Insulin-like Growth Factor-1 Group Research Articles

Enhancement of therapeutic potential of mesenchymal stem cell by IGF-1 delivery in PLGA microspheres for tissue regeneration

The use of stem cell-based treatment systems is prevalent in regenerative medicine. To enhance the regenerative capabilities of stem cells, growth factors are typically incorporated into the treatment system. Nonetheless, traditional hydrogel-encapsulated or heparinized scaffolds that bind factors have limitations. In this study, we prepared a biomaterial strategy using uniform poly(lactic-co-glycolic) acid (PLGA) microspheres (uPLGA-Ms) fabricated by microfluidic to sustain delivery of insulin-like growth factor 1 (IGF-1), a critical protein for hMSCs biological functions. The uPLGA-Ms loaded IGF-1 were highly monodispersed through precise manipulation of the flow rate of the two-phase of the flow-focusing microchannle. The results showed that the uPLGA-Ms stabilize IGF-1 and provide a more efficient sustained delivery and cost-effective of growth factor. Gene expression analysis demonstrated the uPLGA delivery of IGF-1 results in a (enhanced) supported hMSCs expansion, survival, stemness, and secretion abilities comparable with the conventional soluble IGF-1 group. In summary, this material-based strategy to stabilize and sustain delivery of growth factor has broad potential to regeneration of various tissues and organs.

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.

Effects of insulin-like growth factor 1, leukemia inhibitory factor, and basic fibroblast growth factor on goat oocyte maturation and early embryonic development in vitro

In this study, we investigated the effects of insulin-like growth factor 1 (IGF-1), leukemia inhibitory factor (LIF), and basic fibroblast growth factor (bFGF) on the in vitro maturation of goat oocytes and early embryonic development of in vitro-fertilized (IVF) oocytes. We also aimed to prepare an efficient in vitro maturation culture system for goat oocytes as a technical basis for improving both the quality of goat oocytes and the efficiency of embryo production in vitro. The experimental results revealed that the addition of bFGF (40 ng/mL), LIF (20 ng/mL), and IGF-1 (20 ng/mL) to the maturation medium improved the maturation rate of goat oocytes. Compared with the control group, the in vitro maturation rate of oocytes (83.0% vs. 70.93%, P < 0.05) and the development rate of IVF blastocysts (45.88% vs. 35.81%, P < 0.05) in the bFGF, LIF, and IGF-1 (FLI) group were significantly increased. The total number of developing blastocysts (114.40 vs. 83.20, P < 0.05) and the ratio of inner cell mass cells (39.50 vs. 25.33, P < 0.05) were also significantly higher in the FLI group than in the control group. Evaluation of maternal gene expression revealed that FLI could significantly increase the expression levels of DNMT1, ZAR1, and NLRP5 and cumulus cell expansion genes PTX3, TNFAIP6, PTGS2, and HAS2 in mature oocytes (P < 0.01). We indirectly proved that bFGF, LIF, and IGF-1 support goat oocyte maturation and early embryonic development. In summary, this study established a reliable and efficient in vitro goat oocyte maturation culture system using bFGF, LIF, and IGF-1. The results of this study can serve as a technical basis for improving the quality of goat oocytes matured in vitro, potential of early embryonic development, IVF of goat embryos, and in vitro production of other livestock.

The impact of IGF-1 on alveolar bone remodeling and BMP-2 expression in orthodontic tooth movement in diabetic rats.

Orthodontic tooth movement is linked to alveolar bone reconstruction. As a regulator of cell proliferation, insulin-like growth factor 1 (IGF-1) plays an important role in osteoporotic fracture healing. This study aims to investigate the effect of IGF-1 on alveolar bone remodeling in diabetic rats. Sprague Dawley (SD) rats were randomly divided into 3 groups, including a control group, a model group established with streptozotocin (STZ) injection to prepare the diabetic rats (type 1 diabetes), and an IGF-1 group of diabetic rats receiving daily intraperitoneal injections of 1.0 mg/kg IGF-1. Nickel-titanium coil springs were used to pull the first molar forward to establish the model. The maxillary first to third molars and the surrounding alveolar bone were collected to measure tooth movement distance. Hematoxylin and eosin (H&E) staining was applied to detect the pathological changes in the periodontal tissue. Real-time polymerase chain reaction (PCR) and western blot were adopted to measure bone morphogenetic protein 2 (BMP-2) mRNA and protein expression. Enzyme-linked immunosorbent assays (ELISAs) were used to measure interleukin-1α (IL-1α) levels in the serum. The tooth movement distance was significantly decreased, BMP-2 expression was downregulated, and IL-lα levels were enhanced in the model group compared to the control group (p < 0.05). However, the tooth movement distance was increased, BMP-2 expression was increased, and IL-lα levels were reduced in the IGF-1 group compared to the model group (p < 0.05). Hematoxylin and eosin staining showed that alveolar bone destruction was attenuated in the IGF-1 group, while the new bone was not active in the model group. Diabetes can damage alveolar bone remodeling in orthodontic tooth movement. The IGF-1 promotes alveolar bone remodeling by inhibiting inflammation and upregulating BMP-2 expression.

