Low Insulin-like Growth Factor-1 Research Articles

Efficient generation of epigenetic disease model mice by epigenome editing using the piggyBac transposon system

BackgroundEpigenome-edited animal models enable direct demonstration of disease causing epigenetic mutations. Transgenic (TG) mice stably expressing epigenome-editing factors exhibit dramatic and stable changes in target epigenome modifications. Successful germline transmission of a transgene from founder mice to offspring will yield a sufficient number of epigenome-edited mice for phenotypic analysis; however, if the epigenetic mutation has a detrimental phenotypic effect, it can become difficult to obtain the next generation of animals. In this case, the phenotype of founder mice must be analyzed directly. Unfortunately, current TG mouse production efficiency (TG founders per pups born) is relatively low, and improvements would increase the versatility of this technology.ResultsIn the current study, we describe an approach to generate epigenome-edited TG mice using a combination of both the dCas9–SunTag and piggyBac (PB) transposon systems. Using this system, we successfully generated mice with demethylation of the differential methylated region of the H19 gene (H19-DMR), as a model for Silver–Russell syndrome (SRS). SRS is a disorder leading to growth retardation, resulting from low insulin-like growth factor 2 (IGF2) gene expression, often caused by epimutations at the H19-IGF2 locus. Under optimized conditions, the efficiency of TG mice production using the PB system was approximately threefold higher than that using the conventional method. TG mice generated by this system showed demethylation of the targeted DNA region and associated changes in gene expression. In addition, these mice exhibited some features of SRS, including intrauterine and postnatal growth retardation, due to demethylation of H19-DMR.ConclusionsThe dCas9–SunTag and PB systems serve as a simple and reliable platform for conducting direct experiments using epigenome-edited founder mice.

Association Between Insulin-Like Growth Factor-1 and Social Cognition in Huntington's Disease.

Insulin-like growth factor 1 (IGF-1) seems to be involved in the neural circuits associated with social cognition and brain structure. To investigate the association of IGF-1 levels with social cognition and brain structure in Huntington's disease (HD). We evaluated social cognition using the Ekman test in 22 HD patients and 19 matched controls. Brain structure was assessed using standard volume-based voxel-based morphometry and surface-based cortical thickness pipeline. We analyzed the association of IGF-1 levels with social cognition and brain structure using adjusted regression analysis. Social cognition was worse in HD patients (P < 0.001), on antidopaminergic drugs (P=0.02), and with lower IGF-1 levels (P=0.04). In neuroimaging analyses, lower IGF-1 levels were associated with social cognition impairment and atrophy mainly in frontotemporal regions (P < 0.05 corrected). In HD, abnormal IGF-1 function seems to be associated with brain atrophy leading to clinical deficits in social cognition.

Neurotrophic and growth factor response to acute exercise across the lifespan

AbstractBackgroundThere is evidence that aerobic exercise is beneficial to the brain and may reduce risk for cognitive decline and dementia. However, clinical trials have shown the benefits of exercise programs vary amongst individuals. This variability may occur in part due to differences in the physiological biomarker response to acute exercise. Characteristics such as age, sex, and apolipoprotein E4 (APOE4) genotype may affect these responses, but differences in blood processing protocols may introduce additional variability into the measures.MethodWe characterized the blood biomarker response to acute exercise in 80 individuals, including older adults (n=62, mean age 73y) and 18 young controls (n=18, mean age 37). Participants engaged in an acute, 15 minute bout of moderate intensity exercise (45‐55% HRR) following a 5 minute warm‐up. Blood was collected immediately prior to exercise, immediately post exercise, and 40 minutes post exercise. After collection, each timepoint sample was immediately processed for plasma and platelet poor plasma and frozen; this was done to limit release of growth factors from activated platelets post‐blood draw. Time course responses of brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), insulin like growth factor 1 (IGF1) were measured using ELISA in platelet poor plasma. Lactate was measured in plasma (YSI 2500).ResultLinear mixed modeling performed with age, sex, and APOE4 genotype as covariates revealed a significant change in BDNF (p&lt;0.001) and lactate (p&lt;0.001) over time, with the highest levels of lactate observed immediately post‐exercise, while BDNF was elevated at 40 minutes post‐exercise in both young and older adults. There was no significant change with either VEGF or IGF1 over time in response to exercise, although older adults had significantly higher VEGF (p=0.01) and lower IGF1 (p&lt;0.001) compared to young controls across all timepoints.ConclusionWe report here that analysis of the acute exercise response reveals a significant increase in circulating BDNF and lactate, but not VEGF or IGF1, following aerobic exercise in both young controls and older adults. Further investigation into the mechanisms that contribute to these changes and the relevance to additional fluid and imaging brain health biomarkers in this cohort is ongoing.

