGF1R was capable of binding and stimulating its cognate gene promoter. The physiological relevance of this autoregulatory mechanism needs to be further investigated. In addition to its nuclear localization, studies have identified IGF1R in the Golgi apparatus, and this particular distribution correlated with a migratory phenotype. In summary, the newly described roles of InsR and IGF1R as gene regulators, in concert with their atypical pattern of subcellular distribution, add a further layer of complexity to traditional models of cell signaling. Furthermore, and in view of the emerging role of IGF1R as a potential therapeutic target, a better understanding of the mechanisms responsible for nuclear IGF1R transport and identification of IGF1R interactors might help optimize target directed therapies in oncology.