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.

Serum Insulin-Like Growth Factor 1 Levels, Facture Risk Assessment Tool Scores and Bone Disorders in Patients with Primary Biliary Cholangitis.

Insulin-like growth factor 1 (IGF-1) plays an important role in bone growth and maintenance, and its decreased levels are associated with bone disorders. This study aimed to evaluate the association of serum IGF-1 levels with osteoporosis, prevalent fractures and fracture risk based on the Fracture Risk Assessment Tool (FRAX) in patients with primary biliary cholangitis (PBC). This study included 127 consecutive patients with PBC. Based on the baseline serum IGF-1 levels, the participants were classified into the low (L)-, intermediate (I)- and high (H)-IGF-1 groups. According to the FRAX score, high fracture risk was defined as a 10-year major osteoporotic fracture probability (FRAX-MOF) ≥ 20% or a 10-year hip fracture probability (FRAX-HF) ≥ 3%. The serum IGF-1 levels were positively correlated with bone mineral density, and were negatively correlated with the FRAX-MOF/FRAX-HF. The L-IGF-1 group had the highest prevalence of osteoporosis (58.1%), prevalent fracture (48.4%) and high fracture risk (71.0%). Meanwhile, the H-IGF-1 group had the lowest prevalence of osteoporosis (9.7%), prevalent fracture (12.9%) and high fracture risk (9.7%). The prevalence of these events increased stepwise with decreasing serum IGF-1 levels. The cutoff values of IGF-1 for predicting osteoporosis, prevalent fracture and high fracture risk were 61.5 ng/mL (sensitivity/specificity, 0.545/0.894), 69.5 ng/mL (0.633/0.784) and 61.5 ng/mL (0.512/0.929), respectively. Serum IGF-1 levels were associated with bone disorders and the FRAX-derived fracture risk, and may be a useful indicator for initiating therapeutic intervention to prevent the incidence of fracture in patients with PBC.

Insulin-like growth factor-1 inhibits apoptosis of rat gastric smooth muscle cells under high glucose condition via adenosine monophosphate-activated protein kinase (AMPK) pathway.

Diabetic gastroparesis (DGP) is a common chronic complication of diabetes characterized by decreased gastric motility, and an effective number of gastric smooth muscle cells (GSMCs) ensures gastric motility. A previous study documented that apoptosis was present in gastric smooth muscles in rats with DGP and adenosine monophosphate-activated protein kinase (AMPK) was an important factor of apoptosis of rat GSMCs cultured under high glucose conditions. This study aimed to explore the effect of insulin-like growth factor-1 (IGF-1) on apoptosis of high glucose cultured rat GSMCs after silencing of AMPK and elucidate the underlying mechanism. A total of 120 rats were divided into normal control (NC, n = 20), diabetic gastroparesis (DGP, n = 50) and DGP + IGF-1 (n = 50) groups. After establishing the rat model of DGP, rats in the DGP+IGF-1 group received an intraperitoneal injection of IGF-1 at a dose of 1.5 μg/kg/d for 10 weeks. The level of AMPK activity, liver kinase B1 (LKB1) activity, and calcium/calmodulin-dependent protein kinase b (CaMKKb) expression in rat gastric smooth muscle tissues was detected by Western blot analysis. Apoptosis in rat gastric smooth muscle tissues was detected by TUNEL assay. We also cultured rat GSMCs in vitro under high glucose (HG) condition (35 mM), incubated cells with IGF-1, and silenced AMPK with siRNA. The cells were divided into HG, HG + IGF-1, HG + siRNA, and HG + siRNA + IGF-1 groups. The apoptosis rates of rat GSMCs after silencing AMPK were detected by TUNEL assay and flow cytometry, and apoptosis-related protein expression in rat GSMCs was detected by Western blot. IGF-1 decreased LKB1 activity, CaMKKb expression, AMPK activity, and inhibited apoptosis in rat gastric smooth muscle tissues. Compared with rat GSMCs cultured in vitro under HG conditions, apoptosis rates were reduced after treatment with IGF-1 and AMPK silencing (both p < 0.01). Apoptosis rates were higher in the HG + siRNA group compared with the HG + IGF-1 group (p < 0.05). IGF-1 down-regulated the expression of calcium/calmodulin-dependent kinase II (CaMKII) and p53, up-regulated the expression of p21, PLC-b3, PI3K p110 Ser1070, and the activities of Akt, p70S6K, mTORC1, and mTORC2. IGF-1 also up-regulated Bcl-2 expression and down-regulated the expression of BAX and Caspase-3. IGF-1 can inhibit the apoptosis of rat GSMCs under high glucose conditions, its mechanism may be related to the regulation of expression and activity of p53, PI3K, TSC-2, Akt, mTOR, 4E-BP1, p70S6K, p21, CaMKII, and PLC-b3 in rat GSMCs acting through AMPK pathway.

