Serum Free Insulin-like Growth Factor-1 Research Articles

Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia

ABSTRACT Cerebral ischemia is a pathology involving a cascade of cellular mechanisms, leading to the deregulation of proteostasis, including macroautophagy/autophagy, and finally to neuronal death. If it is now accepted that cerebral ischemia induces autophagy, the effect of thrombolysis/energy recovery on proteostasis remains unknown. Here, we investigated the effect of thrombolysis by PLAT/tPA (plasminogen activator, tissue) on autophagy and neuronal death. In two in vitro models of hypoxia reperfusion and an in vivo model of thromboembolic stroke with thrombolysis by PLAT/tPA, we found that ischemia enhances neuronal deleterious autophagy. Interestingly, PLAT/tPA decreases autophagy to mediate neuroprotection by modulating the PI3K-AKT-MTOR pathways both in vitro and in vivo. We identified IGF1R (insulin-like growth factor I receptor; a tyrosine kinase receptor) as the effective receptor and showed in vitro, in vivo and in human stroke patients and that PLAT/tPA is able to degrade IGFBP3 (insulin-like growth factor binding protein 3) to increase IGF1 (insulin-like growth factor 1) bioavailability and thus IGF1R activation. Abbreviations: AKT/protein kinase B: thymoma viral proto-oncogene 1; EGFR: epidermal growth factor receptor; Hx: hypoxia; IGF1: insulin-like growth factor 1; IGF1R: insulin-like growth factor I receptor; IGFBP3: insulin-like growth factor binding protein 3; Ka: Kainate; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/ERK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OGD: oxygen and glucose deprivation; OGDreox: oxygen and glucose deprivation + reoxygentation; PepA: pepstatin A1; PI3K: phosphoinositide 3-kinase; PLAT/tPA: plasminogen activator, tissue; PPP: picropodophyllin; SCH77: SCH772984; ULK1: unc-51 like kinase 1; Wort: wortmannin

Benefits of resistance exercise in lean women with fibromyalgia: involvement of IGF-1 and leptin

BackgroundChronic pain and fatigue improves by exercise in fibromyalgia (FM) but underlying mechanisms are not known. Obesity is increased among FM patients and associates with higher levels of pain. Symptom improvement after aerobic exercise is affected by body mass index (BMI) in FM. Metabolic factors such as insulin-like growth factor 1 (IGF-1) and leptin may be involved. In this study, the aim was to evaluate the role of metabolic factors in lean, overweight and obese women during resistance exercise, in relation to symptom severity and muscle strength in women with FM.MethodsForty-three women participated in supervised progressive resistance exercise, twice weekly for 15-weeks. Serum free and total IGF-1, IGF-binding protein 3 (IGFBP3), adiponectin, leptin and resistin were determined at baseline and after 15-weeks. Level of current pain was rated on a visual analogue scale (0–100 mm). Level of fatigue was rated by multidimensional fatigue inventory (MFI-20) subscale general fatigue (MFIGF). Knee extension force, elbow flexion force and handgrip force were assessed by dynamometers.ResultsFree IGF-1 (p = 0.047), IGFBP3 (p = 0.025) and leptin (p = 0.008) were significantly decreased in lean women (n = 18), but not in the overweight (n = 17) and the obese (n = 8). Lean women with FM benefited from resistance exercise with improvements in current pain (p= 0.039, n = 18), general fatigue (MFIGF, p = 0.022, n = 18) and improved elbow-flexion force (p = 0.017, n = 18). In overweight and obese women with FM there was no significant improvement in pain or fatigue but an improvement in elbow flexion (p = 0.049; p = 0.012) after 15 weeks of resistance exercise.ConclusionThe clearest clinical response to resistance exercise was found in lean patients with FM. In these individuals, individualized resistance exercise was followed by changes in IGF-1 and leptin, reduced pain, fatigue and improved muscular strength. In overweight and obese women FM markers of metabolic signaling and clinical symptoms were unchanged, but strength was improved in the upper limb. Resistance exercise combined with dietary interventions might benefit patients with FM and overweight.Trial registrationThe trial was registered 21 of October 2010 with ClinicalTrials.gov identification number: NCT01226784.

