Increase In Insulin-like Growth factor-I Research Articles

Evaluation of carbonate apatite as a bone substitute in rat extraction sockets from the perspective of mesenchymal stem cells.

Carbonate apatite (CO3Ap) is a major inorganic bone component and an effective bone substitute. To clarify the function of CO3Ap, we compared differences among CO3Ap, hydroxyapatite (HAp), and β-tricalcium phosphate (β-TCP) by focusing on mesenchymal stem cells (MSCs) that have a role in wound healing. For in vivo experiments, maxillary molars were removed and the bone substitute was inserted. MSC accumulation around extraction sockets was significantly promoted in CO3Ap and β-TCP groups. For in vitro experiments, MSCs were cultured with bone substitutes. The differentiation potential and amount of calcium deposition were significantly lower in CO3Ap and HAp groups than in the β-TCP group. Increases in insulin-like growth factor-I and vascular endothelial growth factor were found only in the CO3Ap group. CO3Ap-filled extraction sockets accumulated MSCs, and MSCs cultured in the presence of CO3Ap produced large amounts of growth factors. These results suggest that CO3Ap promotes healing of tooth extraction sockets.

In Vitro Investigation of Insulin-Like Growth Factor-I and Mechano-Growth Factor on Proliferation of Neural Stem Cells in High Glucose Environment

Objective: High glucose levels cause metabolic and vascular complications by affecting the nervous system with an increased risk of stroke and seizures. There are still no effective treatment modalities for the high morbidity and mortality rates detected in such situations. Neural stem cells (NSCs) provide neurogenesis in the nervous system, but high glucose is detrimental to NSCs. This study investigates the intrinsic and extrinsic effects of the growth factors insulin-like growth factor-I (IGF-I) and mechano-growth factor (MGF) on NSCs when exposed to high glucose levels. Thus, the possibility of new treatment options for diabetes patients is explored. Materials and Methods: Rat NSCs grown in cell culture conditions were exposed to a control glucose concentration of 17.5 mM and high concentrations of 27.75, 41.75, and 83.75 mM for 24 h. The high glucose concentrations were designed to recapitulate the in vivo conditions of diabetes mellitus, diabetic ketoacidosis, and hyperglycemia hyperosmolar status. Then, 0.2 μg/ml IGF-I and MGF growth factors were separately added and their expressions in the NCSs investigated by real-time reverse transcription-polymerase chain reaction. The effects of exogenous IGF-I and MGF administration on NSC proliferation under high glucose conditions were measured by BrdU incorporation assay using flow cytometry analysis. Results: A significant increase was detected in the relative gene expression fold changes of IGF-I and MGF in the NSCs. The MGF relative fold change was greater than the IGF-I for each high glucose condition. NSCs exposed to 27.75 mM glucose revealed a 17-fold and 40-fold increase in the IGF-I and MGF gene expressions, respectively; the 41.75 mM glucose similarly revealed 68-and 161-fold increases and the 83.75 mM glucose 75-and 137-fold increases. Exogenous IGF-I administration increased its expression profile, while the administration of MGF lowered its expression. The NSC was in the growth (G0/G1) phase of the cell cycle during the 24 h culture time. The percentage of proliferated NSC decreased to 89% (17.5 mM), 85% (27.75 mM), 50.30% (41.75 mM), and 28.97% (83.75 mM). Surprisingly, the increase in both IGF-I and MGF saved the NSCs from cell death. Conclusion: Exogenous IGF-I and MGF administrations via high glucose environments increased NSC proliferation at the time of injury and protected the NSCs from cell death. The neuroprotective effect of MGF was greater than that of IGF-I. Thus, due to their neurogenesis potential, exogenous IGF-I and MGF could be applied in the treatment of diabetes patients to relieve neural damage.

