RARE DISEASE
Growth delay due to insulin-like growth factor I resistance
Growth delay due to insulin-like growth factor I resistance
Growth delay due to insulin-like growth factor I resistance
Synonyms: Resistance to IGF-1
Synonyms: Resistance to IGF-1
Synonyms: Resistance to IGF-1
Drug discovery
1
drug
With orphan designation
Overview
Growth delay due to insulin-like growth factor I resistance (IGF-I resistance) is a rare genetic disorder caused by IGF1R mutations, chromosomal deletions (e.g., 15q26.3), or ring chromosome 15. It presents with intrauterine/postnatal growth retardation, elevated serum IGF-I levels, microcephaly, and variable intellectual deficits. Dysmorphic features (broad nasal bridge, short fingers) and cardiac defects may occur [1][7][12]. Diagnosis involves genetic testing and biochemical profiling [7][9].
Therapies
Recombinant GH therapy: Partial efficacy in some patients, particularly with heterozygous IGF1R mutations [2][7].
rhIGF-1 therapy: Used in severe GH insensitivity, improves growth velocity but risks hypoglycemia and intracranial hypertension [2][3].
Supportive care: Nutritional interventions, developmental support, and cardiac/dysmorphism monitoring [7][9].
Categories: rare endocrine diseases, rare genetic diseases, rare neurological diseases
Research Papers
378 drug discovery papers about Growth delay due to insulin-like growth factor I resistance, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
378 drug discovery papers about Growth delay due to insulin-like growth factor I resistance, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-05-06 | The kidney and IGF-1 axis as a central regulator of linear growth and adult height in pediatric health and disease
The kidney plays an important role in normal linear growth throughout childhood by regulating systemic insulin-like growth factor-1 (IGF-1) bioavailability through the filtration and processing of IGF-binding proteins and by serving as a target organ for growth hormone (GH). In pediatric chronic kidney disease (CKD), impaired renal function is associated with reduced availability of bioactive IGF-1 despite normal or modestly elevated total IGF-1 concentrations, reflecting altered binding protein dynamics and functional GH–IGF resistance. These changes are frequently accompanied by impaired growth velocity and reduced height, particularly in advanced CKD stages. This review synthesizes experimental and observational evidence examining the role of the kidney and IGF-1 axis in physiological linear growth and CKD-related growth failure. Observational studies demonstrate consistent associations between renal volume, IGF-1 parameters, and height outcomes. Across CKD stages, progressive reductions in free IGF-1 parallel worsening renal function and growth impairment. Recombinant human GH therapy improves growth velocity and may help children achieve near-adult height closer to their genetic potential when initiated early and appropriately monitored. Collectively, these findings support a renal–endocrine model of pediatric growth regulation in health and disease.
2025-11-11 | Mutation in IR or IGF1R produces features of long-lived mice while maintaining metabolic health.
Insulin/insulin growth factor signaling is a conserved pathway that regulates lifespan. However, long-lived loss-of-function mutants often produce insulin resistance, slow growth, and impair reproduction. Recently, a gain-of-function mutation in the kinase insert domain (KID) of the Drosophila insulin/IGF receptor was seen to dominantly extend lifespan without impairing insulin sensitivity, growth, or reproduction. This substitution occurs within residues conserved in mammalian insulin receptor (IR) and insulin growth factor-1 receptor (IGF-1R). We produced 2 knock-in mouse strains that carry the homologous KID Arg/Cys substitution in murine IR or IGF-1R, and we replicated these genotypes in human cells. Cells with heterodimer receptors of IR or IGF-1R induce receptor phosphorylation and phospho-Akt when stimulated with insulin or IGF. Heterodimer receptors of IR fully induce pERK, but ERK was less phosphorylated in cells with IGF-1R heterodimers. Adults with a single KID allele (producing heterodimer receptors) have normal growth and glucose regulation. At 4 months, these mice variably display hormonal markers that associate with successful aging counteraction, including elevated adiponectin and FGF21, as well as reduced leptin and IGF-1. Livers of IGF-1R females show decreased transcriptome-based biological age, which may point toward delayed aging and warrants an actual lifespan experiment. These data suggest that KID mutants may slow mammalian aging while they avoid the complications of insulin resistance.
2025-07-18 | From early growth failure to endocrine recovery: Long-term outcomes and GH therapy in SGA and severely preterm children
Background: Children born small for gestational age (SGA) or severely premature (<32 weeks gestation or <1500 g birth weight) are at elevated risk for persistent growth failure and multiple endocrine abnormalities. These include GH–IGF-1 axis dysfunction, insulin resistance, delayed puberty, altered body composition, and neurocognitive impairment. While many catch up by age 2, approximately 10–15% remain short, reflecting partial GH insensitivity. Growth hormone (GH) therapy has emerged as a cornerstone of treatment, though variability in response remains a concern. Objectives: To review the prevalence and clinical impact of endocrine and growth disturbances in children born SGA or severely premature; to evaluate the efficacy and safety of GH therapy; and to identify predictors of therapeutic response and long-term outcomes. Methods: A structured mini-review was conducted using three ESPE abstracts (2025–2026) and 28 peer-reviewed studies published between 2000 and 2025. Included studies addressed GH therapy in SGA or preterm populations and reported outcomes related to height, body composition, metabolic parameters, puberty, bone density, and neurodevelopment. Results were synthesized into six summary tables and four figures, including a forest plot of final height SDS gains. Results: Endocrine abnormalities were highly prevalent: GH–IGF-1 axis dysfunction (60–80%), growth failure (70%), insulin resistance (30–50%), low bone mineral density (40–60%), and delayed puberty (25%). GH therapy significantly improved linear growth (+2.0 to +2.5 SDS), growth velocity (+10 cm/year), and lean body mass (+10–15%), while reducing central adiposity and fracture risk. Weekly GH formulations (somapacitan) matched daily GH in safety and efficacy. Mild, transient insulin resistance was noted in 5–10% of cases. Early treatment (age 2–4 years), low baseline IGF-1, and better nutritional status predicted better outcomes. Neurodevelopmental improvements were suggested but require further study. Conclusion: SGA and severely preterm children who fail to achieve catch-up growth are at high risk for persistent endocrine and metabolic complications. GH therapy offers substantial benefit when started early and tailored to individual risk factors. Long-term follow-up is essential to monitor not only height outcomes but also metabolic health, puberty, and neurocognitive development. Personalized strategies using genotype, weekly GH regimens, and holistic care models are promising next steps in optimizing therapy.
2025-07-05 | Short stature with elevated IGF-1: Diagnostic pitfalls and growth hormone therapy outcomes across etiologies
Background: Short stature in children is typically linked to low insulin-like growth factor 1 (IGF-1), reflecting growth hormone (GH) deficiency or nutritional deprivation. However, a distinct and diagnostically challenging subgroup presents with short stature despite normal or elevated IGF-1 concentrations. This paradox indicates possible underlying resistance to IGF-1 action or dysregulation of the GH-IGF axis. Etiologies include genetic mutations (e.g., IGF1R, STAT5b), syndromic conditions (e.g., Noonan syndrome), endocrine disorders (e.g., hyperthyroidism, insulin resistance), and exogenous GH administration. The growth response to GH therapy in this population varies widely and remains insufficiently characterized in the literature. Objectives: This review aimed to (1) analyze the diverse causes of short stature with elevated IGF-1 levels, (2) assess growth outcomes after GH therapy across distinct etiological categories, and (3) propose diagnostic and therapeutic strategies to individualize care. Methods: A systematic literature review was conducted using PubMed, Scopus, and Web of Science for studies published between 2000 and 2025. Inclusion criteria encompassed pediatric patients with short stature (height SDS < –2), normal to high IGF-1, and reported GH therapy outcomes. Studies were grouped by etiology into seven categories: IGF-1 resistance, GH resistance, syndromic causes, exogenous GH use, endocrine dysregulation, obesity/metabolic factors, and rare genetic syndromes. Data on growth velocity, IGF-1 dynamics, and final height outcomes were extracted. Study quality and therapeutic impact were evaluated using validated scales. Results: GH therapy outcomes were highly variable. Children with IGF1R haploinsufficiency or partial receptor defects showed modest height gains. In contrast, those with GH resistance (e.g., STAT5b mutations) had poor responses, requiring alternate strategies. Syndromic conditions like Noonan syndrome exhibited attenuated GH sensitivity due to downstream pathway disruptions. Exogenous GH use often elevated IGF-1 without proportional linear growth, necessitating dose adjustment. Obese children and those with endocrine dysregulation showed paradoxical IGF-1 elevations but poor growth outcomes unless the underlying metabolic imbalance was corrected. Conclusions: Short stature with elevated IGF-1 is a heterogeneous condition that cannot be managed by uniform GH therapy. Diagnostic precision—integrating clinical, biochemical, and genetic findings—is essential for predicting response and guiding individualized therapy. A precision medicine framework should guide future interventions, including consideration of IGF-1 analogs and metabolic optimization strategies to improve growth outcomes in resistant cases.