Effects of experimental increase in insulin-like growth factor 1 on feather growth rate, moult intensity and feather quality in a passerine bird.

Moulting is a crucial, yet often overlooked life-history stage in many animals, when they renew their integumental structures. This life-history stage is an energetically demanding somatic growth event that has particular importance in birds because feathers play a crucial role in flight, insulation and communication. Somatic growth processes are regulated by the evolutionarily conserved peptide hormone insulin-like growth factor 1 (IGF-1). However, the role of IGF-1 in feather growth remains unknown. In this study, we captured 41 juvenile free-living bearded reedlings (Panurus biarmicus) that had started their first complete moult and brought them into captivity. Then, we manipulated their circulating IGF-1 levels using poly-(lactic-co-glycolid acid) microparticles (microspheres) that provide a sustained release of IGF-1. The treatment increased IGF-1 levels but did not affect the feather growth rate. However, 2weeks after the treatment, birds in the increased IGF-1 group were moulting more feathers simultaneously than the controls and were at a more advanced stage of moult. Birds with experimentally increased IGF-1 levels had better quality feathers (measured by a lower number of fault bars) than the controls. These results suggest that an increase in IGF-1 does not speed up feather growth, but may alter moult intensity by initiating the renewal of several feathers simultaneously. This may shorten the overall moulting time but may imply costs in terms of IGF-1-induced oxidative stress.

IGF-1 infusion to fetal sheep increases organ growth but not by stimulating nutrient transfer to the fetus.

Insulin-like growth factor-1 (IGF-1) is an important fetal growth factor. However, the role of fetal IGF-1 in increasing placental blood flow, nutrient transfer, and nutrient availability to support fetal growth and protein accretion is not well understood. Catheterized fetuses from late gestation pregnant sheep received an intravenous infusion of LR3 IGF-1 (LR3 IGF-1; n = 8) or saline (SAL; n = 8) for 1 wk. Sheep then underwent a metabolic study to measure uterine and umbilical blood flow, nutrient uptake rates, and fetal protein kinetic rates. By the end of the infusion, fetal weights were not statistically different between groups (SAL: 3.260 ± 0.211 kg, LR3 IGF-1: 3.682 ± 0.183; P = 0.15). Fetal heart, adrenal gland, and spleen weights were higher (P < 0.05), and insulin was lower in LR3 IGF-1 (P < 0.05). Uterine and umbilical blood flow and umbilical uptake rates of glucose, lactate, and oxygen were similar between groups. Umbilical amino acid uptake rates were lower in LR3 IGF-1 (P < 0.05) as were fetal concentrations of multiple amino acids. Fetal protein kinetic rates were similar. LR3 IGF-1 skeletal muscle had higher myoblast proliferation (P < 0.05). In summary, LR3 IGF-1 infusion for 1 wk into late gestation fetal sheep increased the weight of some fetal organs. However, because umbilical amino acid uptake rates and fetal plasma amino acid concentrations were lower in the LR3 IGF-1 group, we speculate that animals treated with LR3 IGF-1 can efficiently utilize available nutrients to support organ-specific growth in the fetus rather than by stimulating placental blood flow or nutrient transfer to the fetus.NEW & NOTEWORTHY After a 1-wk infusion of LR3 IGF-1, late gestation fetal sheep had lower umbilical uptake rates of amino acids, lower fetal arterial amino acid and insulin concentrations, and lower fetal oxygen content; however, LR-3 IGF-1-treated fetuses were still able to effectively utilize the available nutrients and oxygen to support organ growth and myoblast proliferation.