Alterations in insulin-like growth factor system in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by survival motor neuron (SMN) protein deficiency. Insulin-like growth factor-I (IGF-I) is a myotrophic and neurotrophic factor that has been reported to be dysregulated in in vivo SMA model systems. However, detailed analyses of the IGF-I system in SMA patients are missing. In this study, we analyzed the components of the IGF-I system in serum and archived skeletal muscle biopsies of SMA patients. Serum IGF-I, IGF binding protein (IGFBP)-3, and IGFBP-5 levels were analyzed in 11 SMA patients and 13 healthy children by immunoradiometric and enzyme-linked immunosorbent assays. The expression of IGF-I, IGF-I receptor, and IGFBP-5 proteins was investigated by immunofluorescence analysis in the archived skeletal muscle biopsies of nine SMA patients, six patients with non-SMA-related neuromuscular disease and atrophic fibers in muscle biopsy, and four controls. A significant decrease in IGF-I levels (mean ± SD: -1.39 ± 1.46 vs. 0.017 ± 0.83, p=.02) and increase in IGFBP-5 levels (mean ± SD: 2358.5 ± 1617.4ng/mL vs. 1003.4 ± 274.3ng/mL, p=.03) were detected in serum samples of SMA patients compared to healthy controls. Increased expression of IGF-I, IGF-I receptor, and IGFBP-5 was detected in skeletal muscle biopsies of SMA patients and non-SMA neuromuscular diseases, indicating atrophy-specific alterations in the pathway. Our findings suggested that the components of the IGF-I system are altered in SMA patients at both the systemic and tissue-specific levels.

Patients with Alzheimer's Disease Have Increased Levels of Insulin-like Growth Factor-I in Serum but not in Cerebrospinal Fluid.

Insulin-like growth factor-I (IGF-I) is important for amyloid-β (Aβ) metabolism, and also interacts with the brain vasculature. In previous IGF-I studies, it has not been evaluated whether Alzheimer's disease (AD) patients had vascular comorbidities. A cross-sectional study of 40 consecutive non-diabetic AD patients and 36 healthy controls. We measured IGF-I in serum and cerebrospinal fluid (CSF) and also serum insulin. Mixed forms of AD and vascular dementia were excluded. After adjustment for covariates including age, serum IGF-I level was higher in the AD group than in the controls, whereas CSF IGF-I and serum insulin were unchanged. Binary logistic regression confirmed that high serum IGF-I was associated with increased prevalence of AD [adjusted Odds Ratio (OR) = 1.83, 95% confidence interval (CI): 1.005-3.32 per standard deviation (SD) increase in serum IGF-I]. This association was more robust after exclusion of patients receiving treatment with acetylcholinesterase inhibitors or N-methyl D-aspartate (NMDA) receptor antagonists (OR = 2.23, 95 % CI: 1.10-4.48). In the total study population (n = 76) as well in the AD group (n = 40), serum IGF-I correlated negatively with CSF Aβ1-42, and CSF IGF-I correlated positively with CSF/serum albumin ratio, CSF total tau, and CSF phosphorylated tau. In AD patients without major brain vascular comorbidities, serum but not CSF levels of IGF-I were increased after correction for covariates. This association was strengthened by exclusion of patients receiving medical treatment. Overall, the results support the notion of IGF-I resistance in mild AD dementia.

Increases in Bioactive IGF do not Parallel Increases in Total IGF-I During Growth Hormone Treatment of Children Born SGA.

Some children born small for gestational age (SGA) experience supra-physiological insulin-like growth factor-I (IGF-I) concentrations during GH treatment. However, measurements of total IGF-I concentrations may not reflect the bioactive fraction of IGF-I which reaches the IGF-I receptor at target organs. We examined endogenous IGF-bioactivity using an IGF-I kinase receptor activation (KIRA) assay that measures the ability of IGF-I to activate the IGF-IR in vitro. To compare responses of bioactive IGF and total IGF-I concentrations in short GH treated SGA children in the North European Small for Gestational Age Study (NESGAS). In NESGAS, short SGA children (n = 101, 61 males) received GH at 67 µg/kg/day for 1 year. IGF-I concentrations were measured by Immulite immunoassay and bioactive IGF by in-house KIRA assay. Bioactive IGF increased with age in healthy pre-pubertal children (n = 94). SGA children had low-normal bioactive IGF levels at baseline (-0.12 (1.8 SD), increasing significantly after one year of high-dose GH treatment to 1.1 (1.4) SD, P < 0.01. Following high-dose GH, 68% (n = 65) of SGA children had a total IGF-I concentration >2SD (mean IGF-I 2.8 SDS), whereas only 15% (n = 15) had levels of bioactive IGF slightly above normal reference values. At baseline, bioactive IGF (SDS) was significantly correlated to height (SDS) (r = 0.29, P = 0.005), in contrast to IGF-I (SDS) (r = 0.17, P = 0.10). IGF-I (SDS) was inversely correlated to delta height (SDS) after one year of high-dose GH treatment (r = -0.22, P = 0.02). In contrast to total IGF-I concentrations, bioactive IGF stayed within the normal reference ranges for most SGA children during the first year of GH treatment.

Combined administration of microdoses of growth hormone and erythropoietin: Effects on performance and evaluation of GH detection capability using anti-doping methods.