2025-06-25 | Muscle in Endocrinology: From Skeletal Muscle Hormone Regulation to Myokine Secretion and Its Implications in Endocrine–Metabolic Diseases
Skeletal muscle, traditionally recognized for its motor function, has emerged as a key endocrine organ involved in metabolic regulation and interorgan communication. This narrative review addresses the dual role of muscle as a target tissue for classical hormones—such as growth hormone (GH), insulin-like growth factor type 1 (IGF-1), thyroid hormones, and sex steroids—and as a source of myokines, bioactive peptides released in response to muscle contraction that exert autocrine, paracrine, and endocrine effects. Several relevant myokines are discussed, such as irisin and Metrnl-like myokines (Metrnl), which mediate exercise-associated metabolic benefits, including improved insulin sensitivity, induction of thermogenesis in adipose tissue, and immunometabolic modulations. It also examines how muscle endocrine dysfunction, caused by chronic inflammation, hormone resistance, or sedentary lifestyle, contributes to the development and progression of metabolic diseases such as obesity, type 2 diabetes, and sarcopenia, highlighting the importance of muscle mass in the prognosis of these pathologies. Finally, the therapeutic potential of interventions aimed at preserving or enhancing muscle function—through physical exercise, hormone therapy and anabolic agents—is highlighted, together with the growing research on myokines as biomarkers and pharmacological targets. This review expands the understanding of muscle in endocrinology, proposing an integrative approach that recognizes its central role in metabolic health and its potential to innovate the clinical management of endocrine–metabolic diseases.
small molecules
2026-09-23 | Beyond insulin-like growth factor-1 (IGF-1) normalization: portal insulin and hepatic growth hormone (GH) sensitivity across metabolic disease.
Clinical management of growth hormone (GH) deficiency, acromegaly, and diabetes mellitus is dominated by single-analyte targets: serum insulin-like growth factor-1 (IGF-1) in the GH disorders and glycated hemoglobin in diabetes. This reductive framework obscures a central regulatory fact: GH does not autonomously dictate hepatic IGF-1 output. Whether GH is translated into IGF-1 by the hepatocyte is gated by the concentration of insulin reaching the liver through the portal vein. We propose liver sensitivity to GH (LSG), operationally defined as portal-insulin-determined hepatic GH receptor (GHR) availability, as a unifying variable that places type 1 and type 2 diabetes, obesity, liver failure, and acromegaly on a single continuum rather than treating them as separate phenomena. We develop the molecular basis of insulin-dependent GHR regulation, distinguish the divergent roles of portal versus systemic insulin, and argue that this distinction explains why subcutaneous insulin therapy in type 1 diabetes corrects glycemia while leaving the hepatic GH-resistant state intact. We then re-examine the weight-gain liability of insulinotropic antidiabetic agents, the discordant GH/IGF-1 signatures produced by GLP-1 receptor agonists, the prognostic and potentially therapeutic role of IGF-1 in cirrhosis, and the metabolic limitations of current acromegaly treatment targets when viewed through the LSG framework. The aim is to give the treating physician a mechanistic, rather than purely biochemical, account of how metabolism behaves in these states.
2026-04-30 | Bifidobacterium animalis subsp. lactis BL-16 fermented Astragali Radix (W16) promotes the bone growth of juvenile rats via modulation of IGF-1 and gut microbiota.
Short stature in children causes physical and psychological issues. Human growth hormone (hGH) is clinically recommended but has side effects. Probiotics and functional foods are promising alternatives. Astragali Radix, has growth-promoting potential, and fermentation may enhance its bioactivity. Astragali Radix, was fermented with Bifidobacterium animalis subsp. lactis BL-16 to prepare postbiotic W16. Juvenile rats were treated with W16, hGH, or unfermented Astragali Radix. UPLC-Q-TOF/MS metabolomic profiling, bone growth-related gene (igf-1, trap) expression, IGF-1 levels, glucose/insulin concentrations, and gut microbiota were analyzed. W16 enhanced rat body/bone length similarly to hGH, upregulated igf-1/trap, and increased plasma/liver IGF-1-more effectively than unfermented Astragali Radix. Unlike hGH, W16 did not induce insulin resistance. While hGH and Astragali Radix enriched Lactobacillus, W16 uniquely promoted Acetivibrio cellulolyticus (beneficial for bone mineral density). Metabolomic profiling revealed pre- and post-fermentation differences in Astragali Radix. Postbiotic W16 promotes bone growth via regulating growth-related genes, IGF-1 signaling, and gut microbiota. Safer than hGH (no insulin resistance), W16 is a promising functional food candidate for improving short stature in children.
2026-04-04 | Early-Life Protein Nutrition and Enzymatic Regulation: Mechanistic Pathways Linking Growth Faltering, Stunting, and Obesity.
Nutrition in the early years has a significant impact on an individual's long-term development patterns and metabolic health via protein intake and enzymatic pathways. The current literature review analyses the coexistence of malnutrition and obesity by associating a shortage of essential amino acids to stunting via impaired mTORC1/IGF-1 signaling, whereas excessive protein intake in early life is linked to accelerated weight gain, increased adiposity, and a heightened risk of insulin resistance. Several molecular mechanisms link these extremes, including AMPK energy sensing, intestinal dysbiosis, and hormonal dysregulation (leptin/ghrelin imbalance). The development of digestive enzymes such as pepsin activation, pancreatic proteases (trypsin week 14-16), lipase (week 21), and brush-border peptidases impacts food absorption, and enzyme deficits aggravate malabsorption in cases of malnutrition. Maternal health status, infections, and exposure to obesogenic diets during the first 1000 days of life significantly increase the risk of impaired gastrointestinal development and nutrient utilization. Integrative interventions like balanced protein formulas, breastfeeding encouragement, lipid-based supplements, malaria management, and enzyme replacement treatments mitigate the negative consequences. Considering the consequences of early dysregulation in cardio-metabolic processes during a lifetime, personalized nutrition and their pathways modulators can play a pivotal role to prevent it.
2026-03-31 | Growth hormone and glycemic metabolism.
Growth hormone (GH) is secreted in a pulsatile pattern and exerts pleiotropic effects on growth and metabolism. Beyond its role in somatic development, GH is a key regulator of glucose homeostasis through its influence on insulin signaling, lipid mobilization, and substrate partitioning. Chronic disturbances of the GH-IGF-1 axis profoundly affect glucose metabolism. In acromegaly, sustained GH and IGF-1 excess induces systemic insulin resistance via direct antagonism of insulin receptor signaling, increased lipolysis, and elevated free fatty acids, ultimately leading to impaired glucose tolerance or overt diabetes in up to half of patients. Conversely, GH deficiency is characterized by visceral adiposity, low IGF-1, and reduced lean mass, changes that also impair insulin sensitivity through distinct mechanisms. These contrasting phenotypes highlight the dual role of GH in modulating insulin action and glucose control. Notably, insulin resistance in acromegaly is paradoxical in that it occurs despite reduced adipose tissue mass, whereas in GH deficiency it is driven by increased fat accumulation. Therapeutic interventions targeting the GH axis -such as transsphenoidal surgery, somatostatin analogues, GH receptor antagonists, and dopamine agonists- have differential effects on glucose homeostasis, ranging from improvement of insulin sensitivity to further impairment depending on the agent. Recognition of these divergent metabolic consequences is critical for personalized management of patients with acromegaly or GH deficiency. Looking ahead, advances in understanding GH-IGF-1-insulin cross-talk and the molecular drivers of insulin resistance may guide the development of novel therapies aimed at optimizing metabolic outcomes in disorders of the GH axis.
2025-11-24 | De-identified raw metabolic data for the four participants.
Background: Growth hormone (GH) is known to affect insulin and glucose metabolism. Blocking its effects in acromegalic patients improves diabetes and glucose metabolism. We aimed to determine the effect of pegvisomant, a GH receptor antagonist, on insulin resistance, endogenous glucose production (EGP) and lipolysis in insulin resistant non-diabetic men. Methods: Four men between the ages of 18-62 with a BMI of 18-35kg/m 2 , with insulin resistance as defined by a HOMA-IR > 2.77, were treated for four weeks with pegvisomant 20 mg daily. Inpatient metabolic assessments were performed before and after treatment. The main outcome measurements were: change after pegvisomant therapy in insulin sensitivity as measured by hyperinsulinemic euglycemic clamp; and EGP and lipolysis assessed by stable isotope tracer techniques. Results: Insulin like growth factor-1 (IGF-1) concentrations decreased from 134.0 ± 41.5 (mean ± SD) to 72.0 ± 11.7 ng/mL (p = 0.04) after 4 weeks of therapy. Whole body insulin sensitivity index (M/I 3.2 ± 1.3 vs. 3.4 ± 2.4; P = 0.82), as well as suppression of EGP (89.7 ± 26.9 vs. 83.5 ± 21.6%; p = 0.10) and Ra glycerol (59.4 ± 22.1% vs. 61.2 ± 14.4%; p = 0.67) during the clamp were not changed significantly with pegvisomant treatment. Conclusions: Blockade of the GH receptor with pegvisomant for four weeks had no significant effect on insulin/glucose metabolism in a small phase II pilot study of non-diabetic insulin resistant participants without acromegaly.
antibodies
2026-02-05 | Analysis of metabolic status and risk factors of small for gestational age children with catch-up growth in East China.
