Low Serum Insulin-like Growth Factor-1 Research Articles

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

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

Lower serum insulin-like growth factor 2 level in patients with bipolar disorder is associated with the severity of manic symptoms during manic episodes.

Accumulating evidence has indicated that neurodevelopmental defects may underlie the pathophysiology of bipolar disorder (BD). Insulin-like growth factors (IGFs) are a family of neurotrophic factors that are essential for the survival and development of neurons. The present study aims to investigate whether IGF-2 signaling is implicated in the pathophysiological processes of BD. 50 healthy controls and 78 patients with BD, including 23 patients who diagnosed acute depressive episode and 55 patients who diagnosed acute manic episode, were recruited in this study. The 17-item Hamilton Depression Rating Scale (HAMD-17) and the Young Mania Rating Scale (YMRS) were used to assess the severity of the depressive and manic symptoms, respectively. The serum IGF-2 level was determined by an enzyme-linked immunosorbent assay (ELISA). The Kolmogorov-Smirnov and Mann-Whitney U tests were used for between-group comparisons and spearman analysis was used to analyze correlations. Patients with BD had lower serum IGF-2 levels (66.08 ± 21.22 ng/ml) when compared to healthy controls (88.72 ± 31.55 ng/ml). BD patients were divided into manic episode and depressive episode subgroups. We found that serum IGF-2 levels were reduced in both the mania and depression subgroups (mania: 67.19 ± 21.52 ng/ml, depression: 63.43 ± 20.67 ng/ml; P < 0.001), while no significant difference was observed between two groups (P > 0.05). Spearman correlation analyses revealed that the levels of serum IGF-2 were negatively correlated with the YMRS scores in BD patients (r = -0.522, P < 0.001). Furthermore, IGF-2 was found to be an independent contributor to the severity of symptoms in patients with manic episodes (B = -0.610, t = -5.299, P < 0.001). Lower serum IGF-2 levels were found in BD patients and correlated with the severity of the manic symptoms in these patients during manic episodes. These results suggest that reduced IGF-2 levels might be involved in the pathophysiology of BD, and serum IGF-2 could be a peripheral biomarker for the evaluation of the severity of manic symptoms in BD patients.

Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition

Genome-wide association studies (GWAS) have identified a large number of candidate genes believed to affect longitudinal bone growth and bone mass. One of these candidate genes, TMEM263, encodes a poorly characterized plasma membrane protein. Single nucleotide polymorphisms in TMEM263 are associated with bone mineral density in humans and mutations are associated with dwarfism in chicken and severe skeletal dysplasia in at least one human fetus. Whether this genotype-phenotype relationship is causal, however, remains unclear. Here, we determine whether and how TMEM263 is required for postnatal growth. Deletion of the Tmem263 gene in mice causes severe postnatal growth failure, proportional dwarfism, and impaired skeletal acquisition. Mice lacking Tmem263 show no differences in body weight within the first 2 weeks of postnatal life. However, by P21 there is a dramatic growth deficit due to a disrupted growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, which is critical for longitudinal bone growth. Tmem263-null mice have low circulating IGF-1 levels and pronounced reductions in bone mass and growth plate length. The low serum IGF-1 in Tmem263-null mice is associated with reduced hepatic GH receptor (GHR) expression and GH-induced JAK2/STAT5 signaling. A deficit in GH signaling dramatically alters GH-regulated genes and feminizes the liver transcriptome of Tmem263-null male mice, with their expression profile resembling wild-type female, hypophysectomized male, and Stat5b-null male mice. Collectively, our data validates the causal role for Tmem263 in regulating postnatal growth and raises the possibility that rare mutations or variants of TMEM263 may potentially cause GH insensitivity and impair linear growth.

Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition.