Essential Amino Acid Enriched High-Protein Enteral Nutrition Modulates Insulin-Like Growth Factor-1 System Function in a Rat Model of Trauma-Hemorrhagic Shock

BackgroundNutrition support for critically ill patients supplemented with additional modular protein may promote skeletal muscle protein anabolism in addition to counteracting acute nitrogen loss. The present study was designed to investigate whether the essential amino acid (EAA) enriched high-protein enteral nutrition (EN) modulates the insulin-like growth factor-1 (IGF-1) system and activates the mammalian target of rapamycin (mTOR) anabolic signaling pathway in a trauma-hemorrhagic shock (T-HS) rat model.Methodology/Principal FindingsMale Sprague-Dawley rats (n = 90, 278.18±0.94 g) were randomly assigned to 5 groups: (1) normal control, (2) pair-fed, (3) T-HS, (4) T-HS and standard EN, and (5) T-HS and EAA enriched high-protein EN. Six animals from each group were harvested on days 2, 4, and 6 for serum, gastrocnemius, soleus, and extensor digitorum longus sample collection. T-HS significantly reduced muscle mass. Nutrition support maintained muscle mass, especially the EAA enriched high-protein EN. Meanwhile, a pronounced derangement in IGF-1-IGFBPs axis as well as impaired mTOR transduction was observed in the T-HS group. Compared with animals receiving standard EN, those receiving EAA enriched high-protein EN presented 18% higher serum free IGF-1 levels following 3 days of nutrition support and 22% higher after 5 days. These changes were consistent with the concomitant elevation in serum insulin and reduction in corticosterone levels. In addition, phosphorylations of downstream anabolic signaling effectors - including protein kinase B, mTOR, and ribosomal protein S6 kinase1 - increased significantly in rats receiving EAA enriched high-protein EN.Conclusion/SignificanceOur findings firstly demonstrate the beneficial effect of EAA enriched high-protein EN on the metabolic modulation of skeletal muscle protein anabolism by regulating the IGF-1 system and downstream anabolic signaling transduction.

Changes in pain and insulin-like growth factor 1 in fibromyalgia during exercise: the involvement of cerebrospinal inflammatory factors and neuropeptides

IntroductionFibromyalgia (FM) is characterized by chronic pain. Impaired growth hormone responses and reduced serum insulin-like growth factor 1 (IGF-1) are common in FM. The aim was to examine changes in serum IGF-1, cerebrospinal fluid (CSF), neuropeptides, and cytokines during aerobic exercise in FM patients.MethodsIn total, 49 patients (median age, 52 years) with FM were included in the study. They were randomized to either the moderate- to high-intensity Nordic Walking (NW) program (n = 26) or the supervised low-intensity walking (LIW) program (n = 23). Patients participated in blood tests before and after 15 weeks of aerobic exercise. Changes in serum levels of free IGF-1, pain rating on a 0- to 100-mm scale, pain threshold, and 6-minute walk test (6MWT) were examined. CSF, neuropeptides, matrix metalloproteinase 3 (MMP-3), and inflammatory cytokines were determined. Nonparametric tests were used for group comparisons and correlation analyses.ResultsSerum free IGF-1 levels did not change during 15 weeks of exercise between the two groups, although the 6MWT significantly improved in the NW group (p = 0.033) when compared with LIW. Pain did not significantly change in any of the groups, but tended to decrease (p = 0.052) over time in the total group. A tendency toward a correlation was noted between baseline IGF-1 and a decrease of pain in response to exercise (r = 0.278; p = 0.059). When adjusted for age, this tendency disappeared. The change in serum free IGF-1 correlated positively with an alteration in CSF substance P (SP) levels (rs = 0.495; p = 0.072), neuropeptide Y (NPY) (rs = 0.802; p = 0.001), and pain threshold (rs = 0.276; p = 0.058). Differing CSF SP levels correlated positively to a change in pain threshold (rs = 0.600; p = 0.023), whereas the shift in CSF MMP-3 inversely correlated with an altered pain threshold (rs = -0.569; p = 0.034).ConclusionsThe baseline level of serum free IGF-1 did not change during high or low intensity of aerobic exercise. Changes in IGF-1 correlated positively with a variation in CSF SP, NPY, and pain threshold. These data indicate a beneficial role of IGF-1 during exercise in FM.Trial registration: ClinicalTrials.gov NCT00643006.

