Administration Of Insulin-like Growth Factor-1 Research Articles

IGF1 as a Potential Treatment for Rett Syndrome: Safety Assessment in Six Rett Patients

Rett syndrome (RTT) is a devastating neurodevelopmental disorder that affects one in ten thousand girls and has no cure. The majority of RTT patients display mutations in the gene that codes for the methyl-CpG-binding protein 2 (MeCP2). Clinical observations and neurobiological analysis of mouse models suggest that defects in the expression of MeCP2 protein compromise the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function, such as insulin-like growth factor 1 (IGF1), are good candidates for ameliorating the symptoms of RTT. IGF1 and its active peptide, (1–3) IGF1, cross the blood brain barrier, and (1–3) IGF1 ameliorates the symptoms of RTT in a mouse model of the disease; therefore they are ideal treatments for neurodevelopmental disorders, including RTT. We performed a pilot study to establish whether there are major risks associated with IGF1 administration in RTT patients. Six young girls with classic RTT received IGF1 subcutaneous injections twice a day for six months, and they were regularly monitored by their primary care physicians and by the unit for RTT in Versilia Hospital (Italy). This study shows that there are no risks associated with IGF1 administration.

Morphological and Histopathological Changes in Orofacial Structures of Experimentally Developed Acromegaly-Like Rats: An Overview

Tongue enlargement and mandibular prognathism are clinically recognized in almost all patients with acromegaly. An acromegaly-like rat model recently developed by exogenous administration of insulin-like growth factor I (IGF-I) was used to investigate morphological and histopathological changes in orofacial structures and to clarify whether these changes were reversible. Exogenous administration of IGF-I evoked specific enlargement of the tongue with identifiable histopathological changes (increased muscle bundle width, increased space between muscle bundles, and increased epithelial thickness), elongation of the mandibular alveolar bone and ascending ramus, and lateral expansion of the mandibular dental arch. Regarding histopathological changes in the mandibular condyle, the cartilaginous layer width, bone matrix ratio, and number of osteoblasts were all significantly greater in this rat model. After normalization of the circulating IGF-I level, tongue enlargement and histopathological changes in the tongue and mandibular condyle were reversible, whereas morphological skeletal changes in the mandible remained.

IGF-1 restores visual cortex plasticity in adult life by reducing local GABA levels.

The central nervous system architecture is markedly modified by sensory experience during early life, but a decline of plasticity occurs with age. Recent studies have challenged this dogma providing evidence that both pharmacological treatments and paradigms based on the manipulation of environmental stimulation levels can be successfully employed as strategies for enhancing plasticity in the adult nervous system. Insulin-like growth factor 1 (IGF-1) is a peptide implicated in prenatal and postnatal phases of brain development such as neurogenesis, neuronal differentiation, synaptogenesis, and experience-dependent plasticity. Here, using the visual system as a paradigmatic model, we report that IGF-1 reactivates neural plasticity in the adult brain. Exogenous administration of IGF-1 in the adult visual cortex, indeed, restores the susceptibility of cortical neurons to monocular deprivation and promotes the recovery of normal visual functions in adult amblyopic animals. These effects were accompanied by a marked reduction of intracortical GABA levels. Moreover, we show that a transitory increase of IGF-1 expression is associated to the plasticity reinstatement induced by environmental enrichment (EE) and that blocking IGF-1 action by means of the IGF-1 receptor antagonist JB1 prevents EE effects on plasticity processes.

