Low Insulin-like Growth Factor-1 Levels Research Articles

IGF-1 levels in the general population, heart failure patients, and individuals with acromegaly: differences and projections from meta-analyses-a dual perspective.

The complex relationship between insulin-like growth factor 1 (IGF-1) levels and heart failure (HF) is not fully understood, particularly across different populations and conditions. This meta-analysis aims to elucidate the dual perspectives of IGF-1 levels in the general population, HF patients, and individuals with treatment-naïve acromegaly, highlighting IGF-1 as a biomarker and potential therapeutic target in HF management. Studies were searched across multiple electronic databases up to January 2024 and independently identified by reviewers. The outcomes were analyzed using RevMan 5.4 and STATA 15. A total of 25 articles were ultimately included in the analysis. Six studies compared IGF-1 levels between HF patients and non-HF controls, revealing significantly lower IGF-1 levels in HF patients (mean difference -20.93; 95% CI -37.88 to -3.97; p = 0.02). This reduction was consistent across various HF subtypes and severities. In addition, individuals with intermediate IGF-1 levels had a lower risk of developing HF [risk ratio (RR) 0.78; 95% CI 0.74-0.83; p < 0.01] and HF-related mortality (RR 0.98; 95% CI 0.97, 0.99; p < 0.01) compared to those with low IGF-1 levels, suggesting a protective role for maintaining adequate IGF-1 levels. Conversely, treatment-naïve acromegaly patients, characterized by excessively high IGF-1 levels, showed a significantly higher incidence of both diastolic HF [odds ratio (OR) 9.08; 95% CI 6.20-13.29; p < 0.01] and systolic HF (OR 13.1; 95% CI 6.64-25.84; p < 0.01), implicating supraphysiological IGF-1 levels in adverse cardiac outcomes. Our meta-analysis highlights the complex interplay between IGF-1 levels and HF. We found that reduced IGF-1 levels are commonly observed in HF patients and are associated with an increased risk of HF and higher HF-related mortality. Conversely, excessively high levels, as observed in acromegaly, are linked to a higher incidence of HF. Based on these results, it is recommended that cardiac function be closely monitored in patients with reduced IGF-1 levels and in those with acromegaly. These findings suggest that IGF-1 could hold potential prognostic value for risk stratification in HF.

8015 Growth Hormone Axis Dysfunction in PMM2-CDG: Exploring the Role of Dynamic Tests for the Management of Short Stature in Two Pediatric Cases

Abstract Disclosure: G. Del Medico: None. E. Procopio: None. L. Ferri: None. A. Barbato: None. A. Morrone: None. S. Stagi: None. PMM2-CDG is the most prevalent congenital disorder of glycosylation (CDG) and is caused by defective phosphomannomutase2 (PMM2) activity. According to the 2019 guidelines, approximately half of PMM2-CDG patients exhibit short stature and low serum levels of insulin-like growth factor-1 (IGF-1), IGF binding protein 3 (IGFBP3), and acid-labile subunit (ALS). Despite this, there is no expert consensus on the endocrinological management of this condition. We investigated the growth hormone (GH) axis in two 12-year-old female patients with PMM2-CDG. The first patient was compound heterozygote for the most common PMM2 gene variants in Italy, p.(Leu32Arg) and p.(Arg141His). She presented with short stature (&amp;lt; 2 Standard Deviation Score, SDS) and low serum levels of IGF-1 and IGF-BP3 (&amp;lt; 2.5° for age and sex). Bone age was significantly delayed. Tanner stage was prepubertal. Somatotropic response to GH stimulation testing (Levodopa) was normal. After the IGF-1 generation test with recombinant GH, serum IGF-1 increased by 115%. The second patient was compound heterozygote for the known PMM2 pathogenetic variant p.(Ala108Val) and the novel p.(Thr171Asnfs*11) variant (only case described in literature). She presented short stature (&amp;lt; 2 SDS) with near-to-normal IGF-1 and IGF-BP3 serum levels (2.5° for age and sex). Bone age was slightly delayed. Tanner stage was prepubertal. She also exhibited severe obesity, hypertriglyceridemia, and hepatic steatosis. Her somatotropic response to two GH stimulation tests (Levodopa and Arginine) was deficient, probably because of her significant overweight. IGF-1 serum levels didn’t increase after the IGF-1 generation test. Hypoglycosylation in PMM2-CDG impairs the IGF1 system on multiple levels. It destabilizes the ternary complex formed by IGF-1 and glycoproteins IGFBP3 and ALS, therefore reducing the half-life of circulating IGF-1. Hypoglycosylation also reduces IGF1 production by impairing its precursor proIGF-1Ea and its cellular secretion. As a result, PMM2-CDG patients have GH insensitivity, with normal GH production but low levels of IGF-1. However, there is a lack of information in the literature on the use of dynamic tests and hormonal therapies (GH and rhIGF-1) in CDG. The IGF-1 generation test in our patients showed partial GH sensitivity in the first patient and GH insensitivity in the second patient. These observations suggest variability. Some PMM2-CDG patients may benefit from an extended trial with GH therapy, while for GH-insensitive patients a trial with recombinant IGF-1 might be considered. This is one of the first reports that explores the potential role of dynamic tests in PMM2-CDG. As the biochemical effects of hypoglycosylation on the GH-IGF1 pathway are becoming clearer more clinical research is needed to reach a consensus on the management and treatment of short stature in these patients. Presentation: 6/3/2024