Bone loss is ameliorated by fecal microbiota transplantation through SCFA/GPR41/ IGF1 pathway in sickle cell disease mice

Bone loss is common in sickle cell disease (SCD), but the molecular mechanisms is unclear. Serum insulin-like growth factor 1 (IGF1) was low in SCD subjects and SCD mice. To determine if decreased IGF1 associated with low bone mass in SCD is due to reduced SCFA production by gut microbiota, we performed reciprocal fecal microbiota transplantation (FMT) between healthy control (Ctrl) and SCD mice. uCT and histomorphometry analysis of femur showed decreased bone volume/total volume (BV/TV), trabecular number (Tb.N), osteoblast surface/bone surface (Ob.S/BS), mineralizing surface/ bone surface (MS/BS), inter-label thickness (Ir.L.Th) in SCD mice were significantly improved after receiving Ctrl feces. Bone formation genes Alp, Col1, Runx2, and Dmp1 from SCD mice were significantly decreased and were rescued after FMT from Ctrl feces. Transplantation of Ctrl feces increased the butyrate, valerate, and propionate levels in cecal content of SCD mice. Decreased G-coupled protein receptors 41 and 43 (GPR41 and GPR43) mRNA in tibia and lower IGF1 in bone and serum of SCD mice were partially restored after FMT from Ctrl feces. These data indicate that the healthy gut microbiota of Ctrl mice is protective for SCD bone loss through regulating IGF1 in response to impaired bacterial metabolites SCFAs.

Insulin-like growth factor-1 levels are associated with high comorbidity of metabolic disorders in obese subjects; a Japanese single-center, retrospective-study

Insulin like growth factor-1 (IGF-1) plays important roles in metabolic functions, especially in adulthood. Additionally, obese subjects are reportedly predisposed to having low absolute IGF-1 levels. However, the prevalence and clinical characteristics of obese subjects with low IGF-1 levels are unknown. We examined 64 obese subjects with a body mass index (BMI) ≥ 35 kg/m2, with no history of endocrinological disorders, receiving inpatient care. IGF-1 levels were interpreted based on the IGF-1 standard deviation score (SDS) clinically used and standardized by age and sex (low IGF-1 group; ≤ − 2.0 SDS and standard IGF-1 group; − 2.0 < and < + 2.0 SDS). Notably, 26.6% of the subjects had low IGF-1. Body fat mass and percentage, but not BMI, were significantly higher in the low than in the standard IGF-1 group. Furthermore, natural log-transformed high-sensitivity C-reactive protein, and the frequencies of dyslipidemia and hyperuricemia were higher in the low IGF-1 group. Moreover, among the subjects without diabetes, fasting glucose levels were significantly higher in the low IGF-1 group. Stepwise variable selection procedure revealed body fat percentage to be a parameter most strongly associated with low IGF-1. Thus, low IGF-1 levels may be an important marker of adiposity-associated metabolic disorders in obese patients.

Insulin-like growth factor 1 and the hormonal mediation of sibling rivalry

In altricial animals, young are completely dependent on parents for provisioning. The ability to outcompete siblings to receive parental provisioning has clear fitness benefits, and may be mediated by hormones that influence growth. We analyzed the effects of insulin-like growth factor 1 (IGF-1) on body size, growth, and sibling rivalry in eastern bluebirds (Sialia sialis). To determine whether IGF-1 is upregulated in response to the competitive environment, we manipulated brood sizes and examined the effect on IGF-1 levels, nestling body size, growth rate, and behavior. In a separate experiment, we injected nestlings with exogenous IGF-1 to study its impacts on body size, growth rate, and sibling competition. Brood size manipulation did not influence endogenous IGF-1 levels, but male nestlings with higher IGF-1 levels early in the nestling period tended to have greater mass gain than males with lower IGF-1 levels. Nestlings with higher IGF-1 levels also tended to be fed more frequently by parents. In the injection experiment, IGF-1 injected individuals tended to be heavier than vehicle injected young by the end of the nestling period, which suggests that IGF-1 can influence mass gain in bluebirds. IGF-1 has been proposed to be a mediator of life-history strategies and post-hatching behavior. Our results suggest that although bluebird nestlings do not adaptively elevate IGF-1 in response to the presence or number of siblings, IGF-1 may influence growth during the nestling period. These findings shed light on sibling competition, life history strategies, and the hormones that underlie them.