Intranasal administration of insulin-like growth factor-1 protects against lipopolysaccharide-induced injury in the developing rat brain

Our previous studies show that insulin-like growth factor-1 (IGF-1) can either protect against or increase lipopolysaccharide (LPS)-induced damage in the developing brain, depending on the dose, when it is co-administered with LPS through intracerebral injection. To further explore effects of IGF-1 on central inflammation associated brain injury, IGF-1 was administered through intranasal infusion in the current study. Postnatal day 5 (P5) rats were exposed to LPS at a dose of 1 μg/g body weight or sterile saline through intracerebral injection. Recombinant human insulin-like growth factor-1 (rhIGF-1) at a dose of 50 μg/pup or vehicle was administered intranasally 1 or 2 h after the LPS injection. Neonatal LPS exposure resulted in oligodendrocyte (OL) and white matter injury in the P6 or P21 rat brain. The damages include dilatation of lateral ventricles, pyknotic cell death, loss of OL progenitor cells and mature OLs in the cingulum area, and impairment of myelination at the corpus callosum area. Neurological dysfunctions were observed in juvenile rats with neonatal LPS exposure. Intranasal IGF-1 treatment at either 1 or 2 h after LPS exposure significantly attenuated LPS-induced brain injury and improved some behavioral deficits. Intranasal IGF-1 treatment also reduced infiltration of polymorphonuclear (PMN) leukocytes and activation of microglia in the rat brain 24 h after LPS exposure, but it did not prevent the elevation in concentrations of interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNFα) in the LPS-exposed rat brain during the first 24 h. This is an indication that direct anti-inflammation might not be the primary mechanism for the protection of IGF-1, and other mechanisms, such as anti-apoptotic effects, are likely involved in its protective effects.

IGF-1 protects against diabetic features in an in vivo model of Huntington's disease

Huntington's disease (HD) is the most prevalent polyglutamine expansion disorder. HD is caused by an expansion of CAG triplet in the huntingtin (HTT) gene, associated with striatal and cortical neuronal loss. Central and peripheral metabolic abnormalities and altered insulin-like growth factor-1 (IGF-1) levels have been described in HD. Thus, we hypothesized that restoration of IGF-1-mediated signaling pathways could rescue R6/2 mice from metabolic stress and behavioral changes induced by polyglutamine expansion. We analyzed the in vivo effect of continuous peripheral IGF-1 administration on diabetic parameters, body weight and motor behavior in the hemizygous R6/2 mouse model of HD. We used 9 week-old and age-matched wild-type mice, subjected to continuously infused recombinant IGF-I or vehicle, for 14 days. IGF-1 treatment prevented the age-related decrease in body weight in R6/2 mice. Although blood glucose levels were higher in R6/2 mice, they did not reach a diabetic state. Even though, IGF-1 ameliorated poor glycemic control in HD mice. This seemed to be associated with a decrease in blood insulin levels in R6/2 mice, which was increased following IGF-1 infusion. Similarly, blood IGF-1 levels decreased during aging in both wild-type and R6/2 mice, being significantly improved upon its continuous infusion. Although no significant differences were found in motor function in R6/2-treated mice, IGF-1 treatment highly improved paw clasping scores. In summary, these results suggest that IGF-1 has a protective role against HD-associated impaired glucose tolerance, by enhancing blood insulin levels.

Insulin-like Growth Factor 1-mediated Hyperthermia Involves Anterior Hypothalamic Insulin Receptors

The objective is to investigate the role of insulin-like growth factor 1 (IGF-1) in the regulation of core body temperature. Sequencing cDNA libraries from individual warm-sensitive neurons from the preoptic area (POA) of the hypothalamus, a region involved in the central control of thermoregulation, identified neurons that express both IGF-1 receptor (IGF-1R) and insulin receptor transcripts. The effects of administration of IGF-1 into the POA was measured by radiotelemetry monitoring of core temperature, brown adipose tissue (BAT) temperature, metabolic assessment, and imaging of BAT by positron emission tomography of 2-[(18)F]fluoro-2-deoxyglucose uptake combined with computed tomography. IGF-1 injection into the POA caused dose-dependent hyperthermia that could be blocked by pretreatment with the IGF-1R tyrosine kinase inhibitor, PQ401. The IGF-1-evoked hyperthermia involved activation of brown adipose tissue and was accompanied by a switch from glycolysis to fatty acid oxidation as a source of energy as shown by lowered respiratory exchange ratio. Transgenic mice that lack neuronal insulin receptor expression in the brain (NIRKO mice) were unable to mount the full hyperthermic response to IGF-1, suggesting that the IGF-1 mediated hyperthermia is partly dependent on expression of functional neuronal insulin receptors. These data indicate a novel thermoregulatory role for both IGF-1R and neuronal insulin receptors in IGF-1 activation of BAT and hyperthermia. These central effects of IGF-1 signaling may play a role in regulation of metabolic rate, aging, and the risk of developing type 2 diabetes.

