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1.  Neutering Dogs: Effects on Joint Disorders and Cancers in Golden Retrievers 
PLoS ONE  2013;8(2):e55937.
In contrast to European countries, the overwhelming majority of dogs in the U.S. are neutered (including spaying), usually done before one year of age. Given the importance of gonadal hormones in growth and development, this cultural contrast invites an analysis of the multiple organ systems that may be adversely affected by neutering. Using a single breed-specific dataset, the objective was to examine the variables of gender and age at the time of neutering versus leaving dogs gonadally intact, on all diseases occurring with sufficient frequency for statistical analyses. Given its popularity and vulnerability to various cancers and joint disorders, the Golden Retriever was chosen for this study. Veterinary hospital records of 759 client-owned, intact and neutered female and male dogs, 1–8 years old, were examined for diagnoses of hip dysplasia (HD), cranial cruciate ligament tear (CCL), lymphosarcoma (LSA), hemangiosarcoma (HSA), and mast cell tumor (MCT). Patients were classified as intact, or neutered early (<12 mo) or late (≥12 mo). Statistical analyses involved survival analyses and incidence rate comparisons. Outcomes at the 5 percent level of significance are reported. Of early-neutered males, 10 percent were diagnosed with HD, double the occurrence in intact males. There were no cases of CCL diagnosed in intact males or females, but in early-neutered males and females the occurrences were 5 percent and 8 percent, respectively. Almost 10 percent of early-neutered males were diagnosed with LSA, 3 times more than intact males. The percentage of HSA cases in late-neutered females (about 8 percent) was 4 times more than intact and early-neutered females. There were no cases of MCT in intact females, but the occurrence was nearly 6 percent in late-neutered females. The results have health implications for Golden Retriever companion and service dogs, and for oncologists using dogs as models of cancers that occur in humans.
doi:10.1371/journal.pone.0055937
PMCID: PMC3572183  PMID: 23418479
2.  IGF-1 Gene Expression in Rat Colonic Mucosa After Different Exercise Volumes 
The evidence is increasing for a close link between the insulin/insulin-like growth factor (IGF) system and colon cancer prevention by physical exercise. To reveal exercise-induced alterations in colon mucosa, gene expression of IGF-1 and related genes and serum IGF-1 were investigated. Twenty male Wistar rats performed a 12 week voluntary exercise program. Nine rats served as the control group. Gene expression of IGF-1, IGF-1 receptor (IGF-1R) and IGF-binding protein 3 (IGF-BP3) were quantified by real-time RT-PCR. Circulating IGF-1 was analyzed exercise volume-dependent. Based on 3 distinguished groups with low (L-EX, <2629 m·night-1), medium (M-EX, 3003-7458 m·night-1) and high exercise volume (H-EX, >8314 m·night-1), we observed lower serum IGF-1 levels (P < 0.05) in all exercise groups as compared to the control group and IGF-1 levels declined proportional to the increase in exercise volume. A significant (p < 0.05) positive correlation was found between IGF-1 concentration and body mass (r = 0.50) and a significant negative correlation exists between body mass and exercise volume (r = -0.50). Significant differences in colonic mRNA levels of IGF-1, IGF-1R and IGF-BP3 could not be observed. Based on our data we propose that the exercise as well as the body mass reduction leads to a decrease in circulating IGF-1 and this might represent a prime link to colon cancer prevention.
Key pointsThere were significantly lower serum IGF-1 levels in all exercise groups as compared to the control group.GF-1 levels declined proportional to the increase in exercise volume.A significant positive correlation was found between IGF-1 concentration and body mass and a significant negative correlation was found between body mass and exercise volume.Significant differences in colonic mRNA levels of IGF-1, IGF-1R and IGF-BP3 could not be observed.
PMCID: PMC3794482  PMID: 24149475
Cancer prevention; IGF-1R; IGF-BP3; real-time RT PCR; physical exercise
3.  A polymorphic variant of the insulin-like growth factor 1 (IGF-1) receptor correlates with male longevity in the Italian population: a genetic study and evaluation of circulating IGF-1 from the "Treviso Longeva (TRELONG)" study 
BMC Geriatrics  2009;9:19.
Background
An attenuation of the insulin-like growth factor 1 (IGF-1) signaling has been associated with elongation of the lifespan in simple metazoan organisms and in rodents. In humans, IGF-1 level has an age-related modulation with a lower concentration in the elderly, depending on hormonal and genetic factors affecting the IGF-1 receptor gene (IGF-1R).
Methods
In an elderly population from North-eastern Italy (n = 668 subjects, age range 70–106 years) we investigated the IGF-1R polymorphism G3174A (rs2229765) and the plasma concentration of free IGF-1. Frequency distributions were compared using χ2-test "Goodness of Fit" test, and means were compared by one-way analysis of variance (ANOVA); multiple regression analysis was performed using JMP7 for SAS software (SAS Institute, USA). The limit of significance for genetic and biochemical comparison was set at α = 0.05.
Results
Males showed an age-related increase in the A-allele of rs2229765 and a change in the plasma level of IGF-1, which dropped significantly after 85 years of age (85+ group). In the male 85+ group, A/A homozygous subjects had the lowest plasma IGF-1 level. We found no clear correlation between rs2229765 genotype and IGF-1 in the females.
Conclusion
These findings confirm the importance of the rs2229765 minor allele as a genetic predisposing factor for longevity in Italy where a sex-specific pattern for IGF-1 attenuation with ageing was found.
doi:10.1186/1471-2318-9-19
PMCID: PMC2692840  PMID: 19460140
4.  Radioimmunological determination of insulinlike growth factors I and II in normal subjects and in patients with growth disorders and extrapancreatic tumor hypoglycemia. 
Journal of Clinical Investigation  1981;68(5):1321-1330.
Serum levels of immunoreactive insulinlike growth factors (IGF) I and II were determined by a modified IGF I and a new IGF II radioimmunoassay in normal children and adults, and in patients with acromegaly, isolated growth hormone deficiency, and extrapancreatic tumor hypoglycemia. Serum samples were gel filtered by a simple routine procedure at acidic pH to dissociate and separate IGF from the IGF carrier protein. Mean immunoreactive IGF I levels (+/- SD; corrected for crossreactivity of IGF II) were 193 +/- 58 ng/ml in normal adult subjects, 712 +/- 245 ng/ml in acromegalic patients and 24 +/- 14 ng/ml in patients with isolated growth hormone deficiency. The lack of growth hormone alone, irrespective of an otherwise normal hormonal status, appears to be responsible for the drastic decrease of IGF I levels. Oversecretion of growth hormone does not increase the levels of immunoreactive IGF II: mean levels (+/- SD; corrected for crossreactivity of IGF I) in normal and acromegalic subjects are virtually identical (647 +/- 126 and 641 +/- 189 ng/ml, respectively). Apparently, normal growth hormone levels stimulate IGF II production already maximally. However in growth hormone deficiency immunoreactive IGF II is significantly decreased (252 +/- 99 ng/ml). Thus, IGF II, like IGF I, is growth hormone dependent. But in contrast to IGF I, the growth hormone dependence of IGF II seems to become apparent only at subnormal growth hormone levels. In normal children IGF I is age dependent: it is low in newborn cord sera (51 +/- 20 ng/ml) and gradually rises into the adult range with increasing age. At the onset of and during puberty mean IGF I levels lie above prepubertal values. In contrast, IGF II levels in normal children are independent of age and pubertal stage beyond the first year of life, whereas newborns have significantly lower IGF II values. Hypoglycemia resulting from extrapancreatic tumors is not associated with increased immunoreactive IGF I or II levels. IGF I is decreased in most of the sera (mean level +/- SD:56 +/- 39 ng/ml) whereas IGF II lies in the normal range (556 +/- 195 ng/ml).