Abstract 15442: Low Serum Levels of Insulin-like Growth Factor-1 Are Associated With Long-term Risk of Adverse Cardiovascular Events in Diabetic Patients Following Percutaneous Coronary Intervention

Background: Insulin-like growth factor-1 (IGF-1) is a protein which plays protective roles against cardiovascular disorders, including the endothelial dysfunction and the instability of atherosclerotic plaque. However, prognostic implication of serum IGF-1 level has been rarely evaluated in diabetic patients with established coronary artery disease. Methods: This single center observational study involved consecutive 819 diabetic patients underwent percutaneous coronary intervention (PCI) since 2008 to 2018. In frozen-stocked (-80°C) serum, IGF-1 was measured by ELISA assay. Endpoints were set as cardiovascular (CV) death and the composite of CV death, myocardial infarction and ischemic stroke (3-point MACE). The median and the range of follow-up period was 4.0 and 0-10.4 years, respectively. Results: Participants were divided by the median of IGF-1 (75 ng/ml) (low (n=412) and high IGF-1 group (n=407)). Unadjusted Kaplan-Meier analyses with log-rank test showed the significantly higher incidences of CV death and 3P-MACE in low IGF-1 group ( Figures ). Moreover, multivariate Cox proportional hazard analysis adjusted by covariates including age, sex, PCI for acute coronary syndrome, multivessel disease, renal function (eGFR, ml/min/1.73m 2 ) and glycated hemoglobin (HbA1c, %) demonstrated that low IGF-1≤75 ng/ml was associated with substantially increased risk of CV death (Hazard Ratio (HR): 1.9, 95% confidence interval (95%CI): 1.1-3.6, p=0.03) and 3P-MACE (HR 1.7, 95%CI:1.0-2.7, p=0.04), respectively. Conclusion: Findings in this study suggest that serum IGF-1 levels are a useful and independent prognostic indicator in diabetic patients following PCI.

Molecular and cellular effects of insulin-like growth factor-1 and LongR3-IGF-1 on in vitro maturation of bovine oocytes: comparative study

Addition effects of insulin-like growth factor-1 (IGF-1) and its synthetic analogue insulin-like growth factor-1 recombinant-3 (LongR3-IGF-1) after in vitro maturation (IVM) of cattle cumulus-oocyte complexes (COCs) were compared and evaluated on meiotic progression, apoptosis and profile genes of oocyte competence (GDF9, BMP15, BAX, BCL2, OOSP1, IGFBP2, IGBFP4 and IGFBP5), and their respective cumulus cells (AREG, EGFR, FSHR, COX2, BAX, BCL2, IGFBP2, IGFBP4 and IGFBP5). The 739 COCs (n = 10 pools) of bovine ovaries were collected, selected and matured with IGF-1 (100 ng/mL), LongR3-IGF-1 (100 ng/mL), and in two control groups with 0.1% polyvinyl alcohol (PVA) or 10% fetal bovine serum (FBS), for 22–24 h. The statistical analysis was performed by a linear mixed effects model, ANOVA and Tukey tests. There was no statistical difference between experimental groups taken into account the meiotic progression and apoptosis (P > 0.05). Nevertheless, there were statistical differences (P ≤ 0.05) among FBS, IGF-1 and LongR3-IGF-1 groups for IGFBP4 gene expression, and among PVA, IGF-1 and LongR3-IGF-1 for COX2 gene expression in cumulus cells. Moreover, statistical difference was found for BCL2 gene expression between IGF-1, FBS and PVA groups and for IGFBP4 gene expression between LongR3-IGF-1, PVA and FBS in oocytes. There was no statistical difference between experimental groups for other genes evaluated. These results showed a good performance of IVM of bovine oocytes in the presence of LongR3-IGF-1 and the possibility of replacement of IGF-1 and FBS.