Genome-wide association studies (GWAS) have identified a large number of candidate genes believed to affect longitudinal bone growth and bone mass. One of these candidate genes, TMEM263, encodes a poorly characterized plasma membrane protein. Single nucleotide polymorphisms in TMEM263 are associated with bone mineral density in humans and mutations are associated with dwarfism in chicken and severe skeletal dysplasia in at least one human fetus. Whether this genotype-phenotype relationship is causal, however, remains unclear. Here, we determine whether and how TMEM263 is required for postnatal growth. Deletion of the Tmem263 gene in mice causes severe postnatal growth failure, proportional dwarfism, and impaired skeletal acquisition. Mice lacking Tmem263 show no differences in body weight within the first 2 weeks of postnatal life. However, by P21 there is a dramatic growth deficit due to a disrupted growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, which is critical for longitudinal bone growth. Tmem263-null mice have low circulating IGF-1 levels and pronounced reductions in bone mass and growth plate length. The low serum IGF-1 in Tmem263-null mice is associated with reduced hepatic GH receptor (GHR) expression and GH-induced JAK2/STAT5 signaling. A deficit in GH signaling dramatically alters GH-regulated genes and feminizes the liver transcriptome of Tmem263-null male mice, with their expression profile resembling wild-type female, hypophysectomized male, and Stat5b-null male mice. Collectively, our data validates the causal role for Tmem263 in regulating postnatal growth and raises the possibility that rare mutations or variants of TMEM263 may potentially cause GH insensitivity and impair linear growth.

Association between serum insulin-like growth factor 1 levels and the improvements of cognitive impairments in a subgroup of schizophrenia: Preliminary findings

BackgroundNumerous studies have implicated abnormal insulin-like growth factor 1 (IGF-1) in the pathophysiology of schizophrenia, but findings have been inconsistent. MethodsWe conducted a meta-analysis to compare IGF-1 levels in schizophrenia patients with healthy controls and explored factors contributing to variability between estimates. In an independent sample (58 chronic schizophrenia patients and 30 healthy controls), we investigated differences in IGF-1 levels among schizophrenia subgroups with distinct cognitive profiles, identified using k-means clustering based on five cognitive domains from The Repeatable Battery for the Assessment of Neuropsychological Status. Associations between serum IGF-1 levels and clinical and neurocognitive improvements were also examined. ResultsThe meta-analysis revealed significantly lower serum IGF-1 levels in schizophrenia patients compared to healthy controls, albeit with high heterogeneity. Medication status, BMI, and severity of negative symptoms were identified as potential contributors to this heterogeneity. In our independent study, antipsychotic treatment led to a significant increase in IGF-1 levels, and lower pre-treatment serum IGF-1 levels correlated with greater improvement in cognitive deficits, particularly in a subgroup with more severe cognitive symptoms. ConclusionsOur findings support the “IGF-1 deficiency hypothesis” in the pathogenesis of schizophrenia. Further research is crucial to elucidate the role of IGF-1 in the cognitive impairments associated with schizophrenia.

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

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

Lower serum insulin-like growth factor-1 levels are independently associated with anemia in patients undergoing maintenance hemodialysis

The relationship between serum insulin-like growth factor-1 (IGF-1) levels and anemia in patients undergoing maintenance hemodialysis (MHD) remains unclear. This cross-sectional study included patients who underwent MHD treatment for >3 months at our dialysis center in March 2021. Demographic and clinical data were recorded. Blood samples were collected before the hemodialysis sessions, and general serum biochemical parameters, routine blood markers, and serum IGF-1 levels were measured. Patients were divided into a group without anemia (hemoglobin ≥110 g/L) and a group with anemia (hemoglobin <110 g/L), and multivariable linear and binary logistic regression analyses were performed to study the relationship between the levels of serum IGF-1 and anemia. A total of 165 patients (male/female = 99:66) with MHD were enrolled in the study, with a median age of 66.0 (58.0, 75.0) years and a median dialysis vintage of 27.0 (12.0, 55.0) months. The mean hemoglobin level was 96.38 ± 16.72 g/L, and 126 patients had anemia (76.4%). Compared to patients without anemia, patients with anemia had lower serum IGF-1 and triglyceride levels and higher intravenous iron supplementation on dialysis (all p < 0.05). After adjusting for confounding factors in different models, the nine-model multivariate binary logistic regression analyses also confirmed that lower serum IGF-1 levels and serum IGF-1 < 197.03 ng/ml were both independently associated with anemia in patients undergoing MHD. However, further multicenter studies with larger sample sizes are required to confirm these findings.