PMCID: PMC370928  PMID: 7028787
5.  The Effect of Acclydine in Chronic Fatigue Syndrome: A Randomized Controlled Trial 
PLoS Clinical Trials  2007;2(5):e19.
Objectives:
It is unclear whether insulin-like growth factor (IGF) function is involved in the pathophysiology of chronic fatigue syndrome (CFS). Unpublished data and reports in patient organization newsletters suggest that Acclydine, a food supplement, could be effective in the treatment of CFS by increasing biologically active IGF1 levels. Here we aimed to measure the IGF1 and IGF binding protein (IGFBP) 3 status of CFS patients compared to age- and gender-matched neighborhood controls, and to assess the effect of Acclydine on fatigue severity, functional impairment, and biologically active IGF1 level (IGFBP3/IGF1 ratio).
Design:
A randomized, placebo-controlled, double-blind clinical trial.
Setting:
Radboud University Nijmegen Medical Centre, The Netherlands.
Participants:
Fifty-seven adult patients who fulfilled the US Centers for Disease Control and Prevention criteria for CFS. IGF status of 22 CFS patients was compared to that of 22 healthy age- and gender-matched neighborhood control individuals.
Intervention:
Acclydine or placebo for 14 wk.
Outcome measures:
Outcomes were fatigue severity (Checklist Individual Strength, subscale fatigue severity [CIS-fatigue]), functional impairment (Sickness Impact Profile-8 [SIP-8]), and biologically active IGF1 serum concentrations. Analyses were on an intention-to-treat basis.
Results:
There was no difference in IGF status in 22 CFS patients compared to healthy age- and gender-matched control individuals. Treatment with Acclydine did not result in significant differences compared with the placebo group on any of the outcome measures: CIS-fatigue +1.1 (95% CI −4.4 to +6.5, p = 0.70), SIP-8 +59.1 (95% CI −201.7 to +319.8, p = 0.65), and IGFBP3/IGF1 ratio −0.5 (95% CI −2.8 to +1.7, p = 0.63).
Conclusion:
We found no differences in IGF1 status in CFS patients compared to healthy matched neighborhood controls. In addition, the results of this clinical trial do not demonstrate any benefit of Acclydine over placebo in the treatment of CFS.
Editorial Commentary
Background: Chronic fatigue syndrome is a complicated and poorly understood illness. People with the condition experience tiredness that carries on for a long period of time and does not get better with rest. Other symptoms include sleeping problems, muscle and joint pains, concentration difficulties, and headaches. The causes of chronic fatigue syndrome are not known. There is evidence for the effectiveness of certain behavioral interventions, such as exercise therapy and cognitive behavioral therapy, in improving certain symptoms. However, some doctors are concerned that a food supplement called Acclydine, derived from a plant called Solanum dulcamara, is being used and promoted as a treatment for chronic fatigue syndrome when there is little evidence about the efficacy or safety of this supplement.
The researchers here carried out a randomized trial in The Netherlands, recruiting adult patients who met the internationally accepted criteria for chronic fatigue syndrome. The participants were allocated by chance to receive either 14 weeks of treatment with Acclydine together with amino acid supplements or, alternatively, placebo versions of the Acclydine and amino acid tablets. The researchers then measured participants' responses with respect to two primary outcome measures. One of these was how tired participants felt, which was measured using a subscale on a questionnaire called the Checklist Individual Strength scale (CIS-fatigue). The other primary outcome measure was “functional impairment,” which examines how well someone carries out their daily life, using the Sickness Impact Profile (SIP-8) scale. The secondary outcome measures included physical activity levels, day-to-day fatigue levels, and the levels of insulin-like growth factor 1 (IGF1) in blood, a hormone that's thought by some researchers to be related to the severity of chronic fatigue.
What the trial shows: In the trial, 57 people were randomized to receive either Acclydine plus amino acid supplements, or placebo tablets. When comparing scores on the primary outcome measures at the end of the trial, the researchers did not see significant differences between the treatment and placebo groups. Similarly, the results for secondary outcome measures in this trial did not show any significant differences between the treatment and placebo groups.
Strengths and limitations: Strengths of this study include the fact that it is one of the few properly designed studies of a product for which claims have been made of effectiveness in chronic fatigue syndrome. The study was designed as a double-blind trial, in which participants and investigators (those collecting the outcome data) did not know whether an individual received Acclydine or placebo. This procedure should help to minimize bias in assessing outcomes. A key limitation of this study is the relatively small number of participants. However, the investigators considered it unlikely that a larger trial would detect a clinically meaningful effect of Acclydine on these outcome measures for patients with chronic fatigue syndrome.
Contribution to the evidence: Systematic reviews of interventions for the treatment of chronic fatigue syndrome have found evidence for the efficacy of exercise therapy and cognitive behavioral therapy. This trial shows no evidence of efficacy of Acclydine plus amino acid supplements for the treatment of chronic fatigue.
doi:10.1371/journal.pctr.0020019
PMCID: PMC1876596  PMID: 17525791
6.  Lipoprotein Particle Profiles Mark Familial and Sporadic Human Longevity 
PLoS Medicine  2006;3(12):e495.
Background
Genetic and biochemical studies have indicated an important role for lipid metabolism in human longevity. Ashkenazi Jewish centenarians and their offspring have large low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles as compared with control individuals. This profile also coincided with a lower prevalence of disease. Here, we investigate whether this observation can be confirmed for familial longevity in an outbred European population and whether it can be extended to sporadic longevity in the general population.
Methods and Findings
NMR-measured lipoprotein profiles were analyzed in 165 families from the Leiden Longevity Study, consisting of 340 long-lived siblings (females >91 y, males >89 y), 511 of their offspring, and 243 partners of the offspring. Offspring had larger (21.3 versus 21.1 nm; p = 0.020) and fewer (1,470 versus 1,561 nmol/l; p = 0.011) LDL particles than their same-aged partners. This effect was even more prominent in the long-lived siblings (p < 10−3) and could be pinpointed to a reduction specifically in the concentration of small LDL particles. No differences were observed for HDL particle phenotypes. The mean LDL particle sizes in 259 90-y-old singletons from a population-based study were similar to those in the long-lived siblings and thus significantly larger than in partners of the offspring, suggesting that the relevance of this phenotype extends beyond familial longevity. A low concentration of small LDL particles was associated with better overall health among both long-lived siblings (p = 0.003) and 90-y-old singletons (p = 0.007).
Conclusions
Our study indicates that LDL particle profiles mark both familial and sporadic human longevity already in middle age.
