Serum IGF-I Research Articles

Effect of dietary supplementation of yeast culture Saccharomyces cerevisiae in lactating female goats

This study was designed to investigate the effects of adding a novel yeast culture, Saccharomyces cerevisiae refermented sorghum distiller's dried grains with solubles (SSDDGS), to the diets of lactating female goats on lactation performance and lamb growth performance. We divided 10 lactating Dazu black goats of similar age, weight, and offspring into two groups: one fed a pelleted diet with 50 g/day SSDDGS (ET), and the other without SSDDGS as a control (EC) for 7 weeks. We monitor the weight changes of each goat and collect blood and milk samples from experimental ewes at specific times for hormone and milk composition determination. We use ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to detect metabolites in the serum of lactating ewes. Our results showed that SSDDGS supplementation significantly reduced female goats' average daily weight loss during weeks 2–4 of lactation and increased serum IGF-1 and prolactin levels at week 4 (p < 0.05). SSDDGS supplementation in early lactation significantly increased milk protein, lactose, and ash content (p < 0.05). UPLC-MS/MS analysis showed that SSDDGS changed the levels of 58 metabolites in the serum of lactating goats. These metabolites were mainly involved in the sohingolipid signaling pathway, and cysteine, methionine, and sphingolipid metabolism. In summary, Yeast culture SSDDGS reduced weight loss, enhanced milk quality, and modified metabolic profiles in early lactation goats, providing insight into the potential regulatory role and mechanism of yeast culture in lactation female goats.

The association between metabolite profiles and impaired bone microstructure in adult growth hormone deficient rats

BackgroundAdult growth hormone deficiency (AGHD) is associated with an increased risk of fractures and impaired bone microstructure. Understanding the metabolic changes accompanying bone deterioration in AGHD might provide insights into mechanisms behind molecular changes and develop new biomarkers or nutritional strategies for bone destruction. Our study aimed to investigate the association between altered metabolite patterns and impaired bone microstructure in adult rats with growth hormone deficiency.MethodsThirty seven-week-aged adult Lewis dwarf homozygous (dw/dw) rats (five females and five males), and adult Lewis dwarf heterozygous (dw/ +) rats (five females and five males) rats were compared. Micro-computed tomography (Micro-CT) was used to examine the bone's microstructure. Hematoxylin and eosin (H&E) staining were used to quantify the histological characteristics. Liquid chromatography-mass spectrometry untargeted serum metabolomic analysis was applied in the study. ELISA was used to measure serum bone turnover markers and IGF-1 levels.ResultsAdult dw/dw rats exhibited great reductions in trabecular volume bone density (Tb.vBMD), bone volume/total volume (BV/TV), and cortical thickness (Ct. Th) compared with adult dw/ + rats (all p values < 0.05), indicating significant impairment in bone microstructure. The serum metabolite profiles revealed substantial differences between the dw/dw rats and dw/ + rats. A total of 134 differential metabolites in positive ion mode and 49 differential metabolites in negative mode were identified. Five metabolites, including Lysophosphatidylcholine(LPC) 20:3, LPC22:6, LPC22:4, cortisol and histamine levels were upregulated in dw/dw rats. The steroid hormone biosynthesis and bile secretion pathways were the main perturbed metabolic pathways. There were significant associations between differential metabolites and the impaired bone microstructure parameters, indicating that the selected metabolites might serve as potential biomarkers for deteriorated bone microstructure in AGHD.ConclusionAdult dw/dw rats exhibit impaired bone microstructure and distinct serum metabolic profiles, and the altered metabolites were significantly associated with bone microstructure destruction. This provides a new insight into understanding the mechanism of bone deterioration in AGHD patients from a metabolic perspective.

Preoperative nutritional status and serum insulin-like growth factor of children with cyanotic and acyanotic congenital heart disease

