Free IGF-I Research Articles

Profiling growth performance, insulin-like growth factors (IGFs), and IGF-binding proteins (IGFBPs) in rainbow trout lacking IGFBP-2b.

Insulin-like growth factor binding proteins (IGFBP) regulate insulin-like growth factor (IGF) signaling, but IGFBP-specific functions are not well characterized in fishes. A line of rainbow trout (Oncorhynchus mykiss) lacking a functional IGFBP-2b was produced using gene editing and subsequent breeding to an F2 generation. This loss-of-function model (2bKO) was subjected to either continuous feeding or feed deprivation (3 wk) followed by refeeding (1 wk). During continuous feeding, the 2bKO line displayed faster specific growth rate for both body weight and fork length, higher feed intake, and reduced feed conversion ratio compared to a wild type (WT) line. However, loss of IGFBP-2b did not affect the feed deprivation or refeeding response in terms of weight loss or weight gain, respectively. Several components of the IGF/IGFBP system were affected by loss of IGFBP2b. Total serum IGF-1 in the 2bKO line was reduced to 0.5 - 0.8-fold of the WT line although the concentration of free serum IGF-1 was not affected. Gene expression differences include reduced abundance of igfbp1a1, igfbp1b2, igfbp5b2, and igfbp6b1 transcripts, and elevated igf2 and igfbp6b2 transcripts in liver of the 2bKO line. Collectively, these findings suggest that although IGFBP-2b is a carrier of circulating IGF-1 in salmonids, the presence of IGFBP-2a and compensatory responses of other IGF/IGFBP system components support an anabolic response that improved growth performance in the loss-of-function model.

Prepubertal children with obesity have high free IGF-1 levels and accelerated growth despite reduced pappalysin levels.

Prepubertal children with obesity frequently have enhanced growth, accelerated skeletal maturation and changes in the GH-IGF axis. However, the involvement of pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC1, STC2) as regulators of IGF bioavailability has not been studied in obesity. We aimed to determine the effects of childhood obesity and weight reduction on serum levels of PAPP-A, PAPP-A2, STC1 and STC2 and their relationship with IGF bioavailability, growth, and other components of the GH-IGF system. Prepubertal children with severe obesity (150, 50% males/females, age: 7.72 ± 2.05 years, BMI z-score: 4.95 ± 1.70, height z-score: 1.28 ± 1.04) were studied at diagnosis and after a minimum of 0.5 BMI z-score reduction. Two hundred and six healthy age- and sex-matched children were used as controls. Children with obesity had decreased serum concentrations of PAPP-A, PAPP-A2 and STC2, but increased total and free IGF-I (fIGF-I), intact IGFBP-3, ALS, IGF-II and insulin levels, with no difference in the free/total IGF-I ratio. Neither the standardized BMI nor height correlated with any biochemical parameter analyzed. A decrease in IGF-II, insulin, and ALS with an increase in IGFBP-2 and -5, STC2 and PAPP-A were observed after weight loss. Increased circulating total and free IGF-I, insulin and IGF-II may all contribute to the increased rate of prepubertal growth and bone maturation observed in children with obesity, with STC2 possibly being involved.

Implication of Pappalysins and Stanniocalcins in the Bioavailability of IGF-I in Children With Type 1 Diabetes Mellitus.

Anomalies in the growth hormone (GH)/insulin-like growth factor (IGF) axis, are common in children with type 1 diabetes mellitus (T1DM), even in those reaching a normal or near-normal final height. However, concentrations of the IGF bioavailability regulatory factors (pappalysins [PAPP-As] and stanniocalcins [STCs]) have not been reported in children with T1DM. To determine serum concentrations of PAPP-As and STCs in children at diagnosis of T1DM and after insulin treatment and the correlation of these factors with other members of the GH/IGF axis, beta-cell insulin reserve, auxology, and nutritional status. A single-center prospective observational study including 47 patients (59.5% male), with T1DM onset at median age of 9.2 years (interquartile range: 6.3, 11.9) was performed. Blood and anthropometric data were collected at diagnosis and after 6 and 12 months of treatment. At 6 and 12 months after T1DM diagnosis, there was improvement in the metabolic control (decrease in glycated hemoglobin [HbA1c] at 12 months -3.66 [95% CI: -4.81, -2.05], P = .001), as well as in body mass index SD and height SD (not statistically significant). STC2 increased (P < .001) and PAPP-A2 decreased (P < .001) at 6 and 12 months of treatment onset (P < .001), which was concurrent with increased total IGF-I and IGF-binding protein concentrations, with no significant modification in free IGF-I concentrations. HbA1c correlated with PAPP-A2 (r = +0.41; P < .05) and STC2 (r = -0.32; P < .05). Implementation of insulin treatment after T1DM onset modifies various components of the circulating IGF system, including PAPP-A2 and STC2. How these modifications modulate linear growth remains unknown.