8193 Mauriac Syndrome Uncovered, The Insulin Access Impact in Type 1 Diabetes Mellitus

Abstract Disclosure: D.H. Sacoto: None. R. Belokovskaya: None. K. Gebran: None. K. Madani: None. A. De Rosairo: None. D. Patel: None. A.A. Franco-Akel: None. Introduction: Mauriac syndrome is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM). It is reversible with appropriate glycemic control; however, factors affecting healthcare access to insulin are leading to its re-emergence. We present a case of Mauriac syndrome as a complication of uncontrolled T1DM due to insulin access. Case: A 22-year-old Hispanic female with a history of T1DM presented to the emergency department with a two-day history of abdominal pain. She was diagnosed with diabetic ketoacidosis (DKA) (blood glucose: 802 mg/dL; pH 7.14; bicarbonate: 7 mmol/L; anion gap: 34; positive serum ketones). Incidental transaminitis was noted. R factor showed a cholestatic pattern of 0.6 (AST: 136 U/L, ALT: 49 U/L, alkaline phosphatase:286 U/L). US liver revealed an enlarged liver (craniocaudal: 16.5 cm) without biliary obstruction. Her phenotype consisted of short stature (4.8 feet) with a moon face and a protuberant abdomen. Her records revealed a normal karyotype 46 XX, with a bone age of 4 years, pubertal delay, low insulin-like growth factor-1 levels (58 ng/mL), and long-standing hyperlipidemia. Over the years, she experienced multiple DKA episodes in the context of uncontrolled T1DM (hemoglobin A1c:11-13 %). The main problem identified included difficulty with insulin access, specifically related to insurance coverage as well as managing her disease. Glycemic control has significantly improved with continuous glucose monitoring and updated insurance status. Discussion: Mauriac syndrome is characterized by hepatomegaly, transaminitis, delayed pubertal maturation, growth failure, and cushingoid features. Hyperglycemia leads to intrahepatic glycogen deposition and the lack of insulin to lipolysis and ketosis, leading to high cortisol levels and growth delay. Factors leading to uncontrolled T1DM include lack of insulin access. The high cost is considered a major barrier, with an average price per millimeter of insulin tripled from 231 to 736 US dollars. Even patients with insurance tend to have high co-pays and deductibles, with a 61% chance of delay or denial due to pre-approval requirements. Lower socioeconomic status, lack of access to devices such as insulin pumps, migratory status, social support, and ethnic background are other factors related to glycemic control. Our patient belongs to a family of immigrants with low socioeconomic status, which might have contributed to the development of Mauriac syndrome. Since clinical and laboratory abnormalities are reversible with appropriate glycemic control, advocating for policies that facilitate better insulin access is paramount. Presentation: 6/2/2024

