Plasma Insulin-like Growth Factor-1 Levels Research Articles

Abstract 4560: A new IGF-1-integrated Child-Pugh score to risk-stratify patients with hepatocellular carcinoma

Abstract Purpose The Child-Pugh (CP) system is the major tool for assessing the underlying liver condition and guiding therapy decisions in hepatocellular carcinoma (HCC) patients. It is itself relatively quantitative and uses five empirically selected variables, including hepatic encephalopathy and ascites, which are clinically difficult to grade and may vary in severity according to medical management of patients. Insulin-like growth factor-1 (IGF-1) is produced predominantly in the liver, and hence reflects its synthetic function. Our study objective was to build a new CP score by integrating plasma IGF-1 level into the CP parameters to refine its prognostic stratification ability. Patients and Methods We prospectively collected plasma samples and clinical data from 310 individuals with HCC. IGF-1 levels were measured by ELISA and recursive partitioning was used to identify optimal cut points and IGF-1 ranges, using training and validation sets, and established the cut-off values of IGF-1 arranged so as to define the three distinct groups of IGF-1 with increasing liver function severity; A=1, B=2, and C=3. We then constructed the new score by replacing points from ascites and encephalopathy with plasma IGF-1 points; the new score points = 4-11. Finally, we performed log rank test for both systems, and also compared their prognostic abilities using concordance index (c-index). Results Compared with CP system, the new system (c -index = 0.608) improves the capacity in predicting OS and refined the stratification of all classes of the original CP (c-index = 0.573), (p value = 0.0029). Conclusion Replacing ascites and encephalopathy by plasma IGF-1 significantly improved prediction of OS and prognostic stratification of the conventional CP system. After external validation, the new scoring system may become the standard of care in guiding therapy decisions and stratifying HCC patients in clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4560. doi:1538-7445.AM2012-4560

Abnormality of glycometabolism related factors in non-psychotic offspring of schizophrenic patients

Schizophrenic patients appear to have higher rates of abnormality of glycometabolism. It has been suggested that these could be secondary to the use of antipsychotics. However, findings indicate that abnormal glucose metabolism may be potentially involved in the pathogenesis of schizophrenia. The present study examined the fasting plasma levels of glycometabolism related factors in healthy offspring of schizophrenic patients. Our objective was to test the hypothesis that abnormal glucose metabolism might be potentially involved in the pathogenesis of schizophrenia. Thirty-two healthy offspring of schizophrenic inpatients who met DSM-IV criteria for schizophrenia and 37 comparison subjects were recruited. Fasting plasma levels of glucose, insulin, insulin-like growth factor 1 (IGF-1), growth hormone (GH), leptin and cortisol were tested for all subjects. Compared with controls, offspring of schizophrenic patients had significantly higher mean plasma insulin and insulin resistance, and lower mean plasma IGF-1 level. Meanwhile, the mean fasting plasma levels of glucose, GH, leptin and cortisol did not differ significantly between offspring of schizophrenic patients and healthy comparison subjects. Offspring of schizophrenic patients showed significant differences from comparison subjects in glycometabolism related factors. Abnormal glucose metabolism might be potentially involved in the pathogenesis of schizophrenia.

Insulin-like growth factor-1 gene polymorphism in rheumatoid arthritis patients

Objectives: Insulin-like growth factor-1 (IGF-1) regulates several biological functions, and low plasma levels of IGF-1 are known to contribute towards the pathogenesis of rheumatoid arthritis (RA). In view of the biological significance of IGF-1, we investigated the association of RA with the polymorphism of a 192-bp allele which is cytosine–adenosine repeat located 1 kb upstream from the IGF-1 gene transcription site and is known to regulate serum IGF-1 levels.Methods: Blood samples were collected from 52 healthy controls (HC) and 68 RA patients to measure the levels of IGF-1 and to isolate genomic DNA. Polymorphism of the IGF-1 gene was examined using polymerase chain reaction (PCR). Disease severity, duration, and activity were recorded for all RA patients.Results: We observed that 97% of all the subjects who participated in this study showed the presence of a 192-bp allele of the IGF-1 gene. All healthy controls exhibited the presence of 192-bp wild-type allele. All non-carriers of the 192-bp allele were Arabs and had RA. Gender correlated significantly with allele frequencies as 14% of the male and only 2% of the female RA patients were non-carriers of 192-bp allele. Plasma IGF-1 levels were significantly lower (p < 0.01) in RA patients compared to HC, and all RA patients who were non-carriers of the 192-bp allele had a significantly high disease activity score. No correlation was found between the duration of RA and the presence or absence of this allele.Conclusions: This study suggests a possible association of the IGF-1 gene polymorphism with developing RA, particularly in males as non-carriers of the 192-bp allele.