Investigating the IGF axis as a pathway for intergenerational effects.

Early nutritional and growth experiences can impact development, metabolic function, and reproductive outcomes in adulthood, influencing health trajectories in the next generation. The insulin-like growth factor (IGF) axis regulates growth, metabolism, and energetic investment, but whether it plays a role in the pathway linking maternal experience with offspring prenatal development is unclear. To test this, we investigated patterns of maternal developmental weight gain (a proxy of early nutrition), young adult energy stores, age, and parity as predictors of biomarkers of the pregnancy IGF axis (n = 36) using data from the Cebu Longitudinal Health and Nutrition Survey in Metro Cebu, Philippines. We analyzed maternal conditional weight measures at 2, 8, and 22 years of age and leptin at age 22 (a marker of body fat/energy stores) in relation to free IGF-1 and IGFBP-3 in mid/late pregnancy (mean age = 27). Maternal IGF axis measures were also assessed as predictors of offspring fetal growth. Maternal age, parity, and age 22 leptin were associated with pregnancy free IGF-1, offspring birth weight, and offspring skinfold thickness. We find that free IGF-1 levels in pregnancy are more closely related to nutritional status in early adulthood than to preadult developmental nutrition and demonstrate significant effects of young adult leptin on offspring fetal fat mass deposition. We suggest that the previously documented finding that maternal developmental nutrition predicts offspring birth size likely operates through pathways other than the maternal IGF axis, which reflects more recent energy status.

Genetic analysis of the PAPP-A2 gene and evaluation of free IGF-1, IGFBP-5, and ALS concentrations in a group of 22 patients with idiopathic short stature.

Short stature is one of the main reasons for consultation in outpatient clinics and paediatric endocrinology departments and is defined as height below the 3rd centile or less than -2 standard deviations (SDs). The study's overarching aim was to analyse the PAPP-A2 gene at mutation sites described to date and at exons 3, 4, and 5, which encode the fragment of the catalytic domain with the active site of the pregnancy-associated plasma protein A2 (PAPP-A2) protein. The secondary aims of the study were clinical and auxological analysis of a group of patients with idiopathic short stature and biochemical analysis of growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis parameters not assessed as part of the routine diagnosis of short stature, such as free IGF-1, insulin-like growth factor binding protein 5 (IGFBP-5), and acid-labile subunit (ALS) levels. Molecular analysis of the PAPP-A2 gene was performed using polymerase chain reaction (PCR) and direct sequencing. Biochemical analysis of free IGF-1, IGFBP-5, and ALS was performed by enzyme-linked immunosorbent assay (ELISA). The mean height standard deviation score (HSDS) in the study group was -2.95. None of the patients exhibited previously described mutations in the PAPP-A2 gene or mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein. In 4 patients, the known, non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 was found. Free IGF-1 levels correlate better with height and HSDS than total IGF-1 levels. The previously described mutations in the PAPP-A2 gene and mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein were not detected; only the known and non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 of the PAPP-A2 gene was observed.

Increased IGFBP Proteolysis, IGF-I Bioavailability, and Pappalysin Levels in Children With Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is associated with impaired growth hormone (GH) secretion and decreased insulin-like growth factor (IGF)-I levels. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown. We determined serum levels of PAPP-As and STCs in association with IGF axis components in prepubertal and pubertal patients with PWS, also analyzing the effect of GH treatment. Forty children and adolescents with PWS and 120 sex- and age-matched controls were included. The effect of GH was evaluated at 6 months of treatment in 11 children. Children with PWS had lower levels of total IGF-I, total and intact IGFBP-3, acid-labile subunit, intact IGFBP-4, and STC-1, and they had higher concentrations of free IGF-I, IGFBP-5, and PAPP-A. Patients with PWS after pubertal onset had decreased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4 levels, and had increased total IGFBP-4, and STCs concentrations. GH treatment increased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4, with no changes in PAPP-As, STCs, and free IGF-I levels. Standardized height correlated directly with intact IGFBP-3 and inversely with PAPP-As and the free/total IGF-I ratio. The increase in PAPP-A could be involved in increased IGFBP proteolysis, promoting IGF-I bioavailability in children with PWS. Further studies are needed to establish the relationship between growth, GH resistance, and changes in the IGF axis during development and after GH treatment in these patients.