PSUN314 Severe Insulin Resistance Impacts the Growth Hormone-Insulin-Like Growth Factor-I Axis and Linear Growth

Abstract Diabetes and insulin resistance (IR) may impact growth hormone (GH), insulin-like growth factor 1 (IGF-1), and linear growth. Poorly controlled diabetes impairs growth, while high insulin may increase growth. To understand relationships between diabetes, IR, and growth, we examine height, body mass index (BMI), glucose, GH, and IGF- in patient populations with IR, including (in order of increasing IR): congenital generalized lipodystrophy (CGL), heterozygous pathogenic variants of the insulin receptor INSR (+/-), homozygous INSR variants (INSR-/-), and autoantibodies to the insulin receptor (Type B IR). Patients with CGL and INSR +/- have less IR, lower glucose, higher BMI, and higher IGF-1 vs patients with INSR -/- and Type B INSR. Patients with INSR -/- have short stature, while those with CGL have tall stature. GH is comparable in all groups. After remission of Type B IR, patients had normalization of insulin resistance, glucose, and IGF-1, supporting the idea that IR or elevated glucose caused low IGF-1. Our findings suggest that severe IR causes elevated blood glucose with inadequate glucose reaching cells mimicking a starvation state and causing low IGF-1. If this occurs during childhood growth (as in INSR -/-, but not in Type B IR), it leads to short stature. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

PSAT253 Differentiation of Pituitary Hyperplasia From Adenoma in the Setting of Severe Hypothyroidism

Abstract Introduction Pituitary hyperplasia due to long-standing or profound primary hypothyroidism is a rare finding in children. It occurs because of constant stimulation of thyrotrope cells by a thyrotropin-releasing hormone secreted from the hypothalamus due to a lack of negative feedback from thyroid hormones. The clinical presentation and imaging can mimic a pituitary mass. Patients can present with features of hypothyroidism, hyperprolactinemia, and even visual field defects if the hyperplastic pituitary gland compresses the optic chiasm. This case highlights this uncommon finding and discusses subtle clinical signs of hypothyroidism in children. Case Presentation A 10-year-old boy was incidentally found to have a pituitary lesion (15 mm×14 mm) when an MRI of the brain was performed as a healthy volunteer screening procedure. History and physical exam revealed cold intolerance, lack of height growth for 2 years (crossing down from 75th to 25th percentile), and dry skin with the barely palpable thyroid gland. There was no family history of thyroid or auto-immune disease. Evaluation of pituitary hormones showed remarkably high thyroid-stimulating hormone (&amp;gt;500 mcIU/ml) in the setting of undetectable free thyroxine, positive thyroid peroxidase antibody, low insulin-like growth factor-1, mildly elevated prolactin (67.4 mcg/L), and mild macrocytic anemia. Conclusions Differentiation of pituitary hyperplasia from pituitary hormone-secreting or non-secreting adenomas is crucial, as the primary modality of treatment of pituitary hyperplasia secondary to primary hypothyroidism is thyroid hormone replacement and not surgery unless the patient has visual field defects necessitating of decompression of the optic chasm to avoid permanent vision loss. In general, pituitary hyperplasia is described as homogeneously enhancing with the "nipple sign," which is when the pituitary gland has smooth contours, but a central protrusion of a pituitary mass is present. Elevated TRH can also lead to lactotroph hyperplasia, causing increased prolactin. Growth hormone secretion may be reduced by hypothyroidism and/or by damaged somatotroph cells due to space-occupying pituitary hyperplasia. Macrocytic anemia has been reported in patients with hypothyroidism and is thought to be an adaptation to a decreased basal metabolism. Early recognition and treatment of hypothyroidism during childhood is essential for normal growth and development. In children with the prolonged disease, final height may be compromised, and academic performance and psychosocial well-being may decline. Gradual replacement of thyroid hormone to therapeutic doses by slowly escalating doses of levothyroxine may be beneficial to prevent complications of therapy such as pseudotumor cerebri or empty sella due to rapid shrinkage of lactotroph and thyrotrope cells. Previous studies have shown approximately 85% of those with pituitary hyperplasia due to primary hypothyroidism demonstrate decreased pituitary gland size after starting thyroxine replacement and recommend repeating pituitary MRI after 2-4 months. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PMON219 Disparities in Musculoskeletal Health Profiles Across Race and Ethnicity in United States-Based Women with Polycystic Ovary Syndrome per the 2018 International Guideline