6996 Optimal Growth Hormone Response Despite Low Insulin-Like Growth Factor-1: Clinical Picture of an A67T IGF-1 Variant

Abstract Disclosure: E.M. Bomberg: Research Investigator; Self; Novo Nordisk. Z. Wu: Employee; Self; Quest Diagnostics. I. Motorykin: Employee; Self; Quest Diagnostics. J. Torkelson: None. N. Schmitz: None. A. Drilling: None. M.J. McPhaul: Employee; Self; Quest Diagnostics. B.S. Miller: Advisory Board Member; Self; Abbvie, Ascendis Pharma, Biomarin, Bristol-Myers Squibb, Eton Pharmaceuticals, EMD Serono, Endo Pharmaceuticals, GenSci, Novo Nordisk, Pfizer, Inc., Provention Bio, Sanofi, Tolmar. Consulting Fee; Self; Abbvie, Ascendis Pharma, Biomarin, Bristol-Myers Squibb, Eton Pharmaceuticals, EMD Serono, Endo Pharmaceuticals, GenSci, Provention Bio, Sanofi, Tolmar. Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Abbvie, Aeterna Zentaris, Amicus, Foresee Pharmaceuticals, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, Inc., Prevail Therapeutics, Sangamo Therapeutics. Research Investigator; Self; Alexion Pharmaceuticals, Inc., Abbvie, Aeterna Zentaris, Amicus, Foresee Pharmaceuticals, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, Inc., Prevail Therapeutics, Sangamo Therapeutics. Speaker; Self; Biomarin, Novo Nordisk, Pfizer, Inc., Tolmar. Introduction: Insulin-like growth factor-1 (IGF-1) measurements are used for growth hormone (GH) deficiency screening and helpful in monitoring GH treatment effectiveness. However, IGF-1 variants have been reported with mass spectrometry (MS)-based assays, potentially limiting interpretation of reported results. Clinical Case: A 14-year-old male presented for short stature. Evaluation was non-revealing aside from low serum IGF-1 measured via liquid chromatography (LC)-MS assay (58 ng/mL; -3.8 standard deviation score [SDS]), and IGF-Binding Protein 3 (3.7 ug/mL; -1.7 SDS). Height was 148.2 cm (1st percentile, -2.08 SDS; mid-parental height 172.7 cm [31st percentile, -0.48 SDS]), pubertal exam Tanner stage 2, and bone age 2.5 years delayed. A GH stimulation test showed a peak GH of 8.1 ug/L; brain MRI was normal. GH was started at 0.29 mg/kg/wk. One month later, IGF-1 remained low (89 ng/mL; -3.2 SDS) and GH was increased to 0.36 mg/kg/wk, and over time to 0.52 mg/kg/wk due to persistently low IGF-1 (-2.9 to -2.3 SDS), despite reports of good compliance and significant catch-up growth (height increased to 19th percentile, -0.84 SDS). He reported no significant side effects during GH treatment. At 17.5 years old, he returned to clinic reporting self-discontinuing GH 1 month prior. Height was at the 27th percentile (171.5 cm, -0.59 SDS), he was fully pubertal, IGF-1 128 ng/mL (-3.1 SDS), and bone age 1.5 years delayed. Further review of IGF-1 linked reports accompanying lab values directly entered into the electronic health record (EHR; starting 2021) described the presence of a rare heterozygous IGF-1 functional variant with unknown clinical significance based on MS data. Concentration of the variant was expected to be identical to that reported for the wild type IGF-1 protein, potentially explaining the lower than expected values. Analysis of the raw LC-MS data (variant peak at m/z 1098.09, isotopic peak index [IP6], relative retention time [rRT]=0.00 min) was consistent with either an A67T or A70T IGF-1 variant. To resolve this ambiguity, the specimen was reanalyzed with an LC-tandem MS/MS fragmentation method, which identified distinguishing peaks at m/z 503.28 (y5 ion) and 305.18 (y3 ion) characteristic of A67T, a known benign variant. Conclusions: Benign IGF-1 variants should be considered in cases of unexplained low IGF-1 levels, including when these remain low despite increasing GH doses, good adherence, and optimal growth velocity. Presence of IGF-1 variants should not affect GH stimulation results (e.g., GH levels), however, may lower reported IGF-1 levels used to determine need for diagnostic testing and followed when monitoring GH response. Careful review of IGF-1 lab reports and full abstraction of these into the EHR should be performed. Knowing a variant is benign could help providers set lower wild-type IGF-1 targets when monitoring GH response to avoid unnecessarily high GH doses. Presentation: 6/3/2024

Diminished levels of insulin-like growth factor-1 may be a risk factor for peripheral neuropathy in type 2 diabetes patients.

To investigate risk factors for diabetic peripheral neuropathy (DPN) and to explore the connection between insulin-like growth factor-1 (IGF-1) and DPN in individuals with type 2 diabetes. A total of 790 patients with type 2 diabetes participated in a cross-sectional study, divided into two groups: those with DPN (DPN) and those without DPN (non-DPN). Blood samples were taken to measure IGF-1 levels and other biochemical markers. Participants underwent nerve conduction studies and quantitative sensory testing. Patients with DPN exhibited significantly lower levels of IGF-1 compared with non-DPN patients (P < 0.001). IGF-1 was positively correlated with the average amplitude of both motor (P < 0.05) and sensory nerves (P < 0.05), but negatively correlated with the vibration perception threshold (P < 0.05). No significant difference was observed between IGF-1 and nerve conduction velocity (P > 0.05), or the temperature detection threshold (P > 0.05). Multivariate regression analysis identified diabetes duration, HbA1c, and the low levels of IGF-1 as independent risk factors (P < 0.001). Receiver operating characteristic analysis determined that at 8 years duration of diabetes, 8.5% (69.4 mmol/mol) HbA1c and 120 ng/mL IGF-1, the optimal cut-off points, indicated DPN (P < 0.001). A reduction of IGF-1 in patients with DPN suggests a potential protective role against axon injury in large fiber nerves of type 2 diabetes patients.

The positive impact of smoking on poor sleep quality is moderated by IGF1 levels in cerebrospinal fluid: a case-control study among Chinese adults.

Previous research indicates associations between cigarette smoking, insulin-like growth factor-1 (IGF1), and sleep disturbances. This study aimed to examine the association between smoking and sleep quality and investigate the moderating role of IGF1. This case-control study involved 146 Chinese adult males (53 active smokers and 93 non-smokers) from September 2014 to January 2016. Sleep quality and disturbances were evaluated using the Pittsburgh Sleep Quality Index (PSQI), which includes seven scales. Pearson correlation analysis and logistic regression analysis were utilized to examine the link between IGF1 levels in cerebrospinal fluid (CSF) and PSQI scores. The effect of IGF1 was assessed using the moderation effect and simple slope analysis, with adjustments made for potential confounders. Active smokers exhibited significantly higher global PSQI scores and lower IGF1 levels in CSF compared to non-smokers. A significant negative correlation was observed between IGF1 and PSQI scores (â = -0.28, P < 0.001), with a stronger association in non-smokers (Pearson r = -0.30) compared to smokers (Pearson r = -0.01). Smoking was associated with higher global PSQI scores (â = 0.282, P < 0.001), and this association was moderated by IGF1 levels in CSF (â = 0.145, P < 0.05), with a stronger effect at high IGF1 levels (Bsimple = 0.402, p < 0.001) compared to low IGF1 levels (Bsimple = 0.112, p = 0.268). Four subgroup analysis revealed similar results for sleep disturbances (Bsimple = 0.628, P < 0.001), with a marginal moderation effect observed on subjective sleep quality (Bsimple = 0.150, P = 0.070). However, independent associations rather than moderating effects were observed between IGF1 and sleep efficiency and daytime disturbance. We provided evidence to demonstrate the moderation effect of IGF1 on the relationship between smoking and sleep in CSF among Chinese adult males.