Reduction in Pappalysin-2 Levels and Lower IGF-I Bioavailability in Female Adolescents With Anorexia Nervosa.

Anorexia nervosa (AN) can cause severe undernutrition associated with alterations in the IGF axis. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) modulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implications in AN are unknown. We determined serum levels of PAPP-As and STCs in relationship with classical IGF axis parameters in female adolescents with AN and their association with nutritional status and secondary amenorrhea. Parameters of the IGF axis were determined in fasting serum samples of 68 female adolescents with AN at diagnosis and 62 sex- and age-matched controls. Standardized body mass index (BMI) and bone mineral density (BMD) were calculated. Patients with AN had lower concentrations of total and free IGF-I, total IGFBP-3, acid-labile subunit (ALS), insulin, PAPP-A2, STC-1, and STC-2 and higher levels of IGF-II and IGFBP-2. Their free/total IGF-I ratio was decreased and the intact/total IGFBP-3 and -4 ratios increased. BMI was directly related to total IGF-I and intact IGFBP-3 and inversely with IGFBP-2 and intact IGFBP-4. Weight loss was directly correlated with intact IGFBP-4 and negatively with intact IGFBP-3, ALS, STC-2, and PAPP-A2 concentrations. BMD was directly related to intact IGFBP-3 and inversely with intact IGFBP-4 and PAPP-A2 levels. Patients with amenorrhea had lower levels of total IGF-I and IGFBP-3 than those with menses. The reduction of PAPP-A2 in patients with AN may be involved in a decline in IGFBP cleavage, which could underlie the decrease in IGF-I bioavailability that is influenced by nutritional status and amenorrhea.

Analysis of correlation between insulin resistance and severity of acne vulgaris

Blood glucose levels in the disease activate the free IGF-1 which promotes lipogenesis of sebaceous glands thus leading to acne formation. The study was aimed to analyze the correlation between insulin resistance and the severity of acne vulgaris. A total of 100 patients clinically diagnosed with acne vulgaris were enrolled in the study. The severity of the acne was evaluated using the GAGS system. The HOMA-IR index was used for the analysis of insulin resistance. The mean age of the patients was 22.13 years with a predominance of females i.e., 76%. GAGS score revealed 89% of patients had mild acne, 9% of patients had moderate acne and 2% of patients had severe acne. As per the HOMA-IR index cutoff value of 2.5, 35% of patients in our study had insulin resistance. A significant positive correlation was observed between the acne vulgaris and insulin resistance. Early treatment of insulin resistance can help evaluate a patient’s metabolic aspects that should be helpful in the diagnosis and treatment of various other skin conditions associated with it apart from acne vulgaris such as acanthosis nigricans, acrochordons, etc., and improving the health and the quality of care for these patients.