Abstract The magnitude and direction to which alterations in non-fat components of musculoskeletal composition (bone, muscle) may disproportionately impact diverse populations of women with polycystic ovary syndrome (PCOS) are unknown, despite clinical relevance. The uncertainty stems, partly, from heterogeneity in PCOS diagnostic criteria used and technical barriers in the reliable assessment of PCOS. We evaluated whether musculoskeletal (total and regional lean body mass [LBM] and bone mineral density [BMD]) outcomes were different in PCOS (n=126) across 4 prospectively recruited groups matched for age, body mass index, waist to hip ratio, and lack of recent (&amp;lt;3 mos) hormonal contraceptive and metformin use: self-identified (1) White (n=86); (2) Black (n=17); (3) Asian (n=12); and, (4) Hispanic (n=11) women in 3 academic medical centers in NY. PCOS was defined by the Rotterdam criteria using the recommended thresholds of the most recent (2018) PCOS Guideline. Fat and lean tissue mass and BMD were evaluated by dual-energy X-ray absorptiometry. Within the PCOS group, percentages of total body, trunk fat, and appendicular lean mass were comparable across races and ethnicities (All: P≥0.40); in contrast, total LBM and total and regional BMD were different across the groups (All: P&amp;lt;0.002). Post hoc pairwise comparisons revealed Asian women (mean±standard deviation; 39.64±6.42) exhibited lower total LBM vs. Black (53.93±10.60) and White (49.47±8.87; All: P&amp;lt;0.01) but not vs. their Hispanic (46.30±8.77 kg; P=0.29) counterparts. Total, upper, and lower limb BMD were higher in Black women (1.28±1.13; 0.82±0.09; 1.28±0.12) vs. all other counterparts: (White [1.12±0.9; 0.75±0.09; 1.18±0.10;]; Asian [1.09±0.09; 0.67±0.03; 1.08±0.05]; and, Hispanic [1.09±0.09; 0.72±0.15; 1.07±0.10] g/cm2; All: P&amp;lt;0.04), respectively. Similarly, lower limb BMD was compromised in Asian and Hispanic vs. White women (All: P≤0.03). Groups exhibited comparable glucoregulatory status (insulin and glucose responses to a standard 75-g oral glucose tolerance test), blood pressure, androgen status (Ferriman-Gallwey scores, total, free, and bioavailable testosterone), and intermenstrual interval length (All: P≥0.14). Conversely, groups differed by insulin-like-growth-factor-1 (IGF-1) and IGF-2 levels (All: P≤0.05). Post hoc pairwise comparisons showed lower IGF-1 in Black (255.92±145.12) and White (325.42±140.25) vs. Hispanic (549.21±266.26 ng/mL) women (All: P≤0.04). Also, Black women (426.74±82.66) had lower IGF-2 vs. White women (553.07±111.10 ng/mL; P≤0.4). Collectively, Asian women with PCOS show the lowest LBM and BMD, whereas their Black counterparts exhibit higher BMD after matching for age, body mass index, waist to hip ratio, lack of hormonal contraceptive and metformin use, and percentages of total body and trunk fat. Future research should delineate the true effects of PCOS-specific endocrine milieu (e.g., IGF axis) and relevance of genetic variants and/or environmental determinants of musculoskeletal health in this understudied clinical population. If confirmed by larger studies, our observations support the need for population-specific preventative and management considerations in future Guideline recommendations (e.g., PCOS-specific physical activity) to improve musculoskeletal health and associated reproductive and metabolic comorbidities. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

S1291 Low Insulin-Like Growth Factor 1 as a Predictor of Poor Prognosis in Liver Cirrhosis

S1291 Low Insulin-Like Growth Factor 1 as a Predictor of Poor Prognosis in Liver Cirrhosis

Acute effects of low load resistance training with blood flow restriction on serum growth hormone, insulin-like growth factor-1, and testosterone in patients with mild to moderate unilateral knee osteoarthritis