BackgroundMalnutrition is common among children with congenital heart disease (CHD). We compared the anthropometric indices, serum insulin-like growth factor (IGF), and IGF acid-labile subunit (IGFALS) of children with cyanotic and acyanotic CHD before corrective surgery. MethodsThis 82-patient case-control study included 1- to 24-month-old CHD patients referred for corrective surgery. (41 with tetralogy of Fallot [TOF] and 41 with ventricular septal defect [VSD] or atrial septal defect [ASD]). Anthropometric indices represented as Z-scores were used to determine nutritional status. Serum IGF-1 and IGFALS levels were measured. ResultsThe median [quartile] age of the acyanotic group was 8 [7,11] months which was lower than the cyanotic group (11 [8,14.5] months). The prevalence of underweight (weight for age Z [WAZ] < −2), wasting (weight for length Z [WLZ] < −2), and thinness (body mass index Z [BMIZ] < −2) was significantly higher in children with acyanotic than cyanotic children with. WAZ, WLZ, and BMIZ were significantly lower in acyanotic children than cyanotic children with CHD (-2.5±1.2 vs -1.0±1.2, p<0.001 for WAZ, -2.5± 1.5 vs -0.8±1.4, p<0.001 for WLZ, and -2.5±1.5 vs -0.8±1.4, p<0.001 for BMIZ), but length for age Z was not different between the two groups (-1.2±1.0 vs -0.8±1.1, p=0.31). A comparison of preoperative serum albumin, IGF-1, and IGFALS showed no differences. ConclusionsIn CHD children without corrective surgery, moderate to severe underweight and wasting were more common in acyanotic CHD (VSD and ASD) than in cyanotic CHD (TOF), but the higher prevalence of malnutrition was not associated with lower IGF-1 and IGFALS levels.

Effects of saccharomyces cerevisiae fermentation products on growth performance, fecal short chain fatty acids, and microbiota of pre-weaning calves.

This research aims to explore the effects of incorporating saccharomyces cerevisiae fermentation products (SCFP) on growth performance, nutrient digestibility, antioxidant capacity, fecal SCFAs, and microbial composition of pre-weaning calves. Twenty Holstein calves, 10 days old and weighing an average of 48.63±0.91 kg, were randomly assigned to either the control group (CON) or the SCFP group, with 10 calves in each group. The CON group received only a basal diet, while the SCFP group received the starter diet supplemented with 5 g/head/d of SCFP products (NutriTek, Diamond V Cedar Rapids, IA 52404, United States). The pre-trial period lasted for 5 days, followed by a main experimental period of 45 days. The SCFP group had significantly higher final weight, ADG, and FE compared to the control group (p < 0.05). Moreover, the SCFP group exhibited increased apparent digestibility of DM, CP, EE, ADF, Ca, and P (p < 0.05). Additionally, supplementation with SCFP led to elevated content of GH, IGF-1, and GLP-1 in serum. The inclusion of SCFP also raised serum CAT content and reduced serum MDA content in pre-weaning calves. Furthermore, SCFP supplementation influenced the composition of intestinal microflora by decreasing Actinobacteriota abundance and increasing the abundance of Ruminococcus, Lachnospiraceae_AC2044_group, Parabacteroides, and Butyricimonas. The addition of SCFP has a positive impact on the growth performance, nutrient digestibility, antioxidant capacity, and intestinal microflora composition of pre-weaning calves.

Chronic psychosocial stress affects insulin-like growth factor 1 and its receptors in mouse ovaries.

Context Chronic psychosocial stress negatively affects folliculogenesis and oogenesis. Intraovarian mechanisms mediating these effects are poorly understood. Aims This work aimed to find out how chronic psychosocial stress affects ovarian IGF1 and its receptor (IGF1R), as well as Igf1 and Igf1r gene expression in cumulus-oocyte complexes (COCs). It also aimed to address possible protective effects of gonadotropin stimulation on IGF1 ovarian signalling. Methods Female CD1 mice experienced chronic psychosocial stress of 11-day isolation followed by overcrowding for 10days. To verify the model, blood corticosterone levels and the quality of oocytes were evaluated in stressed females. The levels of IGF1/IGF1R, blood IGF1 concentration, and expression of Igf1 /Igf1r in the ovaries were compared in stressed and unstressed females. Key results Psychosocial stress caused an elevation of corticosterone level, which was alleviated by gonadotropin treatment. The stressed mice showed a decreased IGF1 level in the ovaries and a decreased expression of Igf1 and Igf1r in COCs. In the unstressed females, gonadotropin injection decreased the expression of Igf1 and Igf1r ; in the stressed females, the same treatment increased Igf1r expression. Neither stress nor ovarian stimulation with gonadotropins affected the serum IGF1 level. Conclusions Psychosocial stress suppresses IGF1 signalling in the ovaries. Gonadotropin treatment modulates these effects differently in stressed and unstressed animals. Implications The results may have translational value for human reproduction. Ovarian IGF1 can be considered a candidate for further improvement of IVF results in women under conditions of chronic stress.