Very low serum IGF-1 levels are associated with vertebral fractures in adult males with beta-thalassemia major.

Patients with beta-thalassemia major (BTM) often develop several endocrine disorders due to chronic iron overload. They are also prone to osteoporosis and vertebral fractures. Plasmatic insulin-like growth factor-1 (IGF-1) levels are often low in subjects with BTM, which origin is multifactorial. The aim of this study was to evaluate a possible relationship between serum IGF-1 levels and the presence of osteoporosis and/or vertebral fractures. We retrospectively evaluated the occurrence of vertebral fractures in 30 adult male patients affected by BTM (mean age 43.3 ± 7.9years) with low serum IGF-1 (median value 52.4ng/ml, 38.5-83.4). Only 6 of them (20.0%) were diagnosed with GH deficiency (GHD) after GHRH/arginine stimulation test, while 23 (76.7%) had osteoporosis and 12 (40.0%) had known vertebral fractures. All patients except one also showed at least one endocrine disorder. Serum IGF-1 was significantly lower in BTM patients with vertebral fractures compared to patients without vertebral fractures (U = 41.0, p = 0.005) while it was not significantly different between patients with low bone mass compared to patients without low bone mass. The diagnosis of GHD was significantly associated with lower serum IGF-1 (p = 0.001) and vertebral fractures (p = 0.002) but not with low bone mass. After ROC analysis, we found that very low IGF-1 (≤ 50.0ng/dl) was associated with vertebral fractures (sensitivity 83.3%, specificity 75.0%) and was also predictive of GHD (sensitivity 75.0%, specificity 100.0%). Our study shows that, in male patients with BTM, serum IGF-1 ≤ 50.0ng/dl is a marker of vertebral fractures and it is predictive of a diagnosis of GHD.

PAPP-A Levels and IGF-1 Levels in Early-Onset Preeclampsia and Late-Onset Preeclampsia

Introduction: The pathophysiology of preeclampsy is not yet fully understood, but failure of tropoblastinvasion and placentation, which is influenced by factors such as pregnancy-associated plasma proteinA (PAPP-A) and insulin-like growth factor 1 (IGF-1), is thought to play a role.Aims: This study aimed to explore the difference in PAPP-A and IGF-1 levels between Early OnsetPreeclampsia (PEAD) and Late Onset Preeclampsia (PEAL) assuming that the role of PAPP-A andIGF-1 is more significant in the pathogenesis of PEAD than PEAL.Methods: This is an analytical observational study with a cross-partition comparative study design.Clinical data were obtained at Dr. M. Djamil Padang Hospital, while PAPP-A and IGF-1 levels weremeasured at the Biomedical Laboratory of the Faculty of Medicine, Andalas University. Samples aretested according to reagent procedures and analyzed by experts.Results: Average PAPP-A levels were 2.45+0.35 pg/mL in the early onset preeclampsy group and2.85+0.50 pg/mL in the late onset preeclampsy group. These two levels differed statisticallysignificantly (p=0.006). That means that low levels of PAPP-A are associated with and play a role inthe pathogenesis of early onset preeclampsy. Average IGF-1 levels were 4.66+0.91 pg/mL in the earlyonset preeclampsy group and 5.39+0.74 pg/mL in the late-onset preeclampsy group. These two levelsdiffered statistically significantly (p=0.010). That means that low levels of IGF-1 are associated withand play a role in the pathogenesis of early onset preeclampsy. PAPP-A levels were significantlypositively correlated with IGF-1 levels (p=0.000).Conclusion: PAPP-A levels are lower in PEAD than PEAL, as are IGF-1 levels. These findings confirmthe role of PAPP-A and IGF-1 in preeclampsia. Both of these hormones have potential as indicatorsand markers for the prediction and management of preeclampsy in early and late onset periods.

An exploratory study of clinical factors associated with IGF-1 and IGFBP-3 in preterm infants.

Despite advances in parenteral nutrition, postnatal growth failure in very low birthweight (VLBW) preterm infants is common and associated with chronic health problems. Insulin-like growth factor 1 (IGF-1) is positively associated with improved infant growth, but factors which promote IGF-1 levels in this population have not been clearly identified. The objective of this study was to explore early factors that influence IGF-1 in VLBW preterm infants. VLBW infants were enrolled into a prospective, randomized controlled nutrition trial (N = 87). Outcome measures included IGF-1 and IGFBP-3 levels measured at 35 weeks PMA. Linear regression analyses tested the relationships between candidate clinical predictors and levels of IGF-1 and IGFBP-3. Higher protein intake, longer duration of parenteral nutrition, and lower IGFBP-3 levels at 1 week of life were associated with lower IGF-1 levels at 35 weeks PMA. Neither early markers of insulin resistance nor degree of illness were associated with IGF-1 levels at 35 weeks PMA. Optimization of early nutrient intake, and attention to route of delivery, may have a lasting influence on IGF-1/IGFBP-3, and in turn, long-term health outcomes. In very low birthweight preterm infants, early protein intake, duration of parenteral nutrition, and insulin-like growth factor binding protein 3 (IGFBP-3) levels at 1 week of life are positively associated with insulin-like growth factor 1 (IGF-1) levels at 35 weeks postmenstrual age. Data from this study highlight the influence of early nutrition on components of the endocrine axis in preterm infants. Strategies aimed at early initiation of enteral nutrition, as well as optimizing composition of parenteral nutrition, may bolster hormones involved in promoting preterm infant growth.