The combination of growth hormone (GH) and recombinant erythropoietin (rEPO) is thought to be used particularly in endurance sports. Our objective was to reproduce a 2-week administration of rEPO microdoses alone or in combination with GH microdoses (three times a week) on healthy and athletic male subjects and to evaluate if GH had any additional effects compared to EPO treatment alone. The effects of the treatments on hematological parameters and VO2max were studied as well as the detection of GH in serum. While the rEPO microdose regimen was associated with a significant increase in reticulocytes, no clear elevation in hemoglobin concentration (HGB) was observed. Using a correction by plasma volume did not reveal more effects of EPO on HGB. Our results did not show any additional effect when the GH microdoses were co-administered. In addition, no clear increase in VO2max was observed after treatment, with an elevation in only half the subjects in both groups (EPO and EPO+GH). A clear effect of GH on insulin-like growth factor I (IGF-I) was seen but it was lower on procollagen III amino-terminal propeptide (P-III-NP). GH detection using the direct isoform test identified only one subject 24 hours after receiving GH. The GH biomarker test combining IGF-I and P-III-NP was not able to detect the GH administration. However, a longitudinal follow-up of the intraindividual variations showed a significant increase in IGF-I 24 and 48 hours after GH administration in most subjects, while the effect of GH microdoses on P-III-NP was less straightforward.

The visceral adiposity index is associated with insulin sensitivity and IGF-I levels in adults with growth hormone deficiency.

The visceral adiposity index, based on anthropometric and metabolic parameters, has been shown to be related to adipose tissue function and insulin sensitivity. We aimed to evaluate the performance of the visceral adiposity index in adult patients with growth hormone deficiency. We enrolled 52 patients(mean age 51 ± 13 years) with newly diagnosed growth hormone deficiency and 50 matched healthy subjects as controls at baseline. At baseline and after 12 and 24 months of treatment we evaluated anthropometric measures, lipid profile, glucose and insulin during an oral glucose tolerance test, hemoglobin A1c, homeostasis model assessment estimate of insulin resistance, quantitative insulin sensitivity check index, insulin sensitivity index Matsuda, insulin-like growth factor-I and visceral adiposity index. At baseline growth hormone deficiency patients showed higher waist circumference (p < 0.001), low-density lipoprotein cholesterol (p < 0.001) and visceral adiposity index (p = 0.003) with lower insulin sensitivity index (p = 0.007) and high-density lipoprotein cholesterol (p = 0.001) than controls. During growth hormone treatment we observed a significant increase in insulin-like growth factor-I (p < 0.001), high-density lipoprotein (p < 0.001) with a trend toward increase in insulin sensitivity index (p = 0.055) and a significant decrease in total cholesterol (p < 0.001) and visceral adiposity index (p < 0.001), while no significant changes were observed in other clinical and metabolic parameters. The visceral adiposity index was the only parameter that significantly correlated with growth hormone peak at diagnosis (p < 0.001) and with insulin-like growth factor-I and insulin sensitivity index both at diagnosis (p = 0.009 and p < 0.001) and after 12 (p = 0.026 and p = 0.001) and 24 months (p < 0.001 and p = 0.001) of treatment. The visceral adiposity index, which has shown to be associated with both insulin-like growth factor-I and insulin sensitivity, proved to be the most reliable index of metabolic perturbation, among the most common indexes of adiposity assessment and a marker of benefit during treatment in adult growth hormone deficiency patients.

Changes in IGF-I, urinary free cortisol and adipokines during dronabinol therapy in anorexia nervosa: Results from a randomised, controlled trial

ObjectiveAnorexia nervosa (AN) is characterised by complex neuroendocrine disturbances due to severe underweight, physical hyperactivity and purging behaviour. Cannabinoid agonists are used to palliate cachexia of various causes, but their interactions with the hormonal systems that are involved in energy metabolism have not been previously described in humans. Therefore we found it of interest to assess interactions between the synthetic cannabinoid agonist dronabinol and insulin-like growth factor I (IGF-I), urinary free cortisol (UFC) and adipokines in patients with chronic AN. DesignThis was a prospective, double-blind randomised crossover study, conducted at a specialised care centre for eating disorders. The results are based on twenty-four adult women with chronic AN, who completed the study. The participants received dronabinol (oral capsules, 5mg daily) and matching placebo over four weeks, separated by a four-week washout period. Bioactive IGF was determined by a cell-based bioassay, whereas total IGF-I, IGFBP-2 and -3 and the two adipokines leptin and adiponectines were measured by immunoassays. The UFC excretion was determined by mass spectrometry. ResultsAs previously reported, dronabinol treatment caused a small, yet significant increase in BMI as compared to placebo (+0.23kg/m2; P=0.04). This modest weight gain predicted a corresponding increase in bioactive IGF-I, while the amount of daily energy expenditure due to physical activity had a comparable but opposite effect. Nevertheless, neither IGF-I, bioactive IGF nor the IGFBPs levels changed significantly during dronabinol intervention as compared to placebo. Adiponectin also remained unaffected by the weight gain, whereas plasma leptin showed a transient increase at three weeks (P<0.05). UFC levels were decreased during dronabinol intervention. ConclusionOur results showed that low-dosage therapy with the synthetic cannabinoid agonist dronabinol affected neither the concentration nor the activity of the circulating IGF-system in women with severe and chronic AN. However, our results suggest that such treatment may alleviate the increased hypothalamic–pituitary–adrenal axis activity seen in these patients.