Structural and proteomic repercussions of growth hormone receptor deficiency on the pituitary gland: Lessons from a translational pig model.

Growth hormone receptor deficiency (GHRD) results in low serum insulin-like growth factor 1 (IGF1) and high, but non-functional serum growth hormone (GH) levels in human Laron syndrome (LS) patients and animal models. This study investigated the quantitative histomorphological and molecular alterations associated with GHRD. Pituitary glands from 6 months old growth hormone receptor deficient (GHR-KO) and control pigs were analyzed using a quantitative histomorphological approach in paraffin (9 GHR-KO [5 males, 4 females] vs. 11 controls [5 males, 6 females]), ultrathin sections tissue sections (3 male GHR-KO vs. 3 male controls) and label-free proteomics (4 GHR-KO vs. 4 control pigs [2 per sex]). GHR-KO pigs displayed reduced body weights (60% reduction in comparison to controls; p < .0001) and decreased pituitary volumes (54% reduction in comparison to controls; p < .0001). The volume proportion of the adenohypophysis did not differ in GHR-KO and control pituitaries (65% vs. 71%; p = .0506) and GHR-KO adenohypophyses displayed a reduced absolute volume but an unaltered volume density of somatotrophs in comparison to controls (21% vs. 18%; p = .3164). In GHR-KO pigs, somatotroph cells displayed a significantly reduced volume density of granules (23.5%) as compared to controls (67.7%; p < .0001). Holistic proteome analysis of adenohypophysis samples identified 4660 proteins, of which 592 were differentially abundant between the GHR-KO and control groups. In GHR-KO samples, the abundance of somatotropin precursor was decreased, whereas increased abundances of proteins involved in protein production, transport and endoplasmic reticulum (ER) stress were revealed. Increased protein production and secretion as well as significantly reduced proportion of GH-storing granules in somatotroph cells of the adenohypophysis without an increase in volume density of somatotroph cells in the adenohypophysis could explain elevated serum GH levels in GHR-KO pigs.

Lower serum insulin-like growth factor 1 concentrations in patients with chronic insomnia disorder.

Insulin-like growth factor 1 (IGF-1) is a crucial neurotrophin that is produced in the brain and periphery and may play an important role in insomnia and mood disorders. We aimed to analyze its serum concentrations in patients with chronic insomnia disorder (CID). Patients with CID were enrolled in this study and divided into the CID group [Generalized Anxiety Disorder-7 (GAD-7) score < 10] and the CID with anxiety group (GAD-7 score ≥ 10). Age-and sex-matched healthy volunteers were recruited as controls. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality and the GAD-7 and the Patient Health Questionnaire-9 to assess emotional status. All subjects were monitored via polysomnography, and the serum IGF-1 concentrations in their peripheral blood were detected via enzyme-linked immunosorbent assays. We enrolled 65 patients with CID (of whom 35 had anxiety) and 36 controls. The PSQI score and IGF-1 concentration in the CID and CID with anxiety groups were higher than those in the control group. The apparent difference in IGF-1 concentration between the CID and CID with anxiety groups was not statistically significant. The IGF-1 concentration in patients with CID was linearly correlated with the GAD-7 score, PSQI score, and stage 3 non-rapid eye movement (stage N3) time. The serum IGF-1 concentration in patients with CID was lower than that of participants without CID, negatively correlated with anxiety score and sleep quality, and positively correlated with stage N3 time.