ObjectiveTo investigate the acute effects of blood flow restriction (BFR) with single-leg low load resistance exercise and high load resistance exercise on serum insulin-like growth factor-1 (IGF-1), growth hormone (GH), and testosterone in patients with unilateral knee osteoarthritis (OA). MethodsThis study recruited 18 postmenopausal female patients with mild to moderate unilateral knee OA, which was then followed by randomly conducting three resistance exercise protocols by drawing lots: 1. A 30% 1-repetition maximum (1-RM) resistance exercise with BFR of 70% arterial occlusive pressure (AOP) (BFR group); 2. A 70% 1-RM resistance exercise without BFR (RES group); 3. A 30% 1-RM resistance exercise without BFR (CON group). Blood lactate (BLA) and muscle growth related hormone levels were tested at 4-time points: before exercise, immediately after exercise, 15 min after exercise, and 30 min after exercise. ResultsThere was no statistical difference between the indexes in each group before exercise, but the different exercise had different effects on each index and also an interactive effect (P < 0.05). The increase of rating of perceived exertion in the BFR and RES groups, which were of similar magnitude, was greater compared to the levels in the CON group (P < 0.05). Post-exercise BLA levels were lower in the CON group in comparison to the BFR and RES groups (P < 0.05). Rather than the RES group, GH levels of the BFR group were also significantly higher than the CON group (P < 0.05) at 15 min post-exercise. At post- and 15 min after exercise, the CON group recorded significantly lower IGF-1 levels compared to the BFR and RES groups (P < 0.05). At post- and 15 min after exercise, the CON group (P < 0.05) reflected the lowest testosterone levels, followed by the RES group (P < 0.05), and the highest in the BFR group (P < 0.05). ConclusionsMyogenesis-related hormones in women with unilateral knee OA could be increased by high load resistance exercise and low load resistance exercise with BFR on unaffected limb.

Age, GH/IGF-1 levels, tumor volume, T2 hypointensity, and tumor subtype rather than proliferation and invasion are all reliable predictors of biochemical response to somatostatin analogue therapy in patients with acromegaly: A clinicopathological study

PurposeTo determine whether biochemical responses to long-acting forms of first-generation somatostatin analogue (SSA) therapy in patients with acromegaly could be predicted from baseline and postoperative hormone concentrations, and tumor radiological and histopathological characteristics. MethodsA total of 68 patients with acromegaly for whom postoperative SSA therapy was started were categorized according to their responses to treatment (SSA-responders vs. non-responders). The patients were compared based on their demographic characteristics, hormone levels, magnetic resonance imaging (MRI), and histopathological findings. Receiver-operating-characteristic (ROC) curves were constructed using the predictive factors that were significant in the univariate analysis to determinate the optimal cut-off values. ResultsThe SSA-responders were significantly older (p = 0.041). Lower GH at diagnosis (p = 0.036), the postoperative 1st-week GH level (p = 0.027), baseline GH, insulin-like growth factor-1 (IGF-1) and IGF-1% upper limit of normal (ULN) (p = 0.001, p = 0.006, p = 0.023, respectively) were associated with biochemical response. T2-hypointensity and lower tumor volume were more common in the SSA-responders (p = 0.018, p = 0.03, respectively). Compared to sparsely granulated somatotroph tumors, densely granulated somatotroph tumors and other PitNETs causing GH excess including mammosomatotroph and mixed somatotroph and lactotroph tumors were more likely to respond to SSA therapy (p = 0.026, p = 0.03, respectively). The cut-off values generated by ROC curve analysis were GH at diagnosis of ≤8.8 ng/mL, GH at baseline of ≤2.69 ng/mL, IGF-1 at baseline ≤461.5 ng/mL, IGF-1% ULN at baseline ≤180.4%, and tumor volume of ≤1.11 cm3 (all p < 0.05). There were no differences between the groups in terms of tumor invasiveness, proliferative activity (mitotic count per 2 mm2 and Ki-67 labeling index) and quantitative analyses of T2-weighted MRI. ConclusionThis study underscores that advanced age, low baseline GH and IGF-1 at diagnosis, low tumor volume, densely granulated tumor subtype, and T2 hypointensity may help predict biochemical response to SSA therapy in cases of acromegaly. These variables should be assessed with utmost attention for all patients prior to SSA treatment. In cases of possible resistance to SSA therapy, therapeutic activity should be monitored more closely and other therapies should be administered immediately in the event of poor response.