Protective effect of aqueous extracts from Rhizopus oryzae on liver injury induced by carbon tetrachloride in rats.

Hepatoprotective effects of Rhizopus oryzae/ U-1 aqueous extract (RU) were demonstrated in carbon tetrachloride (CCl4 )-induced liver-injured rats. In order to investigate the RU effects, the rats were administered RU at a dose of 10 or 100 mg/kg of body weight for 10 days before induction of the liver injury by oral administration of CCl4 (125 mg/kg body weight). (i) Pretreatment with RU caused a significant decrease in serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities that were increased by the administration of CCl4 . (ii) RU pretreatment (100 mg/kg) increased 5-bromo-2'-deoxyuridine incorporation at 48 h after CCl4 treatment in hepatocytes. (iii) Histological hematoxylin and eosin staining of the liver showed that RU pretreatment reduced the damage induced by CCl4 administration. (iv) Reverse transcriptase PCR analysis showed RU retreatment caused a transient but significant increase in hepatocyte growth factor (HGF) and a sustained and significant increase in insulin-like growth factor-I (IGF-I) gene expression in hepatocytes injured by CCl4 treatment. From these results, we conclude that oral pre-administration of RU was effective to suppress liver injury induced by the subsequent oral CCl4 administration, and RU-induced increase in IGF-I and HGF gene expression may be, even in part, involved in biological actions of RU in rats.

Relationship among insulin resistance, growth hormone, and insulin-like growth factor I concentrations in diestrous Swedish Elkhounds.

BackgroundIn the dog, the normal estrous cycle includes a prolonged luteal phase. Progesterone stimulates local canine mammary growth hormone (GH) production, which may act systemically and contribute to insulin resistance. Swedish Elkhounds are predisposed to progesterone‐related diabetes mellitus, and the relationship among insulin resistance, GH, and insulin‐like growth factor I (IGF‐I) is of particular interest.ObjectiveTo study insulin resistance in relation to GH and IGF‐I in nondiabetic Swedish Elkhounds during diestrus. We also assessed whether alterations in these hormones could predict diestrus‐linked diseases and all‐cause mortality.AnimalsEighty‐four privately owned female intact Swedish Elkhounds >4 years of age.MethodsBlood sampling and clinical examination during luteal phase, with a follow‐up questionnaire after 20 months. Insulin resistance was calculated by homeostasis model assessment (HOMA‐IR).ResultsIn multivariable regression analysis, GH was positively associated with HOMA‐IR (P = .009). An increase in GH of 1 ng/mL was associated with a 12.7% increase in HOMA‐IR. Moreover, C‐peptide was positively associated with IGF‐I (P = .04), and an increase in C‐peptide of 0.1 ng/mL was associated with a 6.9% increase in IGF‐I. Structural equation modeling supported these results. Twenty‐three animals were found to have previously unrecognized mammary masses and had higher GH (P < .0001) and IGF‐I (P = .007) than dogs without mammary masses (n = 61). There was no association between high GH and IGF‐I concentrations at sampling and future mammary masses.ConclusionWe showed that GH was strongly associated with insulin resistance in older Swedish Elkhounds during diestrus.