Central administration of insulin-like growth factor-I decreases depressive-like behavior and brain cytokine expression in mice

Exogenous administration of insulin-like growth factor (IGF)-I has anti-depressant properties in rodent models of depression. However, nothing is known about the anti-depressant properties of IGF-I during inflammation, nor have mechanisms by which IGF-I alters behavior following activation of the innate immune system been clarified. We hypothesized that central IGF-I would diminish depressive-like behavior on a background of an inflammatory response and that it would do so by inducing expression of the brain-derived neurotrophic factor (BDNF) while decreasing pro-inflammatory cytokine expression in the brain. IGF-I (1,000 ng) was administered intracerebroventricularly (i.c.v.) to CD-1 mice. Mice were subsequently given lipopolysaccharide i.c.v. (LPS, 10 ng). Sickness and depressive-like behaviors were assessed followed by analysis of brain steady state mRNA expression. Central LPS elicited typical transient signs of sickness of mice, including body weight loss, reduced feed intake and decreased social exploration toward a novel juvenile. Similarly, LPS increased time of immobility in the tail suspension test (TST). Pretreatment with IGF-I or antidepressants significantly decreased duration of immobility in the TST in both the absence and presence of LPS. To elucidate the mechanisms underlying the anti-depressant action of IGF-I, we quantified steady-state mRNA expression of inflammatory mediators in whole brain using real-time RT-PCR. LPS increased, whereas IGF-I decreased, expression of inflammatory markers interleukin-1ß (IL-1ß), tumor necrosis factor-(TNF)α, inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP). Moreover, IGF-I increased expression of BDNF. These results indicate that IGF-I down regulates glial activation and induces expression of an endogenous growth factor that shares anti-depressant activity. These actions of IGF-I parallel its ability to diminish depressive-like behavior.

Peripheral sensitization caused by insulin-like growth factor 1 contributes to pain hypersensitivity after tissue injury

Sensitization of primary afferent neurons is one of the most important components of pain hypersensitivity after tissue injury. Insulin-like growth factor 1 (IGF-1), involved in wound repair in injured tissue, also plays an important role in maintaining neuronal function. In the present study, we investigated the effect of tissue IGF-1 on nociceptive sensitivity of primary afferent neurons. Local administration of IGF-1 induced thermal and mechanical pain hypersensitivity in a dose-dependent manner, and was attenuated by IGF-1 receptor (IGF1R) inhibition. Tissue but not plasma IGF-1 levels, as determined by enzyme-linked immunosorbent assay, significantly increased after plantar incision. Immunohistochemistry revealed that IGF1R was predominantly expressed in neurons as well as in satellite glial cells in the dorsal root ganglion (DRG). Double-labeling immunohistochemistry showed that IGF1R expression colocalized with peripherin and TRPV1, but not with NF200 in DRG neurons. The IGF1R inhibitor successfully alleviated mechanical allodynia, heat hyperalgesia, and spontaneous pain behavior observed after plantar incision. Expression of phosphorylated Akt in DRG neurons significantly increased after plantar incision and was suppressed by IGF1R inhibition. These results demonstrate that increased tissue IGF-1 production sensitizes primary afferent neurons via the IGF1R/Akt pathway to facilitate pain hypersensitivity after tissue damage.Insulin-like growth factor 1 is synthesized locally after tissue injury and contributes to the sensitization of primary afferent neurons.

Effect of anabolic steroid, IGF-1 and loading on expression of genes involved in collagen metabolism in bovine extensor tendon

BackgroundTendon ruptures have been linked to anabolic steroid usage, suggesting pathological changes in tendon structure due to steroid intake. Anecdotal reports from athletes suggest a protective effect of GH on...