ANGIOGENIC FACTORS AS PREDICTORS OF SURVIVAL IN PATIENTS WITH BONE SARCOMAS

Introduction. Primary bone sarcomas are relatively rare neoplasms. They occur predominantly in adolescents and young adults, are characterized by an aggressive clinical course and a high metastatic potential, have a poor prognosis. In this regard, the problem of stratifying the risk of metastasis and death in order to select the optimal treatment tactics always remains relevant. The study of such markers as endostatin, vascular endothelial growth factor (VEGF), insulin-like growth factors IGF-1, IGF-2 as potentially informative predictors of survival in patients with bone sarcomas is pathogenetically determined by their involvement in the processes of tumor growth and metastasis. Aim – to analyze the relationship between pre-treatment serum levels of endostatin, VEGF, IGF-1 and IGF-2 with overall survival rates in patients with bone sarcomas. Material and methods. An analysis of overall survival rates was carried out in 134 patients with malignant bone tumors aged from 1 to 73 years (Me=27.0 years; Q1–Q3: 18.0 – 43.0 years), among them 87 men (64.9%) and 47 women (35.1%). All patients comprised 4 groups: osteosarcoma (n=58), undifferentiated pleomorphic sarcoma (n=5), Ewing sarcoma (n=29), chondrosarcoma (n=42). In all of them, before the start of specific antitumor treatment, the levels of endostatin, VEGF, IGF-1, and IGF-2 in the blood serum were determined using enzyme immunoassay. The follow-up period ranged from 1 to 229 months (Me=23.0 months; Q1–Q3: 10.0–121.0 months). To analyze overall survival, life tables and Kaplan–Meier curves were constructed. The effect of the studied serum markers on survival rates was assessed using the logrank test and Cox proportional hazards regression model. Results. During observation, death occurred in 51 patients (38.1%). In the group of deceased patients, serum levels of endostatin and IGF-2 were statistically significantly increased compared to the group of surviving patients (p 0.001 and p=0.011, respectively). Kaplan-Meier survival analysis using the logrank test revealed statistically significant differences in overall survival between the four groups of patients with different serum levels of endostatin, IGF-1 and IGF-2. The Cox regression method established the prognostic significance of endostatin as a predictor of overall survival (HR=1.012; p=0.013). Conclusion. Endostatin, IGF-1, IGF-2 can serve as predictors of overall survival of patients with bone sarcomas.

Effect of Bypass Fat on Genital Status and Blood Biochemical Profiles in Pubertal Swamp Buffalo Heifers and Puerperal Swamp Buffalo Cows

Background: The interaction between nutrition and reproduction has long been known to have important implications for the reproductive performance in animal.The present study highlights the effect of by-pass fat supplementation on genital changes and blood biochemical profile in pubertal swamp buffalo heifers and puerperal swamp buffalo cows. Methods: 24 heifers of 2-2.5 years of age and 24 puerperal cows on the day of parturition, irrespective of parity were used as experimental animal. The analytical method was based on the treatment protocols of 3 groups in both heifers and cows (n=8 in each group) viz., treated with oral bypass fat alone (I), oral bypass fat, mineral mixtures and injectable phosphorus (II) and control (III) respectively. Genital status, metabolic hormone (leptin, Ghrelin and IGF-1), reproductive hormone (estrogen and progesterone) and mineral constituents (calcium, phosphorus, zinc and copper) were analyzed on day 0, day 15 and day 30 in heifers and day 15, day 30 and day 45 in cows respectively. Result: Feeding of bypass fat alone or bypass fat fortified with minerals and injectable phosphorus was not found to induce significant genital changes in heifers and cows. The serum leptin and IGF-1 levels were increased significantly (p less than 0.05) in heifers at day 30 in Group I and II. However, a significant rise (p less than 0.05) of leptin was recorded at day 45 in group I and II cows. IG1-1 level was recorded increased significantly only in cows treated with fortified bypass fat (Group II). With the progression of treatment the serum phosphorus level was increased significantly (p less than 0.05) in Group I and II cows. Serum estrogen levels were increased in both heifers and cows with progression of treatment in both Group I and II. However, serum progesterone levels were increased significantly only in heifers of Group I and II with progression of treatment.

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.

Improvement of Bone Metabolism in Prepubertal Girls with Turner Syndrome Following Long-term Pegylated Growth Hormone Treatment.

The study aims to assess the improvement in bone metabolism in prepubertal girls with Turner Syndrome (TS) after long-term polyethylene glycol recombinant human Growth Hormone (PEG-rhGH) treatment. A 12-month longitudinal prospective study was conducted with 28 prepubertal girls diagnosed with TS. Participants were divided into two groups: 18 received PEG-rhGH therapy (0.1-0.25 mg/kg/week) and 10 did not. Anthropometric measurements, bone turnover markers (BTMs), and serum levels of IGF-1, calcium, and phosphate were collected at baseline and after 12 months. BTMs included bone alkaline phosphatase (BAP), Type I collagen propeptide (CICP), Type I collagen telopeptide (CTX), and fibroblast growth factor 23 (FGF23). After 12 months of PEG-rhGH therapy, the treatment group showed significant increases in growth velocity (GV) and height standard deviation scores (HtSDS). Serum IGF-1 levels increased rapidly within one month and remained elevated. BTMs indicated enhanced bone formation, significantly increasing BAP and CICP, while CTX levels remained low. FGF23 levels initially rose slightly but declined below baseline by 12 months. Elevated blood phosphate levels were observed. PEG-rhGH therapy in children with TS significantly improves linear growth and enhances bone formation markers, benefiting bone metabolism.