Spatial distribution of insulin-like growth factor binding protein-2 following hypoxic-ischemic injury

BackgroundInsulin-like growth factor binding protein-2 (IGFBP-2) regulates the bioavailability, transportation, and localization of insulin-like growth factor-I (IGF-I), an effective neuroprotectant in animal stroke models especially when administered intranasally. Therefore, determining IGFBP-2′s endogenous distribution in the normal and ischemic brain is essential in maximizing the neuroprotective potential of the intranasal IGF-I treatment approach. However, current data on IGFBP-2 is limited to mRNA and in situ hybridization studies. The purpose of this study was to determine if there are any changes in IGFBP-2 protein levels and distribution in ischemic brain and also to determine if IGFBPs play a role in the transportation of intranasally administered IGF-I into the brain.ResultsUsing an in vitro approach, we show that ischemia causes changes in the distribution of IGFBP-2 in primary cortical neurons and astrocytes. In addition, we show using the transient middle cerebral artery occlusion (MCAO) model in mice that there is a significant increase in IGFBP-2 levels in the stroke penumbra and core after 72 h. This correlated with an overall increase in IGF-I after stroke, with the highest levels of IGF-I in the stroke core after 72 h. Brain sections from stroke mice indicate that neurons and astrocytes located in the penumbra both have increased expression of IGFBP-2, however, IGFBP-2 was not detected in microglia. We used binding competition studies to show that intranasally administered exogenous IGF-I uptake into the brain is not receptor mediated and is likely facilitated by IGFBPs.ConclusionsThe change in protein levels indicates that IGFBP-2 plays an IGF-I-dependent and -independent role in the brain’s acute (neuroprotection) and chronic (tissue remodeling) response to hypoxic-ischemic injury. Competition studies indicate that IGFBPs may have a role in rapid transportation of exogenous IGF-I from the nasal tissue to the site of injury.

Insulin‐like growth factor I and risk of breast cancer by age and hormone receptor status—A prospective study within the EPIC cohort

Experimental evidence shows cross-talk in mammary cells between estrogen, insulin-like growth factor I (IGF-I) and their respective receptors and possible synergistic effects of estrogen receptor (ER) activation and increased IGF-I signaling with regard to breast tumor development, and epidemiological evidence suggests that circulating IGF-I levels may be related more to the risk of ER-positive than ER-negative breast cancer. Using a case-control study nested within the prospective European EPIC cohort (938 breast cancer cases and 1,394 matched control subjects), we analyzed the relationships of prediagnostic serum IGF-I levels with the risk of estrogen and progesterone receptor-positive and -negative breast tumors. IGF-I levels were positively associated with the risk of ER+ breast tumors overall (pre- and postmenopausal women combined, odds ratio (OR)Q4-Q1 = 1.41 [95% confidence interval (CI) 1.01-1.98] for the highest vs. lowest quartile; OR = 1.17 [95% CI 1.04-1.33] per 1-standard deviation (SD) increase in IGF-I, ptrend = 0.01) and among women who were diagnosed with breast cancer at 50 years or older (ORQ3-Q1 = 1.38 [95% CI 1.01-1.89]; OR = 1.19 [95% CI 1.04-1.36] per 1-SD increase in IGF-I, ptrend = 0.01) but not with receptor-positive disease diagnosed at an earlier age. No statistically significant associations were observed for ER- breast tumors overall and by age at diagnosis. Tests for heterogeneity by receptor status of the tumor were not statistically significant, except for women diagnosed with breast cancer at 50 years or older (phet = 0.03 for ER+/PR+ vs. ER-/PR- disease). Our data add to a global body of evidence indicating that higher circulating IGF-I levels may increase risk specifically of receptor-positive, but not receptor-negative, breast cancer diagnosed at 50 years or older.

Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants

To evaluate the relationships between postnatal change in circulatory insulin-like growth factor-I (IGF-I) concentrations, brain volumes, and developmental outcome at 2 y of age in very preterm infants. IGF-I was measured weekly, and nutritional intake was calculated daily from birth until a postmenstrual age (PMA) of 35 wk. Individual β coefficients for IGF-I, IGF-I(B), representing the rate of increase in IGF-I from birth until a PMA of 35 wk were calculated. Brain magnetic resonance imaging was performed at term age, with segmentation into total brain, cerebellar, gray matter, and unmyelinated white matter volume (UWMV). Developmental outcome was evaluated using Bayley Scales of Infant Development-II. Forty-nine infants, with mean gestational age (GA) of 26.0 wk, were evaluated at mean 24.6 mo corrected age. Higher IGF-I(B), UWMV, and cerebellar volume were associated with a decreased risk for a Mental Developmental Index (MDI) < 85 (odds ratio (95% confidence interval): 0.6 (0.4-0.9), 0.96 (0.94-0.99), and 0.78 (0.6-0.96), respectively). In multivariate analysis, higher IGF-I(B) and higher UWMV combined with female gender constituted the two models with the highest predictive value for MDI > 85. A higher rate of increase in circulating IGF-I is associated with a decreased risk for subnormal MDI at 2 y of corrected age. This relationship is in part dependent on brain volume at term age.