Offspring of families from the Leiden Longevity Study had larger and fewer LDL particles than same-aged partners, suggesting that even in middle age LDL particle profiles are associated with longevity.
Editors' Summary
Background.
It is not clear why some people go on to live longer than others do. Some studies have shown that close relatives of long-lived people are themselves more likely to live for a long time; these findings suggest that there is probably a genetic basis for long life. However, the actual mechanisms involved have not yet been worked out. Some genes coding for proteins involved in fat metabolism, such as APOE, APOB, and CETP, have been associated with long life, suggesting a link between the way fat gets metabolized and the aging process. One study that supports this idea found that the children of 100-year-old people had larger lipoprotein particles (assemblies of proteins and fats that carry cholesterol and triglycerides in the blood) than similarly aged control individuals. However, studies such as this are very prone to “false positive” findings and therefore need to be backed up by confirmatory evidence. In addition, the previous study was performed in a very specific population (Ashkenazi Jewish people), and it is important to find out whether the findings are also true in other populations.
Why Was This Study Done?
The research group carrying out this study wanted to address several distinct questions to do with the genetics of aging. Firstly, they wanted to see if they could confirm previous findings associating large lipoprotein particles with longer life, but looking at people who were more representative of the general European population and not from a genetically isolated population. Secondly, they wanted to see whether this association applied to only long-lived people whose family members were also long-lived, or to long-lived people in general. Finally, they wanted to find out if the large lipoprotein particles were associated with better health.
What Did the Researchers Do and Find?
In the study, the researchers looked at long-lived people from across The Netherlands whose relatives were also long-lived. For this, they recruited 340 men aged over 89 and women aged over 91 into the study, all of whom had at least one similarly long-lived sister or brother. Their children (511 individuals), and the partners of their children (243 people), were also recruited into the study, with the partners acting as “controls.” The researchers also studied 259 people who had just turned 90 years old; these people were included to see whether particular characteristics of lipoproteins existed in long-lived people whose longevity did not run in families. All the participants gave blood samples, and the researchers then measured the size and amount of different lipoprotein particles in these samples. Two types of lipoprotein particles were looked at: low-density lipoprotein (LDL, often termed “bad cholesterol”) and high-density lipoprotein (HDL, sometimes called “good cholesterol”). The researchers found that the children from the long-lived people had larger and fewer LDL particles than their partners (the “control” individuals) just like their long-lived parents. Thus even though the children were not long-lived themselves, LDL particles marked the fact that they have a higher chance of becoming long-lived in the future. Similar changes in LDL particles were found for long-lived people whose relatives were not also long-lived. Interestingly, simply the level of cholesterol—the classical risk factor for cardiovascular disease—did not appear to play a role. Thus it seems that it is not the amount of cholesterol that is important in longevity but how it is packaged. Better health status was also associated with a lower proportion of small LDL particles in the blood, supporting these findings. No characteristics of the HDL particles seemed to be associated with longevity.
What Do These Findings Mean?
These findings confirm those from a previous study in Ashkenazi Jewish people that suggested that the size of LDL particles in the blood was associated with long life. The nature of this association is not clear; some studies indicated that small LDL particles increase the risk of cardiovascular disease but small LDL particles may also be harmless themselves and reflect the efficiency of other processes causally related to aging.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030495.
Wikipedia chapter on senescence (biology of aging) (note that Wikipedia is a free Internet encyclopedia that anyone can edit)
US National Institute on Aging provides information on healthy aging, details of publicly funded research into aging, and other resources for the public
Help the Aged information on research into aging
doi:10.1371/journal.pmed.0030495
PMCID: PMC1716190  PMID: 17194192
7.  Quantitative Ontogeny of Murine Insulin-Like Growth Factor (IGF)-I, IGF-binding Protein-3 and the IGF-related Acid-labile Subunit 
Objective
The mouse serves as an important model for insulin-like (IGF)-related research. However, lack of homologous mouse assays has prevented studies of the normal ontology of the murine IGF-system. Therefore, we developed and validated immunoaassays for murine IGF-I, IGFBP-3 and ALS and studied levels of these analytes in mice.
Methods
Using commercially available reagents, we developed and validated specific enzyme-linked immunosorbent assays (ELISAs) for murine IGF-I, IGFBP-3, and ALS. Levels of these analytes were measured in sera from CD-1 mice, male and female, sampled at 1, 2, 4, 8, 20 and 32 wks of age. In addition, sera from pregnant and post-partum CD-1 mice were also studied.
Results
Validation of specific ELISAs for murine IGF-I, IGFBP-3 and ALS are described; all 3 assays were highly sensitive, precise and accurate. As measured by our homologous ELISA, IGF-I levels (ng/mL, mean±SD) in male mice were relatively low at 1 wk (53±8), rising sharply to peak at 8 wks of age (636±48), and gradually declining thereafter, reaching 395±64 at 32 wks. IGF-I levels in non-pregnant female mice peaked at 4 wks of age (548±77) declined at 8 wks (417±61), then recovered to plateau at 539±78 and 535±88 at 20 and 32 wks, respectively. In male mice, trends in IGFBP-3 were similar to the patterns of IGF-I. However, in non-pregnant female mice, the IGFBP-3 levels declined relatively slowly after peaking at 4-weeks of age, unlike IGF-I levels during this period. ALS levels followed the same pattern as IGF-I in both sexes. IGF-I to IGFBP-3 molar ratios (percent) were similar between sexes, rising continuously with age: ~30% at 1 wk, 80% at 4 wks, 135% at 32 wks. IGF-I was reduced in 8 wk old mice in mid-pregnancy (354±75 vs 417±61 in non-pregnant 8 wk females), reaching a nadir in late-term (146±40), and only partially recovering in the postpartum period (239±23). IGFBP-3 was also lower in late-pregnancy (1245±100 vs 1925±439) and remained depressed post-partum. In contrast to IGF-I and IGFBP-3, ALS increased more than 3-fold in mid-pregnancy (12180±1641 vs 3741±910), followed by a 4-fold decrease in late-pregnancy (2964±489), recovering postpartum (6104±1178).
Conclusions
We report the first ontological studies of IGF-I, IGFBP-3 and ALS in mice using newly-characterized sensitive, homologous immunoassays. Our results indicate that mice have a generally similar pattern in IGF-related axis components, with low levels early in life, increasing to peak during sexual maturation and declining thereafter. Significant gender differences in non-pregnant levels and dramatic changes during pregnancy were also found. Knowledge of the normal developmental changes in the murine IGF system and accurate tools for investigations of this system are a necessary foundation for research in this field.
doi:10.1016/j.ghir.2007.07.007
PMCID: PMC2276237  PMID: 17719253
Acid-labile subunit; Insulin-like growth factor-I; Insulin-like growth factor binding-protein; Mouse insulin-like growth factor
8.  Klotho locus, metabolic traits, and serum hemoglobin in hospitalized older patients: a genetic association analysis 
Age  2011;34(4):949-968.