Genetic association and sequencing of the insulin-like growth factor 1 gene in bipolar affective disorder

Insulin-like growth factor 1 (IGF1) has been shown to have an important role in brain development and function. Studies of IGF1 administration in rodents have shown that it has an anxiolytic and antidepressant effect. A genome-wide association study (GWAS) of the first University College London (UCL) cohort of 506 bipolar affective disorder subjects and 510 controls was carried out. The exons and flanking regions of IGF1 were resequenced, any new polymorphisms found were genotyped in an enlarged UCL sample of 937 cases and 941 controls. GWAS data gave good evidence of allelic and haplotypic association between multiple IGF1 SNP's and bipolar disorder (BD). New polymorphisms were found by resequencing IGF1 region. Data from GWAS and the new markers showed that twelve out of 43 SNPs showed association with BD with the four most significant SNPs having values of 3.7 × 10(-5) , 8.4 × 10(-4) , 2.6 × 10(-4) , and 2.5 × 10(-4) . A 5' promoter microsatellite polymorphism previously correlated with plasma lipoprotein concentration was also associated with BD (P = 0.013). Haplotypic association confirmed association with BD with significance values similar to the single marker SNP values. The marker rs12426318 has also been found to be associated with BD in a second sample. A test of gene wide significance with permutation testing for all markers genotyped at IGF1 was also significant. These data implicate IGF1 as a candidate gene to cause genetic susceptibility to BD.

Does IGF-1 administration after a mild traumatic brain injury in mice activate the adaptive arm of ER stress?

Mild traumatic brain injury (mTBI) induces along with cognitive impairments, both cell death and survival pathways. Previously, IGF-1 (Insulin like growth factor 1) administration prevented TBI-induced damage. This study was aimed at testing the effect of mTBI on ER (endoplasmic reticulum) stress activation and looking for a possible interaction between IGF-1 and ER stress pathways. Mice were subjected to a weight drop closed head injury. Western blot analysis revealed that mTBI induced activation of ATF6 (activating transcription factor 6), but not of CHOP or grp78. IGF-1 administration following mTBI did not change ATF6 or grp78 levels, but significantly elevated CHOP. These results suggest that IGF-1 may exert its neuroprotection via PERK/CHOP, the adaptive arm of the unfolded protein response.

IGF-1 Partially Reproduces Beneficial Effect of Exercise Training on Glucose Tolerance in Normal Rats

Exercise transiently elevates the IGF-1 (insulin-like growth factor 1) level, but whether exogenous IGF-1 administration can reproduce exercise training benefit in glycemic control is currently unknown. This study compared the effect of IGF-1 administration and exercise training on glycogen storage, glucose tolerance, and muscle glucose transporter 4 (GLUT4) protein expression in normal rats. Forty rats were weight matched and evenly assigned to the following 4 groups: control (C), exercise trained (E), IGF-1 treated (I), and exercise-trained + IGF-1 (EI). Same volume of saline or IGF-1 (2 μg/kg BW) was injected daily to the rats. Exercise training consisted of daily 90 min of swimming for the first week and gradually increased to 180 min, twice for the third week. Oral glucose tolerance test (OGTT) was performed in all rats under fasted condition. Muscle tissues were removed at the end of the 3-week treatments (3 days after OGTT). The levels of GLUT4 protein and mRNA were determined in red and white portions of the quadriceps muscle (RQ and WQ). Both exercise training and chronic IGF-1 administration increased GLUT4 expression and improved glucose tolerance without an observed additive effect. Exercise training increased glycogen level in RQ and WQ above control level. Despites chronic IGF-1 administration increased muscle GLUT4 expression above control level, glycogen increase was not observed. Our data suggest that IGF-1 can partially reproduce exercise training effect on improving glycemic control.