Approximately 85-90% patients with small for gestational age (SGA) experience catch-up growth (CUG) by the age of 2, with their height reaching - 2 standard deviation scores (SDS) or 3% of the height of children of the same age and sex. However, SGA patients with CUG (CUG-SGA) tend to be at a higher risk of developing insulin resistance, obesity, metabolic syndrome, and cardiovascular diseases. This study explored the metabolic conditions of CUG-SGA patients in East China and analyzes the risk factors that may contribute to metabolic issues. This multi-center study in East China involved 151 SGA patients aged 2-8 years. Patients were categorized into two groups: CUG-SGA (height not below - 2 SDS among the children of the same age and gender) and NCUG-SGA (SGA patients without CUG, height below - 2 SDS among the children of the same age and gender). Tests for insulin-like growth factor 1 (IGF-1), blood glucose (BG), insulin (INS), triglycerides (TG), total cholesterol (TC), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and leptin (LEP) were conducted after a 12-hour fast. Body mass index (BMI) and homeostatic model assessment for insulin resistance (HOMA-IR) were calculated. (1) Out of 151 SGA patients, 82 were girls and 69 were boys. There were 85 patients in CUG-SGA group, including 38 girls and 47 boys. There were 66 patients in NCUG-SGA group, including 44 girls and 22 boys. The height SDS (H-SDS) and weight SDS (W-SDS) of CUG-SGA group were significantly higher than those of NCUG-SGA group (P < 0.05). (2) The level of IGF-1 SDS, ALT, and GGT in the CUG-SGA group were significantly higher than those in the NCUG-SGA group (P < 0.01). The level of W-SDS, LEP, INS, and HOMA-IR in the CUG-SGA group are significantly higher than those of the NCUG-SGA group (P < 0.05). (3) Correlation analysis in SGA patients indicated positive correlations between BG and W-SDS, LEP, and GGT (P < 0.05). INS was positively correlated with IGF-1 SDS, GGT (P < 0.01), and W-SDS (P < 0.05). HOMA-IR was positively correlated with IGF-1 SDS (P < 0.01). TC was positively correlated with LEP (P < 0.05), and TG was negatively correlated with IGF-1 SDS (P < 0.01). (4) After further controlling for confounding factors and performing multiple regression analyses, the results showed that BMI-SDS had a significant positive effect on INS and a significant negative effect on HOMA-IR. IGF-1 had a significant positive effect on INS and HOMA-IR, and a significant negative effect on TG. LEP had a significant positive effect on BG, INS, HOMA-IR, TC, and TG. ALT had a significant negative effect on INS and HOMA-IR, and a significant positive effect on TC and TG. GGT had a significant positive effect on BG, INS, HOMA-IR, TC, and TG. (1) IGF-1 SDS was significantly positively correlated with fasting INS (FINS) and HOMA-IR, and exerted a significant positive effect on fasting BG. If IGF-1 levels in CUG-SGA infants remain persistently high, careful monitoring of changes in glucose metabolism is warranted. (2) CUG-SGA patients had higher LEP resistance compared to NCUG-SGA patients, potentially contributing to future metabolic issues. (3) Elevated ALT and GGT levels in SGA patients may warrant close monitoring of glucose metabolism, particularly in CUG-SGA patients.
2024-02-23 | Increased capacity to maintain glucose homeostasis in a transgenic mouse expressing human but not mouse growth hormone with developing high fat diet-related insulin resistance, steatosis and adipose dysfunction
ABSTRACT Objective Differences in primate and non-primate growth hormone (GH) genes can affect their regulation and function. This includes the ability of human (h) but not mouse (m) GH to bind the prolactin (PRL) receptor (PRLR) as well as the GH receptor (GHR). Potential differential effects were assessed in male hGH- or mGH-expressing mice and fed high fat diet (HFD) versus regular chow diet (RCD). Pancreas and epididymal white adipose tissue (eWAT) gene expression and/or related function were targeted as the pancreas responds to both PRLR and GHR signaling and catabolic effects like lipolytic activity are more directly attributable to GH and GHR signaling. Design A transgenic CD-1 mouse expressing hGH but not mGH under hypothalamic control was generated to compare with wild type CD-1 mice and size and bone density determined. Glucose clearance, islet area, insulin and insulin-like growth factor (IGF) -2 gene expression were assessed as well as serum glucose and insulin levels in mice fed a HFD versus RCD for 8 and 24 weeks. Adiposity, liver and serum triglycerides as well as eWAT cell area, cytokine (leptin and adiponectin) and senescence-related marker (p21 CIP1 and p16 INK4a ) RNA levels were also assessed. Results Male hGH-expressing transgenic CD-1[ΔmGH.hGH] mice have significantly lower liver IGF-1 RNA levels and are smaller based on length and weight than wild type CD-1[mGH] mice. They also have ∼1.5-fold higher total body fat and serum triglyceride levels. However, CD-1[ΔmGH.hGH] and CD-1[mGH] mice grow at the same rate with similar cortical and trabecular bone densities. Unlike CD-1[mGH] mice, there was no significant delay in glucose clearance in CD-1[ΔmGH.hGH] mice after 8 weeks on a HFD versus RCD; while basal (RCD) serum insulin levels were similar, fasting glucose levels were lower and pancreas IGF-2 RNA levels were increased in CD-1[ΔmGH.hGH] mice. However, both CD-1[ΔmGH.hGH] and CD-1[mGH] showed evidence of increased insulin resistance after 24 weeks on HFD, including delayed glucose clearance in spite of increased pancreatic islet area and insulin production as well as signs of liver steatosis and increased hepatic triglyceride levels. These increases correlated with elevated PRLR but not GHR RNA levels. Assessment of eWAT revealed >2-fold larger adipocytes in CD-1[ΔmGH.hGH] compared to CD-1 [mGH] mice fed RCD at both 12 and 28 weeks. This was associated with an ∼2.6-fold increase in leptin RNA levels at 12 weeks and ∼58% lower adiponectin RNA levels at 28 weeks. A >2-fold increase in p21 CIP1 transcript levels was also detected in eWAT from both CD-1[ΔmGH.hGH] and CD-1 [mGH] mice fed RCD with age (28 versus 12 weeks) but were unaffected by diet. However, a >2-fold increase in p16 INK4a RNA levels was observed after 24 weeks on HFD. Conclusions While limited to observations in the male, transgenic CD-1[ΔmGH.hGH] mice exhibit signs of GH insufficiency and eWAT adipocyte dysfunction. These mice also show an initial resistance to the negative effects of HFD on glucose clearance when compared to CD-1[mGH] mice, which is potentially related to a differential effect of hGH versus mGH on pancreas development and/or function.
2022-06-24 | Cixutumumab reveals a critical role for IGF-1 in adipose and hepatic tissue remodelling during the development of diet-induced obesity.
High fat diet (HFD)-induced obesity leads to perturbation in the storage function of white adipose tissue (WAT) resulting in deposition of lipids in tissues ill-equipped to deal with this challenge. The role of insulin like growth factor-1 (IGF-1) in the systemic and organ-specific responses to HFD is unclear. Using cixutumumab, a monoclonal antibody that internalizes and degrades cell surface IGF-1 receptors (IGF-1 R), leaving insulin receptor expression unchanged we aimed to establish the role of IGF-1 R in the response to a HFD. Mice treated with cixutumumab fed standard chow developed mild hyperinsulinemia with no change in WAT. When challenged by HFD mice treated with cixutumumab had reduced weight gain, reduced WAT expansion, and reduced hepatic lipid vacuole formation. In HFD-fed mice, cixutumumab led to reduced levels of genes encoding proteins important in fatty acid metabolism in WAT and liver. Cixutumumab protected against blunting of insulin-stimulated phosphorylation of Akt in liver of HFD fed mice. These data reveal an important role for IGF-1 R in the WAT and hepatic response to short-term nutrient excess. IGF-1 R inhibition during HFD leads to a lipodystrophic phenotype with a failure of WAT lipid storage and protection from HFD-induced hepatic insulin resistance.
2017-09-29 | Disrupting IGF Signaling in Adult Mice Conditions Leanness, Resilient Energy Metabolism, and High Growth Hormone Pulses.
Growth hormone (GH) and insulinlike growth factor (IGF) promote aging and age-related pathologies. Inhibiting this pathway by targeting IGF receptor (IGF-1R) is a promising strategy to extend life span, alleviate age-related diseases, and reduce tumor growth. Although anti-IGF-1R agents are being developed, long-term effects of IGF-1R blockade remain unknown. In this study, we used ubiquitous inducible IGF-1R knockout (UBIKOR) to suppress signaling in all adult tissues and screened health extensively. Surprisingly, UBIKOR mice showed no overt defects and presented with rather inconspicuous health, including normal cognition. Endocrine GH and IGF-1 were strongly upregulated without causing acromegaly. UBIKOR mice were strikingly lean with coordinate changes in body composition and organ size. They were insulin resistant but preserved physiological energy expenditure and displayed enhanced fasting metabolic flexibility. Thus, long-term IGF-1R blockade generated beneficial effects on aging-relevant metabolism, but exposed to high GH. This needs to be considered when targeting IGF-1R to protect from neurodegeneration, retard aging, or fight cancer.
2015-01-09 | Improved glucose metabolism in vitro and in vivo by an allosteric monoclonal antibody that increases insulin receptor binding affinity.
Previously we reported studies of XMetA, an agonist antibody to the insulin receptor (INSR). We have now utilized phage display to identify XMetS, a novel monoclonal antibody to the INSR. Biophysical studies demonstrated that XMetS bound to the human and mouse INSR with picomolar affinity. Unlike monoclonal antibody XMetA, XMetS alone had little or no agonist effect on the INSR. However, XMetS was a strong positive allosteric modulator of the INSR that increased the binding affinity for insulin nearly 20-fold. XMetS potentiated insulin-stimulated INSR signaling ∼15-fold or greater including; autophosphorylation of the INSR, phosphorylation of Akt, a major enzyme in the metabolic pathway, and phosphorylation of Erk, a major enzyme in the growth pathway. The enhanced signaling effects of XMetS were more pronounced with Akt than with Erk. In cultured cells, XMetS also enhanced insulin-stimulated glucose transport. In contrast to its effects on the INSR, XMetS did not potentiate IGF-1 activation of the IGF-1 receptor. We studied the effect of XMetS treatment in two mouse models of insulin resistance and diabetes. The first was the diet induced obesity mouse, a hyperinsulinemic, insulin resistant animal, and the second was the multi-low dose streptozotocin/high-fat diet mouse, an insulinopenic, insulin resistant animal. In both models, XMetS normalized fasting blood glucose levels and glucose tolerance. In concert with its ability to potentiate insulin action at the INSR, XMetS reduced insulin and C-peptide levels in both mouse models. XMetS improved the response to exogenous insulin without causing hypoglycemia. These data indicate that an allosteric monoclonal antibody can be generated that markedly enhances the binding affinity of insulin to the INSR. These data also suggest that an INSR monoclonal antibody with these characteristics may have the potential to both improve glucose metabolism in insulinopenic type 2 diabetes mellitus and correct compensatory hyperinsulinism in insulin resistant conditions.
gene therapies
2026-06-15 | GH-resistant (Laron) mice: gene therapy with a liver-specific GH receptor causes unbalanced upregulation of female-biased and growth-related genes.