There is currently no evidence that high serum leptin and low insulin-like growth factor-1 levels characterise fibromyalgia.

There is currently no evidence that high serum leptin and low insulin-like growth factor-1 levels characterise fibromyalgia.

Insulin-like growth factor 1 associated with altered immune responses in preterm infants and pigs

BackgroundPreterm infants show low blood levels of insulin-like growth factor 1 (IGF-1), known to be negatively correlated with Interleukin-6 (IL-6). We hypothesized that circulating IGF-1 is associated with systemic immune-markers following preterm birth and that exogenous IGF-1 supplementation modulates immune development in preterm pigs, used as model for preterm infants.MethodsPlasma levels of IGF-1 and 29 inflammatory markers were measured in very preterm infants (n = 221). In preterm pigs, systemic immune development, assessed by in vitro challenge, was compared between IGF-1 treated (2.25 mg/kg/day) and control animals.ResultsPreterm infants with lowest gestational age and birth weight showed the lowest IGF-1 levels, which were correlated not only with IL-6, but a range of immune-markers. IGF-1 supplementation to preterm pigs reduced plasma IL-10 and Interferon-γ (IFN-γ), IL-2 responses to challenge and reduced expression of genes related to Th1 polarization. In vitro addition of IGF-1 (100 ng/mL) further reduced the IL-2 and IFN-γ responses but increased IL-10 response.ConclusionsIn preterm infants, plasma IGF-1 correlated with several immune markers, while supplementing IGF-1 to preterm pigs tended to reduce Th1 immune responses. Future studies should document whether IGF-1 supplementation to preterm infants affects immune development and sensitivity to infection.ImpactSupplementation of insulin-like growth factor 1 (IGF-1) to preterm infants has been proposed to promote postnatal growth, but its impact on the developing immune system is largely unknown.In a cohort of very preterm infants, low gestational age and birth weight were the primary predictors of low plasma levels of IGF-1, which in turn were associated with plasma immune markers. Meanwhile, in immature preterm pigs, experimental supplementation of IGF-1 reduced Th1-related immune responses in early life.Supplementation of IGF-1 to preterm infants may affect the developing immune system, which needs consideration when evaluating overall impact on neonatal health.

Regulation of IGF1R by MicroRNA-15b Contributes to the Anticancer Effects of Calorie Restriction in a Murine C3-TAg Model of Triple-Negative Breast Cancer.

Calorie restriction (CR) inhibits triple-negative breast cancer (TNBC) progression in several preclinical models in association with decreased insulin-like growth factor 1 (IGF1) signaling. To investigate the impact of CR on microRNAs (miRs) that target the IGF1/IGF1R pathway, we used the spontaneous murine model of TNBC, C3(1)/SV40 T-antigen (C3-TAg). In C3-TAg mice, CR reduced body weight, IGF1 levels, and TNBC progression. We evaluated the tumoral expression of 10 miRs. CR increased the expression of miR-199a-3p, miR-199a-5p, miR-486, and miR-15b. However, only miR-15b expression correlated with tumorigenicity in the M28, M6, and M6C C3-TAg cell lines of TNBC progression. Overexpressing miR-15b reduced the proliferation of mouse (M6) and human (MDA-MB-231) cell lines. Serum restriction alone or in combination with low levels of recombinant IGF1 significantly upregulated miR-15b expression and reduced Igf1r in M6 cells. These effects were reversed by the pharmacological inhibition of IGFR with BMS754807. In silico analysis using miR web tools predicted that miR-15b targets genes associated with IGF1/mTOR pathways and the cell cycle. Our findings suggest that CR in association with reduced IGF1 levels could upregulate miR-15b to downregulate Igf1r and contribute to the anticancer effects of CR. Thus, miR-15b may be a therapeutic target for mimicking the beneficial effects of CR against TNBC.

Insulin-like growth factor 1 predicts decompensation and long-term prognosis in patients with compensated cirrhosis.

