Congenital Insulin-like Growth Factor-1 Deficiencies Research Articles

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.

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.

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.

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.

Identification of nephronectin as a new target for IGF1 action.

The growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis has a key role in normal growth and development. Laron syndrome (LS) is a type of dwarfism that results from mutation of the GH receptor, leading to congenital IGF1 deficiency. Epidemiological studies have shown that LS patients are protected from cancer. Genome-wide profiling led to the identification of a series of metabolic genes whose differential expression in LS might be linked to cancer protection. Nephronectin (NPNT) is an intracellular and secreted extracellular matrix protein with important roles in kidney development. NPNT was identified as the top-downregulated gene in LS-derived cells in comparison with ethnic-, age- and gender-matched controls (p-value=0.0148; fold-change=-3.12 versus controls). NPNT has not been previously linked to the IGF1 signaling pathway. The present study was aimed at evaluating the hypothesis that NPNT is a new target for IGF1 action and that decreased expression of NPNT in LS is correlated with cancer protection. Basal and IGF1-stimulated NPNT expression were assessed in LS lymphoblastoid cells as well as in human breast and prostate cancer cells. NPNT silencing experiments were conducted using siRNA methodology. We provide evidence that IGF1 stimulates NPNT expression in LS-derived lymphoblastoids and various cancer cell lines. In addition, we demonstrate that NPNT silencing results in diminished activation of the AKT and ERK1/2 pathways, with ensuing decreases in cellular proliferation. Our data identified the NPNT gene as a target for IGF1 action. The clinical implications of the functional and physical interactions between NPNT and the IGF1 pathway merit further investigation.

Genome-Wide Profiling of Laron Syndrome Patients Identifies Novel Cancer Protection Pathways.

Laron syndrome (LS), or primary growth hormone resistance, is a prototypical congenital insulin-like growth factor 1 (IGF1) deficiency. The recent epidemiological finding that LS patients do not develop cancer is of major scientific and clinical relevance. Epidemiological data suggest that congenital IGF1 deficiency confers protection against the development of malignancies. This ‘experiment of nature’ reflects the critical role of IGF1 in tumor biology. The present review article provides an overview of recently conducted genome-wide profiling analyses aimed at identifying mechanisms and signaling pathways that are directly responsible for the link between life-time low IGF1 levels and protection from tumor development. The review underscores the concept that ‘data mining’ an orphan disease might translate into new developments in oncology.

Neuroglial Involvement in Abnormal Glutamate Transport in the Cochlear Nuclei of the Igf1 -/- Mouse.

Insulin-like growth factor 1 (IGF-1) is a powerful regulator of synaptic activity and a deficit in this protein has a profound impact on neurotransmission, mostly on excitatory synapses in both the developing and mature auditory system. Adult Igf1−/− mice are animal models for the study of human syndromic deafness; they show altered cochlear projection patterns into abnormally developed auditory neurons along with impaired glutamate uptake in the cochlear nuclei, phenomena that probably reflect disruptions in neuronal circuits. To determine the cellular mechanisms that might be involved in regulating excitatory synaptic plasticity in 4-month-old Igf1−/− mice, modifications to neuroglia, astroglial glutamate transporters (GLTs) and metabotropic glutamate receptors (mGluRs) were assessed in the cochlear nuclei. The Igf1−/− mice show significant decreases in IBA1 (an ionized calcium-binding adapter) and glial fibrillary acidic protein (GFAP) mRNA expression and protein accumulation, as well as dampened mGluR expression in conjunction with enhanced glutamate transporter 1 (GLT1) expression. By contrast, no differences were observed in the expression of glutamate aspartate transporter (GLAST) between these Igf1−/− mice and their heterozygous or wildtype littermates. These observations suggest that congenital IGF-1 deficiency may lead to alterations in microglia and astrocytes, an upregulation of GLT1, and the downregulation of groups I, II and III mGluRs. Understanding the molecular, biochemical and morphological mechanisms underlying neuronal plasticity in a mouse model of hearing deficits will give us insight into new therapeutic strategies that could help to maintain or even improve residual hearing when human deafness is related to IGF-1 deficiency.

Differential expression of IGFBPs in Laron syndrome-derived lymphoblastoid cell lines: Potential correlation with reduced cancer incidence

Laron syndrome (LS), or primary growth hormone (GH) insensitivity, is a growth disorder that results from mutation of the GH-receptor (GHR) gene leading to congenital insulin-like growth factor-1 (IGF-1) deficiency. Recent epidemiological studies have shown that LS patients are protected from cancer development. Genome-wide profiling identified genes and signaling pathways that are differentially represented in LS patients, and that may contribute to cancer protection. The present study was aimed at evaluating the hypothesis that IGF binding proteins (IGFBPs) are differentially expressed in LS, most probably as a result of low circulating levels of IGF-1. Furthermore, we postulated that IGFBPs might be differentially regulated by oxidative stress in this condition and, therefore, may contribute to cancer evasion. Our results show that IGFBP-3, which is predominantly protective, was highly expressed in LS-derived lymphoblastoid cells in comparison to control cells from the same ethnic group. On the other hand, levels of IGFBP-2, -4, -5, and -6 were diminished in LS patients, as demonstrated by RQ-PCR, Western immunoblots and confocal immunofluorescence. In addition, our data provide evidence for a pattern of IGFBP response to H2O2 treatment that might be associated with distinct expression of apoptosis markers (BCL2, pro-caspase-9, pro-caspase-3) in LS. In summary, differential expression of specific IGFBPs in LS might be correlated with cellular mechanisms underlying cancer protection and, probably, additional phenotypes due to congenital IGF-1 deficiency.