Low-Plasma Insulin-Like Growth Factor-1 Associates With Increased Mortality in Chronic Kidney Disease Patients With Reduced Muscle Strength

Chronic kidney disease (CKD) leads to metabolic and nutritional abnormalities including resistance to insulin-like growth factor-1 (IGF-1) action, and reduced muscle mass and strength. Low IGF-1 as well as low hand-grip muscle strength (HGS) are independent predictors of increased mortality in CKD patients. In 685 patients (CKD Stage 3-5, median age 58years; 62% men), baseline measurements of IGF-1, HGS, subjective global assessment (SGA), lean body mass index (LBMI), and metabolic and inflammatory biomarkers potentially linked to IGF-1 were analyzed in relation to mortality during 5years of follow-up. We compared survival in 4 groups with high or low (cut-offs defined by receiver operating characteristic curve analysis) levels of IGF-1 and HGS. Patients with low IGF-1 were older; had lower BMI, HGS, and LBMI, were more likely to have diabetes, cardiovascular disease (CVD), and malnutrition (SGA >1); and had high-sensitivity C-reactive protein levels. During 5years of follow-up, 208 patients died. The mortality rate was highest among patients with Low IGF-1+Low HGS. In competing-risk regression analysis, Low IGF-1+Low HGS was independently associated with 2.8 times higher all-cause mortality risk than Low IGF-1+High HGS, after adjusting for Framingham's CVD risk score, presence of CVD, SGA, dialysis status, high-sensitivity C-reactive protein, albumin, LBMI, and sample time in freezer. Low IGF-1 was associated with increased all-cause mortality in patients who also had low HGS but not in those with high HGS, suggesting that the association of IGF-1 with survival in CKD patients depends on nutritional status.

Down-Regulation of Insulin Like Growth Factor 1 Involved in Alzheimer's Disease via MAPK, Ras, and FoxO Signaling Pathways.

The inability to halt or even delay the course of Alzheimer's disease (AD) forces the development of new molecular signatures and therapeutic strategies. Insulin like growth factor 1 (IGF1) is a promising target for AD treatment, yet exact mechanisms of AD ascribed to IGF1 remain elusive. Herein, gene expression profiles of 195 samples were analyzed and 19,245 background genes were generated, among which 4,424 differentially expressed genes (DEGs) were overlapped between AD/control and IGF1-low/high groups. Based on such DEGs, seven co-expression modules were established by weight gene correlation network analysis (WGCNA). The turquoise module had the strongest correlation with AD and IGF1-low expression, the DEGs of which were enriched in GABAergic synapse, long-term potentiation, mitogen-activated protein kinase (MAPK), Ras, and forkhead box O (FoxO) signaling pathways. Furthermore, cross-talking pathways of IGF1, including MAPK, Ras, and FoxO signaling pathways were identified in the protein-protein interaction network. According to the area under the curve (AUC) analysis, down-regulation of IGF1 exhibited good diagnostic performance in AD prediction. Collectively, our findings highlight the involvement of low IGF1 in AD pathogenesis via MAPK, Ras, and FoxO signaling pathways, which might advance strategies for the prevention and therapy of AD based on IGF1 target.

Discovery of dipeptidyl peptidase-4 inhibitor specific biomarker in non-alcoholic fatty liver disease mouse models using modified basket trial.

Background/AimsWe aimed to define an optimal target population and drug-specific biomarkers that may predict dipeptidyl peptidase (DPP)-4 inhibitor responses in non-alcoholic fatty liver disease (NAFLD).MethodsAn exploration study (study I) was performed using three different NAFLD models (basket study design; high-fat diet [HFD], methionine choline-deficient diet [MCD], and high-cholesterol Western diet [WD] models). RNA transcriptome analysis was performed on pre-studied liver tissues to identify biomarkers that could predict the response to DPP-4 inhibitors. In the validation study (study II), the HFD-induced NAFLD model was divided into high and low hepatic insulin-like growth factor binding protein 1 (Igfbp-1) groups based on the pre-study liver biopsy.ResultsDPP-4 inhibitor attenuated the NAFLD activity score and fibrosis stage in the HFD model but not in the WD and MCD models. The overall response rate was 19% across the modified basket NAFLD trial and 42%, 25%, and 0% in the HFD, WD, and MCD models. Hepatic Igfbp-1 expression was higher in the responder group than in the non-responder group in pre-study biopsy samples. In contrast, hepatic Igfbp-1 expression was lower in the responder group than in the non-responder group in the end-study biopsy samples. DPP-4 inhibitor response rates were 83% and 17% in the baseline hepatic high Igfbp-1 and low Igfbp-1 groups, respectively. Hepatic messenger RNA Igfbp-1 expression was positively correlated with serum IGFBP-1 levels.ConclusionsThe DPP-4 inhibitor response was higher in the HFD phenotype and pre-treatment levels of hepatic or serum IGFBP-1 were high.

Relationship between growth hormone deficiency and nonalcoholic fatty liver disease in patients with pituitary stalk interruption syndrome.