Insulin-like growth factor 1 (IGF-1), which is primarily produced in hepatocytes and is associated with liver functional reserve, plays a crucial role in the pathological condition of cirrhosis. This study aimed to investigate the usefulness of serum IGF-1 levels for predicting the long-term prognosis and decompensation development in patients with cirrhosis. We retrospectively evaluated 148 patients with cirrhosis and divided them into three groups according to baseline IGF-1 levels: low (L)-, intermediate (I)-, and high (H)-IGF-1 groups. The cumulative survival rates were compared among these groups in compensated and decompensated cirrhosis, respectively. Significant and independent factors associated with mortality and decompensation development were identified using Cox proportional hazards regression analysis. The median observation period was 57.1 (41.7-63.2) months. Thirty (20.3%) patients died of liver disease-related events and 21 (22.3%) patients with compensated cirrhosis developed decompensation. Multivariate analysis identified low serum IGF-1 levels as a significant and independent factor associated with mortality (all patients: hazard ratio [HR], 0.967; p = 0.004; patients with compensated cirrhosis: HR, 0.927; p = 0.002). The cumulative survival rates were significantly lower in the L-IGF-1 group than in the H-IGF-1 and I-IGF-1 groups (all patients: p < 0.001 and = 0.009; patients with compensated cirrhosis: p = 0.012 and 0.003, respectively). However, in decompensated cirrhosis, the cumulative survival rates demonstrated no significant differences among the three groups. The cumulative decompensation incidence rates were significantly higher in the L-IGF-1 group than in the H-IGF-1 and I-IGF-1 groups (p < 0.001 and = 0.009, respectively). Low serum IGF-1 levels were significantly and independently associated with decompensation development (HR, 0.939; p < 0.001). Low serum IGF-1 levels were significantly and independently associated with decompensation development and poor long-term prognosis in patients with compensated cirrhosis. Therefore, IGF-1 may be useful for predicting decompensation-related events and should be regularly monitored in the management of compensated phase.

Long-term opioid treatment and endocrine measures in chronic non-cancer pain patients.

The prevalence of chronic non-cancer pain (CNCP) has increased dramatically the past decades, which combined with indiscriminate use of prescribed opioids has become a public health problem. Endocrine dysfunction may be a complication of long-term opioid treatment (L-TOT), but the evidence is limited. This study aimed at investigating the associations between L-TOT and endocrine measures in CNCP patients. Cortisol (spot and after stimulation), thyrotropin (TSH), thyroxin (T4), insulin-like growth factor 1 (IGF-1), prolactin (PRL), 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone (DHEAS), sex hormone-binding globulin (SHBG), total testosterone (TT) and free testosterone (fT) were measured. Group comparisons were done between CNCP patients in L-TOT and controls as well as between patients on high- or low-dose morphine equivalents. Eighty-two CNCP patients (38 in L-TOT and 44 controls not receiving opioids) were included. Low TT (p = 0.004) and fT concentrations (p < 0.001), high SHBG (p = 0.042), low DEAS (p = 0.017) and low IGF-1 (p = 0.003) in men were found when comparing those in L-TOT to controls and high PRL (p = 0.018), low IGF-1 standard deviation score (SDS) (p = 0.006) along with a lesser, but normal cortisol response to stimulation (p = 0.016; p = 0.012) were found when comparing L-TOT to controls. Finally, a correlation between low IGF-1 levels and high opioid dose was observed (p < 0.001). Our study not only supports previous findings but even more interestingly disclosed new associations. We recommend future studies to investigate endocrine effects of opioids in larger, longitudinal studies. In the meanwhile, we recommend monitoring endocrine function in CNCP patients when prescribing L-TOT. This clinical study found associations between L-TOT, androgens, growth hormone and prolactin in patients with CNCP compared to controls. The results support previous studies as well as add new knowledge to the field, including an association between high opioid dose and low growth hormone levels. Compared to existing research this study has strict inclusion/exclusion criteria, a fixed time period for blood sample collection, and adjustments for potential confounders, which has not been done before.

Compensatory Growth Is Accompanied by Changes in Insulin-Like Growth Factor 1 but Not Markers of Cellular Aging in a Long-Lived Seabird.

AbstractDeveloping organisms often plastically modify growth in response to environmental circumstances, which may be adaptive but is expected to entail long-term costs. However, the mechanisms that mediate these growth adjustments and any associated costs are less well understood. In vertebrates, one mechanism that may be important in this context is the highly conserved signaling factor insulin-like growth factor 1 (IGF-1), which is frequently positively related to postnatal growth and negatively related to longevity. To test this idea, we exposed captive Franklin's gulls (Leucophaeus pipixcan) to a physiologically relevant nutritional stressor by restricting food availability during postnatal development and examined the effects on growth, IGF-1, and two potential biomarkers of cellular and organismal aging (oxidative stress and telomeres). During food restriction, experimental chicks gained body mass more slowly and had lower IGF-1 levels than controls. Following food restriction, experimental chicks underwent compensatory growth, which was accompanied by an increase in IGF-1 levels. Interestingly, however, there were no significant effects of the experimental treatment or of variation in IGF-1 levels on oxidative stress or telomeres. These findings suggest that IGF-1 is responsive to changes in resource availability but is not associated with increased markers of cellular aging during development in this relatively long-lived species.