A molecular memory booster

For many – if not all – of us, cognitive enhancement is desirable, but agents that would truly improve memory are hard to find. Unexpectedly, the product of an imprinted gene emerges as a promising candidate. See Article p.491 An understanding of the mechanisms of memory enhancement is vital for broadening our knowledge of memory processes, as well as for potential clinical applications. Yet very little is known about it. Experiments in rats now show that the administration of insulin-like growth factor II (IGF-II), a protein typically implicated in somatic tissue growth and repair, significantly enhances memory retention, promotes the memory proxy known as long-term potentiation and prevents forgetting. IGF-II acts by initiating a network of signalling cascades that can lead to synaptic potentiation and are most effective within a short time frame immediately following learning. IGF-II is therefore a potential target for modulating cognitive enhancement.

Insulin-Like Growth Factor-1 (IGF-1) Reduces ischemic changes and increases circulating angiogenic factors in experimentally - induced myocardial infarction in rats

BackgroundCoronary artery disease is a global health concern in the present day with limited therapies. Extensive efforts have been devoted to find molecular therapies to enhance perfusion and function of the ischemic myocardium. Aim of the present study was to look into the effects of insulin like growth factor -1 (IGF-1) on circulating angiogenic factors after myocardial ischemia in rats.MethodsAdult male Sprague-Dawley rats were randomly divided into 10-days control, myocardial infarction, IGF-1 alone (2 μg/rat/day) and ISO+IGF-1 groups. Isoproterenol (ISO), a synthetic catecholamine was used to induce myocardial infarction. Serum transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) levels were checked after 10-days of IGF-1 administration.ResultsThere was a significant increase in heart weight after IGF-1 treatment. A significant increase in cardiac enzyme level (CK-MB and LDH) was seen in isoproterenol treated rats when compared to control group. IGF-1treatment induced a significant increase in serum angiogenic factors, IGF-1, VEGF and TGF beta levels. IGF-1 also reduced the ischemic changes in the myocardium when compared to the isoproterenol alone treated group.ConclusionsIn conclusion, treatment with insulin-like growth factor-1 (IGF-1) in myocardial infarction significantly increased circulating angiogenic growth factors like IGF-1, VEGF and TGF beta thus, protecting against myocardial ischemia.

Effects of insulin-like growth factor–I and platelet-rich plasma on sciatic nerve crush injury in a rat model

Local administration of insulin-like growth factor-I (IGF-I) has been shown to increase the rate of axon regeneration in crush-injured and freeze-injured rat sciatic nerves. Local administration of platelet-rich plasma (PRP) has been also shown to have a measurable effect on facial nerve regeneration after transection in a rat model. The objective of the study was to compare the effects of locally administered IGF-I and PRP on the parameters of the Sciatic Function Index (SFI), sensory function (SF), axon count, and myelin thickness/axon diameter ratio (G-ratio) in a rat model of crush-injured sciatic nerves. The right sciatic nerve of Wistar albino rats (24 animals) was crushed using a Yasargil-Phynox aneurysm clip for 45 minutes. All animals were randomly divided into 3 groups: Group 1 (control group) was treated with saline, Group 2 was treated with IGF-I, and Group 3 was treated with PRP. Injections were performed using the tissue expander's injection port with a connecting tube directed at the crush-injured site. Functional recovery was assessed with improvement in the SFI. Recovery of sensory function was using the pinch test. Histopathological examination was performed 3 months after the injury. The SFI showed an improved functional recovery in the IGF-I-treated animals (Group 2) compared with the saline-treated animals (Group 1) 30 days after the injury. In IGF-I-treated rats, sensory function returned to the baseline level significantly faster than in saline-treated and PRP-treated rats as shown in values between SF-2 and SF-7. The G-ratios were found to be significantly higher in both experimental groups than in the control group. This study suggests that the application of IGF-I to the crush-injured site may expedite the functional recovery of paralyzed muscle by increasing the rate of axon regeneration.