Growth hormone (GH) receptor (GHR) mutations give rise to GH-resistance (Laron syndrome). We previously treated GH-resistant Ghr-/- mice (Laron mice) with adeno-associated virus (AAV) delivering mouse (m)Ghr controlled by a constitutively active liver-specific promoter (HLP). A single injection of AAV-HLP-mGHR resulted in a significant but limited increase in body length and weight, consistent with studies of IGF-1 treatment in humans and mice. Here, we performed RNA-seq on male and female mouse livers comprising the following groups: GHR+/+ (wild-type), GHR-/- (Laron), AAV-HLP-mGHR-treated GHR-/- (treatment group), and AAV-HLP-Luc (Luciferase)-treated GHR-/- (control group). Only four genes showed significant differential expression in GHR -/- mouse liver following Luciferase vector treatment, indicating minimal effect of the AAV-HLP vector. AAV-HLP-mGHR stimulated significant expression changes in 448 genes compared to AAV-HLP-Luc control, substantially fewer than the 2781 genes whose expression was altered in GHR-/- compared to GHR+/+. AAV-HLP-mGHR treatment induced the GH-responsive IGF signaling genes Igf1 and Igfals ~16-fold compared to AAV-HLP-Luc control, but only to 40-45% of GHR+/+ liver levels. The treatment also upregulated a small subset of genes beyond GHR+/+ expression levels (p-adj < 0.05), including the proto-oncogenes Ascl1, Tmprss4, and others. Finally, genes dysregulated upon GHR loss and upregulated in livers of AAV-HLP-mGHR-treated mice were significantly enriched for sex-biased genes, consistent with the major role of GH and GHR in regulating liver sex differences. While gene replacement therapy is a potential therapy for Laron syndrome, an unregulated constitutively active promoter may drive unexpected and unbalanced changes in liver gene expression that will require monitoring.
2025-08-30 | Injection of lentiviral vectors expressing GH and IGF1 increases body and muscle mass in male rats.
The aim of this study was to increase growth hormone (GH1) and insulin-like growth factor-1 (IGF1) levels in rat muscle indirectly through the transduction of C2C12 cells via lentivectors and to compare their effects on muscle mass. The coding sequences of GH1, IGF1, and GH1-IGF1, linked by the 2 A self-cleaving peptide to enable polycistronic expression, were synthesized, cloned and inserted into the pCDH vector. Recombinant pseudolentiviruses containing our target genes were produced in HEK293T cells. C2C12 cells were transduced with pseudo lentiviruses and selected through resistance to puromycin antibiotics. The expression of the GH1 and IGF1 genes at the mRNA and protein levels was verified by RT-PCR and Western blotting, respectively. The recombinant pseudo lentiviruses and transduced C2C12 cells were injected into the tibialis anterior (TA), gastrocnemius and quadriceps muscle groups of eight-week-old rats. The body weights of the rats were measured weekly for eight weeks after the injection. The leg weight and histology of the muscle after eight weeks were also measured. The results revealed the expression of the GH1 and IGF1 genes at the mRNA and protein levels in C2C12 cells. An increase in both hormones, either directly or indirectly through C2C12 cells, increased the animal body weight, leg weight, and muscle fibre size after eight weeks. The direct and indirect transfer of IGF1 increased body weight, leg weight and muscle fibre size more than did the direct or indirect transfer of GH1. In the direct transfer groups, the body weight was greater than that in the indirect transfer groups after eight weeks. We demonstrated that nonpituitary secretion of GH1 mimicked some physiological effects of pituitary GH1 in a rat model. Further investigations are needed to study other possible effects of extra copy of GH1 and IGF1 genes over a longer period on other tissues.
2022-09-14 | Disruption of Growth Hormone Receptor in Adipocytes Improves Insulin Sensitivity and Lifespan in Mice.
Growth hormone receptor knockout (GHRKO) mice have been used for 25 years to uncover some of the many actions of growth hormone (GH). Since they are extremely long-lived with enhanced insulin sensitivity and protected from multiple age-related diseases, they are often used to study healthy aging. To determine the effect that adipose tissue has on the GHRKO phenotype, our laboratory recently created and characterized adipocyte-specific GHRKO (AdGHRKO) mice, which have increased adiposity but appear healthy with enhanced insulin sensitivity. To test the hypothesis that removal of GH action in adipocytes might partially replicate the increased lifespan and healthspan observed in global GHRKO mice, we assessed adiposity, cytokines/adipokines, glucose homeostasis, frailty, and lifespan in aging AdGHRKO mice of both sexes. Our results show that disrupting the GH receptor gene in adipocytes improved insulin sensitivity at advanced age and increased lifespan in male AdGHRKO mice. AdGHRKO mice also exhibited increased fat mass, reduced circulating levels of insulin, c-peptide, adiponectin, resistin, and improved frailty scores with increased grip strength at advanced ages. Comparison of published mean lifespan data from GHRKO mice to that from AdGHRKO and muscle-specific GHRKO mice suggests that approximately 23% of lifespan extension in male GHRKO is due to GHR disruption in adipocytes vs approximately 19% in muscle. Females benefited less from GHR disruption in these 2 tissues with approximately 19% and approximately 0%, respectively. These data indicate that removal of GH's action, even in a single tissue, is sufficient for observable health benefits that promote long-term health, reduce frailty, and increase longevity.
2022-06-20 | First use of gene therapy to treat growth hormone resistant dwarfism in a mouse model.
The only treatment tested for growth hormone receptor (GHR) defective Laron Syndrome (LS) is injections of recombinant insulin-like-growth factor 1 (rhIGF1). The response is suboptimal and associated with progressive obesity. In this study, we treated 4-5-week-old Laron dwarf mice (GHR-/-) with an adeno-associated virus expressing murine GHR (AAV-GHR) injection at a dose of 4 × 1010 vector genome per mouse. Serum growth hormone (GH) levels decreased, and GH-responsive IGF1, IGF binding protein 3 (IGFBP3) and acid labile subunit (ALS) increased. There was a significant but limited increase in body weight and length, similar to the response to rhIGF1 treatment in LS patients. All the major organs increased in weight except the brain. Our study is the first to use gene therapy to treat GH-receptor deficiency. We propose that gene therapy with AAV-GHR may eventually be useful for the treatment of human LS.
2017-05-31 | Growth Hormone Control of Hepatic Lipid Metabolism.
In humans, low levels of growth hormone (GH) and its mediator, IGF-1, associate with hepatic lipid accumulation. In mice, congenital liver-specific ablation of the GH receptor (GHR) results in reductions in circulating IGF-1 and hepatic steatosis, associated with systemic insulin resistance. Due to the intricate relationship between GH and IGF-1, the relative contribution of each hormone to the development of hepatic steatosis is unclear. Our goal was to dissect the mechanisms by which hepatic GH resistance leads to steatosis and overall insulin resistance, independent of IGF-1. We have generated a combined mouse model with liver-specific ablation of GHR in which we restored liver IGF-1 expression via the hepatic IGF-1 transgene. We found that liver GHR ablation leads to increases in lipid uptake, de novo lipogenesis, hyperinsulinemia, and hyperglycemia accompanied with severe insulin resistance and increased body adiposity and serum lipids. Restoration of IGF-1 improved overall insulin sensitivity and lipid profile in serum and reduced body adiposity, but was insufficient to protect against steatosis-induced hepatic inflammation or oxidative stress. We conclude that the impaired metabolism in states of GH resistance results from direct actions of GH on lipid uptake and de novo lipogenesis, whereas its actions on extrahepatic tissues are mediated by IGF-1.
other
2023-01-23 | Probiotic Paenibacillus polymyxa HGA4C and Bacillus licheniformis HGA8B combination improved growth performance, enzymatic profile, gene expression and disease resistance in Oreochromisniloticus.
Bacterial consortium containing two bacterial strains such as Paenibacillus polymyxa HGA4C and Bacillus licheniformis HGA8B incorporated in the diet of Oreochromis niloticus at a concentration of 1 × 106 CFU g-1 (PB1) and 1 × 108 CFU g-1 (PB2) revealed the probiotic potentials of the bacterial combination. The probiotic feed enhanced the growth performance, digestive enzymes, and antioxidant enzymes in the liver and intestine. Probiotic mediated growth enhancement was further substantiated by the up-regulation of genes such as GHR-1, GHR-2, IGF-1, and IGF-2 and the up-regulation of immune-related genes viz. TLR-2, IL-10, and TNF-α were also significantly modulated by probiotics supplementation. The intestinal MUC 2 gene expression revealed the mucosal remodification and the disease resistance of the fish challenged with Aeromonas hydrophila (MTCC-1739) was improved by the probiotic supplementation. Based on these results the new probiotic supplementation feed can be possibly marketed to help aquaculture farmers to alleviate many of the problems associated with fish farming.
2017-06-05 | Long-lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high-fat diet on metabolic function and energy expenditure.