Klotho (KL) gene has been involved in severe alterations of physiological biochemical parameters leading to premature aging-like phenotypes and strikingly shortening lifespan. KL participates to the regulation of a number of intracellular biochemical pathways, including lipid profile and glucose metabolism. Aim of this study was to investigate the possible association between KL locus and biological parameters commonly accepted as indicators of the clinical status in hospitalized older patients. We genotyped the single-nucleotide polymorphisms (SNPs) rs9536314, rs1207568, and rs564481 at the KL locus in 594 hospitalized older patients (65–99 years), consecutively attending a geriatric ward, and tested the association of these KL variants with biological quantitative traits using analyses of covariance and genetic risk score models. Significant associations of rs9536314 with serum levels of hemoglobin, albumin, and high-density lipoprotein cholesterol (HDL-C) as well as significant associations of rs564481 with serum levels of hemoglobin, fasting insulin, and fasting glucose were observed. Gender-segregated analyses confirmed these associations, and suggested that the associations of KL genotypes with HDL-C, fasting glucose and fasting insulin levels may be driven by the female gender, while the association with serum levels of hemoglobin may be driven by the male gender. The association of KL genotypes with creatinine levels was found only in females, while the association with insulin-like growth factor-1 (IGF-1) and lymphocytes count (LC) was found only in males. The genetic risk score (GRS) models further confirmed significant associations among KL SNPs and hemoglobin, total cholesterol, and HDL-C. Gender-segregated analyses with the GRS-tagged approach confirmed the associations with HDL-C, fasting glucose, and fasting insulin levels in females, and with hemoglobin and LC in males. Our findings suggested that KL locus may influence quantitative traits such as serum levels of lipid, fasting glucose, albumin and hemoglobin in hospitalized older patients, with some gender differences suggested for creatinine, IGF-1 levels, and LC, thus being one of the genetic factors possibly contributing to age-related diseases and longevity.
doi:10.1007/s11357-011-9273-x
PMCID: PMC3682056  PMID: 21695423
Klotho; Chromosome 13; High-density lipoprotein cholesterol; Total cholesterol; Fasting glucose; Fasting insulin; Insulin-like growth factor-1; Hemoglobin; Creatinine; Albumin; Lymphocytes
9.  Relation between insulin-like growth factor-I, body mass index, and clinical status in cystic fibrosis 
Archives of Disease in Childhood  1997;76(4):304-309.
Accepted 26 October 1996

OBJECTIVES—Despite improved nutrition and intensive treatment, subjects with cystic fibrosis have difficulty in maintaining anabolism during intercurrent infections, which can result in reduced body mass index and impaired skeletal growth. Insulin-like growth factor-I (IGF-I) and its binding protein IGFBP3 are sensitive to changes in nutritional status. The aim of this study was to determine the relation between circulating concentrations of these peptides, body mass index, and clinical status in cystic fibrosis.
METHODS—Serum concentrations of IGF-I and IGFBP3 were measured in 197 subjects (108 males, 89 females; mean age 9.69 years, range 0.41-17.9 years) and these data were analysed with respect to body mass index, pubertal stage, and clinical status as assessed by Shwachman score and forced expiratory volume in one second (FEV1 ).
RESULTS—The mean height SD score of the children studied was −0.2 (SD 1.14) and the body mass index SD score −0.26 (1.4). The body mass index SD score declined with increasing age (r=−0.18) and paralleled changes in IGF-I concentrations, which also declined. The IGF-I SD score (calculated from control data) correlated with age (r=−0.53). The abnormalities were most obvious during late puberty, when IGF-I and IGFBP3 concentrations were significantly reduced compared with those in control subjects matched for pubertal stage. The IGF-I SD score correlated with height SD score (r=0.14) and the decline in IGF-I concentrations with the fall in body mass index SD score (r=0.42). IGF-I SD scores also correlated with the Shwachman score (r=0.33) and FEV1 (r=0.17).
CONCLUSIONS—The close relation between declining IGF-I and IGFBP3 concentrations and body mass index in patients with cystic fibrosis may simply reflect poor nutritional status and insulin hyposecretion. Nevertheless, IGF-I deficiency could also contribute towards the catabolism observed in these patients, and IGF-I SD scores correlated with other measures of clinical status such as the Shwachman score and FEV1.


• The fall in body mass index with increasing age in children with cystic fibrosis parallels the decline in concentrations of IGF-I and its principal binding protein, IGFB3
• The close relation between body mass index and IGF-I concentrations in cystic fibrosis may reflect poor nutrition or insulin hyposecretion
• Nevertheless, low IGF-I concentrations may contribute directly to the fall in body mass index with increasing age
PMCID: PMC1717156  PMID: 9166020
10.  Insulin, IGF-1 and longevity 
Aging and Disease  2010;1(2):147-157.
It has been demonstrated in invertebrate species that the evolutionarily conserved insulin and insulin-like growth factor (IGF) signaling (IIS) pathway plays a major role in the control of longevity. In the roundworm Caenorhabditis elegans, single mutations that diminish insulin/IGF-1 signaling can increase lifespan more than twofold and cause the animal to remain active and youthful much longer than normal. Likewise, substantial increases in lifespan are associated with mutations that reduce insulin/IGF-1 signaling in the fruit fly Drosophila melanogaster. In invertebrates, multiple insulin-like ligands exist that bind to a common single insulin/IGF-1 like receptor. In contrast, in mammals, different receptors exist that bind insulin, IGF-1 and IGF-2 with different affinities. In several mouse models, mutations that are associated with decreased GH/IGF-1 signaling or decreased insulin signaling have been associated with enhanced lifespan. However, the increased complexity of the mammalian insulin/IGF-1 system has made it difficult to separate the roles of insulin, GH and IGF-1 in mammalian longevity. Likewise, the relevance of reduced insulin and IGF-1 signaling in human longevity remains controversial. However, studies on the genetic and metabolic characteristics that are associated with healthy longevity and old age survival suggest that the conserved ancient IIS pathway may also play a role in human longevity.
PMCID: PMC3295030  PMID: 22396862
Insulin; IGF-1; longevity; signaling
11.  Effects of Systemic and Local Administration of Recombinant Human IGF-I (rhIGF-I) on De Novo Bone Formation in an Aged Mouse Model 
DO was used in an aged mouse model to determine if systemically and/or locally administered rhIGF-I improved osteoblastogenesis and new bone formation. Local and systemic rhIGF-I treatment increased new bone formation. However, only systemic delivery produced measurable concentrations of rhIGF-I in the circulation.
Introduction
Human and rodent research supports a primary role for IGF-I in bone formation. Significant roles for both endocrine and paracrine/autocrine IGF-I have been suggested for normal osteoblastogenesis and bone formation. We have assessed, using a mouse model of distraction osteogenesis (DO), the impact of continuous administration of recombinant human (rh)IGF-I, delivered either locally to the distraction site or absorbed systemically, on bone formation in an aged mouse model.
Materials and Methods
DO was performed in aged mice (18-month-old C57BL/6 male mice), which were distracted at 0.15 mm daily. At the time of osteotomy, miniosmotic pumps were inserted subcutaneously to (1) deliver vehicle or rhIGF-I subcutaneously for systemic delivery or (2) deliver vehicle or rhIGF-I directly to the newly forming bone through infusion tubing routed subcutaneously from the pump to the distraction site. Serum concentrations of mouse IGF-I, human IGF-I, and osteocalcin were determined at the end of the study.