Predictive value of IGF-1/IGFBP-3 ratio for thyroid nodules in type 2 diabetic mellitus.

To explore the predictive value of the IGF-1/IGFBP-3 ratio for the presence of thyroid nodules in patients with type 2 diabetes mellitus (T2DM). This observational study prospectively enrolled patients with T2DM at the Second Hospital of Jilin University between May 2021 and January 2022. Thyroid nodule (TN) status was determined by ultrasonography. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value of the serum IGF-1/IGFBP-3 molar ratio for TNs. Multivariable logistic regression analysis was conducted to identify risk factors for thyroid nodules in patients with T2DM. A total of 122 patients (mean age ± standard deviation: 52.57 ± 11.71 years; 74 males) were enrolled. 37.7% (n=46) of patients did not have TNs, while 62.3% (n=76) had TNs. The duration of diabetes, age, and HDL-C level were significantly higher in the T2DM group with TNs compared to the group without TNs (all P < 0.05). The area under the ROC curve (AUC) for the combination of IGF-1, IGFBP-3, and the serum IGF-1/IGFBP-3 molar ratio in predicting TNs in T2DM patients was 0.619 (P < 0.001). Additionally, multivariable logistic regression analysis revealed that the duration of diabetes, age, fasting plasma glucose (FPG), fasting insulin (FINS), thyroid-stimulating hormone (TSH), IGF-1, and IGFBP-3 levels were independent risk factors for thyroid nodules, while the serum IGF-1/IGFBP-3 molar ratio level was an independent protective factor for thyroid nodules in patients with T2DM (all P < 0.05). The combination of IGF-1, IGFBP-3, and the serum IGF-1/IGFBP-3 molar ratio may have a better predictive value for TNs in T2DM patients than using any single marker alone. The duration of diabetes, age, FPG, FINS, TSH, IGF-1, IGFBP-3, and the serum IGF-1/IGFBP-3 molar ratio levels were independently associated with thyroid nodules in patients with T2DM.

7148 Fake Fingerstick: Artifactual Hypoglycemia in a Hospitalized patient with Systemic Sclerosis

Abstract Disclosure: S. Shteyman: None. F. Mirza: None. Introduction: Artifactual hypoglycemia is a problem in hospitalized patients. It often leads to unnecessary use of resources and creates anxiety for the patient and medical team. We describe a case of a 60-year-old female with history of systemic sclerosis (Raynaud, telangiectasias, esophageal dysmotility, interstitial lung disease, pulmonary hypertension), rheumatoid arthritis, autoimmune hepatitis and hypothyroidism who initially presented to the hospital emergency department with bilateral lower extremity radiculopathy, and new onset urine incontinence. She underwent spine surgery initially, followed by emergent left upper extremity thrombectomy two days later. Postoperatively, she was noted to have fingerstick glucose of 34 mg/dL. Dextrose and juice were given, and endocrinology service was consulted. The patient was monitored with 2 hourly fingerstick glucose and was noted to have frequent hypoglycemia on fingerstick monitoring. Serum glucose in AM labs was consistently within normal limits. Patient denied both adrenergic and neuroglycopenic symptoms during periods of “hypoglycemia”. She was asked to fast till fingerstick glucose was noted to be at 43 mg/dl, when blood was drawn for serum glucose, insulin, proinsulin, C-peptide, B-hydroxybutyric acid, IGF-2, insulin AB, and sulfonylurea panel, prior to giving her any dextrose. She was asymptomatic at the time. All labs were within normal limits, with serum glucose at 119 mg/dL. At that point, artifactual hypoglycemia was suspected. Serum glucose was checked twice again when fingerstick glucose was noted to be &amp;lt;45mg/dL, and corresponding serum glucose was noted to be normal at both times (&amp;gt;100 mg/dL). Decision of artifactual hypoglycemia was made and fingerstick glucose monitoring was discontinued in this non-diabetic patient, with recommendation to check serum glucose only if symptoms of hypoglycemia occur, as fingerstick glucose values were not reliable. Fasting serum glucose continued to be normal for the remainder of the hospitalization. Discussion: There have been a handful cases of artifactual hypoglycemia reported in patients with CREST, systemic sclerosis, and Raynaud’s disease. It is thought to be due to abnormal small vasculature causing delayed transit of blood through capillaries, and increased uptake of glucose into the interstitial tissue. Some recommend using earlobe sticks as a replacement for fingerstick glucose monitoring in these patients. Future research can explore if continuous glucose monitoring can be used reliably in these patients. Presentation: 6/1/2024