Pituitary stalk interruption syndrome (PSIS), characterized by thinning or disappearance of the pituitary stalk, hypoplasia of the anterior pituitary, and an ectopic posterior pituitary, can lead to congenital combined pituitary hormone deficiency. There is a high prevalence of various metabolic disorders, including nonalcoholic fatty liver disease (NAFLD), in this population. To investigate the characteristics of NAFLD in Chinese adult patients with PSIS and its association with growth hormone deficiency. Retrospective cross-sectional study in a tertiary referral center of China. Adult patients with PSIS diagnosed, followed up between September 2019 and August 2021, were consecutively enrolled. Abdominal ultrasonography images were evaluated and noninvasive fibrosis scores were determined to assess the severity of NAFLD. Anthropometric, clinical, and biochemical parameters were compared between patients with and without NAFLD. Logistic regression was performed to assess the independent effects of insulin-like growth factor-1 (IGF-1) on NAFLD. A total of 93 patients (77 men, 16 women, mean age: 29.6 ± 7.1 years) were included. The prevalence of NAFLD and advanced fibrosis/cirrhosis was 50.5% and 4.3%, respectively. Insufficient hormone therapy and prominent metabolic disorders, including central obesity, dyslipidemia, insulin resistance, and metabolic syndrome, were more common in the NAFLD (+) group. After adjusting for multiple variables, IGF-1 &lt;-2 standard deviation score (SDS) was found to be associated with an increased prevalence of NAFLD (odds ratio [OR]: 4.92, 95% confidence interval [CI]: 1.21-24.55, p = .035). Per 1 SDS increase in IGF-1 was associated with a 27% lower risk of NAFLD (OR: 0.73, 95% CI: 0.52-0.97, p = .042). NAFLD is a frequent comorbidity among Chinese adult patients with PSIS and is strongly associated with lower IGF-1 levels. Timely and appropriate hormone replacement, particularly growth hormone may contribute to decreasing the risk of NAFLD in these patients.

Vitamin D, insulin-like growth factor-1, and stunting in children with transfusion-dependent thalassemia

Background Transfusion-dependent thalassemia (TDT) has a major impact on a child’s growth and is associated with stunting, risk of vitamin D deficiency, and decreased insulin-like growth factor-1 (IGF-1). To date, the relationship between vitamin D levels and stunting in TDT remains unclear. Futhermore, the role of vitamin D and IGF-1 in mediating stunting in TDT patients is still unknown. &#x0D; Objective To investigate the relationship between stunting and vitamin D as well as IGF-1 levels in children with TDT.&#x0D; Methods This cross-sectional study involved 50 TDT children aged 5 to 18 years, included consecutively from the Pediatric Hemato-oncology Outpatient Clinic, Dr. Soetomo Hospital, Surabaya, East Java. Subjects were divided into two groups: stunted (S) and not stunted (NS). Vitamin D and IGF-1 were evaluated by antibody competitive immunoassay and sandwich-enzyme-linked immunosorbent assay (ELISA), respectively. Age, sex, and duration of repeated transfusion were analyzed as confounding factors.&#x0D; Results Median IGF-1 levels were 91.43 (13.67-192.86) ng/mL and 161.53 (17.99-363.01) ng/mL in the S and NS groups, respectively (P=0.011). Mean vitamin D levels were 20 (+ 5.71) ng/mL and 20.46 (5.25) ng/mL in the S and NS groups, respectively (P=0.765). The correlation coefficient (r) of vitamin D and IGF-I levels was not significant. Multivariate analysis showed that low IGF-1 levels, male, and longer duration of repeated transfusions were associated with stunting in children with TDT. &#x0D; Conclusion Low IGF-1 level is associated with stunting in children with TDT. Vitamin D is not significantly associated with either stunting or IGF-1 in children with TDT.

Growth in Children with HLA-Conferred Susceptibility to Type 1 Diabetes.

The incidence of type 1 diabetes (T1D) is increasing throughout the world. This trend may be explained by the accelerator hypothesis. Our study investigated growth, its biochemical markers, and their associations with the development of diabetes-associated autoantibodies (DAAB) in 219 children with genetic risk for T1D. Subjects were divided into risk groups based on their human leukocyte antigen genotype. Children in the moderate- to high-risk group were significantly taller when corrected to mid-parental height and had a lower insulin-like growth factor 1 (IGF-1)/IGF-1 binding protein (IGFBP-3) molar ratio than those in the low-risk group (corrected height standard deviation score 0.22±0.93 vs. −0.04±0.84, P<0.05; molar ratio 0.199±0.035 vs. 0.211+0.039, P<0.05). Children with DAAB tended to be taller and to have a higher body mass index than those with no DAAB. Our results suggest that the accelerator hypothesis explaining the increasing incidence of T1D may not solely be dependent on environmental factors, but could be partially genetically determined.