Results
New bone formation observed in DO gaps showed a significant increase in new bone formation in rhIGF-I–treated mice, irrespective of delivery route. However, detectable levels of human IGF-I were found only in the serum of animals receiving rhIGF-I systemically. Osteocalcin levels did not differ between controls and rhIGF-I–treated groups.
Conclusions
Locally and systemically delivered rhIGF-I both produce significant increases in new bone formed in an aged mouse model in which new bone formation is normally markedly impaired, suggesting that rhIGF-I may improve senile osteoporosis. Because systemic administration of IGF-I can result in untoward side effects, including an increased risk for cancer, the findings that locally delivered IGF-I improves bone regeneration without increasing circulating IGF-I levels suggests that this delivery route may be preferable in an at-risk, aged population.
doi:10.1359/JBMR.060618
PMCID: PMC2424402  PMID: 16939394
osteoporosis; limb lengthening; distraction osteogenesis; anabolic agents; aging
12.  The efficacy of octreotide LAR in acromegalic patients as primary or secondary therapy 
Objective:
The objective of this study was to investigate the efficacy of octreotide therapy in acromegalic patients as primary or secondary therapy.
Methods:
Ten acromegalic patients diagnosed at the Endocrinology Clinic in Sarajevo (seven females and three males, mean age 55.2 ± 7.2 years, age range 40–65 years, five patients with microadenoma and five patients with macroadenoma) were treated with octreotide. Among them, 60% of patients were operated on and the majority of the procedures were performed transnasaly (90%). That group of patients had recidivism of disease (pituitary adenoma and acromegaly). The concentration of human growth hormone (HGH) and insulin-like growth factor 1 (IGF-1) was evaluated at 0, 6 and 12 months, while magnetic resonance imaging (MRI) was taken before the treatment and 12 months after. Eight patients received octreotide 30 mg/28 days, one patient received a dose of 20 mg and the other received 60 mg/28 days.
Results:
Before treatment growth hormone (GH) levels were 50.87 ± 10.56 ng/ml (range: 26–64.9), IGF-1 were 776.66 ± 118.40 ng/ml (range: 526–934). Four patients (40%) were treated with primary octreotide treatment and six patients (60%) with secondary somatostatin analog treatment. At the beginning of therapy, there were no differences in terms of age, HGH levels and IGF-1 levels between primary and secondary treatment groups (p > 0.05). The difference between groups was only in regard to the size of tumors (p = 0.01). After 6 and 12 months the GH levels decreased to 1.61 ± 0.86 ng/ml (range: 0.7–2.65) and 1.85 ± 2.40 ng/ml (range: 0.0–8.3), respectively, while the IGF-1 became 305.90 ± 43.19 ng/ml after 6 months of treatment (range: 240–376) and 256.99 ± 71.43 ng/ml after 12 months of octreotide treatment (range: 126–325), respectively. The pituitary adenomas size prior to treatment was 9.57 mm, while after 12 months of treatment, the size decreased to 8.0 mm. After therapy, a GH decrease to less than 2.5 ng/ml was achieved in 90% of cases; tumor size decrease was achieved in 60% while normalization of IGF-1 was achieved in 100% of the patients, respectively. All differences about HGH and IGF-1 in each group were statistically significant (p < 0.05). In the group of acromegalic patients treated with octreotide LAR as primary therapy, the difference was more significant for GH and IGF-1 than for adenomas size.
Conclusions:
Octreotide treatment of acromegaly not only decreases GH and IGF-1 concentrations, but also appears to diminish the size of the tumor in about 60% of cases. The somatostatin analogs are more efficient in the primary treatment of acromegalic patients, due to the fact that primary therapy is as effective as secondary therapy but primary therapy has small advantages when compared with secondary octreotide therapy because no surgical treatment is required before.
doi:10.1177/2042018811434728
PMCID: PMC3474646  PMID: 23148190
acromegaly; human growth hormone; insulin-like growth factor I; octreotide; pituitary adenoma
13.  A Survey of Correlation Between Insulin-Like Growth Factor-I (IGF-I) Levels and Severity of Liver Cirrhosis 
Hepatitis Monthly  2013;13(2):e6181.
Background
Insulin-like growth factor is a polypeptide with endocrine, autocrine and paracrine effects which its structure is similar to the insulin molecule. While various tissues secrete IGF-1, 90% of the circulating IGF-1 is secreted by liver. Cirrhosis of liver is a condition accompanied by decreased level of IGF-1, in which the level of IGF-1 may be further decreased thorough the progression of the disease.
Objectives
The aim of the present study was to demonstrate the relation between the IGF-1 levels and severity of liver disease according to Child- Pugh and Model for end stage liver diseases (MELD) Scores.
Patients and Method
This was a descriptive-analytic cross sectional study performed on patients with cirrhosis admitted to gastroenterology clinic of Imam Khomeini Hospital in Tehran, Iran during the years 2007-2008. The diagnosis was based on liver biopsy. Initially for all patients, laboratory investigations including IGF-1, CBC, liver Enzymes, Alkaline phosphates, serum Albumin, Creatinine, direct and total Bilirubin were conducted. Also ultrasound and endoscopy were performed for evaluation of ascites and varices.
Results
100 patients with cirrhosis with a male to Female ratio of 63:37 and a mean age of 44.4 ± 15 years were enrolled in the study. Median IGF-1 was 92.95 ± 91.51 ng/mL. 14 patients (14%) had IGF-1 within normal limits while 86 patients (86%) had abnormal IGF-1 levels. In all patients the correlation coefficient between IGF-1 and MELD was -0.317 (P = 0.001) and 0.478 between IGF-1 and Child- Pugh (P < 0.001).
Conclusions
Our findings showed that IGF-1 can be used as an index for evaluating the severity of cirrhosis; also it can be used for determining the severity of the disease, when liver biopsy is not possible.
doi:10.5812/hepatmon.6181
PMCID: PMC3628001  PMID: 23599716
Insulin-Like Growth Factor I; Liver Cirrhosis; Child
14.  Brain IGF-1 Receptors Control Mammalian Growth and Lifespan through a Neuroendocrine Mechanism 
PLoS Biology  2008;6(10):e254.
Mutations that decrease insulin-like growth factor (IGF) and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R) efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.
Author Summary
Using a mouse model relevant for humans, we showed that lifespan can be significantly extended by reducing the signaling selectively of a protein called IGF-I in the central nervous system. This effect occurred through changes in specific neuroendocrine pathways. Dissecting the pathophysiological mechanism, we discovered that IGF receptors in the mammalian brain efficiently steered the development of the somatotropic axis, which in turn affected the individual growth trajectory and lifespan. Our work confirms experimentally that continuously low IGF-I and low growth hormone levels favor extended lifespan and postpone age-related mortality. Together with other recent reports, our results further challenge the view that administration of GH can prevent, or even counteract human aging. This knowledge is important since growth hormone is often prescribed to elderly people in an attempt to compensate the unwanted effects of aging. Growth hormone and IGF-I are also substances frequently used for doping in sports.