Free Insulin-Like Growth Factor-1 Levels in Bladder Growth following Spinal Cord Injury Experimentally

Introduction: To determine the levels of spinal cord injury (SCI) on free insulin-like growth factor-1 (IGF-1) content in the bladder and the possible role of free IGF-1 in growth in hypertrophic bladders in an experimental model. Materials and Methods: The contents of free IGF-1 and protein in paraplegic and non-paraplegic rats which was induced experimentally by SCI were measured. The wet weights of the bladders were also determined. The results gained were compared. Results: The mean bladder free IGF-1 level in paraplegic rats was significantly higher than the corresponding bladder free IGF-1 level in sham-operated bladder (p < 0.05). Mean wet weight bladder in paraplegic rats was significantly higher than the sham-operated rats (p < 0.05). Paraplegic bladder had a significantly higher mean protein content than the sham-operated bladder (p < 0.05). Serum free IGF-1 levels in the two groups were not different. Conclusion: Our pilot study reveals that free IGF-1 may be effective in SCI.

Free insulin-like growth factor 1 in the vitreous fluid of diabetic patients with proliferative diabetic retinopathy: a case-control study.

The aim of the study was to evaluate the vitreous levels of free insulin-like growth factor 1 (IGF-1) in patients with proliferative diabetic retinopathy (PDR). For this, a total of 36 diabetic patients with PDR (group A) and 28 non-diabetic patients (group B) in whom a vitrectomy was performed were compared. Both groups were matched by age, sex and serum-free IGF-1. In a subgroup of diabetic patients (n =21) and non-diabetic patients (n =13), vitreous and serum total IGF-1, IGF-binding protein 1 (IGFBP-1) and IGFBP-3 were also determined. Serum and vitreous levels of free IGF-1, total IGF-1, IGFBP-1 and IGFBP-3 were measured by immunological methods. Vitreal proteins were assessed by a turbidimetric method and adjusted for vitreous haemoglobin. Vitreous levels of free IGF-1 were elevated in group A (median, 0.16 ng/ml; range 0.06-0.57 ng/ml) in comparison with group B (median, 0.12 ng/ml; range 0.06-0.22 ng/ml; P <0.001); however, after adjusting for vitreal proteins, free IGF-1 levels were significantly lower in group A in comparison with group B [0.05 ng/mg (0.01-0.45 ng/mg) versus 0.15 ng/mg (0.07-0.66 ng/mg); P <0.001]. The relatively lower free IGF-1 level observed in group A could not be attributed to differences in the distribution of intravitreous IGFBP-1 and IGFBP-3 in relation to total IGF-1. Notably, the contribution of free IGF-1 to total IGF-1 in vitreous fluid was 10% in group A and 42% in group B; these percentages largely exceed that obtained in serum (<1%). Our results suggest that although there is an enhancement of intravitreous free IGF-1 in diabetic patients due to serum diffusion, a deficit in its intraocular production also exists. In addition, these findings support the concept that intraocular-produced free IGF-1 plays a relevant role in retinal homoeostasis.

Free insulin-like growth factor 1 in the vitreous fluid of diabetic patients with proliferative diabetic retinopathy: a case-control study

The aim of the study was to evaluate the vitreous levels of free insulin-like growth factor 1 (IGF-1) in patients with proliferative diabetic retinopathy (PDR). For this, a total of 36 diabetic patients with PDR (group A) and 28 non-diabetic patients (group B) in whom a vitrectomy was performed were compared. Both groups were matched by age, sex and serum-free IGF-1. In a subgroup of diabetic patients (n = 21) and non-diabetic patients (n = 13), vitreous and serum total IGF-1, IGF-binding protein 1 (IGFBP-1) and IGFBP-3 were also determined. Serum and vitreous levels of free IGF-1, total IGF-1, IGFBP-1 and IGFBP-3 were measured by immunological methods. Vitreal proteins were assessed by a turbidimetric method and adjusted for vitreous haemoglobin. Vitreous levels of free IGF-1 were elevated in group A (median, 0.16ng/ml; range 0.06–0.57ng/ml) in comparison with group B (median, 0.12ng/ml; range 0.06–0.22ng/ml; P&lt;0.001); however, after adjusting for vitreal proteins, free IGF-1 levels were significantly lower in group A in comparison with group B [0.05ng/mg (0.01–0.45ng/mg) versus 0.15ng/mg (0.07–0.66ng/mg); P&lt;0.001]. The relatively lower free IGF-1 level observed in group A could not be attributed to differences in the distribution of intravitreous IGFBP-1 and IGFBP-3 in relation to total IGF-1. Notably, the contribution of free IGF-1 to total IGF-1 in vitreous fluid was 10% in group A and 42% in group B; these percentages largely exceed that obtained in serum (&lt;1%). Our results suggest that although there is an enhancement of intravitreous free IGF-1 in diabetic patients due to serum diffusion, a deficit in its intraocular production also exists. In addition, these findings support the concept that intraocular-produced free IGF-1 plays a relevant role in retinal homoeostasis.