Genome-wide profiling of congenital insulin-like growth factor-1 deficient patients: translational implications in cancer prevention and metabolism

Laron syndrome (LS) is a rare genetic disorder identified in the 1950s by Professor Zvi Laron. LS results from mutation of the growth hormone receptor (GH-R) gene, leading to congenital insulin-like growth factor-1 (IGF1) deficiency and dwarfism. Recent epidemiological studies have shown that LS patients do not develop cancer, emphasizing the crucial role of the IGF1 axis in cancer biology. Genome-wide profiling of LS patients conducted in our laboratory led to the identification of genes and signaling pathways that are over- or under-represented in LS compared to healthy controls of the same age range and ethnic group. Differentially expressed genes may be responsible for the association between lifetime low IGF1 values and protection from cancer. This experiment of nature may provide invaluable information that might translate into novel therapeutic approaches in modern oncology.

Identification of signaling pathways associated with cancer protection in Laron syndrome.

The growth hormone (GH)-insulin-like growth factor-1 (IGF1) pathway emerged in recent years as a critical player in cancer biology. Enhanced expression or activation of specific components of the GH-IGF1 axis, including the IGF1 receptor (IGF1R), is consistently associated with a transformed phenotype. Recent epidemiological studies have shown that patients with Laron syndrome (LS), the best-characterized entity among the congenital IGF1 deficiencies, seem to be protected from cancer development. To identify IGF1-dependent genes and signaling pathways associated with cancer protection in LS, we conducted a genome-wide analysis using immortalized lymphoblastoid cells derived from LS patients and healthy controls of the same gender, age range, and ethnic origin. Our analyses identified a collection of genes that are either over- or under-represented in LS-derived lymphoblastoids. Gene differential expression occurs in several gene families, including cell cycle, metabolic control, cytokine-cytokine receptor interaction, Jak-STAT signaling, and PI3K-AKT signaling. Major differences between LS and healthy controls were also noticed in pathways associated with cell cycle distribution, apoptosis, and autophagy. Our results highlight the key role of the GH-IGF1 axis in the initiation and progression of cancer. Furthermore, data are consistent with the concept that homozygous congenital IGF1 deficiency may confer protection against future tumor development.

Effect of insulin‐like growth factor‐1 deficiency or administration on the occurrence of acne

The role of growth hormone, insulin, and insulin-like growth factor-1 (IGF-1) in the development of acne is incompletely understood. To study the effect of the absence of IGF-1 and its pharmacologic replacement on the occurrence of acne vulgaris. Laron syndrome (LS) is characterized by congenital IGF-1 deficiency. The study group consisted of 21 patients with classical LS, who underwent puberty: 13 (8 male, 5 female) untreated and under regular follow-up until age 20?48 years; and 8 (2 male, 6 female) treated with IGF-1 (70-200 μg/kg/day), including 6 adults (2 male, treated at age 14.5-29 years and 4 female, treated at age 30-37 years) and 2 adolescents (2 female, treated at age 3.5-16 years). The medical files were reviewed for occurrence of acne and the corresponding sex hormone levels, and the findings were compared between the treated and untreated patients. Puberty was delayed in all untreated patients. Only one patient had slight acne at age 22 years, when he reached full puberty. Among the 2 IGF-1 treated male patients, none acquired acne. Among the 6 treated female patients, 3 had signs of hyperandrogenism (oligo-amenorrhea) and acne during IGF-1 over-dosage. On reduction of the IGF-1 dose (to 50 μg/kg/day) or cessation of treatment, the acne disappeared in all 3 patients. This study demonstrates for the first time that serum IGF-1 deficiency prevents the occurrence of acne. The findings suggest that an interaction between IGF-1 and androgens is necessary for the development of acne.

Abnormalities of the axial and proximal appendicular skeleton in adults with Laron syndrome (growth hormone insensitivity)

To investigate abnormalities in the skeleton (with the exclusion of the skull, cervical spine, hands and feet) in patients with Laron syndrome, who have an inborn growth hormone resistance and congenital insulin-like growth factor-1 (IGF-1) deficiency. The study group was composed of 15 untreated patients with Laron syndrome (seven male and eight female) aged 21-68 years. Plain films of the axial and appendicular skeleton were evaluated retrospectively for abnormalities in structure and shape. The cortical width of the long bones was evaluated qualitatively and quantitatively (in the upper humerus and mid-femur), and the cortical index was calculated and compared with published references. Measurements were taken of the mid-anteroposterior and cranio-caudal diameters of the vertebral body and spinous process at L3, the interpedicular distance at L1 and L5, and the sacral slope. Thoracic and lumbar osteophytes were graded on a 5-point scale. Values were compared with a control group of 20 healthy persons matched for age. The skeleton appeared small in all patients. No signs of osteopenia were visible. The cortex of the long bones appeared thick in the upper limbs in 11 patients and in the lower limbs in four. Compared with the reference values, the cortical width was thicker than average in the humerus and thinner in the femur. The vertebral diameters at L3 and the interpedicular distances at L1 and L5 were significantly smaller in the patients than in the control subjects (P<0.001); however, at L5 the canal was wider, relative to the vertebral body. The study group had a higher rate of anterior osteophytes in the lumbar spine than the controls had, and their osteophytes were also significantly larger. In the six patients for whom radiographs of the upper extremity in its entirety were available on one film, the ulna appeared to be rotated. In one 22-year-old man, multiple epiphyses were still open. Congenital IGF-1 deficiency leads to skeletal abnormalities characterized by small bones, narrow spinal canal, and delayed bone age. The limitation in elbow distensibility common to patients with Laron syndrome may be related to a marked retroversion of the humeral head.