Inactivating IGF receptors in the brain decreased growth hormone and IGF-I, and increased lifespan in healthy mice. Such neuroendocrine longevity could be a physiological response to environment.
doi:10.1371/journal.pbio.0060254
PMCID: PMC2573928  PMID: 18959478
15.  Growth hormone – insulin-like growth factor-I axis and bone mineral density in adults with thalassemia major 
Introduction:
Bone disease and short stature are frequent clinical features of patients with beta-thalassaemia major. Dysfunction of the GH-IGF-1 axis has been described in many thalassemics children and adolescents with short stature and reduced growth velocity. Assessment of the GH-IGF-1 axis in short adults with TM after attainment of final height may be required to select those who are candidates for replacement therapy and to prevent the development of bone disease. The aim of our study was to investigate GH secretion in adult thalassemic patients in relation to their bone mineral density (BMD) and serum ferritin concentrations.
Materials and Methods:
We performed clonidine stimulation test in 30 thalassemic patients (18 males, 12 females) with a mean age of 31.5± 7.2 years. The cut-off level for GH response was set at 7ug/l, according to the literature. Serum ferritin, IGF-I, liver enzymes, alkaline phosphatase (ALP) and type 1 Collagen Carboxy Telopeptide (CCT1) were also determined.
Results:
We diagnosed GH deficiency (GHD) in 12 patients (40%) and IGF-I deficiency (IGF-I SDS <-2) was diagnosed in 20 patients (67%). Adult patients with TM had significantly decreased IGF-I concentrations and bone mineral density (BMD) at the femur neck and lumbar spine compared to normal controls. Thalassemic patients with GHD and IGF-I deficiency had significantly lower BMD T score at the lumbar spine compared to patients with normal GH and IGF-I levels. Thalassemic patients had higher serum CCT1 concentrations compared to normal controls. Peak GH levels were correlated significantly with IGF- I concentrations and IGF-I levels were correlated significantly with the height SDS (HtSDS) of thalassemic patients. Neither GH peak nor IGF-I concentrations were correlated to serum ferritin concentrations.
Conclusions:
We conclude that GH status should be tested in adult thalassemic patients especially those with short stature and/or decreased BMD. Clonidine test appears to be effective and safe in adults with TM. If the diagnosis of adult GHD is established, GH treatment may be considered for possible improvement of bone mineral density and heart function in patients with TM.
doi:10.4103/2230-8210.126525
PMCID: PMC3968729  PMID: 24701427
Bone mineral density; ferritin; GH deficiency GHD; insulin like growth factor –I; growth; growth hormone; prevalence; thalassemia
16.  Insulin-like Growth Factor (IGF)-I and IGF-II Contribute Differentially to the Phenotype of Pregnancy Associated Plasma Protein-A Knock-out Mice 
Context
Insulin-like growth factor (IGF) signaling is essential for achieving optimal body size during fetal development, peak bone mass during puberty, and maximal fecundity in the reproductive period. IGF-II is considered the main fetal IGF, whereas IGF-I is more important postnatally. Pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF signaling through cleavage of inhibitory IGF binding proteins. Conversely, inhibition of PAPP-A results in reduced local IGF action. Thus, PAPP-A knock-out (KO) mice are born as proportional dwarfs due to the dysregulation of IGF-II signaling during early embryogenesis that impacts body size. Relaxation of IgfII imprinting through mutation of a reciprocally imprinted downstream gene, H19, which allowed transcription of IGF-II from the normally silent maternal allele, rescued the dwarf phenotype of PAPP-A KO mice.
Objective
To determine the effect of increased IGF-II expression on postnatal phenotypes of PAPP-A KO mice.
Design
Young adult wild-type (WT), PAPP-A KO, H19 mutant (ΔH19/WT) and ΔH19/PAPP-A KO mice were characterized for skeletal phenotype (peripheral quantitative computed tomography at the midshaft and distal metaphysis of the femur) and reproductive phenotype (time to first litter, time between litters, pups per litter).
Results
Serum IGF-II levels were significantly increased in ΔH19/WT and ΔH19/PAPP-A KO mice compared to WT and PAPP-A KO mice; serum IGF-I levels were not affected by H19 mutation. PAPP-A KO mice had reductions in cortical thickness and in cortical and trabecular area, bone mineral content and bone mineral density compared to WT mice. There were no significant differences between PAPP-A KO and ΔH19/PAPP-A KO mice in any of the bone parameters. PAPP-A KO crossed with (x) PAPP-A KO had a longer time until first litter, normal time between subsequent litters, and significantly reduced number of pups per litter compared to WT × WT. ΔH19/PAPP-A KO × ΔH19/PAPP-A KO had an even longer time to first litter, but also longer time between litters. This phenotype was associated with female ΔH19/PAPP-A KO mice. Furthermore, these ΔH19/PAPP-A KO mouse mothers failed to care for their pups.
Conclusions
An increase in IGF-II expression did not rescue the skeletal and reproductive deficiencies associated with reduced local IGF-I signaling in PAPP-A KO mice. In addition, the data suggest a potential new role for genomic imprinting at the IgfII/H19 locus affecting maternal behavior.
doi:10.1016/j.ghir.2011.06.002
PMCID: PMC3171618  PMID: 21802327
Pregnancy-associated plasma protein-A; insulin-like growth factor-II; imprinting; bone mass; reproduction
17.  Administration of insulin-like growth factor-I (IGF-I) peptides for three days stimulates proliferation of the small intestinal epithelium in rats. 
Gut  1995;37(5):630-638.
It has previously been shown that longterm administration of insulin-like growth factor-I (IGF-I) or the analogue Long R3 IGF-I (LR3IGF-I) selectively stimulate growth of the gastrointestinal tract in gut resected, dexamethasone treated, and normal rats. In this study, the short-term effects of IGF-I administration on intestinal proliferation have been investigated. Female rats (110 g, five-six/group) were infused for three days with 2.5 mg/kg/day of either IGF-I or LR3IGF-I and compared with vehicle treated or untreated control rats. LR3IGF-I but not IGF-I increased body weight and wet tissue weight of the small and large intestine (+20%), compared with controls. Tissue weight responses were independent of food intake and were reflected in the histology of the tissue. In LR3IGF-I treated animals, duodenal and ileal crypts length were increased by 13 and 22%, respectively, associated with an increase in crypt cell number. No such histological changes were seen in IGF-I treated rats. Tritiated thymidine labelling indices were significantly increased after administration of either IGF-I or LR3IGF-I (up to 14%) in both the duodenum and ileum. In IGF-I treated rats, increased nuclear labelling was not associated with an increase in the crypt compartment. In contrast, LR3IGF-I induced proportional increments in thymidine labelling and crypt size, suggesting that LR3IGF-I is not only more potent than the native peptide but also induced proliferative events more rapidly. In the colon, the thymidine labelling index was low, however, a non-significant increase in the number of cells labelled with thymidine was seen. These results suggest that within a three day treatment period intestinal mitogenesis is more advanced in animals treated with LR3IGF-I. The differences in proliferative response between the two peptides may be accounted for by variations in pharmacokinetics, clearance rates, and interactions with circulating and tissue specific binding proteins.