FRI326 Hypophysitis: A Formidable Diagnostic Challenge

Abstract Disclosure: S. Pandey: None. C. Houston: None. Background: Hypophysitis, defined as inflammation of the pituitary gland, may pose a formidable diagnostic challenge due to its protean clinical manifestations and growing spectrum of potential causes. We present a case of a young man with presumed hypophysitis in whom the etiology remains unknown. Case Summary: A previously healthy 20-year-old male with bilateral gynecomastia was referred to the endocrinology clinic. He reported a 1-year history of worsening fatigue, weight gain, intermittent headaches, bilateral breast enlargement, lack of morning erections, polydipsia, and polyuria. His childhood growth and pubertal development were reportedly normal. He denied prior head or testicular trauma, major systemic illnesses, and chronic opiate or glucocorticoid use. His physical exam was remarkable only for scant facial hair and bilateral nontender gynecomastia. His visual fields were normal, and sense of smell was intact. Laboratory evaluation at 8am revealed low total and free testosterone of 32 ng/dL (240-950) and 0.98 ng/dL (5.25-20.7), respectively, with LH of 1.4 mIU/mL (1.0-12.0) and FSH of 1.9 mIU/mL (1.0-12.0). Free T4, prolactin, IGF-1, and serum sodium were all within normal ranges. Serum cortisol was modestly elevated at 22.3 ug/dL (3.7-19.4) with normal ACTH of 49 pg/mL (7.2-63.0). Pituitary MRI showed diffuse thickening and enhancement of the pituitary stalk, compatible with infundibular hypophysitis, without evidence of mass effect upon the native gland or surrounding structures. Additional testing showed normal levels of serum calcium, iron, ferritin, ESR, and antinuclear antibodies. After overnight water deprivation, his serum sodium was elevated at 156 mmol/L (134-144) with low urine osmolality of 121 mOsmol/kg (300-900). He was started on desmopressin and testosterone, and close clinical monitoring was enacted. Conclusion: The diagnosis of hypophysitis poses multiple challenges. Its clinical manifestations can vary widely, including symptoms related to mass effect and/or symptoms of pituitary dysfunction. Diagnosis is often presumptive based on history and exam, biochemical evaluation, and neuroimaging. The spectrum of potential causes is broad and growing, including infiltrative, infectious, neoplastic, immunoglobulin G4-related, immunotherapy-induced, other autoimmune, and paraneoplastic causes. It is often a humbling experience for clinicians to narrow this exhaustive differential. Pituitary biopsy is the gold standard for diagnosis but poses significant risks, so is reserved for cases when the diagnosis remains uncertain or malignancy is suspected. Close clinical monitoring and re-evaluation is an acceptable alternative in select cases. Presentation: Friday, June 16, 2023

THU506 A Not-So-Simple Case Of Hyperparathyroidism

Abstract Disclosure: P.J. Bhatt: None. S. Rabiei: None. V. Kantorovich: None. Multiple endocrine neoplasia 1 (MEN-1) is a rare autosomal dominant disorder caused by an inactivating mutation of the MEN-1 tumor suppressor gene and is associated with tumors of the parathyroid (95%), endocrine pancreas (40-70%) and anterior pituitary (30-40%). Primary hyperparathyroidism is the most frequent and earliest expression of MEN1 syndrome with a typical onset at age 20-25 in inherited cases, reaching 100% penetrance after age 50. Current guidelines recommend genetic testing in all individuals with primary hyperparathyroidism diagnosed at a young age, with multiglandular disease, or with family history of primary hyperparathyroidism. A 58 year old female with a history of L. breast cancer, pulmonary embolisms, DM2, and recurrent nephrolithiasis was diagnosed with primary hyperparathyroidism at age 36 and had a parathyroidectomy with 3.5 gland removal and later a total thyroidectomy. She continued to be symptomatic and was found to have an ectopic parathyroid gland in her chest requiring parathyroid gland reimplantation 18 years later. After 3 years, she was admitted for a CHF exacerbation and a pancreatic tail lesion was incidentally discovered. There was no mention of pancreatic lesions prior to this reading. Family history was pertinent for a father with nephrolithiasis. Her daughter had recurrent nephrolithiasis, hyperparathyroidism and was found to have a MEN 1 variant of uncertain significance, prompting the patient to seek genetic counseling. 22 years after her initial diagnosis of hyperparathyroidism, she tested positive for a likely pathologic heterozygous variant mutation of the MEN1 gene called 1747C&amp;gt;T. At endocrinology follow-up, she was asymptomatic. Labs showed elevated Chromogranin A at 1,799 ng/ dL [&amp;lt;311] and gastrin 174pg/mL [&amp;lt;/=100]. FSH, LH, prolactin, free alpha subunit, cortisol, and IGF-1 were normal. Further imaging confirmed a DOTATATE-avid 1.1cm nodular lesion in the pancreatic tail, concerning for a neuroendocrine tumor. MEN1 gene mutation is associated with MEN1 syndrome, familial isolated hyperparathyroidism and has an autosomal dominant predisposition to thyroid cancer and paraganglioma-pheochromocytoma syndrome. The 1747C&amp;gt;T sequence change creates a premature translational stop signal in the MEN1 gene and disrupts the NLS2 domain of the MEN1 protein, which is important for DNA binding and repression of cell proliferation. Upon diagnosis of multiglandular hyperparathyroidism, the patient should have been sent for genetic testing and instead, became an example of a multisystem failure to identify and provide necessary testing and treatment. Until her variant diagnosis, her pancreatic tumor was not identified as such. The main cause of mortality in MEN-1 patients is malignant spread of neuroendocrine tumors, hence early detection and prompt treatment are of the utmost importance to preserve quality of life and improve survival. Presentation: Thursday, June 15, 2023