Effect of Insulin-Like Growth Factor-1 on Bone Formation of Bone Marrow Mesenchymal Stem Cells Under High Glucose Environment by Regulating Insulin Like Growth Factor Binding Protein 2(IGFBP-2)/p38 Pathway

Diabetes easily affects the biological properties of bone marrow mesenchymal stem cells (BMSCs). Insulin-like growth factor-1 (IGF-1) promotes bone healing during osteoporotic fractures. However, IGF-1's effect on BMSCs high glucose is unclear. Rat BMSCs were assigned into control group, high glucose group, and IGF-1 group in which BMSCs were transfected with pc-DNA 3.1-IGF-1 plasmid on the basis of high glucose followed by analysis of IGF-1, RUNX2 and OPN mRNA level by real time PCR, cell proliferation by MTT assay, alkaline phosphatase (ALP) activity, IGFBP-2 level by ELISA, and p38 phosphorylation by Western blot. High glucose group showed significantly decreased IGF-1, RUNX2 and OPN mRNA level, reduced ALP activity, IGFBP-2 expression and p38 phosphorylation compared to control group (P &lt; 0 05). Transfection of IGF-1 plasmid under high-glucose environment significantly upregulated IGF-1, RUNX2 and OPN mRNA, increased ALP activity, IGFBP-2 expression and p38 phosphorylation compared to high-glucose group (P &lt; 0 05). IGF-1 expression is reduced in high glucose environment. Up-regulation of IGF-1 can promote BMSCs osteogenic differentiation through the IGFBP-2/p38 pathway.

IGF-1 Interacted With Obesity in Prognosis Prediction in HER2-Positive Breast Cancer Patients.

Purpose: Dysmetabolism and high circulating insulin-like growth factor 1 (IGF-1) would increase breast cancer risk, but its association with survival in HER2+ breast cancer patients has not been well-studied. Herein, we aim to evaluate the prognostic value of IGF-1 and metabolic abnormalities in HER2+ population.Patients and Methods: HER2+ breast cancer patients treated in Ruijin Hospital between November 2012 and June 2017 were retrospectively analyzed. Median value of circulating IGF-1 was adopted to classify low or high IGF-1 group. Metabolic syndrome (MetS) was defined using AHA/NHLBI criteria. Overweight was defined by body mass index (BMI) ≥ 24.0 kg/m2 in Chinese population.Results: Overall, 679 patients were included and 209 had synchronous MetS. High IGF-1 level was more common in pre/peri-menopausal women (P < 0.001) and high IGFBP-3 patients (P < 0.001). After a median follow-up of 36 months, 52 patients had disease recurrences. IGF-1 level was not associated with recurrence-free survival (RFS, P = 0.620) in the whole population. However, exploratory subgroup analysis found that BMI and IGF-1 interacted in predicting RFS (P = 0.009). For non-overweight patients, high IGF-1 showed a superior 4-years RFS (91.1 vs. 85.0%; HR 0.53, 95% CI 0.27–1.00, P = 0.049) compared with patients with low IGF-1 level. In contrast, for overweight patients, high IGF-1 was associated with an impaired 4-years RFS (88.3 vs. 95.7%, HR 3.20, 95% CI 1.00–10.21, P = 0.038). Furthermore, high IGF-1 level was independently associated with better OS in the whole (HR 0.26, 95% CI 0.08–0.82, P = 0.044) as well as non-overweight population (HR 0.15, 95% CI 0.03–0.68, P = 0.005).Conclusions: IGF-1 level was not associated with RFS in HER2+ breast cancer patients. However, IGF-1 and BMI had significant interaction in disease outcome prediction in HER2+ patients. High IGF-1 was protective in non-overweight patients, but risk factor for those overweight, which deserves further evaluation.

Intervertebral disc degeneration in mice with type II diabetes induced by leptin receptor deficiency