Growth hormone (GH) signaling stimulates the production of IGF-1; however, increased GH signaling may induce insulin resistance and can reduce life expectancy in both mice and humans. Interestingly, disruption of GH signaling by reducing plasma GH levels significantly improves health span and extends lifespan in mice, as observed in Ames dwarf mice. In addition, these mice have increased adiposity, yet are more insulin sensitive compared to control mice. Metabolic stressors such as high-fat diet (HFD) promote obesity and may alter longevity through the GH signaling pathway. Therefore, our objective was to investigate the effects of a HFD (metabolic stressor) on genetic mechanisms that regulate metabolism during aging. We show that Ames dwarf mice fed HFD for 12 weeks had an increase in subcutaneous and visceral adiposity as a result of diet-induced obesity, yet are more insulin sensitive and have higher levels of adiponectin compared to control mice fed HFD. Furthermore, energy expenditure was higher in Ames dwarf mice fed HFD than in control mice fed HFD. Additionally, we show that transplant of epididymal white adipose tissue (eWAT) from Ames dwarf mice fed HFD into control mice fed HFD improves their insulin sensitivity. We conclude that Ames dwarf mice are resistant to the detrimental metabolic effects of HFD and that visceral adipose tissue of Ames dwarf mice improves insulin sensitivity in control mice fed HFD.
proteins
2026-05-06 | The kidney and IGF-1 axis as a central regulator of linear growth and adult height in pediatric health and disease
The kidney plays an important role in normal linear growth throughout childhood by regulating systemic insulin-like growth factor-1 (IGF-1) bioavailability through the filtration and processing of IGF-binding proteins and by serving as a target organ for growth hormone (GH). In pediatric chronic kidney disease (CKD), impaired renal function is associated with reduced availability of bioactive IGF-1 despite normal or modestly elevated total IGF-1 concentrations, reflecting altered binding protein dynamics and functional GH–IGF resistance. These changes are frequently accompanied by impaired growth velocity and reduced height, particularly in advanced CKD stages. This review synthesizes experimental and observational evidence examining the role of the kidney and IGF-1 axis in physiological linear growth and CKD-related growth failure. Observational studies demonstrate consistent associations between renal volume, IGF-1 parameters, and height outcomes. Across CKD stages, progressive reductions in free IGF-1 parallel worsening renal function and growth impairment. Recombinant human GH therapy improves growth velocity and may help children achieve near-adult height closer to their genetic potential when initiated early and appropriately monitored. Collectively, these findings support a renal–endocrine model of pediatric growth regulation in health and disease.
2025-11-11 | Mutation in IR or IGF1R produces features of long-lived mice while maintaining metabolic health.
Insulin/insulin growth factor signaling is a conserved pathway that regulates lifespan. However, long-lived loss-of-function mutants often produce insulin resistance, slow growth, and impair reproduction. Recently, a gain-of-function mutation in the kinase insert domain (KID) of the Drosophila insulin/IGF receptor was seen to dominantly extend lifespan without impairing insulin sensitivity, growth, or reproduction. This substitution occurs within residues conserved in mammalian insulin receptor (IR) and insulin growth factor-1 receptor (IGF-1R). We produced 2 knock-in mouse strains that carry the homologous KID Arg/Cys substitution in murine IR or IGF-1R, and we replicated these genotypes in human cells. Cells with heterodimer receptors of IR or IGF-1R induce receptor phosphorylation and phospho-Akt when stimulated with insulin or IGF. Heterodimer receptors of IR fully induce pERK, but ERK was less phosphorylated in cells with IGF-1R heterodimers. Adults with a single KID allele (producing heterodimer receptors) have normal growth and glucose regulation. At 4 months, these mice variably display hormonal markers that associate with successful aging counteraction, including elevated adiponectin and FGF21, as well as reduced leptin and IGF-1. Livers of IGF-1R females show decreased transcriptome-based biological age, which may point toward delayed aging and warrants an actual lifespan experiment. These data suggest that KID mutants may slow mammalian aging while they avoid the complications of insulin resistance.
2025-07-18 | From early growth failure to endocrine recovery: Long-term outcomes and GH therapy in SGA and severely preterm children
Background: Children born small for gestational age (SGA) or severely premature (<32 weeks gestation or <1500 g birth weight) are at elevated risk for persistent growth failure and multiple endocrine abnormalities. These include GH–IGF-1 axis dysfunction, insulin resistance, delayed puberty, altered body composition, and neurocognitive impairment. While many catch up by age 2, approximately 10–15% remain short, reflecting partial GH insensitivity. Growth hormone (GH) therapy has emerged as a cornerstone of treatment, though variability in response remains a concern. Objectives: To review the prevalence and clinical impact of endocrine and growth disturbances in children born SGA or severely premature; to evaluate the efficacy and safety of GH therapy; and to identify predictors of therapeutic response and long-term outcomes. Methods: A structured mini-review was conducted using three ESPE abstracts (2025–2026) and 28 peer-reviewed studies published between 2000 and 2025. Included studies addressed GH therapy in SGA or preterm populations and reported outcomes related to height, body composition, metabolic parameters, puberty, bone density, and neurodevelopment. Results were synthesized into six summary tables and four figures, including a forest plot of final height SDS gains. Results: Endocrine abnormalities were highly prevalent: GH–IGF-1 axis dysfunction (60–80%), growth failure (70%), insulin resistance (30–50%), low bone mineral density (40–60%), and delayed puberty (25%). GH therapy significantly improved linear growth (+2.0 to +2.5 SDS), growth velocity (+10 cm/year), and lean body mass (+10–15%), while reducing central adiposity and fracture risk. Weekly GH formulations (somapacitan) matched daily GH in safety and efficacy. Mild, transient insulin resistance was noted in 5–10% of cases. Early treatment (age 2–4 years), low baseline IGF-1, and better nutritional status predicted better outcomes. Neurodevelopmental improvements were suggested but require further study. Conclusion: SGA and severely preterm children who fail to achieve catch-up growth are at high risk for persistent endocrine and metabolic complications. GH therapy offers substantial benefit when started early and tailored to individual risk factors. Long-term follow-up is essential to monitor not only height outcomes but also metabolic health, puberty, and neurocognitive development. Personalized strategies using genotype, weekly GH regimens, and holistic care models are promising next steps in optimizing therapy.
2025-07-05 | Short stature with elevated IGF-1: Diagnostic pitfalls and growth hormone therapy outcomes across etiologies
Background: Short stature in children is typically linked to low insulin-like growth factor 1 (IGF-1), reflecting growth hormone (GH) deficiency or nutritional deprivation. However, a distinct and diagnostically challenging subgroup presents with short stature despite normal or elevated IGF-1 concentrations. This paradox indicates possible underlying resistance to IGF-1 action or dysregulation of the GH-IGF axis. Etiologies include genetic mutations (e.g., IGF1R, STAT5b), syndromic conditions (e.g., Noonan syndrome), endocrine disorders (e.g., hyperthyroidism, insulin resistance), and exogenous GH administration. The growth response to GH therapy in this population varies widely and remains insufficiently characterized in the literature. Objectives: This review aimed to (1) analyze the diverse causes of short stature with elevated IGF-1 levels, (2) assess growth outcomes after GH therapy across distinct etiological categories, and (3) propose diagnostic and therapeutic strategies to individualize care. Methods: A systematic literature review was conducted using PubMed, Scopus, and Web of Science for studies published between 2000 and 2025. Inclusion criteria encompassed pediatric patients with short stature (height SDS < –2), normal to high IGF-1, and reported GH therapy outcomes. Studies were grouped by etiology into seven categories: IGF-1 resistance, GH resistance, syndromic causes, exogenous GH use, endocrine dysregulation, obesity/metabolic factors, and rare genetic syndromes. Data on growth velocity, IGF-1 dynamics, and final height outcomes were extracted. Study quality and therapeutic impact were evaluated using validated scales. Results: GH therapy outcomes were highly variable. Children with IGF1R haploinsufficiency or partial receptor defects showed modest height gains. In contrast, those with GH resistance (e.g., STAT5b mutations) had poor responses, requiring alternate strategies. Syndromic conditions like Noonan syndrome exhibited attenuated GH sensitivity due to downstream pathway disruptions. Exogenous GH use often elevated IGF-1 without proportional linear growth, necessitating dose adjustment. Obese children and those with endocrine dysregulation showed paradoxical IGF-1 elevations but poor growth outcomes unless the underlying metabolic imbalance was corrected. Conclusions: Short stature with elevated IGF-1 is a heterogeneous condition that cannot be managed by uniform GH therapy. Diagnostic precision—integrating clinical, biochemical, and genetic findings—is essential for predicting response and guiding individualized therapy. A precision medicine framework should guide future interventions, including consideration of IGF-1 analogs and metabolic optimization strategies to improve growth outcomes in resistant cases.
2025-06-25 | Muscle in Endocrinology: From Skeletal Muscle Hormone Regulation to Myokine Secretion and Its Implications in Endocrine–Metabolic Diseases
Skeletal muscle, traditionally recognized for its motor function, has emerged as a key endocrine organ involved in metabolic regulation and interorgan communication. This narrative review addresses the dual role of muscle as a target tissue for classical hormones—such as growth hormone (GH), insulin-like growth factor type 1 (IGF-1), thyroid hormones, and sex steroids—and as a source of myokines, bioactive peptides released in response to muscle contraction that exert autocrine, paracrine, and endocrine effects. Several relevant myokines are discussed, such as irisin and Metrnl-like myokines (Metrnl), which mediate exercise-associated metabolic benefits, including improved insulin sensitivity, induction of thermogenesis in adipose tissue, and immunometabolic modulations. It also examines how muscle endocrine dysfunction, caused by chronic inflammation, hormone resistance, or sedentary lifestyle, contributes to the development and progression of metabolic diseases such as obesity, type 2 diabetes, and sarcopenia, highlighting the importance of muscle mass in the prognosis of these pathologies. Finally, the therapeutic potential of interventions aimed at preserving or enhancing muscle function—through physical exercise, hormone therapy and anabolic agents—is highlighted, together with the growing research on myokines as biomarkers and pharmacological targets. This review expands the understanding of muscle in endocrinology, proposing an integrative approach that recognizes its central role in metabolic health and its potential to innovate the clinical management of endocrine–metabolic diseases.
small molecules
2026-09-23 | Beyond insulin-like growth factor-1 (IGF-1) normalization: portal insulin and hepatic growth hormone (GH) sensitivity across metabolic disease.