THU171 Reference Intervals For Bioavailable IGF-I Values In Dutch Healthy Children, Adolescents And Young Adults

Abstract Disclosure: K. Pellikaan: None. M. Elizabeth: None. A.C. Hokken-Koelega: None. S.A. van den Berg: None. L. de Graaff-Herder: None. Background: Immunoreactive ‘total’ IGF-I is the main biochemical marker for titration of growth hormone (GH) treatment. However, in several endocrine disorders like Prader-Willi syndrome (PWS) and Silver-Russell syndrome, total IGF-I levels are often higher than expected based on GH dose and clinical effects. When patients reach total IGF-I concentrations above +2SDS, fear of negative long-term effects makes clinicians reduce GH dose. This dose reduction often leads to a deterioration in body composition, growth (in children) and quality of life, which suggests that bioavailability of IGF-I is reduced in patients with these disorders. Measurement of bioavailable IGF-I could improve GH dose titration. However, use of bioavailable IGF-I assays has been hindered by the lack of proper reference intervals. We report reference intervals of bioavailable IGF-I in a large group of healthy children, adolescents and adults. Methods: Serum was collected of 260 Dutch healthy controls aged 1-21 years. Total IGF-I and unbound, bioavailable IGF-I were measured manually using Ansh Labs total and free IGF-I assays. We calculated male and female age-related reference intervals for total and bioavailable IGF-I. Results: We present male and female age-related reference intervals. Both total and bioavailable IGF-I increased with age and were significantly higher in females than in males (p &amp;lt; 0.001). Conclusions: the reported reference intervals for bioavailable IGF-I concentrations will facilitate the use of bioavailable IGF-I levels as an alternative marker for GH dose titration in patients with disorders in which total IGF-I levels are unreliable. Presentation: Thursday, June 15, 2023

The Effect of Metformin on Plasma Prolactin Levels in Young Women with Autoimmune Thyroiditis.

Metformin decreases elevated prolactin levels, which are frequently found in patients with thyroid disorders. The aim of this study was to investigate whether thyroid autoimmunity modulates the impact of metformin on lactotrope secretory function. This study compared two matched groups of young women with prediabetes and mild-to-moderate prolactin excess: 28 subjects with coexisting euthyroid autoimmune thyroiditis (group 1) and 28 individuals without thyroid disorders (group 2), treated for six months with metformin (3 g daily). Thyroid antibody titers, glucose homeostasis markers, prolactin, thyrotropin, free thyroid hormones, FSH, LH, ACTH, IGF-1 and hsCRP were assessed at the beginning and at the end of the study. At entry, the study groups differed in antibody titers and hsCRP levels. Although the improvement in glucose homeostasis and the decrease in hsCRP levels were observed in both study groups, they were more pronounced in group 2. Only in group 2 did metformin reduce circulating prolactin levels (both total and monomeric). Prolactin-lowering properties of metformin positively correlated with baseline prolactin levels, baseline antibody titers (in group 1) and with the degree of reduction in hsCRP levels. The obtained results suggest that autoimmune thyroiditis may attenuate the impact of metformin on lactotrope secretory function.

Vitamin D Status Determines the Impact of Metformin on Gonadotropin Levels in Postmenopausal Women.

Metformin was found to decrease elevated levels of anterior pituitary hormones. Its impact on lactotrope secretory function was absent in women with vitamin D insufficiency. This study investigated whether vitamin D status determines metformin action on overactive gonadotropes. We compared the effect of six-month metformin treatment on the plasma levels of gonadotropins, TSH, prolactin, ACTH, estradiol, free thyroid hormones, IGF-1, and 25-hydroxyvitamin D, as well as on glucose homeostasis markers between three matched groups of postmenopausal women at high risk for diabetes: untreated subjects with vitamin D insufficiency (group A), untreated women with normal vitamin D status (group B), and individuals receiving vitamin D supplementation with normal 25-hydroxyvitamin D levels (group C). Only in groups B and C did metformin reduce FSH levels and tend to decrease LH levels, and these effects correlated with baseline gonadotropin levels, baseline 25-hydroxyvitamin D levels, and the improvement in insulin sensitivity. Follow-up gonadotropin levels were higher in group A than in the other two groups. The drug did not affect circulating levels of TSH, prolactin, ACTH, estradiol, free thyroid hormones, IGF-1, or 25-hydroxyvitamin D. The obtained results suggest that the impact of metformin on gonadotropin secretion in women after menopause is determined by vitamin D status.