BackgroundThe leptin receptor-deficient knockout (db/db) mouse is a well-established model for studying type II diabetes mellitus (T2DM). T2DM is an important risk factor of intervertebral disc degeneration (IVDD). Although the relationship between type I diabetes and IVDD has been reported by many studies, few studies have reported the effects of T2DM on IVDD in db/db mice model.MethodsMice were separated into 3 groups: wild-type (WT), db/db, and IGF-1 groups (leptin receptor-deficient mice were treated with insulin-like growth factor-1 (IGF-1). To observe the effects of T2DM and glucose-lowering treatment on IVDD, IGF-1 injection was used. The IVD phenotype was detected by H&E and safranin O fast green staining among db/db, WT and IGF-1 mice. The levels of blood glucose and weight in mice were also recorded. The changes in the mass of the trabecular bone in the fifth lumbar vertebra were documented by micro-computed tomography (micro-CT). Tunnel assays were used to detect cell apoptosis in each group.ResultsThe weight of the mice were 27.68 ± 1.6 g in WT group, which was less than 57.56 ± 4.8 g in db/db group, and 52.17 ± 3.7 g in IGF-1 injected group (P < 0.05). The blood glucose levels were also significantly higher in the db/db mice group. T2DM caused by leptin receptor knockout showed an association with significantly decreased vertebral bone mass and increased IVDD when compared to WT mice. The db/db mice induced by leptin deletion showed a higher percentage of MMP3 expression as well as cell apoptosis in IVDD mice than WT mice (P < 0.05), while IGF-1 treatment reversed this situation (P < 0.05).ConclusionsT2DM induced by leptin receptor knockout led to IVDD by increasing the levels of MMP3 and promoting cell apoptosis. IGF-1 treatment partially rescue the phenotype of IVDD induced by leptin receptor knockout.

The Role of Insulin, IGF-1 and PRAS40 in the Processes of Oncogenesis in Women with Type 2 Diabetes Mellitus and Endometrial Cancer

The objective of the research was to investigate the content of insulin, insulin-like growth factor-1 and phosphorylated protein kinase proline-rich Akt substrate of 40kDa and to determine their role in the activation of oncogenesis processes in women with type 2 diabetes mellitus and endometrial cancer.&#x0D; Materials and methods. There were examined 46 women who were divided into 4 groups: Group I included healthy women; Group II comprised women with type 2 diabetes mellitus; Group III included women with endometrial cancer; Group IV comprised women with endometrial cancer and co-existent type 2 diabetes mellitus. The levels of insulin, insulin-like growth factor-1, phospho- proline-rich Akt substrate of 40kDa were determined by immune-enzyme analysis. The compensation of diabetes mellitus was evaluated by hemoglobin A1c level using method of ion-exchange chromatography. The results obtained were analyzed using statistical analysis.&#x0D; Results. Women of all study groups had increased levels of insulin and insulin-like growth factor-1 as compared to the control group (p&lt;0.05). The level of phospho-proline-rich Akt substrate of 40kDa increased in the patients of Group II (p&lt;0.05) and the patients of Group III (p&lt;0.05) and decreased in the patients of Group IV (p&lt;0.05). According to correlation analysis, phospho-proline-rich Akt substrate of 40kDa was found to correlate with body mass index, insulin and insulin-like growth factor-1 in Group II, body mass index and insulin-like growth factor-1 in Group III and body mass index in Group IV (p&lt;0.05).&#x0D; Conclusions. There was found an association between type 2 diabetes mellitus and endometrial cancer through obesity, hyperinsulinemia and insulin-like growth factor-1. The increase in phospho- proline-rich Akt substrate of 40kDa level was a sign of activation of mTOR and oncogenesis processes in the patients with type 2 diabetes mellitus. The decrease in phospho-proline-rich Akt substrate of 40kDa in the patients with endometrial cancer and co-existent type 2 diabetes mellitus can be explained by the influence of other intracellular regulatory systems or the effects of antidiabetic drugs, that requires additional study.

Combination of HGF and IGF-1 promotes connexin 43 expression and improves ventricular arrhythmia after myocardial infarction through activating the MAPK/ERK and MAPK/p38 signaling pathways in a rat model.

In this study, we hypothesized that the combination of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) alters the expression of connexin 43 (Cx43) and results in a reduced frequency of induced ventricular arrhythmia in rats after myocardial infarction (MI) and explored the preliminary mechanisms involved. Cardiomyocytes were cultured in vitro in medium with PBS, HGF, IGF-1, GFs (HGF + IGF-1), HGF + p38 inhibitor, HGF + ERK inhibitor, IGF-1 + p38 inhibitor or IGF-1 + ERK inhibitor. The expression of Cx43 was tested by real-time PCR and Western blotting after 48 hours. MI was induced in 48 male Sprague-Dawley rats. The rats were randomly divided into four groups and received an injection of PBS, HGF, IGF-1 or GFs into the infarct border zone two weeks after MI. Six weeks after injection, the expression levels of Cx43 and programmed stimulation-induced ventricular arrhythmias were examined. In vitro, the expression of Cx43 mRNA and the Cx43 protein in cardiomyocytes was higher in the HGF, IGF-1, and GFs groups than in the PBS group. GFs had a combinatorial effect on the Cx43 mRNA level but not on the Cx43 protein level. There was a significant reduction in Cx43 mRNA and Cx43 protein levels in the IGF-1 + p38 inhibitor group and IGF-1 + ERK inhibitor group compared to the IGF-1 group. In vivo, programmed stimulation significantly decreased the frequency of ventricular arrhythmia in the GFs, HGF and IGF-1 groups, and this effect was accompanied by increased immunohistochemical staining for Cx43, myocardial Cx43 protein levels and Cx43 mRNA levels in the infarct border zone of the left ventricle compared with those in the PBS group. The combinatorial effect of GFs on Cx43 expression was only observed at the mRNA level. Both HGF and IGF-1 enhanced the expression of Cx43 and improved induced ventricular arrhythmia in rats with MI. Both synergistic and antagonistic effects of HGF and IGF-1 were not observed. In addition, IGF-1 may function through the MAPK/p38 and ERK1/2 signaling pathways to regulate Cx43 expression.