Clinical management of growth hormone (GH) deficiency, acromegaly, and diabetes mellitus is dominated by single-analyte targets: serum insulin-like growth factor-1 (IGF-1) in the GH disorders and glycated hemoglobin in diabetes. This reductive framework obscures a central regulatory fact: GH does not autonomously dictate hepatic IGF-1 output. Whether GH is translated into IGF-1 by the hepatocyte is gated by the concentration of insulin reaching the liver through the portal vein. We propose liver sensitivity to GH (LSG), operationally defined as portal-insulin-determined hepatic GH receptor (GHR) availability, as a unifying variable that places type 1 and type 2 diabetes, obesity, liver failure, and acromegaly on a single continuum rather than treating them as separate phenomena. We develop the molecular basis of insulin-dependent GHR regulation, distinguish the divergent roles of portal versus systemic insulin, and argue that this distinction explains why subcutaneous insulin therapy in type 1 diabetes corrects glycemia while leaving the hepatic GH-resistant state intact. We then re-examine the weight-gain liability of insulinotropic antidiabetic agents, the discordant GH/IGF-1 signatures produced by GLP-1 receptor agonists, the prognostic and potentially therapeutic role of IGF-1 in cirrhosis, and the metabolic limitations of current acromegaly treatment targets when viewed through the LSG framework. The aim is to give the treating physician a mechanistic, rather than purely biochemical, account of how metabolism behaves in these states.
2026-04-30 | Bifidobacterium animalis subsp. lactis BL-16 fermented Astragali Radix (W16) promotes the bone growth of juvenile rats via modulation of IGF-1 and gut microbiota.
Short stature in children causes physical and psychological issues. Human growth hormone (hGH) is clinically recommended but has side effects. Probiotics and functional foods are promising alternatives. Astragali Radix, has growth-promoting potential, and fermentation may enhance its bioactivity. Astragali Radix, was fermented with Bifidobacterium animalis subsp. lactis BL-16 to prepare postbiotic W16. Juvenile rats were treated with W16, hGH, or unfermented Astragali Radix. UPLC-Q-TOF/MS metabolomic profiling, bone growth-related gene (igf-1, trap) expression, IGF-1 levels, glucose/insulin concentrations, and gut microbiota were analyzed. W16 enhanced rat body/bone length similarly to hGH, upregulated igf-1/trap, and increased plasma/liver IGF-1-more effectively than unfermented Astragali Radix. Unlike hGH, W16 did not induce insulin resistance. While hGH and Astragali Radix enriched Lactobacillus, W16 uniquely promoted Acetivibrio cellulolyticus (beneficial for bone mineral density). Metabolomic profiling revealed pre- and post-fermentation differences in Astragali Radix. Postbiotic W16 promotes bone growth via regulating growth-related genes, IGF-1 signaling, and gut microbiota. Safer than hGH (no insulin resistance), W16 is a promising functional food candidate for improving short stature in children.
2026-04-04 | Early-Life Protein Nutrition and Enzymatic Regulation: Mechanistic Pathways Linking Growth Faltering, Stunting, and Obesity.
Nutrition in the early years has a significant impact on an individual's long-term development patterns and metabolic health via protein intake and enzymatic pathways. The current literature review analyses the coexistence of malnutrition and obesity by associating a shortage of essential amino acids to stunting via impaired mTORC1/IGF-1 signaling, whereas excessive protein intake in early life is linked to accelerated weight gain, increased adiposity, and a heightened risk of insulin resistance. Several molecular mechanisms link these extremes, including AMPK energy sensing, intestinal dysbiosis, and hormonal dysregulation (leptin/ghrelin imbalance). The development of digestive enzymes such as pepsin activation, pancreatic proteases (trypsin week 14-16), lipase (week 21), and brush-border peptidases impacts food absorption, and enzyme deficits aggravate malabsorption in cases of malnutrition. Maternal health status, infections, and exposure to obesogenic diets during the first 1000 days of life significantly increase the risk of impaired gastrointestinal development and nutrient utilization. Integrative interventions like balanced protein formulas, breastfeeding encouragement, lipid-based supplements, malaria management, and enzyme replacement treatments mitigate the negative consequences. Considering the consequences of early dysregulation in cardio-metabolic processes during a lifetime, personalized nutrition and their pathways modulators can play a pivotal role to prevent it.
2026-03-31 | Growth hormone and glycemic metabolism.
Growth hormone (GH) is secreted in a pulsatile pattern and exerts pleiotropic effects on growth and metabolism. Beyond its role in somatic development, GH is a key regulator of glucose homeostasis through its influence on insulin signaling, lipid mobilization, and substrate partitioning. Chronic disturbances of the GH-IGF-1 axis profoundly affect glucose metabolism. In acromegaly, sustained GH and IGF-1 excess induces systemic insulin resistance via direct antagonism of insulin receptor signaling, increased lipolysis, and elevated free fatty acids, ultimately leading to impaired glucose tolerance or overt diabetes in up to half of patients. Conversely, GH deficiency is characterized by visceral adiposity, low IGF-1, and reduced lean mass, changes that also impair insulin sensitivity through distinct mechanisms. These contrasting phenotypes highlight the dual role of GH in modulating insulin action and glucose control. Notably, insulin resistance in acromegaly is paradoxical in that it occurs despite reduced adipose tissue mass, whereas in GH deficiency it is driven by increased fat accumulation. Therapeutic interventions targeting the GH axis -such as transsphenoidal surgery, somatostatin analogues, GH receptor antagonists, and dopamine agonists- have differential effects on glucose homeostasis, ranging from improvement of insulin sensitivity to further impairment depending on the agent. Recognition of these divergent metabolic consequences is critical for personalized management of patients with acromegaly or GH deficiency. Looking ahead, advances in understanding GH-IGF-1-insulin cross-talk and the molecular drivers of insulin resistance may guide the development of novel therapies aimed at optimizing metabolic outcomes in disorders of the GH axis.
2025-11-24 | De-identified raw metabolic data for the four participants.
Background: Growth hormone (GH) is known to affect insulin and glucose metabolism. Blocking its effects in acromegalic patients improves diabetes and glucose metabolism. We aimed to determine the effect of pegvisomant, a GH receptor antagonist, on insulin resistance, endogenous glucose production (EGP) and lipolysis in insulin resistant non-diabetic men. Methods: Four men between the ages of 18-62 with a BMI of 18-35kg/m 2 , with insulin resistance as defined by a HOMA-IR > 2.77, were treated for four weeks with pegvisomant 20 mg daily. Inpatient metabolic assessments were performed before and after treatment. The main outcome measurements were: change after pegvisomant therapy in insulin sensitivity as measured by hyperinsulinemic euglycemic clamp; and EGP and lipolysis assessed by stable isotope tracer techniques. Results: Insulin like growth factor-1 (IGF-1) concentrations decreased from 134.0 ± 41.5 (mean ± SD) to 72.0 ± 11.7 ng/mL (p = 0.04) after 4 weeks of therapy. Whole body insulin sensitivity index (M/I 3.2 ± 1.3 vs. 3.4 ± 2.4; P = 0.82), as well as suppression of EGP (89.7 ± 26.9 vs. 83.5 ± 21.6%; p = 0.10) and Ra glycerol (59.4 ± 22.1% vs. 61.2 ± 14.4%; p = 0.67) during the clamp were not changed significantly with pegvisomant treatment. Conclusions: Blockade of the GH receptor with pegvisomant for four weeks had no significant effect on insulin/glucose metabolism in a small phase II pilot study of non-diabetic insulin resistant participants without acromegaly.
antibodies
2026-02-05 | Analysis of metabolic status and risk factors of small for gestational age children with catch-up growth in East China.
Approximately 85-90% patients with small for gestational age (SGA) experience catch-up growth (CUG) by the age of 2, with their height reaching - 2 standard deviation scores (SDS) or 3% of the height of children of the same age and sex. However, SGA patients with CUG (CUG-SGA) tend to be at a higher risk of developing insulin resistance, obesity, metabolic syndrome, and cardiovascular diseases. This study explored the metabolic conditions of CUG-SGA patients in East China and analyzes the risk factors that may contribute to metabolic issues. This multi-center study in East China involved 151 SGA patients aged 2-8 years. Patients were categorized into two groups: CUG-SGA (height not below - 2 SDS among the children of the same age and gender) and NCUG-SGA (SGA patients without CUG, height below - 2 SDS among the children of the same age and gender). Tests for insulin-like growth factor 1 (IGF-1), blood glucose (BG), insulin (INS), triglycerides (TG), total cholesterol (TC), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and leptin (LEP) were conducted after a 12-hour fast. Body mass index (BMI) and homeostatic model assessment for insulin resistance (HOMA-IR) were calculated. (1) Out of 151 SGA patients, 82 were girls and 69 were boys. There were 85 patients in CUG-SGA group, including 38 girls and 47 boys. There were 66 patients in NCUG-SGA group, including 44 girls and 22 boys. The height SDS (H-SDS) and weight SDS (W-SDS) of CUG-SGA group were significantly higher than those of NCUG-SGA group (P < 0.05). (2) The level of IGF-1 SDS, ALT, and GGT in the CUG-SGA group were significantly higher than those in the NCUG-SGA group (P < 0.01). The level of W-SDS, LEP, INS, and HOMA-IR in the CUG-SGA group are significantly higher than those of the NCUG-SGA group (P < 0.05). (3) Correlation analysis in SGA patients indicated positive correlations between BG and W-SDS, LEP, and GGT (P < 0.05). INS was positively correlated with IGF-1 SDS, GGT (P < 0.01), and W-SDS (P < 0.05). HOMA-IR was positively correlated with IGF-1 SDS (P < 0.01). TC was positively correlated with LEP (P < 0.05), and TG was negatively correlated with IGF-1 SDS (P < 0.01). (4) After further controlling for confounding factors and performing multiple regression analyses, the results showed that BMI-SDS had a significant positive effect on INS and a significant negative effect on HOMA-IR. IGF-1 had a significant positive effect on INS and HOMA-IR, and a significant negative effect on TG. LEP had a significant positive effect on BG, INS, HOMA-IR, TC, and TG. ALT had a significant negative effect on INS and HOMA-IR, and a significant positive effect on TC and TG. GGT had a significant positive effect on BG, INS, HOMA-IR, TC, and TG. (1) IGF-1 SDS was significantly positively correlated with fasting INS (FINS) and HOMA-IR, and exerted a significant positive effect on fasting BG. If IGF-1 levels in CUG-SGA infants remain persistently high, careful monitoring of changes in glucose metabolism is warranted. (2) CUG-SGA patients had higher LEP resistance compared to NCUG-SGA patients, potentially contributing to future metabolic issues. (3) Elevated ALT and GGT levels in SGA patients may warrant close monitoring of glucose metabolism, particularly in CUG-SGA patients.