Phenotypic differences in children conceived from fresh and thawed embryos in in vitro fertilization compared with naturally conceived children

To determine whether anthropometric and biochemical features differ in invitro fertilization (IVF) children conceived via fresh (IVFF) or thawed (IVFT) embryo transfer compared with naturally conceived controls. A cross-sectional controlled study. University clinical research unit. Healthy prepubertal children (3.5-11.0 years), singletons, born at term (>37 weeks), who were either naturally conceived (controls; n = 94) or IVF children conceived via the transfer of a fresh (IVFF; n = 72) or thawed (IVFT; n = 43) embryo. None. Assessments of anthropometry (adjusted for parental variables), dual-energy X-ray absorptiometry-derived body composition, fasting plasma growth factors, lipids, and parameters of glucose regulation. The IVFF but not the IVFT children weighed less at birth than the control children. The IVFF children were taller than both the controls and IVFT children. Sex-specific analyses showed height differences among girls, with IVFF girls being taller than their control and IVFT counterparts. Taller stature in IVFF children was associated with increased insulin-like growth factor I (IGF-I) concentrations compared with controls, whereas the IVFT children displayed increased IGF-II and decreased insulin-like growth factor binding protein 3 (IGFBP-3) concentrations compared with the controls. More favorable lipid profiles were also evident in IVFF but not IVFT children compared with the control children. These preliminary findings highlight that the transfer of a fresh versus a thawed IVF embryo affects height, plasma growth factor, and lipid profiles in childhood. Therefore, embryo derivation should be considered when assessing physical and biochemical phenotype of IVF children.

The effects of local insulin application to lumbar spinal fusions in a rat model

The rates of pseudoarthrosis after a single-level spinal fusion have been reported up to 35%, and the agents that increase the rate of fusion have an important role in decreasing pseudoarthrosis after spinal fusion. Previous studies have analyzed the effects of local insulin application to an autograft in a rat segmental defect model. Defects treated with a time-released insulin implant had significantly more new bone formation and greater quality of bone compared with controls based on histology and histomorphometry. A time-released insulin implant may have similar effects when applied in a lumbar spinal fusion model. This study analyzes the effects of a local time-released insulin implant applied to the fusion bed in a rat posterolateral lumbar spinal fusion model. Our hypothesis was twofold: first, a time-released insulin implant applied to the autograft bed in a rat posterolateral lumbar fusion will increase the rate of successful fusion and second, will alter the local environment of the fusion site by increasing the levels of local growth factors. Animal model (Institutional Animal Care and Use Committee approved) using 40 adult male Sprague-Dawley rats. Forty skeletally mature Sprague-Dawley rats weighing approximately 500 g each underwent posterolateral intertransverse lumbar fusions with iliac crest autograft from L4 to L5 using a Wiltse-type approach. After exposure of the transverse processes and high-speed burr decortication, a Linplant (Linshin Canada, Inc., ON, Canada) consisting of 95% microrecrystalized palmitic acid and 5% bovine insulin (experimental group) or a sham implant consisting of only palmitic acid (control group) was implanted on the fusion bed with iliac crest autograft. As per the manufacturer, the Linplant has a release rate of 2 U/day for a minimum of 40 days. The transverse processes and autograft beds of 10 animals from the experimental and 10 from the control group were harvested atDay 4 and analyzed for growth factors. The remaining 20 spines were harvested at 8 weeks andunderwent a radiographic examination, manual palpation, and microcomputed tomographic (micro-CT) examination. One of the 8-week control animals died on postoperative Day 1, likely due to anesthesia. In the groups sacrificed at Day 4, there was a significant increase in insulinlike growth factor-I (IGF-I) in the insulin treatment group compared with the controls (0.185 vs. 0.129; p=.001). No significant differences were demonstrated in the levels of transforming growth factor beta-1, platelet-derived growth factor-AB, and vascular endothelial growth factor between the groups (p=.461, .452, and .767 respectively). Based on the radiographs, 1 of 9 controls had a solid bilateral fusion mass, 2 of 9 had unilateral fusion mass, 3 of 9 had small fusion mass bilaterally, and 3 of 9 had graft resorption. The treatment group had solid bilateral fusion mass in 6 of 10 and unilateral fusion mass in 4 of 10, whereas a small bilateral fusion mass and graft resorption were not observed. The difference between the groups was significant (p=.0067). Based on manual palpation, only 1 of 9 controls was considered fused, 4 of 9 were partially fused, and 4 of 9 were not fused. In the treatment group, there were 6 of 10 fusions, 3 of 10 partial fusions, and 1 of 10 were not fused. The difference between the groups was significant (p=.0084). Based on the micro-CT, the mean bone volume of the control group was 126.7 mm(3) and 203.8 mm(3) in the insulin treatment group. The difference between the groups was significant (p=.0007). This study demonstrates the potential role of a time-released insulin implant as a bone graft enhancer using a rat posterolateral intertransverse lumbar fusion model. The insulin-treatment group had significantly higher fusion rates based on the radiographs and manual palpation and had significantly higher levels of IGF-I and significantly more bone volume on micro-CT.