Five-Year Therapy with Recombinant Human Insulin-Like Growth Factor-1 in a Patient with PAPP-A2 Deficiency

Introduction: The metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) cleaves insulin-like growth factor (IGF)-binding proteins 3 and 5 to release bioactive IGF-I from its ternary complex. Patients with mutations in PAPP-A2 have growth failure and low free IGF-I despite elevated total IGF-I. We describe 5-year treatment response to recombinant human IGF-1 (rhIGF-1) in a patient with PAPP-A2 deficiency, and the phenotype of PAPP-A2 deficiency in three siblings. Methods: Two siblings (P2, P3) with PAPP-A2 deficiency were recruited for rhIGF-1 therapy at 120 μg/kg subcutaneous twice daily, along with a third sibling (P1) for phenotyping. We evaluated efficacy and safety of rhIGF-1 therapy, including effect on metabolic measures and bone mineral density (BMD). Results: Treatment with rhIGF-1 was started in 10.4-year- (P3) and 14.5-year (P2)-old brothers. P2 discontinued therapy due to pseudotumor cerebri. P3 continued rhIGF-1 for 5 years; height velocity increased (3.0 cm/year at baseline; 5.0–7.6 cm/year thereafter) as did height SDS (+0.6). P3’s pubertal onset was at 12.4 year. BMD height-adjusted Z-score modestly improved for lumbar spine (+0.4), and decreased in forearm (−0.2) and hip (−0.3). All siblings had hyperinsulinemia. Impaired glucose tolerance (IGT) resolved in P1. P2 showed worsening glucose tolerance (2-h glucose: 225 mg/dL). Impaired fasting glucose and hyperinsulinemia initially resolved for P3, but IGT (2-h glucose: 152 mg/dL) developed during puberty. Conclusion: Therapy with rhIGF-1 modestly improved linear growth in one patient with PAPP-A2 deficiency, but without true catch-up. Therapy was associated with pseudotumor cerebri in a sibling. Initial improvement in BMD and glycemic pattern on rhIGF-1 was not sustained during puberty.

Role of insulin-like growth factor, pro-inflammatory and anti-inflammatory cytokines, transcription factors and adipokines in development of hepatocellular carcinoma in metabolic syndrome

Conflicting data on the role of the metabolic syndrome (MS) in the development of hepatocellular carcinoma (HCC) require studies on the influence of molecular factors that are important in the development of HCC in MS, which was the goal of our review. Publications (scientific articles and reviews) over the past 10 years were studied and analyzed using the databases Web of Science, Scopus, PubMed, RSCI. The terms used for the search were “metabolic syndrome and non-alcoholic fatty liver disease”, “metabolic syndrome and non-alcoholic steatohepatitis”, “metabolic syndrome and hepatocellular carcinoma”. The total number of publications studied in all databases exceeded 570 units, while the review presents the most significant results at the present stage. Insulin resistance and obesity, through the development of a systemic chronic inflammatory state, lead to increased inflammation and fibrosis in the liver, which are prodromal signs of hepatocarcinogenesis, increase the production of insulin-like growth factor-1 and disrupt the regulation of the insulin-like growth factor pathway. People with HCC have been shown to overexpress IGF-2. IGF-binding proteins, due to the reduced bioavailability of free IGF-1 and IGF-2 in the circulation, are able to inhibit the growth of HCC. In MS, a pro-inflammatory state is detected, which is caused by the production of cytokines by adipocytes (IL-6, IL-8, IL-1β, tumor necrosis factor α (TNFα), VEGF and chemokine ligands 2 and 5), which recruit immune cells, promoting angiogenesis and enhancing chronic inflammation. Transcription factors (PPAR) are involved in hepatocarcinogenesis, the significance of different factors is not fully understood. Leptin has a positive prognostic value in HCC, improving overall survival, and visfatin has a negative effect on hepatocarcinogenesis. Activation of PAI-1 inhibits the progression of HCC through PPARγ stimulation. Adiponectin may be a prognostic marker in HCC, with a lower serum concentration positively correlated with worse prognosis.