2024-02-23 | Increased capacity to maintain glucose homeostasis in a transgenic mouse expressing human but not mouse growth hormone with developing high fat diet-related insulin resistance, steatosis and adipose dysfunction
ABSTRACT Objective Differences in primate and non-primate growth hormone (GH) genes can affect their regulation and function. This includes the ability of human (h) but not mouse (m) GH to bind the prolactin (PRL) receptor (PRLR) as well as the GH receptor (GHR). Potential differential effects were assessed in male hGH- or mGH-expressing mice and fed high fat diet (HFD) versus regular chow diet (RCD). Pancreas and epididymal white adipose tissue (eWAT) gene expression and/or related function were targeted as the pancreas responds to both PRLR and GHR signaling and catabolic effects like lipolytic activity are more directly attributable to GH and GHR signaling. Design A transgenic CD-1 mouse expressing hGH but not mGH under hypothalamic control was generated to compare with wild type CD-1 mice and size and bone density determined. Glucose clearance, islet area, insulin and insulin-like growth factor (IGF) -2 gene expression were assessed as well as serum glucose and insulin levels in mice fed a HFD versus RCD for 8 and 24 weeks. Adiposity, liver and serum triglycerides as well as eWAT cell area, cytokine (leptin and adiponectin) and senescence-related marker (p21 CIP1 and p16 INK4a ) RNA levels were also assessed. Results Male hGH-expressing transgenic CD-1[ΔmGH.hGH] mice have significantly lower liver IGF-1 RNA levels and are smaller based on length and weight than wild type CD-1[mGH] mice. They also have ∼1.5-fold higher total body fat and serum triglyceride levels. However, CD-1[ΔmGH.hGH] and CD-1[mGH] mice grow at the same rate with similar cortical and trabecular bone densities. Unlike CD-1[mGH] mice, there was no significant delay in glucose clearance in CD-1[ΔmGH.hGH] mice after 8 weeks on a HFD versus RCD; while basal (RCD) serum insulin levels were similar, fasting glucose levels were lower and pancreas IGF-2 RNA levels were increased in CD-1[ΔmGH.hGH] mice. However, both CD-1[ΔmGH.hGH] and CD-1[mGH] showed evidence of increased insulin resistance after 24 weeks on HFD, including delayed glucose clearance in spite of increased pancreatic islet area and insulin production as well as signs of liver steatosis and increased hepatic triglyceride levels. These increases correlated with elevated PRLR but not GHR RNA levels. Assessment of eWAT revealed >2-fold larger adipocytes in CD-1[ΔmGH.hGH] compared to CD-1 [mGH] mice fed RCD at both 12 and 28 weeks. This was associated with an ∼2.6-fold increase in leptin RNA levels at 12 weeks and ∼58% lower adiponectin RNA levels at 28 weeks. A >2-fold increase in p21 CIP1 transcript levels was also detected in eWAT from both CD-1[ΔmGH.hGH] and CD-1 [mGH] mice fed RCD with age (28 versus 12 weeks) but were unaffected by diet. However, a >2-fold increase in p16 INK4a RNA levels was observed after 24 weeks on HFD. Conclusions While limited to observations in the male, transgenic CD-1[ΔmGH.hGH] mice exhibit signs of GH insufficiency and eWAT adipocyte dysfunction. These mice also show an initial resistance to the negative effects of HFD on glucose clearance when compared to CD-1[mGH] mice, which is potentially related to a differential effect of hGH versus mGH on pancreas development and/or function.
2022-06-24 | Cixutumumab reveals a critical role for IGF-1 in adipose and hepatic tissue remodelling during the development of diet-induced obesity.
High fat diet (HFD)-induced obesity leads to perturbation in the storage function of white adipose tissue (WAT) resulting in deposition of lipids in tissues ill-equipped to deal with this challenge. The role of insulin like growth factor-1 (IGF-1) in the systemic and organ-specific responses to HFD is unclear. Using cixutumumab, a monoclonal antibody that internalizes and degrades cell surface IGF-1 receptors (IGF-1 R), leaving insulin receptor expression unchanged we aimed to establish the role of IGF-1 R in the response to a HFD. Mice treated with cixutumumab fed standard chow developed mild hyperinsulinemia with no change in WAT. When challenged by HFD mice treated with cixutumumab had reduced weight gain, reduced WAT expansion, and reduced hepatic lipid vacuole formation. In HFD-fed mice, cixutumumab led to reduced levels of genes encoding proteins important in fatty acid metabolism in WAT and liver. Cixutumumab protected against blunting of insulin-stimulated phosphorylation of Akt in liver of HFD fed mice. These data reveal an important role for IGF-1 R in the WAT and hepatic response to short-term nutrient excess. IGF-1 R inhibition during HFD leads to a lipodystrophic phenotype with a failure of WAT lipid storage and protection from HFD-induced hepatic insulin resistance.
2017-09-29 | Disrupting IGF Signaling in Adult Mice Conditions Leanness, Resilient Energy Metabolism, and High Growth Hormone Pulses.
Growth hormone (GH) and insulinlike growth factor (IGF) promote aging and age-related pathologies. Inhibiting this pathway by targeting IGF receptor (IGF-1R) is a promising strategy to extend life span, alleviate age-related diseases, and reduce tumor growth. Although anti-IGF-1R agents are being developed, long-term effects of IGF-1R blockade remain unknown. In this study, we used ubiquitous inducible IGF-1R knockout (UBIKOR) to suppress signaling in all adult tissues and screened health extensively. Surprisingly, UBIKOR mice showed no overt defects and presented with rather inconspicuous health, including normal cognition. Endocrine GH and IGF-1 were strongly upregulated without causing acromegaly. UBIKOR mice were strikingly lean with coordinate changes in body composition and organ size. They were insulin resistant but preserved physiological energy expenditure and displayed enhanced fasting metabolic flexibility. Thus, long-term IGF-1R blockade generated beneficial effects on aging-relevant metabolism, but exposed to high GH. This needs to be considered when targeting IGF-1R to protect from neurodegeneration, retard aging, or fight cancer.
2015-01-09 | Improved glucose metabolism in vitro and in vivo by an allosteric monoclonal antibody that increases insulin receptor binding affinity.
Previously we reported studies of XMetA, an agonist antibody to the insulin receptor (INSR). We have now utilized phage display to identify XMetS, a novel monoclonal antibody to the INSR. Biophysical studies demonstrated that XMetS bound to the human and mouse INSR with picomolar affinity. Unlike monoclonal antibody XMetA, XMetS alone had little or no agonist effect on the INSR. However, XMetS was a strong positive allosteric modulator of the INSR that increased the binding affinity for insulin nearly 20-fold. XMetS potentiated insulin-stimulated INSR signaling ∼15-fold or greater including; autophosphorylation of the INSR, phosphorylation of Akt, a major enzyme in the metabolic pathway, and phosphorylation of Erk, a major enzyme in the growth pathway. The enhanced signaling effects of XMetS were more pronounced with Akt than with Erk. In cultured cells, XMetS also enhanced insulin-stimulated glucose transport. In contrast to its effects on the INSR, XMetS did not potentiate IGF-1 activation of the IGF-1 receptor. We studied the effect of XMetS treatment in two mouse models of insulin resistance and diabetes. The first was the diet induced obesity mouse, a hyperinsulinemic, insulin resistant animal, and the second was the multi-low dose streptozotocin/high-fat diet mouse, an insulinopenic, insulin resistant animal. In both models, XMetS normalized fasting blood glucose levels and glucose tolerance. In concert with its ability to potentiate insulin action at the INSR, XMetS reduced insulin and C-peptide levels in both mouse models. XMetS improved the response to exogenous insulin without causing hypoglycemia. These data indicate that an allosteric monoclonal antibody can be generated that markedly enhances the binding affinity of insulin to the INSR. These data also suggest that an INSR monoclonal antibody with these characteristics may have the potential to both improve glucose metabolism in insulinopenic type 2 diabetes mellitus and correct compensatory hyperinsulinism in insulin resistant conditions.
gene therapies
2026-06-15 | GH-resistant (Laron) mice: gene therapy with a liver-specific GH receptor causes unbalanced upregulation of female-biased and growth-related genes.