Abstract #1404780: Implementing a Screening Protocol for Endocrinopathies in Patients with Secondary Hemochromatosis due to Sickle Cell Anemia

Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy characterized by hemolytic anemia, intermittent small vessel occlusion, and organ dysfunction. Red blood cell transfusions are a therapeutic mainstay in SCD, which can lead to iron overload and endocrine disease. However, due to diagnostic difficulties and lack of data, there is not a wide consensus in approach. This has led to many practitioners screening for endocrinopathies only once patients are symptomatic. In this study, we implemented a standardized protocol for screening of iron overload and certain endocrinopathies in a single-study cohort of patients with SCD to assess viability in real-world practice and to detect disease prior to significant burden. We studied 19 patients diagnosed with SCD or sickle-cell trait (SCT) at a single institution. Patients had serum testing for ferritin and a metabolic panel at usual clinical visits. Iron overload was diagnosed with serum ferritin levels of at least 1000 ng/mL. If iron overload was detected, additional testing for 25-Hydroxyvitamin D (OHD), Thyroid Stimulating Hormone (TSH), Parathyroid Hormone (PTH), and Insulin-Like Growth Factor-1 (IGF-1) was obtained. Nineteen patients (12 men and 7 women) were included with a mean age of 32 years old. Twelve patients and seven patients were diagnosed with SCD and SCT, respectively. The average ferritin levels of SCD and SCT patients were 4874 and 270 ng/mL, respectively. Nine patients had ferritin levels greater than 1000 ng/mL, eight of which were diagnosed with SCD, one was diagnosed with SCT, and seven of which were prescribed iron chelation therapy. Of these nine patients, the average random glucose was 103 ng/mL. The average serum calcium corrected for albumin levels was 9.3 ng/mL. Seven of eight patients were found to have low 25-OHD levels with two of four patients showing elevated serum PTH. One of six patients had abnormal thyroid testing, with an elevated TSH and normal free thyroxine. Three of five patients showed abnormal IGF-1 testing, with low IGF-1 levels and low IGF-1 binding protein levels. This study successfully implemented a protocol for screening for endocrinopathies in a cohort of SCD and SCT patients at a single institution. We showed evidence that many patients with iron overload demonstrated abnormalities in 25-OHD, PTH, TSH, and IGF-1. The few studies that have been done to analyze this topic have shown findings of growth failure, osteopenia, hypogonadism, hypothyroidism, and glucose intolerance in SCD and SCT patients. This study did not explore bone disease or sex hormone function due to difficulty in performing these tests and obtaining insurance payor coverage. An additional limitation includes low sample size. However, this study replicates real-world care for these patients due to these barriers, making these methods easily translatable to other clinical settings. Our findings suggest implementation of a standardized protocol for iron overload and endocrinopathy screening in SCD and SCT patients is not only viable but could also detect disease before symptom onset when intervention is more effective.

Association of Body Mass Index with Insulin-like Growth Factor-1 Levels among 3227 Chinese Children Aged 2–18 Years

Insulin-like growth factor-1 (IGF-1) levels are affected by nutritional status, yet there is limited research exploring the association between body mass index (BMI) and IGF-1 levels among children. This cross-sectional study included 3227 children aged 2-18 years without specific diseases, whose height, weight, and pubertal stages were measured and assessed by pediatricians. BMI standard deviation scores (BMISDS) were used to categorize children as underweight (BMISDS < -2); normal-weight (-2 ≤ BMISDS ≤ 1); overweight (1 < BMISDS ≤ 2); and obese (BMISDS > 2). Children were divided into low-level (<-0.67 SD) and nonlow-level (≥-0.67 SD) groups based on IGF-1 standard deviation scores (IGF-1SDS). The association between IGF-1 and BMI as categorical and continuous variables was explored by Binary logistic regression, the restrictive cubic spline model, and the generalized additive model. Models were adjusted by height and pubertal development. Recursive algorithm and multivariate piecewise linear regression were further utilized to assess the threshold of the smooth curve. IGF-1 levels varied by BMI categories, with the highest levels observed in the overweight group. The proportion of low IGF-1 levels in underweight, normal-weight, overweight, and obese groups was 32.1%, 14.2%, 8.4%, and 6.5%, respectively. The risk odds of low IGF-1 levels in underweight children were 2.86-, 2.20-, and 2.25-fold higher than in children with normal weight before adjustment, after adjustment for height, and after adjustment for height and puberty, respectively. When analyzing the association between BMI and low IGF-1 levels, dose-response analysis demonstrated an inverted J-shaped relationship between BMISDS and low IGF-1 levels. Lower or higher BMISDS increased the odds of low IGF-1 levels, and significance was retained in underweight children but not in obese children. When BMI and IGF-1 levels were used as continuous variables, the relationship between the BMISDS and IGF-1SDS followed a nonlinear inverted U shape. IGF-1SDS increased with the increase of BMISDS (β = 0.174, 95% CI: 0.141 to 0.208, p < 0.01) when BMISDS was less than 1.71 standard deviation (SD) and decreased with the increase of BMISDS (β = -0.358, 95% CI: -0.474 to -0.241, p < 0.01) when BMISDS was greater than 1.71 SD. The relationship between BMI and IGF-1 levels was found to depend on the type of variable, and extremely low or high BMI values could result in a tendency toward low IGF-1 levels, emphasizing the importance of maintaining a normal BMI range for normal IGF-1 levels.