Long non-coding RNA HAND2-AS1 downregulation predicts poor survival of patients with end-stage dilated cardiomyopathy.

ObjectiveInsulin-like growth factor-1 (IGF-1) signaling is inhibited in end-stage dilated cardiomyopathy (DCM), and recombinant IGF-1 improves cardiac function in DCM patients. Long non-coding (lnc)RNA HAND2-AS1 was previously shown to be involved in cancer development, but its role in DCM is unknown. The present study investigated the involvement of IGF-1 and HAND2-AS1 in DCM.MethodsPlasma HAND2-AS1 was detected by quantitative real-time PCR. IGF-1 plasma levels were measured by a human IGF-1 enzyme-linked immunosorbent assay. All experiments were performed in triplicate. Pearson’s correlation coefficient analyzed correlations between levels of IGF-1 and HAND2-AS1. Patients were divided into high and low IGF-1 or lncRNA HAND2-AS1 groups, and survival curves were plotted and compared by the Kaplan–Meier method and log-rank test, respectively.ResultsPlasma levels of IGF-1 and lncRNA HAND2-AS1 were significantly lower in end-stage DCM patients than in healthy controls, and were only positively correlated in end-stage DCM patients. A follow-up study revealed that low levels of IGF-1 or lncRNA HAND2-AS1 were significantly associated with poor survival. In the human cardiomyocyte cell line AC16, lncRNA HAND2-AS1 overexpression failed to alter IGF-1 levels and IGF-1 overexpression did not affect lncRNA HAND2-AS1 expression.ConclusionsLncRNA HAND2-AS1 may participate in end-stage dilated cardiomyopathy.

Cotreatment of IGF1 and Fadrozole Upregulates the Expression of RSPO1, SOX9, and AMH in Chicken Embryos

Insulin-like growth factor-1 (IGF1) and anti-aromatase synergistically increase the rate and stability of female-to-male sex reversal as well as pre- and postnatal weight gains in hatched chickens. This study aimed at assessing gene expression profiles of chicken embryos treated with IGF1 and fadrozole. Day 3.5 fertile eggs were in ovo injected with one of IGF1, fadrozole anti-aromatase, combined IGF1 and fadrozole, or sham injection. The expression profile was studied on day 6 and day 11 of the embryonic development following gonadal differentiation. On day 6 of embryonic development, simultaneous injection of IGF1 and fadrozole significantly upregulated the expression of RSPO1, AMH, and SOX9 in genetically female embryos compared to single injections and control groups. Also, a higher expression of ESR1 and BMP4 was observed in genetically male embryos on day 6 compared to the control group. In day 11 embryos, a higher expression of BMP4 was detected in both males and females of the IGF1 and fadrozole-administered group compared to the sham injection cohort. In conclusion, the results of this study indicate that combined effects of IGF1 and fadrozole induce female-to-male sex reversal by increasing the expression of testis developmental factors rather than attenuating ovary developmental factors.