6459 A Novel Long-Acting GH Receptor Antagonist Optimizing Therapeutic Efficacy and Duration

Abstract Disclosure: C. Ku: None. C. Kang: None. J. Oh: None. E. Wang: None. H. Song: None. K. Park: None. B. Kim: None. K. Kim: None. S. You: None. S. Park: None. E. Lee: None. Background: Forty to sixty percent of acromegalic patients undergo medical treatment, utilizing somatostatin analogues, dopamine agonists, and GH receptor (GHR) antagonists. The GHR antagonist, pegvisomant exhibits the most robust efficacy in reducing IGF-1 levels in acromegalic patients. However, pegvisomant faces several clinical limitations, such as poor compliance due to the necessity of daily injections. This study aimed to develop a novel, long-acting fusion GHR antagonist with optimized therapeutic efficacy and duration. Method: Twelve mutant proteins with alterations in the C-terminal and N-terminal regions of GHR were generated to confirm the GHR binding affinity and inhibitory potency compared with pegvisomant, which was evaluated with STAT5b luciferase reporter assay. Several carriers were engineered into selected mutant GHRs to increase the therapeutic duration. For in vivo experiments, single or repetitive injection of GHR antagonists were applied to acromegalic mouse model (somatotroph specific Aip knock out (sAIPKO) mice). Pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in New Zealand White (NZW) rabbits. Result: Four out of the 12 GHR mutants exhibited higher affinity and stronger inhibitory potency toward human GHR when compared to pegvisomant. Specifically, three GHR mutants significantly reduced serum IGF-1 levels in sAIPKO mice following daily injections of 20 mg/kg for 7 days (52.3±6.0 to 5.9±1.3, 50.3±3.5 to 32.3±2.3, and 49.8±3.7 to 13.9±4.3 ng/mL; all p &amp;lt; 0.05). Among them, S4020N exhibited the lowest EC50 value for GHR binding affinity in in vitro analysis containing human GHR (0.594 nM) and mouse GHR (0.891 nM). Following fusion with each long-acting carrier, S4020N with the Fc carrier protein (ALT-B5) demonstrated the highest binding affinity and the strongest inhibitory potency toward human GHR, surpassing pegvisomant by 14 and 25 times, respectively. Administration of ALT-B5 (80 mg/kg) and pegvisomant (24 mg/kg) at a 3-day interval revealed the superior efficacy of ALT-B5 over pegvisomant (1879±219.4 vs. 3800±355.9 ng*hr/mL IGF-1 AUC for 5 days in ALT-B5 and pegvisomant, respectively; p &amp;lt; 0.01). In PK/PD studies, ALT-B5 was administered at doses of 3 mg/kg and 10 mg/kg in NZW rabbits, and PK/PD parameters were compared with the same molar concentration of pegvisomant. ALT-B5 exhibited the longest therapeutic duration and the highest efficacy compared to pegvisomant. Conclusion: ALT-B5 exhibited the longest duration and highest effectiveness in lowering IGF-1 levels. ALT-B5 emerges as a potential novel therapeutic option for acromegaly. Presentation: 6/1/2024