PMCID: PMC1382866  PMID: 8549937
18.  Mathematical modelling to restore circulating IGF-1 concentrations in children with Crohn's disease-induced growth failure: a pharmacokinetic study 
BMJ Open  2013;3(5):e002737.
Objectives
Children with Crohn's disease grow poorly, and inflammation depresses the response of insulin-like growth factor-1 (IGF-1) to growth hormone. Correcting the inflammation normalises growth velocity; however, removing inflammation cannot be achieved in all children. Our lack of understanding of IGF-1 kinetics has hampered its use, particularly as high IGF-1 concentrations over long periods may predispose to colon cancer. We hypothesised that mathematical modelling of IGF-1 would define dosing regimes that return IGF-1 concentrations into the normal range, without reaching values that risk cancer.
Design
Pharmacokinetic intervention study.
Setting
Tertiary paediatric gastroenterology unit.
Participants
8 children (M:F; 4:4) entered the study. All completed: 5 South Asian British; 2 White British; 1 African British. Inclusion criteria: Children over 10 years with active Crohn's disease (C reactive protein >10 mg/l or erythrocyte sedimentation rate >25 mm/h) and height velocity <–2 SD score. Exclusion criteria: closed epiphyses; corticosteroids within 3 months; neoplasia or known hypersensitivity to recombinant human IGF-1 (rhIGF-1).
Interventions
Subcutaneous rhIGF-1 (120 μg/kg) per dose over two admissions: the first as a single dose and the second as twice daily doses over 5 days.
Primary outcome
Significant increase in circulating IGF-1.
Secondary outcomes
Incidence of side effects of IGF-1. A mathematical model of circulating IGF-1 (Ac) was developed to include parameters of endogenous synthesis (Ksyn); exogenous uptake (Ka) from the subcutaneous dose (As): and IGF-1 clearance: where dAc/dt=Ksyn − Kout×Ac+Ka×As.
Results
Subcutaneous IGF-1 increased concentrations, which were maintained on twice daily doses. In covariate analysis, disease activity reduced Ksyn (p<0.001). Optimal dosing was derived from least squares regression fitted to a dataset of 384 Crohn's patients, with model parameters assigned by simulation.
Conclusions
By using age, weight and disease activity scaling in IGF-1 dosing, over 95% of children will have normalised IGF-1 concentrations below +2.5 SDs of the normal population mean, a level not associated with cancer risk.
doi:10.1136/bmjopen-2013-002737
PMCID: PMC3664353  PMID: 23793696
insulin-like growth factor-1; adolescent; inflammatory bowel disease; pharmacokinetics; height
19.  Race/ethnic Variation in Serum Levels of IGF-I and IGFBP-3 in US Adults 
Objectives
The IGF axis plays a significant role in normal growth and development and variation in IGFs is associated with health outcomes. Past studies report variation in IGF levels among race/ethnic groups known to differ in disease incidence. This paper reports on race/ethnic variation in serum levels of IGF-I and IGF-BP3 in a nationally representative and ethnically diverse sample of US adults.
Design
Serum IGF-I and IGFBP-3 levels from the fasting subsample (n = 6061) of respondents to the US National Health and Nutrition Examination Survey III (NHANES III) were analyzed using an IGF-I ELISA (Diagnostic Systems Laboratory (DSL) 10–5600) and an IGFBP-3 IRMA (DSL 6600). The NHANES is a combined examination and interview survey of a nationally representative sample of US adults. Regression analyses were used to estimate cross-sectional associations between the IGF axis and demographic variables.
Results
In unadjusted analyses, serum IGF-I levels were higher in males than in females, and IGFBP-3 levels were higher in females than in males. Both analytes were lower in older adults. Univariate analyses indicate that serum levels of IGF-I are lower in female Non-Hispanic Whites (NHW) (256 [4.9]) and Hispanics (249 [6.6]) than in Non-Hispanic Blacks (NHB) (281 [4.9]). However, in males, IGF levels in NHWs (287 [3.6]) and NHBs (284 [4.3]) are similar and levels in Mexican-Americans are only moderately reduced (265 [3.4]). Notably, NHB’s have the highest molar ratio of IGF-I:IGFBP-3 at all ages. After adjustment for age and BMI, gender and race/ethnicity differences persist.
Conclusions
These cross-sectional data support exploration of the IGF axis as an explanation for some race/ethnic differences in cancer incidence.
doi:10.1016/j.ghir.2008.08.005
PMCID: PMC2702997  PMID: 18812263
Cancer; Insulin-Like Growth Factor; Race/Ethnicity; Age
20.  Zebrafish IGF Genes: Gene Duplication, Conservation and Divergence, and Novel Roles in Midline and Notochord Development 
PLoS ONE  2009;4(9):e7026.
Insulin-like growth factors (IGFs) are key regulators of development, growth, and longevity. In most vertebrate species including humans, there is one IGF-1 gene and one IGF-2 gene. Here we report the identification and functional characterization of 4 distinct IGF genes (termed as igf-1a, -1b, -2a, and -2b) in zebrafish. These genes encode 4 structurally distinct and functional IGF peptides. IGF-1a and IGF-2a mRNAs were detected in multiple tissues in adult fish. IGF-1b mRNA was detected only in the gonad and IGF-2b mRNA only in the liver. Functional analysis showed that all 4 IGFs caused similar developmental defects but with different potencies. Many of these embryos had fully or partially duplicated notochords, suggesting that an excess of IGF signaling causes defects in the midline formation and an expansion of the notochord. IGF-2a, the most potent IGF, was analyzed in depth. IGF-2a expression caused defects in the midline formation and expansion of the notochord but it did not alter the anterior neural patterning. These results not only provide new insights into the functional conservation and divergence of the multiple igf genes but also reveal a novel role of IGF signaling in midline formation and notochord development in a vertebrate model.
doi:10.1371/journal.pone.0007026
PMCID: PMC2738950  PMID: 19759899
21.  IGF1R levels in the brain negatively correlate with longevity in 16 rodent species 
Aging (Albany NY)  2013;5(4):304-314.
The insulin/insulin-like growth factor signaling (IIS) pathway is a major conserved regulator of aging. Nematode, fruit fly and mouse mutants with reduced IIS signaling exhibit extended lifespan. These mutants are often dwarfs leading to the idea that small body mass correlates with longevity within species. However, when different species are compared, larger animals are typically longer-lived. Hence, the role of IIS in the evolution of life history traits remains unresolved. Here we used comparative approach to test whether IGF1R signaling changes in response to selection on lifespan or body mass and whether specific tissues are involved. The IGF1R levels in the heart, lungs, kidneys, and brains of sixteen rodent species with highly diverse lifespans and body masses were measured via immunoblot after epitope conservation analysis. We report that IGF1R levels display strong negative correlation with maximum lifespan only in brain tissue and no significant correlations with body mass for any organ. The brain-IGF1R and lifespan correlation holds when phylogenetic non-independence of data-points is taken into account. These results suggest that modulation of IGF1R signaling in nervous tissue, but not in the peripheral tissues, is an important factor in the evolution of longevity in mammals.