The Impaired Growth Induced by Zinc Deficiency in Rats Is Associated with Decreased Expression of the Hepatic Insulin-like Growth Factor I and Growth Hormone Receptor Genes

This study was conducted to determine whether dietary zinc status affects the expression of the insulin-like growth factor I and growth hormone receptor/growth hormone binding protein genes in the liver of growing rats. Weanling male Sprague-Dawley rats were randomly allotted to zinc-deficient, pair-fed or ad libitum-fed dietary treatments and fed diets containing no added zinc for 14 d. Zinc acetate was added to the deionized, distilled water (30 mg/L) provided to pair-fed and ad libitum-fed rats. As expected, zinc deficiency significantly reduced growth rate by 60% and was associated with a significantly lower serum insulin-like growth factor I concentration (46 and 67% lower than pair-fed and ad libitum-fed rats, respectively). The reduction in serum insulin-like growth factor I concentration was associated with a decrease in insulin-like growth factor I gene expression. The abundance of the 7.5-kb insulin-like growth factor I mRNA transcript in zinc-deficient and pair-fed rats was 14 and 31% that of the ad libitum-fed rats. The 0.8–1.2-kb insulin-like growth factor I transcript also was significantly lower in the zinc-deficient and pair-fed rats. In contrast, the abundance of the 1.8-kb insulin-like growth factor I transcript was unaffected by zinc deficiency. The growth hormone receptor mRNA levels of zinc-deficient and pair-fed rats were 17 and 50% and their growth hormone binding protein mRNA levels were 46 and 65% those of the ad libitum-fed rats. In summary, zinc deficiency markedly decreases expression of the insulin-like growth factor I and growth hormone receptor genes. The mechanisms that account for the decreases are obscure. Nonetheless, our results indicate that the growth retardation caused by zinc deficiency is associated with defects in the growth hormone receptor signaling pathway.

CTCF variant begets to short stature by down-regulation of IGF1.

Pathogenic variants in the transcription factor CCCTC-binding factor (CTCF) are associated with mental retardation, autosomal dominant 21 (MRD21, MIM#615502). Current studies supported the strong relationship between CTCF variants and growth, yet the mechanism of CTCF mutation leading to short stature is not known. Clinical information, treatment regimens, and follow-up outcomes of a patient with MRD21 were collected. The possible pathogenic mechanisms of CTCF variants leading to short stature were investigated using immortalized lymphocyte cell lines (LCLs), HEK-293T, and immortalized normal human liver cell lines (LO2). This patient received long-term treatment with recombinant human growth hormone (rhGH) which resulted in an increased height of 1.0 SDS. She had low serum insulin-like growth factor 1 (IGF1) before the treatment and the IGF1 level was not significantly increased during the treatment (-1.38 ± 0.61 SDS). The finding suggested that the CTCF R567W variant could have impaired IGF1 production pathway. We further demonstrated that the mutant CTCF had a reduced ability to bind to the promoter region of IGF1, consequently significantly reducing the transcriptional activation and expression of IGF1. Our novel results demonstrated a direct positive regulation of CTCF on the transcription of the IGF1 promoter. The impaired IGF1 expression due to CTCF mutation may explain the substandard effect of rhGH treatment on MRD21 patients. This study provided novel insights into the molecular basis of CTCF-associated disorder.

Association between Bone-Related Physiological Substances and Oral Function in Community-Dwelling Older People.