Insulin-Like Growth Factor-1–Loaded Polymeric Poly(Lactic-Co-Glycolic) Acid Microspheres Improved Erectile Function in a Rat Model of Bilateral Cavernous Nerve Injury

BackgroundPrevious studies have documented improvement in erectile function after bilateral cavernous nerve injury (BCNI) in rats with the use of pioglitazone. Our group determined this improvement to be mediated by the insulin-like growth factor-1 (IGF-1) pathway. AimTo eliminate the systemic effects of pioglitazone and evaluate the local delivery of IGF-1 by polymeric microspheres after BCNI in the rat. MethodsMale Sprague–Dawley rats aged 10–12 weeks were assigned at random to 3 groups: sham operation with phosphate buffered saline (PBS)-loaded microspheres (sham group), crush injury with PBS-loaded microspheres (crush group), and crush injury with IGF-1–loaded microspheres (IGF-1 group). Poly(lactic-co-glycolic) acid microspheres were injected underneath the major pelvic ganglion (MPG). IGF-1 was released at approximately 30 ng/mL/day per MPG per rat. OutcomesFunctional results were demonstrated by maximal intracavernosal pressure (ICP) normalized to mean arterial pressure (MAP). Protein-level analysis data of IGF-1 receptor (IGF-1R), extracellular signal–regulated kinase (ERK)-1/2, and neuronal nitric oxide synthase (nNOS) were obtained using Western blot analysis and immunohistochemistry for both the cavernosal tissue and the MPG and cavernous nerve (CN). ResultsAt 2 weeks after nerve injury, animals treated with IGF-1 demonstrated improved erectile functional recovery (ICP/MAP) at all voltages compared with BCNI (2.5V, P = .001; 5V, P < .001; 7.5V, P < .001). Western blot results revealed that up-regulation of the IGF-1R and ERK-1/2 in both the nervous and erectile tissue was associated with improved erectile function recovery. There were no significant between-group differences in nNOS protein levels in cavernosal tissue, but there was an up-regulation of nNOS in the MPG and CN. Immunohistochemistry confirmed these trends. Clinical TranslationLocal up-regulation of the IGF-1R in the neurovascular bed at the time of nerve injury may help men preserve erectile function after pelvic surgery, such as radical prostatectomy, eliminating the need for systemic therapy. Strengths & LimitationsThis study demonstrates that local drug delivery to the MPG and CN can affect the CN tissue downstream, but did not investigate the potential effects of up-regulation of the growth factor receptors on prostate cancer tissue. ConclusionStimulating the IGF-1R at the level of the CN has the potential to mitigate erectile dysfunction in men after radical prostatectomy, but further research is needed to evaluate the safety of this growth factor in the setting of prostate cancer.Haney NM, Talwar S, Akula PK, et al. Insulin-Like Growth Factor-1–Loaded Polymeric Poly(Lactic-Co-Glycolic) Acid Microspheres Improved Erectile Function in a Rat Model of Bilateral Cavernous Nerve Injury. J Sex Med 2019;16:383–393.

Role of PI3K/Akt signaling pathway in propofol-induced inhibition of migration and invasion ability of human non-small cell lung cancer H1975 cells

Objective To evaluate the role of phosphatidylinositol 3-kinase/serine-threonine kinase (PI3K/Akt) signaling pathway in propofol-induced inhibition of migration and invasion ability of human non-small cell lung cancer H1975 cells. Methods H1975 cells were divided into 4 groups(n=36 each)using a random number table method: control group (group C), 20 μg/ml propofol group (group P), 0.5 ng/ml PI3K/Akt signaling pathway activator insulin-like growth factor 1 (IGF-1) group (group IGF-1), and 20 μg/ml propofol plus 0.5 ng/ml IGF-1 group (group P+ IGF-1). The migration and invasion ability of H1975 cells was determined by wound healing assay and Transwell invasion assay, respectively.The expression of phosphorylated Akt (p-Akt) and matrix metalloproteinase-9 (MMP-9) was assessed by Western blot. Results Compared with group C, and the ability of migration and invasion was significantly reduced, and the expression of p-Akt and MMP-9 was down-regulated in group P, and the ability of migration and invasion was significantly enhanced, and the expression of p-Akt and MMP-9 was up-regulated in group IGF-1 (P<0.05). Compared with group P, the ability of migration and invasion was significantly enhanced, and the expression of p-Akt and MMP-9 was up-regulated in group P+ IGF-1 (P<0.05). Compared with group IGF-1, the ability of migration and invasion was significantly reduced, and the expression of p-Akt and MMP-9 was down-regulated in group P+ IGF-1 (P<0.05). Conclusion The mechanism by which propofol inhibits migration and invasion ability of human non-small cell lung cancer H1975 cells is related to blocking PI3K/Akt signaling pathway. Key words: 1-Phosphatidylinositol 3-kinase; Protein kinase C; Propofol; Carcinoma, non-small-cell lung; Cell movement