7673 Genetic Analysis and Clinical Characterization of Patients with Congenital Hypopituitarism Due to Gene Defects

Abstract Disclosure: T.M. Sasson: None. I.J. Arnhold: None. B.B. Mendonca: None. L.R. Carvalho: None. Introduction: Congenital hypopituitarism is characterized by the deficiency of one or more hormones secreted by the anterior pituitary gland. The genetics of this pathology is complex, and the molecular diagnosis is established in approximately 13% of cases. Objectives: The aim of the present study is to characterize the phenotype harboring pathogenic variants causing congenital hypopituitarism. Methods: Among 393 subjects with congenital hypopituitarism followed up at a tertiary health center, 57 subjects (14,5%) were selected due to a confirmed molecular diagnosis by exome in 9 subjects or by gene panel or Sanger sequencing in 48 subjects. This was a retrospective study where data from medical records, clinical, laboratory and radiological characteristics were analyzed. Results: The most frequent variants identified by sequencing analyzes were in the following genes: PROP1 (29.8%), GH1 (22.8%), GHRHR (15.7%), followed by GLI2, OTX2, HESX1, POU1F1, TGIF1, GHRS, CDH2, SATB1, SOX3 e LZTR1. Consanguinity was reported in 50% of cases, and there was the presence of familial cases of short stature in 60%. The average age at the start of follow-up was 11.1 years (11 SD), 40% of them were male and 52.3% had physical stigmata typical of GH deficiency. Regarding hormonal deficiencies, 27 (47%) had isolated Growth Hormone Deficiency (DGHI) and the others, multiple deficiencies. MRI study of the pituitary gland showed some alteration in 66%, 54% of whom had adenohypophysis hypoplasia and 31% had an ectopic or non-visualized neurohypophysis. From 29 patients with IGF-1 levels available, 28 were below the reference range for sex and age. The serum GH peak after the stimulus test was on average 1.28 ng/mL (1.4SD), of these, only 4 cases had GH peak between 3.3 and 5.0 ng/mL and 1 patient with low IGF-1 and an ectopic neurohypophysis had GH peak of 6.0 ng/mL in a glucagon test. Regarding growth, the initial height in z-score was -4.8 and the average growth at the end of the first year of treatment was 10.7cm, with the average height after this period of Z-3.35. The average of final delta target height (final height Z-score minus the target height Z-score) of patients who underwent hormonal treatment was -0,53 (good response = delta &amp;lt;-1.5). Conclusion: In subjects with congenital hypopituitarism and an established molecular diagnosis, the most frequently affected genes were PROP1 and GH1, the great majority presented a stimulated GH peak &amp;lt; 3.3 ng/mL (only one patient had GH &amp;gt; 5), low basal serum IGF-1 and good increase in growth speed at the end of the first year of treatment with recovery of final height at the end of GH therapy. Presentation: 6/3/2024

6509 IGF-1 receptor and insulin receptor in LepRb neurons coordinates body growth, reproduction, and metabolism

Abstract Disclosure: M. Wang: None. J.W. Hill: None. Growth and reproduction are tightly linked. Growth hormone (GH) deficiency results in a profound suppression of postnatal growth accompanied by severely delayed puberty and reproductive senescence, while GH excess is correlated with the reverse. The specific mechanism underlying this delay is undefined. Although leptin receptor (LepRb)-expressing neurons are known to link body growth and reproduction, the role of insulin-like growth factor 1 receptor (IGF1R) signaling in LepRb neuron function is unknown. Previous studies have shown that IGF-1 and insulin can bind to each other’s receptor, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we created mice lacking IGF1R exclusively in LepRb neurons (IGF1RLepRb mice) and mice simultaneously lacking IGF1R and IR in LepRb neurons (IGF1R/IRLepRb mice) to test if IGF1R and insulin receptor (IR) cooperatively regulate metabolic and reproductive functions. IGF1RLepRb and IGF1R/IRLepRb mice displayed delayed onset of puberty and impaired fertility in both sexes, which suggested that both IGF1R and IR in LepRb neurons are required for normal reproduction. Additionally, we found transient growth retardation in IGF1RLepRb and IGF1R/IRLepRb mice. Loss of IGF1R in LepRb neurons led to lower serum IGF-1 and GH levels in male mice and impaired trabecular and cortical bone development in mice of both sexes. Only transient and mild changes were noticed in the body weight. However, we found IGF1R and IR in LepRb neurons jointly regulate body mass composition, energy homeostasis and glucose homeostasis, as shown by elevated fat mass composition, low energy expenditure and low physical activity in IGF1R/IRLepRb mice. Taken together, these studies identify the unique and cooperative role of LepRb IGF1R and IRs in the regulation of body growth, reproduction, and metabolism. Presentation: 6/3/2024