Background: Oral dysfunction is related to long-term cares including activities of daily living. The objective of this study was to determine the association between oral function and the bone-related physiological substances osteocalcin (OC) and insulin-like growth factor-1 (IGF-1). Methods: The study participants were 139 community-dwelling older people in Japan. Evaluation of oral dysfunction was based on subjective judgment by each participant. Blood analysis included OC, IGF-1, and albumin. Results: Univariate and multiple logistic analyses showed that IGF-1 was significantly associated with a “decline in masticatory function” (p = 0.0074 and p = 0.0308, respectively). Receiver operating characteristic curve analysis of IGF-1 levels revealed a threshold score of 108 ng/mL (p < 0.01) for discriminating a “decline in masticatory function”. Logistic regression analysis revealed that participants with an IGF-1 level ≤108 ng/mL had an odds ratio of 4.31 (p < 0.05) for a “decline in masticatory function”. No significant association was found between the OC level and oral dysfunction. Conclusions: These results suggest a possible relationship between lower serum IGF-1 levels and a decline in masticatory dysfunction in community-dwelling older people.

Alterations in the fecal microbiota and serum metabolome in unstable angina pectoris patients.

Unstable angina pectoris (UAP) is a type of Coronary artery disease (CAD) characterized by a series of angina symptoms. Insulin-like growth factor 1 (IGF-1) system may be related to CAD. However, the correlation between the IGF-1 system, metabolism, and gut microbiota has not been studied. In the present study, we investigated the alterations of serum IGF-1 system, metabolomics, and gut microbiota in patients with UAP. Serum and stool samples from healthy volunteers and UAP patients were collected. Serum metabolomics, PAPP-A, IGF-1, IGFBP-4, STC2, hs-CRP, TNF-α, and IL-6 were detected in serum samples by LC-MS, and commercial ELISA kits, respectively. Fecal short-chain fatty acids (SCFAs) were measured by gas chromatography. 16S rDNA was used to measure the changes of the gut microbiota. The correlation of the above indicators was analyzed. There were 24 upregulated and 31 downregulated metabolites in the serum of UAP patients compared to those in the controls. Pathway analysis showed that these metabolites were enriched in pathways including linoleic acid metabolism, amino acid metabolism, starch metabolism, sucrose metabolism, and citrate cycle (TCA cycle), etc. Additionally, the UAP patients had lower fecal levels of 2-hydroxyisobutyric acid and succinic acid. 16S rDNA sequencing results showed that the relative abundances of Bacteroidetes, Synergistetes, Lactobacillaceae, Burkholderiaceae, Synergistaceae, and Subdoligranulum were significantly higher in the UAP patients than the healthy subjects. Moreover, the UAP patients had lower serum IGF-1, IGFBP-4, and STC2 and higher serum inflammatory cytokines (hs-CRP, TNF-α, and IL-6) levels than the healthy controls. Furthermore, there was a strong correlation between serum amino acids and IL-6, which played an important role in the development of UAP. These results indicated that the UAP patients had decreased serum IGF-1 level and imbalanced amino acids metabolism, which may be caused by the altered gut microbiota. It may provide a new therapeutic strategy for unstable angina pectoris.

Low bone mass in Noonan syndrome children correlates with decreased muscle mass and low IGF-1 levels.

Although musculoskeletal abnormalities have long been described in patients with Noonan syndrome (NS), only a few studies have investigated the bone status of these patients. The aim of this retrospective observational study was to describe the bone health of children with NS. Thirty-five patients with a genetically confirmed diagnosis of NS were enrolled. We analyzed the axial skeleton (lumbar spine) using dual energy X-ray absorptiometry and the appendicular skeleton (hand) with the BoneXpert system. Bone metabolism markers, including mineral homeostasis parameters, serum 25-hydroxy vitamin D (25-OHD) levels and markers of bone formation and resorption were also reported. Compared to the general population, axial and appendicular bone mass was significantly decreased in children with NS (p<0.0001). Serum 25-OHD levels were low in about half of the patients and were negatively correlated with age (r=-0.52; p<0.0001). Patients with NS exhibited reduced bone formation marker levels and increased bone resorption marker levels (p<0.0001). No gender difference or genotype-phenotype correlations were found for the different bone parameters. Muscle mass and, to a lesser extent, serum insulin-like growth factor 1 (IGF-1) levels were independent predictors of whole-body bone mineral content (p<0.0001 for both parameters; adjusted R2=0.97). In conclusion, bone mass is reduced in children with NS and correlates with decreased muscle mass and low serum IGF-1 levels. These data justify addressing all potential threats to bone health including sufficient calcium and vitamin D intake, regular physical exercise, and hormone replacement therapy.