Defective IGF-1 prohormone N-glycosylation and reduced IGF-1 receptor signaling activation in congenital disorders of glycosylation

The insulin-like growth factor-1 (IGF-1) signaling pathway is crucial for the regulation of growth and development. The correct processing of the IGF-1Ea prohormone (proIGF-1Ea) and the IGF-1 receptor (IGF-1R) peptide precursor requires proper N-glycosylation. Deficiencies of N-linked glycosylation lead to a clinically heterogeneous group of inherited diseases called Congenital Disorders of Glycosylation (CDG). The impact of N-glycosylation defects on IGF-1/IGF-1R signaling components is largely unknown. In this study, using dermal fibroblasts from patients with different CDG [PMM2-CDG (n = 7); ALG3-CDG (n = 2); ALG8-CDG (n = 1); GMPPB-CDG (n = 1)], we analyzed the glycosylation pattern of the proIGF-1Ea, IGF-1 secretion efficiency and IGF-1R signaling activity. ALG3-CDG, ALG8-CDG, GMPPB-CDG and some PMM2-CDG fibroblasts showed hypoglycosylation of the proIGF-1Ea and lower IGF-1 secretion when compared with control (CTR). Lower IGF-1 serum concentration was observed in ALG3-CDG, ALG8-CDG and in some patients with PMM2-CDG, supporting our in vitro data. Furthermore, reduced IGF-1R expression level was observed in ALG3-CDG, ALG8-CDG and in some PMM2-CDG fibroblasts. IGF-1-induced IGF-1R activation was lower in most PMM2-CDG fibroblasts and was associated with decreased ERK1/2 phosphorylation as compared to CTR. In general, CDG fibroblasts showed a slight upregulation of Endoplasmic Reticulum (ER) stress genes compared with CTR, uncovering mild ER stress in CDG cells. ER-stress-related gene expression negatively correlated with fibroblasts IGF-1 secretion. This study provides new evidence of a direct link between N-glycosylation defects found in CDG and the impairment of IGF-1/IGF-1R signaling components. Further studies are warranted to determine the clinical consequences of reduced systemic IGF-1 availability and local activity in patients with CDG.

Relationship between Anterior Pituitary Volume and IGF-1 Serum Levels in Soldiers with Mild Traumatic Brain Injury History.

A high mild traumatic brain injury (mTBI) incidence rate exists in military and sport. Hypopituitarism is an mTBI sequela; however, few studies have examined this phenomenon in those with an mTBI history. This cross-sectional study of Special Operations Forces combat soldiers aimed 1) to relate anterior pituitary gland volumes (actual and normalized) to insulin-like growth factor 1 (IGF-1) concentrations, 2) to examine the effect of mTBI history on anterior pituitary gland volumes (actual and normalized) and IGF-1 concentrations, and 3) to measure the odds of demonstrating lower anterior pituitary gland volumes (actual and normalized) or IGF-1 concentrations if self-reporting mTBI history. Anterior pituitary gland volumes were manually segmented from T1-weighted 3D brain MRI sequences; IGF-1 serum concentrations were quantified using commercial enzyme-linked immunosorbent assays. Correlations and linear regression were used to determine the association between IGF-1 serum concentration and anterior pituitary gland volume (n = 74). Independent samples t-tests were used to compare outcomes between mTBI groups and logistic regression models were fit to test the odds of demonstrating IGF-1 concentration or anterior pituitary volume less than sample median based on mTBI group (n = 54). A significant linear relationship between the subjects' anterior pituitary gland volumes and IGF-1 concentrations (r72 = 0.35, P = 0.002) was observed. Soldiers with mTBI history had lower IGF-1 concentrations (P < 0.001) and lower anterior pituitary gland volumes (P = 0.037) and were at greater odds for IGF-1 serum concentrations less than the sample median (odds ratio = 5.73; 95% confidence interval = 1.77-18.55). Anterior pituitary gland volume was associated with IGF-1 serum concentrations. Mild TBI history may be adversely associated with anterior pituitary gland volumes and IGF-1 concentrations. Longitudinal IGF-1 and anterior pituitary gland monitoring may be indicated in those who report one or more mTBI.