6545 Weekly Somapacitan Reduces Serum C-reactive Protein Levels in Adult Patients with Growth Hormone Deficiency

Abstract Disclosure: Y. Seki: None. S. Morimoto: None. M. Ikemoto: None. N. Takano: None. K. Yamashita: None. K. Bokuda: None. D. Watanabe: None. A. Ichihara: None. Background: Adult growth hormone deficiency (GHD) is known to be associated with increased inflammation. Our previous research revealed a significant association between GHD and elevated serum C-reactive protein (CRP) levels. Limited studies have demonstrated a significant association between GH replacement therapies and CRP levels; only two reports showed a significant reduction in serum CRP levels with daily somatropin. This study aimed to investigate the effects of weekly somapacitan on serum CRP levels in adult patients with GHD. Methods: We prospectively observed serum CRP levels as the primary outcome before and 6 months after somapacitan treatment in adult patients with GHD with no history of GH supplementation therapy within the past 6 months. Secondary outcomes included anthropometric data, IGF-1 levels, and kidney and liver functions. The somapacitan dose was titrated based on IGF-1 levels during the 6-month treatment period. Results: Eight adult patients (mean age 50±17, male 4 [50%]) with GHD received weekly somapacitan treatment. Of the patients, 2 (25%) had ACTH deficiency, 2 (25%) had TSH deficiency, and 2 (25%) had gonadotropin deficiency. Two patients (25%) were on glucocorticoid replacement. The somapacitan dose at 6 months was 1.9 (1.5-2.6) mg/week. Weekly somapacitan significantly increased serum IGF-1 level (48 [29-122] to 125 [63-205] ng/mL, P = 0.001) and IGF-1 SD score (-3.3 [-5.3-0.9] to -0.7 [-3.0-0.8], P = 0.008) and significantly decreased serum CRP level (0.243 [0.056-0.464] to 0.093 [0.036-0.290] ng/mL, P = 0.008). However, it did not affect body weight (80.6±11.6 to 79.8±10.5 kg, P = 0.67) or serum creatinine (0.74±0.13 to 0.68±0.21 mg/dL, P = 0.35) and alanine aminotransferase (60 [20-99] to 48 [21-85] U/L, P = 0.23) levels. Changes in CRP levels were significantly correlated with changes in IGF-1 levels (rs = -0.83, P = 0.010) and IGF-1 SD scores (rs = -0.79, P = 0.021). Conclusion: GH supplementation therapy with weekly somapacitan reduced serum CRP levels in adult patients with GHD without affecting body composition or kidney and liver functions. Presentation: 6/3/2024

A single-center, double-blind, randomized, placebo-controlled, two-arm study to evaluate the safety and efficacy of once-weekly sirolimus (rapamycin) on muscle strength and endurance in older adults following a 13-week exercise program

BackgroundAging leads to a decline in muscle mass and strength, contributing to frailty and decreased quality of life. Sirolimus (rapamycin) , an mTOR inhibitor, has shown potential in preclinical studies to extend lifespan and improve health span. This study evaluates the safety and efficacy of once-weekly sirolimus (rapamycin) administration on muscle strength and endurance in older adults engaged in a 13-week exercise program.MethodsThis randomized, double-blind, placebo-controlled trial will enroll 40 participants aged 65–85. Participants will be randomly assigned to receive either sirolimus (rapamycin) 6 mg/week or placebo for 13 weeks, in conjunction with an at-home exercise program. The primary outcome measure is the change in muscle strength and endurance, assessed by the 30-Second Chair-Stand Test. Secondary outcome measures include adverse events, changes in muscle strength and endurance as measured by the 6-min walk test, handgrip strength, and participant-reported outcomes using the SF-36 survey. Assessments will be conducted at baseline, mid-intervention (week 6), and post-intervention (week 13). Blood samples will be collected for hematology and biochemistry analyses, including full blood count, urea and electrolytes, liver function tests, HbA1c, lipids, serum IGF-1, and hs-CRP. DNA methylation will be analyzed using TruDiagnostic™ to explore changes in biological age.DiscussionThis study aims to provide insights into the potential benefits of intermittent sirolimus (rapamycin) administration on muscle performance in older adults. By alternating periods of mTOR inhibition through rapamycin and activation via exercise, this study will explore a novel approach to enhancing muscle strength and endurance in the aging population. The results could have significant implications for developing interventions to improve physical function and overall health outcomes in older adults. Safety and tolerability will also be closely monitored to ensure the feasibility of this regimen for wider application.Trial registrationAustralia New Zealand Clinical Trials Registry, ACTRN12624000790549. Registered on 26 June 2024 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12624000790549.

Cutoff values for the associations between serum IGF-1 levels and muscle mass and strength: insights from a 4-year cohort study

Cutoff values for the associations between serum IGF-1 levels and muscle mass and strength: insights from a 4-year cohort study

The Transcriptome Characterization of the Hypothalamus and the Identification of Key Genes during Sexual Maturation in Goats.