Prostatic fluid-free insulin-like growth factor-1 in relation to prostate cancer.

To establish the feasibility of measuring free insulin-like growth factor-1 (IGF-1) in prostatic fluid and to determine if there is a difference in free IGF-1 levels in the prostatic fluid of patients with prostatic adenocarcinoma and in normal men. Prostatic fluid samples were collected from men with histologically confirmed prostate cancer and from control subjects with no malignancy. Prostatic fluid and serum free IGF-1 levels were measured in duplicate by radioimmunoassay, and the differences analysed using the Mann-Whitney U-test and Pearson correlation. Prostatic fluid free IGF-1 concentrations did not differ significantly (P = 0.23) and there was no difference in serum free IGF-1 levels between the groups. While serum PSA level was significantly correlated with age (P < 0.001) the free IGF-1 level of prostatic fluid was not. There was also no correlation between prostatic fluid free IGF-1 and serum PSA levels. Free IGF-1 can be detected in prostatic fluid with acceptable sensitivity. However, the free IGF-1 level in prostatic fluid does not help to detect patients with prostate cancer and is not a tumour marker.

Free insulin-like growth factor-1 and unilateral complete ureteral obstruction in the rat

Objectives. To determine the effect of unilateral ureteral obstruction on renal free insulin-like growth factor-1 (IGF-1) content in the kidneys and the possible role of free IGF-1 in compensatory growth in the nonobstructed kidney in an experimental model. Methods. The content of free IGF-1 and total protein in the obstructed and nonobstructed kidneys were measured 7 days after unilateral ureteral obstruction. The weights of the kidneys were also determined. The results were compared with those of the sham-operated animals. Results. The mean renal free IGF-1 level of the obstructed kidneys was significantly lower than the mean renal free IGF-1 level of the sham-operated kidneys ( P = 0.03), and the mean renal free IGF-1 level of the nonobstructed kidneys was significantly higher than the mean renal free IGF-1 level of the sham-operated kidneys ( P <0.0001). The serum free IGF-1 levels in the two groups were not different. The mean weight of the obstructed and nonobstructed kidneys was significantly higher than those of the sham-operated kidneys (1.49 ± 0.09 and 1.03 ± 0.03 versus 0.88 ± 0.02 g, P <0.0001 and P = 0.006, respectively). The obstructed kidneys had significantly lower mean protein content than the nonobstructed kidneys and had significantly higher mean protein content than the sham-operated kidneys ( P <0.0001 and P = 0.0004, respectively). Conclusions. Our results reveal that compensatory renal growth is driven by a rise in the free IGF-1 concentration after unilateral ureteral obstruction.

Pharmacokinetics of insulin-like growth factor-1 in advanced chronic renal failure

Information regarding the impact of chronic renal failure (CRF) on IGF-1 serum clearance is limited. Thus we evaluated the pharmacokinetics of insulin-like growth factor-1 (IGF-1) in six normal adults and six adults with advanced CRF (serum creatinine 7 +/- 0.8 mg/dl). All subjects were given 80 micrograms/kg recombinant human IGF-1 s.c. and blood was sampled over 48 hours. Baseline total serum IGF-1 levels were similar in both groups, but peak levels were elevated significantly in CRF; this was apparently related to the reduced distribution volume in CRF subjects. CRF did not affect the metabolic clearance rate (MCR) of total serum IGF-1. Immunoreactive IGF binding protein-3 (IGFBP-3) levels were greater in CRF. Western immunoblots revealed that the apparent increase in IGFBP-3 was largely due to an increase in immunoreactive fragments. IGFBP-3 protease activity was not increased. Thus IGFBP fragment accumulation likely reflects reduced fragment clearance. Western ligand blots revealed elevated 30 and 34 kDa IGFBP levels and IGFBP products in CRF serum. Serum acid labile subunit levels were unchanged in CRF. Peak free IGF-1 levels and the MCR of free IGF-1 did not differ between groups. In both groups the MCR of free IGF-1 exceeded the MCR of total IGF-1 by approximately 30-fold. These data suggest that in CRF patients receiving s.c. IGF-1: (a) total serum IGF-1 levels are increased as a result of elevated circulating IGFBPs that may restrict the distribution of IGF-1 beyond plasma; (b) serum free IGF-1 levels are not altered; and (c) the IGF-1 MCR is unchanged in CRF. Thus, in advanced CRF, apart from a reduction in the total IGF-1 volume of distribution the pharmacokinetics of IGF-1 are largely unaltered.