Growth Hormone and Counterregulation in the Pathogenesis of Diabetes.

Canonical growth hormone (GH)-dependent signaling is essential for growth and counterregulatory responses to hypoglycemia, but also may contribute to glucose homeostasis (even in the absence of hypoglycemia) via its impact on metabolism of carbohydrates, lipids and proteins, body composition, and cardiovascular risk profile. The aim of this review is to summarize recent data implicating GH action in metabolic control, including both IGF-1-dependent and -independent pathways, and its potential role as target for T2D therapy. Experimental blockade of the GHR can modulate glucose metabolism. Moreover, the soluble form of the GH receptor (GHR, or GHBP) was recently identified as a mediator of improvement in glycemic control in patients with T2D randomized to bariatric surgery vs. medical therapy. Reductions in GHR were accompanied by increases in plasma GH, but unchanged levels of both total and free IGF-1. Likewise, hepatic GHR expression is reduced following both RYGB and VSG in rodents. Emerging data indicate that GH signaling is important for regulation of long-term glucose metabolism in T2D. Future studies will be required to dissect tissue-specific GH signaling and sensitivity and their contributions to systemic glucose metabolism.

Cationic peptide carriers enable long-term delivery of insulin-like growth factor-1 to suppress osteoarthritis-induced matrix degradation

BackgroundInsulin-like growth factor-1 (IGF-1) has the potential to be used for osteoarthritis (OA) treatment but has not been evaluated in clinics yet owing to toxicity concerns. It suffers from short intra-joint residence time and a lack of cartilage targeting following its intra-articular administration. Here, we synthesize an electrically charged cationic formulation of IGF-1 by using a short-length arginine-rich, hydrophilic cationic peptide carrier (CPC) with a net charge of +14, designed for rapid and high uptake and retention in both healthy and arthritic cartilage.MethodsIGF-1 was conjugated to CPC by using a site-specific sulfhydryl reaction via a bifunctional linker. Intra-cartilage depth of penetration and retention of CPC-IGF-1 was compared with the unmodified IGF-1. The therapeutic effectiveness of a single dose of CPC-IGF-1 was compared with free IGF-1 in an IL-1α-challenged cartilage explant culture post-traumatic OA model.ResultsCPC-IGF-1 rapidly penetrated through the full thickness of cartilage creating a drug depot owing to electrostatic interactions with negatively charged aggrecan-glycosaminoglycans (GAGs). CPC-IGF-1 remained bound within the tissue while unmodified IGF-1 cleared out. Treatment with a single dose of CPC-IGF-1 effectively suppressed IL-1α-induced GAG loss and nitrite release and rescued cell metabolism and viability throughout the 16-day culture period, while free IGF at the equivalent dose was not effective.ConclusionsCPC-mediated depot delivery of IGF-1 protected cartilage by suppressing cytokine-induced catabolism with only a single dose. CPC is a versatile cationic motif that can be used for intra-cartilage delivery of other similar-sized drugs.

Insulin-like growth factor-I biocompartmentalization across blood, interstitial fluid and muscle, before and after 3 months of chronic resistance exercise.