The intricate involvement of the Insulin-like growth factor receptor signaling in mild traumatic brain injury in mice

Insulin-like growth factor-1 (IGF-1) was suggested as a potential neuroprotective treatment for traumatic brain injury (TBI) induced damage (cognitive as well as cellular). The main goal of the present study was to evaluate the role of the IGF-1R activation in spatial memory outcome following mild traumatic brain injury. mTBI-induced phosphorylation of IGF-1R, AKT and ERK1/2, in mice hippocampus, which was inhibited when mice were pretreated with the selective IGF-1R inhibitor AG1024. IGF-1 administration prevented spatial memory deficits following mTBI. Surprisingly, blocking the IGF-1R signaling in mTBI mice did not augment the spatial memory deficit. In addition, this data imply an intriguing and complex role of the IGF-1 signaling axis in the cellular and behavioral events following mTBI.

Differential regulation of igf1 and igf1r mRNA levels in the two hepatic lobes following intrauterine growth restriction and its treatment with intra-amniotic insulin-like growth factor-1 in ovine fetuses

Intrauterine growth restriction (IUGR) has life-long health implications, yet there is no effective prenatal treatment. Daily intra-amniotic administration of insulin-like growth factor (IGF)-1 to IUGR fetal sheep improves fetal gut maturation but suppresses hepatic igf1 gene expression. Fetal hepatic blood supply is regulated, in part, by shunting of oxygen- and nutrient-rich umbilical venous blood through the ductus venosus, with the left hepatic lobe predominantly supplied by umbilical venous blood and the right hepatic lobe predominantly supplied by the portal circulation. We hypothesised that: (1) once-weekly intra-amniotic IGF-1 treatment of IUGR would be effective in promoting gut maturation; and (2) IUGR and its treatment with intra-amniotic IGF-1 would differentially affect igf1 and igf1r mRNA expression in the two hepatic lobes. IUGR fetuses received 360 µg IGF-1 or saline intra-amniotically once weekly from 110 until 131 days gestation. Treatment of IUGR fetuses with IGF-1 reversed impaired gut growth. In unembolised, untreated control fetuses, igf1 mRNA levels were 19% lower in the right hepatic lobe than in the left; in IUGR fetuses, igf1 and igf1r mRNA levels were sixfold higher in the right lobe. IGF-1 treatment reduced igf1 and igf1r mRNA levels in both lobes compared with IUGR fetuses. Thus, weekly intra-amniotic IGF-1 treatment, a clinically feasible approach, reverses the impaired gut development seen in IUGR. Furthermore, igf1 and igf1r mRNA levels are differentially expressed in the two hepatic lobes and relative expression in the two lobes is altered by both IUGR and intra-amniotic IGF-1 treatment.

Insulin-like growth factor-1 stimulation of hypothalamic KiSS-1 gene expression is mediated by Akt: effect of alcohol

Kisspeptin, as well as insulin-like growth factor-1 (IGF-1), act centrally to stimulate luteinizing hormone-releasing hormone (LHRH) secretion at puberty. IGF-1 can induce KiSS-1 gene expression as an early pubertal event; however, the signaling pathway mediating this effect is not known. Since alcohol (ALC) blocks IGF-1 induced LHRH release acutely, we assessed whether this drug could affect IGF-1 stimulated prepubertal KiSS-1 gene expression following a binge type of exposure. Immature female rats were administered either ALC (3 g/kg) or water via gastric gavage at 07.30 h. At 09.00 h the ALC and control groups were subdivided where half received either saline or IGF-1 (200 ng) into the third ventricle. A second dose of ALC (1.5, 2 and 3 g/kg) or water was administered at 11.30 h. These regimens produced moderate blood alcohol concentrations of 77, 89 and 117 mg/dl, respectively, over the time course of the experiment. Rats were sacrificed 6 h after the IGF-1 injection and tissues containing the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei were collected. IGF-1 stimulated ( P<0.01) KiSS-1 gene expression in the AVPV nucleus at 6 h, but did not affect expression of the kisspeptin receptor, GPR54. While ALC did not alter basal expression of either gene, its dose dependently blocked IGF-1-induced KiSS-1 gene expression in the AVPV nucleus. No changes were observed in the ARC nucleus. Assessment of IGF-1 signaling indicated that the acute administration of IGF-1, ALC, or both did not alter the basal expression of IGF-1 receptor protein. However, IGF-1 stimulated ( P<0.05) phosphorylated Akt protein over basal levels, an action blocked by ALC. Our results indicate that the IGF-1 induction of KiSS-1 gene expression is mediated by Akt activation, and that ALC alters this important prepubertal action of IGF-1.