Growth hormone (GH) receptor (GHR) mutations give rise to GH-resistance (Laron syndrome). We previously treated GH-resistant Ghr-/- mice (Laron mice) with adeno-associated virus (AAV) delivering mouse (m)Ghr controlled by a constitutively active liver-specific promoter (HLP). A single injection of AAV-HLP-mGHR resulted in a significant but limited increase in body length and weight, consistent with studies of IGF-1 treatment in humans and mice. Here, we performed RNA-seq on male and female mouse livers comprising the following groups: GHR+/+ (wild-type), GHR-/- (Laron), AAV-HLP-mGHR-treated GHR-/- (treatment group), and AAV-HLP-Luc (Luciferase)-treated GHR-/- (control group). Only four genes showed significant differential expression in GHR -/- mouse liver following Luciferase vector treatment, indicating minimal effect of the AAV-HLP vector. AAV-HLP-mGHR stimulated significant expression changes in 448 genes compared to AAV-HLP-Luc control, substantially fewer than the 2781 genes whose expression was altered in GHR-/- compared to GHR+/+. AAV-HLP-mGHR treatment induced the GH-responsive IGF signaling genes Igf1 and Igfals ~16-fold compared to AAV-HLP-Luc control, but only to 40-45% of GHR+/+ liver levels. The treatment also upregulated a small subset of genes beyond GHR+/+ expression levels (p-adj < 0.05), including the proto-oncogenes Ascl1, Tmprss4, and others. Finally, genes dysregulated upon GHR loss and upregulated in livers of AAV-HLP-mGHR-treated mice were significantly enriched for sex-biased genes, consistent with the major role of GH and GHR in regulating liver sex differences. While gene replacement therapy is a potential therapy for Laron syndrome, an unregulated constitutively active promoter may drive unexpected and unbalanced changes in liver gene expression that will require monitoring.
2025-08-30 | Injection of lentiviral vectors expressing GH and IGF1 increases body and muscle mass in male rats.
The aim of this study was to increase growth hormone (GH1) and insulin-like growth factor-1 (IGF1) levels in rat muscle indirectly through the transduction of C2C12 cells via lentivectors and to compare their effects on muscle mass. The coding sequences of GH1, IGF1, and GH1-IGF1, linked by the 2 A self-cleaving peptide to enable polycistronic expression, were synthesized, cloned and inserted into the pCDH vector. Recombinant pseudolentiviruses containing our target genes were produced in HEK293T cells. C2C12 cells were transduced with pseudo lentiviruses and selected through resistance to puromycin antibiotics. The expression of the GH1 and IGF1 genes at the mRNA and protein levels was verified by RT-PCR and Western blotting, respectively. The recombinant pseudo lentiviruses and transduced C2C12 cells were injected into the tibialis anterior (TA), gastrocnemius and quadriceps muscle groups of eight-week-old rats. The body weights of the rats were measured weekly for eight weeks after the injection. The leg weight and histology of the muscle after eight weeks were also measured. The results revealed the expression of the GH1 and IGF1 genes at the mRNA and protein levels in C2C12 cells. An increase in both hormones, either directly or indirectly through C2C12 cells, increased the animal body weight, leg weight, and muscle fibre size after eight weeks. The direct and indirect transfer of IGF1 increased body weight, leg weight and muscle fibre size more than did the direct or indirect transfer of GH1. In the direct transfer groups, the body weight was greater than that in the indirect transfer groups after eight weeks. We demonstrated that nonpituitary secretion of GH1 mimicked some physiological effects of pituitary GH1 in a rat model. Further investigations are needed to study other possible effects of extra copy of GH1 and IGF1 genes over a longer period on other tissues.
2022-09-14 | Disruption of Growth Hormone Receptor in Adipocytes Improves Insulin Sensitivity and Lifespan in Mice.
Growth hormone receptor knockout (GHRKO) mice have been used for 25 years to uncover some of the many actions of growth hormone (GH). Since they are extremely long-lived with enhanced insulin sensitivity and protected from multiple age-related diseases, they are often used to study healthy aging. To determine the effect that adipose tissue has on the GHRKO phenotype, our laboratory recently created and characterized adipocyte-specific GHRKO (AdGHRKO) mice, which have increased adiposity but appear healthy with enhanced insulin sensitivity. To test the hypothesis that removal of GH action in adipocytes might partially replicate the increased lifespan and healthspan observed in global GHRKO mice, we assessed adiposity, cytokines/adipokines, glucose homeostasis, frailty, and lifespan in aging AdGHRKO mice of both sexes. Our results show that disrupting the GH receptor gene in adipocytes improved insulin sensitivity at advanced age and increased lifespan in male AdGHRKO mice. AdGHRKO mice also exhibited increased fat mass, reduced circulating levels of insulin, c-peptide, adiponectin, resistin, and improved frailty scores with increased grip strength at advanced ages. Comparison of published mean lifespan data from GHRKO mice to that from AdGHRKO and muscle-specific GHRKO mice suggests that approximately 23% of lifespan extension in male GHRKO is due to GHR disruption in adipocytes vs approximately 19% in muscle. Females benefited less from GHR disruption in these 2 tissues with approximately 19% and approximately 0%, respectively. These data indicate that removal of GH's action, even in a single tissue, is sufficient for observable health benefits that promote long-term health, reduce frailty, and increase longevity.
2022-06-20 | First use of gene therapy to treat growth hormone resistant dwarfism in a mouse model.
The only treatment tested for growth hormone receptor (GHR) defective Laron Syndrome (LS) is injections of recombinant insulin-like-growth factor 1 (rhIGF1). The response is suboptimal and associated with progressive obesity. In this study, we treated 4-5-week-old Laron dwarf mice (GHR-/-) with an adeno-associated virus expressing murine GHR (AAV-GHR) injection at a dose of 4 × 1010 vector genome per mouse. Serum growth hormone (GH) levels decreased, and GH-responsive IGF1, IGF binding protein 3 (IGFBP3) and acid labile subunit (ALS) increased. There was a significant but limited increase in body weight and length, similar to the response to rhIGF1 treatment in LS patients. All the major organs increased in weight except the brain. Our study is the first to use gene therapy to treat GH-receptor deficiency. We propose that gene therapy with AAV-GHR may eventually be useful for the treatment of human LS.
2017-05-31 | Growth Hormone Control of Hepatic Lipid Metabolism.
In humans, low levels of growth hormone (GH) and its mediator, IGF-1, associate with hepatic lipid accumulation. In mice, congenital liver-specific ablation of the GH receptor (GHR) results in reductions in circulating IGF-1 and hepatic steatosis, associated with systemic insulin resistance. Due to the intricate relationship between GH and IGF-1, the relative contribution of each hormone to the development of hepatic steatosis is unclear. Our goal was to dissect the mechanisms by which hepatic GH resistance leads to steatosis and overall insulin resistance, independent of IGF-1. We have generated a combined mouse model with liver-specific ablation of GHR in which we restored liver IGF-1 expression via the hepatic IGF-1 transgene. We found that liver GHR ablation leads to increases in lipid uptake, de novo lipogenesis, hyperinsulinemia, and hyperglycemia accompanied with severe insulin resistance and increased body adiposity and serum lipids. Restoration of IGF-1 improved overall insulin sensitivity and lipid profile in serum and reduced body adiposity, but was insufficient to protect against steatosis-induced hepatic inflammation or oxidative stress. We conclude that the impaired metabolism in states of GH resistance results from direct actions of GH on lipid uptake and de novo lipogenesis, whereas its actions on extrahepatic tissues are mediated by IGF-1.
other
2023-01-23 | Probiotic Paenibacillus polymyxa HGA4C and Bacillus licheniformis HGA8B combination improved growth performance, enzymatic profile, gene expression and disease resistance in Oreochromisniloticus.
Bacterial consortium containing two bacterial strains such as Paenibacillus polymyxa HGA4C and Bacillus licheniformis HGA8B incorporated in the diet of Oreochromis niloticus at a concentration of 1 × 106 CFU g-1 (PB1) and 1 × 108 CFU g-1 (PB2) revealed the probiotic potentials of the bacterial combination. The probiotic feed enhanced the growth performance, digestive enzymes, and antioxidant enzymes in the liver and intestine. Probiotic mediated growth enhancement was further substantiated by the up-regulation of genes such as GHR-1, GHR-2, IGF-1, and IGF-2 and the up-regulation of immune-related genes viz. TLR-2, IL-10, and TNF-α were also significantly modulated by probiotics supplementation. The intestinal MUC 2 gene expression revealed the mucosal remodification and the disease resistance of the fish challenged with Aeromonas hydrophila (MTCC-1739) was improved by the probiotic supplementation. Based on these results the new probiotic supplementation feed can be possibly marketed to help aquaculture farmers to alleviate many of the problems associated with fish farming.
2017-06-05 | Long-lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high-fat diet on metabolic function and energy expenditure.
Growth hormone (GH) signaling stimulates the production of IGF-1; however, increased GH signaling may induce insulin resistance and can reduce life expectancy in both mice and humans. Interestingly, disruption of GH signaling by reducing plasma GH levels significantly improves health span and extends lifespan in mice, as observed in Ames dwarf mice. In addition, these mice have increased adiposity, yet are more insulin sensitive compared to control mice. Metabolic stressors such as high-fat diet (HFD) promote obesity and may alter longevity through the GH signaling pathway. Therefore, our objective was to investigate the effects of a HFD (metabolic stressor) on genetic mechanisms that regulate metabolism during aging. We show that Ames dwarf mice fed HFD for 12 weeks had an increase in subcutaneous and visceral adiposity as a result of diet-induced obesity, yet are more insulin sensitive and have higher levels of adiponectin compared to control mice fed HFD. Furthermore, energy expenditure was higher in Ames dwarf mice fed HFD than in control mice fed HFD. Additionally, we show that transplant of epididymal white adipose tissue (eWAT) from Ames dwarf mice fed HFD into control mice fed HFD improves their insulin sensitivity. We conclude that Ames dwarf mice are resistant to the detrimental metabolic effects of HFD and that visceral adipose tissue of Ames dwarf mice improves insulin sensitivity in control mice fed HFD.
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Drug Discovery Landscape
1 orphan drug designation for Growth delay due to insulin-like growth factor I resistance, including 1 approved therapy.
1 orphan drug designation for Growth delay due to insulin-like growth factor I resistance, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
somatropin [rDNA] [Genotropin] | proteins | FDA | Approved | Pharmacia and Upjohn Company |
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