Diabetes Mellitus and Cancer

Diabetes and cancer are frequent diseases with important impact on human health all the world. Last epidemiologic studies suggests that patients with diabetes are at significantly higher risk for many forms of cancer. Type 2 diabetes and cancer share many risk factors. Increased insulin-like growth factor I (IGF-I) and reactive oxygen species can rol play in carcinogenesis. The systemic chronical inflammation which can result in a protumorigenic conditions. Hyperinsulinemia increases the risk of cancer in healthy people and it can partly explain obesity-cancer risk. The other point of view very important and difficult issue the medical treatment and dietary of diabetic patients with cancer.

The Effects of Local Insulin Application to Lumbar Spinal Fusions in a Rat Model

BACKGROUND CONTEXT: The rates of pseudoarthrosis after a single-level spinal fusion have been reported up to 35%, and the agents that increase the rate of fusion have an important role in decreasing pseudoarthrosis after spinal fusion. Previous studies have analyzed the effects of local insulin application to an autograft in a rat segmental defect model. Defects treated with a timereleased insulin implant had significantly more new bone formation and greater quality of bone compared with controls based on histology and histomorphometry. A time-released insulin implant may have similar effects when applied in a lumbar spinal fusion model. PURPOSE: This study analyzes the effects of a local time-released insulin implant applied to the fusion bed in a rat posterolateral lumbar spinal fusion model. Our hypothesis was twofold: first, a time-released insulin implant applied to the autograft bed in a rat posterolateral lumbar fusion will increase the rate of successful fusion and second, will alter the local environment of the fusion site by increasing the levels of local growth factors. STUDY DESIGN: Animal model (Institutional Animal Care and Use Committee approved) using 40 adult male Sprague-Dawley rats. METHODS: Forty skeletally mature Sprague-Dawley rats weighing approximately 500 g each underwent posterolateral intertransverse lumbar fusions with iliac crest autograft from L4 to L5 using a Wiltse-type approach. After exposure of the transverse processes and high-speed burr decortication, a Linplant (Linshin Canada, Inc., ON, Canada) consisting of 95% microrecrystalized palmitic acid and 5% bovine insulin (experimental group) or a sham implant consisting of only palmitic acid (control group) was implanted on the fusion bed with iliac crest autograft. As per the manufacturer, the Linplant has a release rate of 2 U/day for a minimum of 40 days. The transverse processes and autograft beds of 10 animals from the experimental and 10 from the control group were harvested at Day 4 and analyzed for growth factors. The remaining 20 spines were harvested at 8 weeks and underwent a radiographic examination, manual palpation, and microcomputed tomographic (micro-CT) examination. RESULTS: One of the 8-week control animals died on postoperative Day 1, likely due to anesthesia. In the groups sacrificed at Day 4, there was a significant increase in insulinlike growth factor-I (IGF-I) in the insulin treatment group compared with the controls (0.185 vs. 0.129; p5.001). No significant differences were demonstrated in the levels of transforming growth factor beta-1,

IGF-I measurement across blood, interstitial fluid, and muscle biocompartments following explosive, high-power exercise