Associations of Serum Insulin-Like Growth Factor 1 with New Cardiovascular Events and Subsequent Death in Hemodialysis Patients: The DREAM Cohort.

Aim: Patients with chronic kidney disease (CKD) have elevated risk of death from cardiovascular disease (CVD). A low serum insulin-like growth factor 1 (IGF-1) level is known to predict higher risk for all-cause mortality in incident dialysis patients, although it is unknown whether IGF-1 predicts cardiovascular outcomes. Methods: This was a prospective cohort study of maintenance hemodialysis patients followed up for 5 years. Serum IGF-1 levels were measured at baseline, and patients were divided into IGF-1 tertiles. The key outcomes were all-cause mortality, a composite of new CVD, and death after new CVD events. Additional outcomes were hospitalization for infection and subsequent death. Association was analyzed using Cox proportional hazards models. Results: In the 516 patients that were analyzed, we identified 106 all-cause deaths, 190 new CVD events, and 61 subsequent deaths. In addition, there were 169 hospitalizations for infection and 47 subsequent deaths. The risk of all-cause death was the highest in the lowest IGF-1 tertile, and this association remained significant in multivariable-adjusted models. Regarding CVD outcomes, IGF-1 was not associated with new CVD events but significantly associated with subsequent death in adjusted models. Similarly, IGF-1 was not an independent predictor of hospitalization for infection, but it predicted subsequent death. Conclusions: A low IGF-1 level was not a significant predictor of new CVD events but an independent predictor of subsequent death in hemodialysis patients. Since similar associations with infection outcomes were observed, IGF-1 may be a biomarker of fragility or frailty in this population.

A low serum IGF-1 is correlated with sarcopenia in subjects with type 1 diabetes mellitus: Findings from a post-hoc analysis of the iDIAMOND study

AimOur previous study revealed that sarcopenia was frequently observed in subjects with type 1 diabetes mellitus (T1DM). However, the factors associated with sarcopenia that are related to T1DM have not yet been clarified. Insulin-like growth factor-1 (IGF-1) has been shown to play a role in skeletal muscle growth, differentiation, and regeneration. The present study, therefore, investigated the association between the serum IGF-1 level and sarcopenia and low skeletal muscle mass in subjects with T1DM. MethodsThis cross-sectional study enrolled subjects with T1DM (n = 168) and without diabetes (n = 59) who had had their clinical data on serum IGF-1 collected in the iDIAMOND study. ResultsThe z-score of serum IGF-1 was significantly lower in the subjects with T1DM than that in those without diabetes (p < 0.001). Among subjects with T1DM, the z-score of serum IGF-1 was significantly lower in sarcopenic subjects than in non-sarcopenic subjects. The multivariable logistic regression analysis showed that the serum IGF-1 z-score was an independent determinant of sarcopenia and a low skeletal muscle mass index, but not low grip strength nor slow gait speed in subjects with T1DM. ConclusionsA low serum IGF-1 level is correlated with sarcopenia and low skeletal muscle mass in subjects with T1DM.