This investigation examined the influence of 12-week ballistic resistance training programs on the IGF-I system in circulation, interstitial fluid, and skeletal muscle, at rest and in response to acute exercise. Seventeen college-aged subjects (11 women/6 men; 21.7 ± 3.7 yr) completed an acute ballistic exercise bout before and after the training program. Blood samples were collected pre-, mid-, and postexercise and analyzed for serum total IGF-I, free IGF-I, and IGF binding proteins (IGFBPs) 1-4. Dialysate and interstitial free IGF-I were analyzed in vastus lateralis (VL) interstitial fluid collected pre- and postexercise via microdialysis. Pre- and postexercise VL muscle biopsies were analyzed for IGF-I protein expression, IGF-I receptor phosphorylation (p-IGF-IR), and AKT phosphorylation (p-AKT). Following training, basal serum IGF-I, free IGF-I, IGFBP-2, and IGFBP-3 decreased whereas IGFBP-1 and IGFBP-4 increased. Training reduced basal dialysate and interstitial free IGF-I but had no effect on basal skeletal muscle IGF-I, p-IGF-IR, or p-AKT. Acute exercise elicited transient changes in IGF-I system concentrations and downstream anabolic signaling both pre- and posttraining; training did not affect this acute exercise response. Posttraining, acute exercise-induced changes in dialysate/interstitial free IGF-I were strongly correlated with the changes in intramuscular IGF-I expression, p-IGF-IR, and p-AKT. The divergent influence of resistance training on circulating/interstitial and skeletal muscle IGF-I demonstrates the importance of concurrent, multiple biocompartment analysis when examining the IGF-I system. As training elicited muscle hypertrophy, these findings indicate that IGF-I's anabolic effects on skeletal muscle are mediated by local, rather than systemic mechanisms.NEW & NOTEWORTHY In the first investigation to assess resistance training's effects on the IGF-I system in serum, interstitial fluid, and skeletal muscle, training decreased basal circulating and interstitial IGF-I but did not alter basal intramuscular IGF-I protein activity. Posttraining, acute exercise-induced interstitial IGF-I increases were strongly correlated with intramuscular IGF-I expression and signaling. These findings highlight the importance of multibiocompartment measurement when analyzing IGF-I and suggest that IGF-I's role in hypertrophic adaptations is locally mediated.

Free Insulin-like Growth Factor (IGF)-I in Children with PWS.

In children with Prader–Willi syndrome (PWS), the standard growth hormone (GH) dose often results in high immunoreactive IGF-I levels. These high immunoreactive IGF-I levels lead to concern because their long-term effects are unknown. As a result, clinicians have to lower the GH dose, which worsens body composition and quality of life. As clinical features do not seem to correspond to immunoreactive IGF-I values, it is questionable whether immunoreactive IGF-I is a suitable marker for GH dosing, or whether another parameter better reflects IGF-I bioavailability and bioactivity. We, therefore, investigate serum immunoreactive IGF-I, free IGF-I and IGFBP-3 levels in 70 GH-treated children with PWS. Our study showed that, although immunoreactive IGF-I levels were high (>2 SDS) in the vast majority of prepubertal and pubertal children, free IGF-I SDS levels were <0 SDS in most and <1 SDS in all. Free IGF-I correlated with the immunoreactive IGF-I, IGFBP-3 and IGF-I/IGFBP-3 ratio. We conclude that there is a major discrepancy between immunoreactive and free IGF-I levels. While in the majority of GH-treated children with PWS, immunoreactive IGF-I levels were high, free IGF-I levels were <0 SDS in most. Our data appear to be very reassuring and suggest that free IGF-I levels should also be taken into consideration when the immunoreactive IGF-I levels are >2 SDS in GH-treated children with PWS.

Hormonal patterns in men with prediabetes and diabetes in NHANES III: possible links with prostate cancer.

Pathways involving sex hormones and insulin-like growth factors (IGFs) have been proposed to explain, in part, the lower risk of prostate cancer among men with diabetes. To gain insights into potential biological mechanisms we explored differences in serum concentrations of sex hormones and IGFs across the trajectory from normoglycemia to prediabetes to poorly controlled diabetes. Using cross-sectional data from the National Health and Nutrition Examination Survey III we examined differences in levels of circulating sex hormones, sex hormone-binding globulin (SHBG), IGF-1, and IFG-binding protein 3 (IGFBP-3), according to diabetes status: no diabetes [n = 648], prediabetes [n = 578], undiagnosed diabetes [n = 106], well-controlled diabetes [n = 42], and poorly controlled diabetes [n = 56]. Adjusted geometric mean concentrations were derived using multivariable linear regression, adjusted for age, race, and other lifestyle factors. Total testosterone concentrations were lower among prediabetics (4.89ng/mL, 95% confidence interval (CI) 4.95-5.21) than men without prediabetes/diabetes (5.29ng/mL, 95% CI 5.06-5.53) but did not reduce further across diabetes groups. Concentrations of estradiol, estimated free testosterone, SHGB, IGF-1, and IGFBP-3 did not differ. While the ratio of IGF-1 to IGFBP-3 was lower among men with prediabetics and undiagnosed diabetes than men without prediabetes/diabetes, there was no trend across groups. A positive trend for the ratio of estradiol-to-testosterone levels was observed across groups (p trend = 0.045). Our findings do not provide clear support for either an androgen driven or IGF-driven pathway for the inverse association between diabetes and prostate cancer risk.