Laron syndrome in South Indian children – A descriptive study

Objectives: The objectives of this study were to describe the clinical and biochemical features of five children with Laron syndrome (LS) from South India. Material and Methods: This is a prospective descriptive case series of five children with clinical and biochemical features of LS managed over 5 years. Results: Five children (two girls and three boys) with LS with the mean age group of 5.9 ± 1.7 years and the mean age at diagnosis of 2.7 ± 0.8 years are described. All children were born out of consanguinity and all had typical phenotypic facies of LS. The mean Z-scores of height, weight, and body mass index on follow-up for the cohort were −7.0 ± 1.6, −5.9 ± 2.8, and −0.1 ± 0.7, respectively, and they were within ± 2 SD of the mean for children in LS chart. The median basal growth hormone level for age was 13 ng/mL and the median growth hormone levels at 30 min, 60 min, 90 min, and 120 min post-stimulation test were 35 ng/mL, 35 ng/mL, 44 ng/mL, and 50 ng/mL, respectively. All of them had insulin-like growth factor-1 (IGF-1) levels less than the 3rd percentile and no increment during the IGF-1 generation test. The prevalence of micropenis was 100% and one child had symptomatic hypoglycemic episodes. Genetic analysis was performed in two boys and both harbored variants in the growth hormone receptor gene. Conclusion: LS should be suspected in children with clinical features of growth hormone deficiency along with elevated growth hormone levels and low IGF-1 levels with no increment of IGF-1 in the IGF-1 generation test.

Inflammation induces stunting by lowering bone mass via GH/IGF-1 inhibition in very preterm infants.

Sustained systemic inflammatory response (SIR) was associated with poor postnatal growth in very preterm infants (VPI). We hypothesize that VPI with sustained SIR will exhibit linear growth retardation related to lower bone mass accrual mediated by GH/IGF-1 axis inhibition at term corrected age (CA). C-reactive protein (CRP), procalcitonin (PCT), growth hormone (GH), insulin-like growth factor 1 (IGF-1), calcium, phosphorus, alkaline phosphatase, anthropometric, nutritional, neonatal and maternal data were collected prospectively in 23 infants <32 weeks gestational age. Body composition using dual-energy X-ray absorptiometry was performed at term CA. Analysis was undertaken with multiple linear regression models. At term CA 11 infants with sustained SIR compared with 12 infants without sustained SIR present significantly lower IGF-1, length z-score (LZS), bone mineral content (BMC) and lean mass (LM), and higher GH and fat mass (FM). LZS was associated significantly with PCT, BMC with IGF-1, FM and LM with CRP, GH with bronchopulmonary dysplasia and CRP, and IGF-1 with invasive mechanical ventilation, CRP and PCT. In addition to the known effect on linear growth failure, sustained SIR induces lower bone mass accrual related to higher GH and lower IGF-1 levels in VPI. Very preterm infants (VPI) with sustained systemic inflammatory response (SIR) compared with VPI without SIR present stunting, lower bone mass, higher GH and lower IGF-1 levels at term corrected age. SIR may help to explain the influence of non-nutritional factors on growth and body composition in VPI. SIR induces postnatal stunting related to lower bone mass accrual via GH/IGF-1 axis inhibition in VPI. VPI with SIR need special attention to minimize inflammatory stress, which could result in improved postnatal growth. Research on inflammatory-endocrine interactions involved in the pathophysiology of postnatal stunting is needed as a basis for new interventional approaches.

Association of umbilical cord insulin-like growth factor 1 levels with severe retinopathy in extremely preterm infants.

The association between umbilical cord blood insulin-like growth factor 1 (IGF-1) levels and retinopathy of prematurity (ROP) remains unclear. This study aimed to investigate whether umbilical cord blood IGF-1 levels can predict the development of severe ROP in extremely preterm infants. This hospital-based retrospective cohort study included infants born at <37 weeks gestational age (GA) between 2019 and 2021 and then classified them into the two GA groups: extremely preterm, <28 weeks and preterm infants, 28-36 weeks. Extremely preterm infants were further subclassified into two groups according to the laser treatment as follows: the severe ROP (ROP-Tx) and ROP (No ROP-Tx) groups. Median umbilical cord blood IGF-1 values were compared between the groups. Perinatal risk factors were identified by univariate and multivariate analyses. Finally, umbilical cord IGF-1 cut-off values requiring ROP treatment with laser were determined by receiver operating characteristic (ROC) curve analyses. A total of 205 infants were enrolled, with 32 being extremely preterm (ROP-Tx: n=11; No ROP-Tx: n=21) and 173 being preterm. IGF-1 levels were significantly lower in extremely preterm (13.5ng/mL) than preterm infants (36ng/mL, p<0.001). In extremely preterm infants, IGF-1 levels were significantly lower in the ROP-Tx group than the No ROP-Tx group (10 vs. 19ng/mL, respectively, p=0.024). Only GA, umbilical cord blood IGF-1 levels, birth head circumference, and birth chest circumference were identified as risk factors by univariate analysis (p<0.05). Multivariate analysis showed that only umbilical cord blood IGF-1 was an independent risk factor (odds ratio: 1.26, p=0.021). ROC curves revealed an IGF-1 cut-off value of 14ng/mL. The need of laser treatment for ROP was found to be associated with low umbilical cord blood IGF-1 levels in extremely preterm infants. Umbilical cord blood IGF-1 can be used as a biomarker for the risk of developing severe ROP.