The Association of Insulin-Like Growth Factor-1 With Bone Mineral Density in Survivors of Childhood Acute Leukemia

Abstract Background: The purpose of the current study is to investigate bone mineral deficit of children in survivors of childhood acute leukemia and examine the association of insulin-like growth factor-1 (IGF-1) with bone mineral density (BMD) status and the presence of osteoporosis. Methods: In a cross-sectional study of children diagnosed with different types of acute leukemia at age between 6 months and 18 years, serum IGF-1 and IGFBP-3, were assessed in relation to lumbar spine BMD (LSBMD) by using dual-energy x-ray absorptiometry and non-traumatic vertebral fracture by lateral thoracolumbar spine radiographs. Standard deviation scores (SDS) were calculated based on the age- and gender-adjusted population mean. Results: Among 189 children after completion of acute leukemia treatment, 22 (11.6%) children had LSBMD SDS less than -2.0 while 80 (42.3 %) children were diagnosed with osteoporosis. Mean areal BMD and LSBMD SDS of the subjects were 0.862±0.197 g/cm2 and -0.6±1.6, respectively. IGF-1 and IGFBP-3 were lower in children with LSBMD lower than -2.0 (P&amp;lt;0.05) and those with osteoporosis (P&amp;lt;0.05). LSBMD SDS showed linear correlation with serum IGF-1 (P=0.041). Low serum IGF-1 level (OR=0.724, P=0.042) and elder age of leukemia diagnosis (OR=1.089, P=0.023) were suggested risk factor of the occurrence of osteoporosis. Conclusions: Substantial number of survivors from childhood acute leukemia undergo bone mineral deficits, and serum IGF-1 status could be a prognostic factor associated with bone mass acquisition and future occurrence of osteoporosis.

Expression of IGF-1, IGF-1 Receptor and Growth Hormone Receptor in Hepatic Tissue in Adults Across the Spectrum of Nonalcoholic Fatty Liver Disease (NAFLD)

Background: Obesity is a state of relative growth hormone (GH) and insulin-like growth factor-1 (IGF-1) deficiency, and the GH/IGF-1 axis has been implicated in the pathophysiology of nonalcoholic fatty liver disease (NAFLD) and the progression to steatohepatitis (NASH) in preclinical models and human studies. GH has both lipolytic and anti-inflammatory properties while IGF-1 has been implicated in reducing hepatic fibrosis and promoting hepatic regeneration. The GH/IGF-1 axis may be a therapeutic target in NAFLD/NASH, however, IGF-1, IGF-1 receptor (IGF-1R) and GH receptor (GHR) expression in adult human hepatic tissue has not been studied across the spectrum of disease severity. Methods: We quantified IGF-1, IGF-1R, and GHR gene expression in hepatic tissue from 318 adults with obesity using the Nanostring nCounter assay. Subjects were classified into four categories of disease severity based on histopathology: normal liver histology (NLH) (n=76, 24%), steatosis only (Steatosis) (n=88, 28%), NASH without fibrosis (NASH F0) (n=72, 23%), and NASH with fibrosis (NASH F1-F4) (n=82, 26%). Gene expression analysis is presented as normalized gene counts by group with p-value of the generalized linear model controlled for age, sex and BMI. Results: Mean (±SD) age (whole cohort 44.0±12 years) and BMI (whole cohort 46.8±7.2 kg/m2) did not differ across groups (p=0.2 for both). ALT was higher with increasing disease severity (NLH 30.1±26.7, Steatosis 31.9±15.7, NASH F0 35.7±16.5, NASH F1-4 48.4±34.9, p<0.001). IGF-1 gene expression was lower in all NAFLD/NASH groups compared to the NLH reference group (NLH 485.4±292.7; Steatosis 396.3±238.0, p=0.04; NASH F0 349.8±220.1, p=0.01 and NASH F1-4 341.2±268.6, p=0.03, all p-values vs NLH). There was no difference in IGF-1R or GHR gene expression across disease severity groups (IGF-1R NLH 43.3±10.2, Steatosis 41.4±11.6, NASH F0 38.8±8.8 and NASH F1-4 39.1±8.1, p>0.05 between any disease state; GHR NLH 6382±2366, Steatosis 6544±2699, NASH F0 7220±2542 and NASH F1-4 5997±2352, p>0.05 between any disease state). Conclusion: We demonstrated that IGF-1 gene expression was lower in liver tissue from patients with NAFLD and NASH than healthy controls. This is consistent with our prior finding that histologic NASH and fibrosis are associated with lower serum IGF-1 levels. Moreover, we demonstrated that hepatic IGF-1R and GHR gene expression is not lower in liver tissue from patients with NAFLD and does not decline across disease severity. This reinforces our prior finding that GHR staining intensity and zonality by immunohistochemistry does not change with increasing disease severity in NAFLD/NASH. These data demonstrate that the GH axis is relatively suppressed but that expression of GHR and IGF-1R receptors is stable with worsening disease severity in NAFLD/NASH, suggesting that GH augmentation may be a viable therapeutic target in NAFLD.