Sexual maturation in goats is a dynamic process regulated precisely by the hypothalamic-pituitary-gonadal axis and is essential for reproduction. The hypothalamus plays a crucial role in this process and is the control center of the reproductive activity. It is significant to study the molecular mechanisms in the hypothalamus regulating sexual maturation in goats. We analyzed the serum hormone profiles and hypothalamic mRNA expression profiles of female goats during sexual development (1 day old (neonatal, D1, n = 5), 2 months old (prepuberty, M2, n = 5), 4 months old (sexual maturity, M4, n = 5), and 6 months old (breeding period, M6, n = 5)). The results indicated that from D1 to M6, serum hormone levels, including FSH, LH, progesterone, estradiol, IGF1, and leptin, exhibited an initial increase followed by a decline, peaking at M4. Furthermore, we identified a total of 508 differentially expressed genes in the hypothalamus, with a total of four distinct expression patterns. Nuclear receptor subfamily 1, group D, member 1 (NR1D1), glucagon-like peptide 1 receptor (GLP1R), and gonadotropin-releasing hormone 1 (GnRH-1) may contribute to hormone secretion, energy metabolism, and signal transduction during goat sexual maturation via circadian rhythm regulation, ECM receptor interactions, neuroactive ligand-receptor interactions, and Wnt signaling pathways. This investigation offers novel insights into the molecular mechanisms governing the hypothalamic regulation of goat sexual maturation.

A field study to optimize protein and lipid levels in diet for cage-cultured subadult rockfish Sebastes schlegelii

A feeding trial was conducted to evaluate growth, body composition, serum biochemistry, digestion and metabolism, and oxidation resistence of S. schlegelii fed 9 diets in a 3×3 factorial design (protein levels: 44 %, 48 %, 52 %; lipid levels: 6 %, 10 %, 14 %), to optimize protein and lipid levels for practical feed formula. Rockfish (114.25 g) were stocked into 27 cages in an offshore system and fed test diets to satiation twice daily for 8 weeks. Growth increased but feed conversion rate decreased with dietary protein increasing. Increasing dietary protein to >48 % led to reduced feeding intake but increased protein efficiency ratio. Lipid efficiency ratio increased with dietary protein increasing but decreased with dietary lipid increasing. Hepatosomatic index decreased coupling with the increases in condition factor and liver lipid content as dietary lipid increased to 14 %. Intraperitoneal fat ratio increased with dietary lipid increasing. Increasing dietary protein to > 48 % significantly elevated serum total protein and glucose concentrations, hepatic glycogen synthase activity. High-protein (52 %) diets elevated serum albumin and urea nitrogen concentrations, hepatic pyruvate kinase and alanine aminotransferase (ALT) activities but downregulated hepatic growth-hormone (GH) receptor. Activities of trypsin, lipase, serum superoxide dismutase and total antioxidant capacity decreased with the dietary lipid increasing. Increasing dietary lipid to > 10 % reduced serum GH concentration, and high-lipid (14 %) diets significantly enhanced serum triglyceride concentration and hepatic transaminases activities, and resulted in a visual increase of adipocytes in liver. Serum cholesterol and low-density lipoprotein decreased as dietary protein increased to 48–52 % or dietary lipid >10 %. Hepatic succinate dehydrogenase activity and serum IGF-1 significantly increased while hepatic fatty acid synthetase decreased as dietary protein increased to >48 % or dietary lipid >10 %. High-protein (52 %) diet or high-lipid (14 %) diet elevated serum malonaldehyde concentration. These findings suggested 48 % protein and 10 % lipid were the optimal in diet for subadult S. schlegelii.

Anthropometric measurements of children with neurofibromatosis type I: impact of plexiform neurofibroma volume and treatment.

In children and adolescents/young adults (CAYA) with neurofibromatosis type I (NF1), associations between anthropometric measurements, plexiform neurofibroma (pNF) tumor volume (TV), and treatment history are unknown. We retrospectively investigated anthropometrics in CAYA on the National Cancer Institute (NCI) NF1 Natural History Study who had pNF TV assessed by imaging (n = 106). We determined CDC height/weight percentiles and estimated Preece-Baines (PB) height growth curve parameters. We evaluated variables that could impact height/weight including: (1) pNF volume, (2) pNF directed therapy, and (3) serum IGF-1. 23% of males and 20% of females had height <5th percentile; 13% of males had weight <5th percentile. Estimated median final adult height for males was 171.6 cm (CDC 23rd percentile) and for females was 156.2 cm (CDC 14th percentile). Inverse associations between height and weight percentiles and pNF volume were observed (Spearman's r = -0.277, -0.216, respectively). Estimated median final height was not meaningfully affected by patients who received pNF-directed treatment with MEK inhibitor. 52% of low serum IGF-1 measurements were concurrent with a height percentile <5th. Greater than expected percentages of patients had height/weight <5th percentile, and median final adult heights were <CDC 25th percentile. pNF volume was inversely associated with height/weight percentiles. Children and adolescents/young adults with neurofibromatosis type I (NF1) seen at a research hospital have lower height and weight percentiles than normative populations. Growth percentiles are inversely associated with plexiform neurofibroma tumor volumes and impacted little by MEKi treatment history in this subset of patients. These findings align with prior investigations of growth in the NF1 population but are the first to examine the association with tumor burden.