PMCID: PMC3651522  PMID: 23651613
aging; IGF1 receptor; rodents; comparative approach; life span
22.  Overexpression of insulin-like growth factor-I receptor as a pertinent biomarker for hepatocytes malignant transformation 
AIM: To investigate the dynamic features of insulin-like growth factor-I receptor (IGF-IR) expression in rat hepatocarcinogenesis, and the relationship between IGF-IR and hepatocytes malignant transformation at mRNA or protein level.
METHODS: Hepatoma models were made by inducing with 2-fluorenylacetamide (2-FAA) on male Sprague-Dawley rats. Morphological changes of hepatocytes were observed by pathological Hematoxylin and eosin staining, the dynamic expressions of liver and serum IGF-IR were quantitatively analyzed by an enzyme-linked immunosorbent assay. The distribution of hepatic IGF-IR was located by immunohistochemistry. The fragments of IGF-IR gene were amplified by reverse transcription-polymerase chain reaction, and confirmed by sequencing.
RESULTS: Rat hepatocytes after induced by 2-FAA were changed dynamically from granule-like degeneration, precancerous to hepatoma formation with the progressing increasing of hepatic mRNA or IGF-IR expression. The incidences of liver IGF-IR, IGF-IR mRNA, specific IGF-IR concentration (ng/mg wet liver), and serum IGF-IR level (ng/mL) were 0.0%, 0.0%, 0.63 ± 0.17, and 1.33 ± 0.47 in the control; 50.0%, 61.1%, 0.65 ± 0.2, and 1.51 ± 0.46 in the degeneration; 88.9%, 100%, 0.66 ± 0.14, and 1.92 ± 0.29 in the precancerosis; and 100%, 100%, 0.96 ± 0.09, and 2.43 ± 0.57 in the cancerous group, respectively. IGF-IR expression in the cancerous group was significantly higher (P < 0.01) than that in any of other groups at mRNA or protein level. The closely positive IGF-IR relationship was found between livers and sera (r = 0.91, t = 14.222, P < 0.01), respectively.
CONCLUSION: IGF-IR expression may participate in rat hepatocarcinogenesis and its abnormality should be an early marker for hepatocytes malignant transformation.
doi:10.3748/wjg.v19.i36.6084
PMCID: PMC3785631  PMID: 24106410
Hepatoma; Insulin-like growth factor-I receptor; Immunohistochemistry; Gene amplification; Sequencing; Rat hepatoma model
23.  Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels 
Aging cell  2009;8(3):277-287.
Summary
To better characterize aging in mice, the Jackson Aging Center carried out a lifespan study of 31 genetically-diverse inbred mouse strains housed in a specific pathogen-free facility. We carried out clinical assessments every 6 months, measuring multiple age-related phenotypes including neuromuscular, kidney and heart function, body composition, bone density, hematology, hormonal levels, and immune system parameters. In a concurrent cross-sectional study of the same 31 strains at 6, 12, and 20 months, we carried out more invasive measurements followed by necropsy to assess apoptosis, DNA repair, chromosome fragility, and histopathology. In this report, which is the initial paper of a series, we describe the study design, median lifespans, and circulating IGF1 levels at 6, 12 and 18 months for the first cohort of 32 females and 32 males of each strain. Survival curves varied dramatically among strains with median lifespans ranging from 251 to 964 days. Plasma IGF1 levels, which also varied considerably at each time point, showed an inverse correlation with median lifespan at 6 months (R=−0.33, P=0.01). This correlation became stronger if the short-lived strains with a median lifespan<600 days were removed from the analysis (R=−0.53, P<0.01). These results support the hypothesis that the IGF1 pathway plays a key role in regulating longevity in mice and indicates that common genetic mechanisms may exist for regulating IGF1 levels and lifespan.
doi:10.1111/j.1474-9726.2009.00478.x
PMCID: PMC2768517  PMID: 19627267
genetics; mice; longevity; IGF1; aging
24.  Non-islet cell tumor-induced hypoglycemia: a report of five cases and brief review of the literature 
Summary
We describe the clinical presentation, diagnostic and management issues in five cases of non-islet cell tumor hypoglycemia (NICTH), diagnosed at a tertiary care institute over a period of 15 years. The clinical, laboratory, and histopathological findings of these patients along with diagnostic utility of IGF2:IGF1 ratio are discussed. The mean age of presentation was 52 years, with a male predominance (3:2). Three patients presented with recurrent episodes of fasting hypoglycemia and it was detected in other two patients during hospitalization. Two patients had acromegaloid features that regressed following treatment. One patient had hypokalemia. Low levels of insulin, C-peptide, GH, and IGF1 were invariably found in all. The IGF2 level was elevated in only one patient; however, IGF2:IGF1 ratio was more than 10 in four of the five patients. The mean tumor size was 16.4 cm and mean weight was 3.6 kg. Four patients had mesenchymal tumors and one had epithelial tumor. NICTH is a rare cause of hypoglycemia. Hypoinsulinemic hypoglycemia with low IGF1 and IGF2:IGF1 ratio more than 10 is suggestive of this entity.
Learning points
NICTH should be considered in patients presenting with tumor of mesenchymal origin and hypoglycemia.Hypoinsulinemic hypoglycemia with low IGF1 is a strong biochemical evidence of NICTH.IGF2:IGF1 ratio of more than 10 is a complementary investigation in the absence of an assay facility for IGF2.
doi:10.1530/EDM-13-0046
PMCID: PMC3922193  PMID: 24616774
25.  The lack of effect of specific overexpression of IGF-1 in the central nervous system or skeletal muscle on pathophysiology in the G93A SOD-1 mouse model of ALS 
Experimental neurology  2007;207(1):52-63.
The ability of insulin like growth factor 1 (IGF-1) to prevent the pathophysiology associated with amyotrophic lateral sclerosis (ALS) is currently being explored with animal models and in clinical trials with patients. Several studies have reported positive effects of IGF-1 in reducing motor neuron death, delaying the onset of motor performance decline, and increasing life span, in SOD-1 mouse models of ALS and in one clinical trial. However, a second clinical trial produced no positive results raising questions about the therapeutic efficacy of IGF-1. To investigate the effect of specific and sustained IGF-1 expression in skeletal muscle or central nervous system on motor performance, life span, and motor neuron survival, human-IGF-1-transgenic mice were crossed with the G93A SOD-1 mutant model of ALS. No significant differences were found in onset of motor performance decline, life span, or motor neuron survival in the spinal cord, between SOD+/IGF-1+ and SOD+/IGF-1- hybrid mice. IGF-1 concentration levels, measured by radioimmunoassay, were found to be highly increased throughout life in the central nervous system (CNS) and skeletal muscle of IGF-1 transgenic hybrid mice. Additionally, increased CNS weight in SOD+ mice crossbred with CNS IGF-1 transgenic mice demonstrates that IGF-1 overexpression is biologically active even after the disease is fully developed. Taken together, these results raise questions concerning the therapeutic value of IGF-1 and indicate that further studies are needed to examine the relationship between methods of IGF-1 administration and its potential therapeutic value.
doi:10.1016/j.expneurol.2007.05.016
PMCID: PMC2043146  PMID: 17597610
Amyotrophic Lateral Sclerosis; Insulin-like growth factor-1; motor neuron; cell death; skeletal muscle; transgenic; G93A SOD-1; motor performance

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