Insulin-like growth factor-I (IGF-I) resides across different biocompartments [blood, interstitial fluid (ISF), and muscle]. Whether circulating IGF-I responses to exercise reflect local events remains uncertain. We measured the IGF-I response to plyometric exercise across blood, ISF, and muscle biopsy from the vastus lateralis. Twenty volunteers (8 men, 12 women, 22 ± 1 yr) performed 10 sets of 10 plyometric jump repetitions at a 40% 1-repetition maximum. Blood, ISF, and muscle samples were taken pre- and postexercise. Circulating IGF-I increased postexercise: total IGF-I (preexercise = 546 ± 42, midexercise = 585 ± 43, postexercise = 597 ± 45, +30 = 557 ± 42, +60 = 536 ± 40, +120 = 567 ± 42 ng/ml; midexercise, postexercise, and +120 greater than preexercise, P < 0.05); Free IGF-I (preexercise = 0.83 ± 0.09, midexercise = 0.78 ± 0.10, postexercise = 0.79 ± 0.11, +30 = 0.93 ± 0.10, +60 = 0.88 ± 0.10, + 120 = 0.91 ± 0.11 ng/ml; +30 greater than all other preceding time points, P < 0.05). No exercise-induced changes were observed for ISF IGF-I (preexercise = 2.35 ± 0.29, postexercise = 2.46 ± 0.35 ng/ml). No changes were observed for skeletal muscle IGF-I protein, although IGF-I mRNA content increased ∼40% postexercise. The increase in circulating total and free IGF-I was not correlated with increases in ISF IGF-I or muscle IGF-I protein content. Our data indicate that exercise-induced increases in circulating IGF-I are not reflective of local IGF-I signaling.

12-Month effects of once-weekly sustained-release growth hormone treatment in adults with GH deficiency

The weekly sustained-release recombinant human GH formulation LB03002, showed beneficial effects in GH-deficient (GHD) adults in a previous 26-week double-blind study. Prior studies of long-acting GH preparations in adults have only been conducted for 6 or 8 months, so the effects of longer-term use are unknown; this is important to address, as replacement is given for many years in GHD adults. This open-label, 26-week study extension evaluated longer-term safety and efficacy of LB03002 over 52 weeks in adults with GHD who had previously been randomized to GH, and provides additional safety and efficacy data over 26 weeks in the cohort who had previously been randomized to placebo. Of 147 adults with GHD who completed a preceding study, 136 patients continued in this open-label study to receive LB03002 over an additional 26 weeks. This represented a continuation of long-acting GH for 26 weeks in the cohort who took this medication in the prior study (LB03002 Throughout group), and describes the first use of long-acting GH in the cohort that was randomized to placebo in the prior study (Switched to LB03002 group). The LB03002 dose was adjusted according to serum insulin-like growth factor-I (IGF-I) levels. LB03002 treatment demonstrated mean significant decreases from baseline in fat mass (FM) for both 26 (Switched group, P = 0.001) and 52 weeks (Throughout group, P = 0.002) of 1.11 (1.95) kg and 1.06 (3.16) kg, respectively. Prolonged GH treatment was effective in sustaining the increase in lean body mass (LBM), serum IGF-I and IGFBP-3 levels achieved during the first 26 weeks. Long-term treatment with the sustained-release weekly GH preparation over both 26 and 52 weeks in adults with GHD demonstrated a sustained reduction of FM with a favorable safety profile. This study extends prior knowledge about long-acting GH because it reports the most prolonged treatment of adults with any long-acting GH preparation, thereby confirming the value and safety of such agents for long-term GH replacement.

A cross-sectional analysis of the association between diet and insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-2, and IGFBP-3 in men in the United Kingdom

There is evidence of associations between insulin-like growth factor I (IGF-I), IGF-II, insulin-like binding protein-2 (IGFBP-2), IGFBP-3, and prostate cancer risk. This study examines the association between dietary factors associated with prostate cancer and serum levels of these peptides. A cross-sectional analysis of self-reported 12-month dietary intake with serum IGF and IGFBP levels was performed using data from 1,798 subjects screened negative for prostate cancer as part of a UK multicenter trial comparing treatments for this condition. Multivariable linear regression models tested associations of diet with IGFs and IGFBPs. For a one standard deviation (SD) increase in dairy product and dairy protein intake, IGF-I increased by 5.28ng/mL (95% confidence interval: 2.64, 7.92ng/mL) and 6.02ng/mL (3.34, 8.71ng/mL), respectively. A 25% increase in calcium and selenium intake was associated with an increase in IGF-I of 5.92ng/mL (3.77, 8.07ng/mL) and 2.61ng/mL (1.10, 4.13ng/mL), respectively. A one SD increase in animal protein was associated with a decrease in IGFBP-2 of 6.20% (-8.91, -3.41%), and there was some evidence of an inverse association with dairy protein and calcium. There was no evidence of any dietary associations with IGFBP-3 or IGF-II. Diet is associated with IGF-I and IGFBP-2 levels in men in the UK, and these peptides warrant further investigation as part of randomized trials of dietary interventions to reduce the risk or progression of prostate cancer. There is no evidence that IGF-II or IGFBP-3 are mediators of dietary associations with prostate cancer.