Growth hormone receptor knockout to reduce the size of donor pigs for preclinical xenotransplantation studies.

Many genetically multi-modified donor lines for xenotransplantation have a background of domestic pigs with rapid body and organ growth. The intrinsic growth potential of porcine xeno-organs may impair their long-term function after orthotopic transplantation in non-human primate models. Since growth hormone is a major stimulator of postnatal growth, we deleted its receptor (GHR-KO) to reduce the size of donor pigs in one step. Heart weight and proteome profile of myocardium were investigated in GHR-KO and control pigs. GHR-KO mutations were introduced using CRISPR/Cas9 in an α1,3-galactosyltransferase (GGTA1)-deficient background expressing the human cluster of differentiation (hCD46) and human thrombomodulin (hTHBD) to generate quadruple-modified (4GM) pigs. At age 6months, GHR-KO pigs had a 61% reduced body weight and a 63% reduced heart weight compared with controls. The mean minimal diameter of cardiomyocytes was 28% reduced. A holistic proteome study of myocardium samples from the two groups did not reveal prominent differences. Two 4GM founder sows had low serum insulin-like growth factor 1 (IGF1) levels (24±1ng/mL) and reached body weights of 70.3 and 73.4kg at 9months. Control pigs with IGF1 levels of 228±24ng/mL reached this weight range three months earlier. The 4GM sows showed normal sexual development and were mated with genetically multi-modified boars. Offspring revealed the expected Mendelian transmission of the genetic modifications and consistent expression of the transgenes. GHR-KO donor pigs can be used at an age beyond the steepest phase of their growth curve, potentially reducing the problem of xeno-organ overgrowth in preclinical studies.

Low Serum Branched-Chain Amino Acid and Insulin-Like Growth Factor-1 Levels Are Associated with Sarcopenia and Slow Gait Speed in Patients with Liver Cirrhosis.

Branched-chain amino acid (BCAA) and insulin-like growth factor 1 (IGF-1) are essential for muscle protein synthesis. We investigated the association of serum BCAA and IGF-1 levels with sarcopenia and gait speed in 192 patients with liver cirrhosis (LC). Sarcopenia was diagnosed according to the Japan Society of Hepatology criteria. Slow gait speed was defined as <1.0 m/s. Subjects were divided into three groups based on baseline BCAA or IGF-1 levels: low (L), intermediate (I), and high (H) groups. The L-BCAA group had the highest prevalence of sarcopenia (60.4%, p < 0.001) and slow gait speed (56.3%, p = 0.008), whereas the H-BCAA group had the lowest prevalence of sarcopenia (8.5%, p < 0.001). The L-IGF-1 group showed the highest prevalence of sarcopenia (46.9%, p < 0.001), whereas the H-IGF-1 group had the lowest prevalence of sarcopenia (10.0%, p < 0.001) and slow gait speed (18.0%, p = 0.003). Using the optimal BCAA and IGF-1 cutoff values for predicting sarcopenia (372 μmol/L and 48.5 ng/mL, respectively), the sensitivity and specificity were 0.709 and 0.759 for BCAA and 0.636 and 0.715 for IGF-1, respectively. Low serum BCAA and IGF-1 levels were associated with sarcopenia and slow gait speed in patients with LC.