Interaction of myocardial insulin receptor and IGF receptor signaling in exercise-induced cardiac hypertrophy

Insulin-like growth factor-1 (IGF-1) signaling has recently been implicated in the development of cardiac hypertrophy after long-term endurance training, via mechanisms that may involve energetic stress. Given the potential overlap of insulin and IGF-1 signaling we sought to determine if both signaling pathways could contribute to exercise-induced cardiac hypertrophy following shorter-term exercise training. Studies were performed in mice with cardiac-specific IGF-1 receptor (IGF1R) knockout (CIGFRKO), mice with cardiac-specific insulin receptor (IR) knockout (CIRKO), CIGFRKO mice that lacked one IR allele in cardiomyocytes (IGFR−/−IR+/−), and CIRKO mice that lacked one IGF1R allele in cardiomyocytes (IGFR+/−IR−/−). Intravenous administration of IGF-1 or 75 hours of swimming over 4 weeks increased IGF1R tyrosine phosphorylation in the heart in control and CIRKO mice but not in CIGFRKO mice. Intriguingly, IR tyrosine phosphorylation in the heart was also increased following IGF-1 administration or exercise training in control and CIGFRKO mice but not in CIRKO mice. The extent of cardiac hypertrophy following exercise training in CIGFRKO and CIRKO mice was comparable to that in control mice. In contrast, exercise-induced cardiac hypertrophy was significantly attenuated in IGFR−/−IR+/− and IGFR+/−IR−/− mice. Thus, IGF-1 and exercise activates both IGF1R and IR in the heart, and IGF1R- and IR-mediated signals may serve redundant roles in the hypertrophic responses of the heart to exercise training.

Effects of Local and Sustained Release of FGF, IGF, and GH on Germ Cells in Unilateral Undescended Testis in Rats

To evaluate the effects of the local release of fibroblast growth factor (FGF), insulin-like growth factor (IGF), and growth hormone (GH) on a germ cell population of ipsilateral undescended and contralateral descended testes of rats with a surgically created unilateral abdominal testis for 12 weeks and after the application of growth factors after orchidopexy. Forty 4-week old male Wistar albino rats were divided into 5 groups as follows: group 1, sham; group 2, gelatin; group 3, FGF; group 4, IGF; and group 5, GH. In the sham group, the right testis was exposed and sutured with 5-0 silk sutures. In groups 2-5, a right intra-abdominal testis was surgically created. After 12 weeks, orchidopexy was performed, and 1 cm(2) gelatin films were sutured to the right testes, either unloaded (group 2), or containing 2.5 microg FGF (group 3), 5 microg IGF (group 4), or 5 microg GH (group 5). After 30 days, both testes were removed for histopathologic investigation and DNA flow cytometry. The mean seminiferous tubular diameters (MSTDs), mean testicular biopsy scores (MTBSs), and percentages of haploid (1n) cells were calculated. Ipsilateral MSTD and MTBS significantly decreased in the gelatin and FGF groups compared with the sham, IGF, and GH groups. Contralateral MSTDs and MTBSs did not differ among groups. The haploid cell percentage significantly decreased in the ipsilateral and contralateral testes of the gelatin group compared with the sham, FGF, IGF, and GH groups. Local release of IGF and GH resulted in the preservation of germ cell histology in the ipsilateral testes of rats with a surgically created unilateral undescended testis for 12 weeks and after orchidopexy. The administration of IGF, GH, and FGF increased the haploid germ cell population in both ipsilateral undescended and contralateral descended testes.