Energy-preserving effects of IGF-1 antagonize starvation-induced cardiac autophagy

Insulin-like growth factor 1 (IGF-1) is known to exert cardioprotective actions. However, it remains unknown if autophagy, a major adaptive response to nutritional stress, contributes to IGF-1-mediated cardioprotection. We subjected cultured neonatal rat cardiomyocytes, as well as live mice, to nutritional stress and assessed cell death and autophagic rates. Nutritional stress induced by serum/glucose deprivation strongly induced autophagy and cell death, and both responses were inhibited by IGF-1. The Akt/mammalian target of rapamycin (mTOR) pathway mediated the effects of IGF-1 upon autophagy. Importantly, starvation also decreased intracellular ATP levels and oxygen consumption leading to AMP-activated protein kinase (AMPK) activation; IGF-1 increased mitochondrial Ca(2+) uptake and mitochondrial respiration in nutrient-starved cells. IGF-1 also rescued ATP levels, reduced AMPK phosphorylation and increased p70(S6K) phosphorylation, which indicates that in addition to Akt/mTOR, IGF-1 inhibits autophagy by the AMPK/mTOR axis. In mice harbouring a liver-specific igf1 deletion, which dramatically reduces IGF-1 plasma levels, AMPK activity and autophagy were increased, and significant heart weight loss was observed in comparison with wild-type starved animals, revealing the importance of IGF-1 in maintaining cardiac adaptability to nutritional insults in vivo. Our data support the cardioprotective actions of IGF-1, which, by rescuing the mitochondrial metabolism and the energetic state of cells, reduces cell death and controls the potentially harmful autophagic response to nutritional challenges. IGF-1, therefore, may prove beneficial to mitigate damage induced by excessive nutrient-related stress, including ischaemic disease in multiple tissues.

The relationship between insulin-like growth factor-1 and metabolic syndrome, independent of adiponectin

Background Insulin-like growth factor-1 (IGF-1) is associated with obesity and aging, and was recently linked to metabolic syndrome (MetS) and insulin resistance. However, little is known about the relationship between IGF-1 and adiponectin (adiponectin), another marker of MetS. Methods We measured the plasma IGF-1 and adiponectin levels of 3099 subjects (1869 males, 55.9 ± 10.8 y). We applied the Korean-modified International Diabetes Foundation (k-IDF) criteria for determination of, and risk assessment for, MetS. Results K-IDF criteria-based MetS occurred in 37.0% (n = 1146) of patients. IGF-1 (91.5 vs. 97.3 ng/ml, p < 0.001) and adiponectin (3.95 vs. 4.23 μg/ml, p < 0.001) were significantly lower in MetS patients than without MetS. Lower IGF-1 was associated with increasing numbers of MetS abnormalities, independent of adiponectin (p for trend < 0.001, F = 12.615, p < 0.001 in ANCOVA). MetS prevalence in individuals with both high IGF-1 and adiponectin levels (6.7%, n = 206) was significantly lower than in other groups. Both high IGF-1 and adiponectin group was associated with reduced MetS risk after adjusting for other confounding factors (OR 0.694, 95% CI 0.493–0.977, p = 0.036). Conclusions IGF-1 was associated with MetS independent of adiponectin in our study. The independent relationship between IGF-1 and MetS provides insight into the pathophysiologic mechanisms of MetS.

Novel View on Stem Cell Compartment and Aging - a Number of Pluripotent Very Small Embryonic Like Stem Cells and Hematopoietic Stem Cells in Murine Bone Marrow Is High in Several Long-Living and Reduced in Short-Living Murine Strains and Unexpectedly Inversely Correlates in These Animals with Plasma Growth Hormone/Insulin-Like Growth Factor-1 Level

Abstract LBA-5 Background:It is known that an increase in caloric intake leads to increase in plasma growth hormone (GH) level that subsequently induces secretion of insulin-like growth factor-1 (IGF-1) from liver, what leads to accelerated aging (Nature 2010;464:504). On the other hand, caloric restriction and a resulting decrease in plasma IGF-1 level has the opposite effect and extends lifespan. It also known that adult tissues contain a population of pluripotent very small embryonic like stem cells (VSELs) that play as postulated an important role in rejuvenation of long term hematopoietic stem cells (LT-HSCs) in bone marrow (BM) Leukemia 2011; doi:10.1038/leu.2011.73, Exp. Hematology 2011;39:225–237). As we observed previously, the number of these cells in murine BM decreases with age and VSELs are kept quiescent in BM and protected from premature depletion by erasure of the somatic imprint in differentially methylated regions (DMRs) of some paternally imprinted genes involved in insulin/insulin growth factors signaling (IIS) such as e.g., Igf2-H19 and RasGRF1 (Leukemia 2009;23:2042). Hypothesis:To explain and connect these phenomena together, we hypothesized that prolonged insulin/insulin growth factors signaling (IIS) prematurely depletes VSELs from the adult tissues and in BM may negatively impact on population of HSCs. Material and Methods:The number of VSELs and HSCs in long living murine strains with inborn low level of circulating IGF-1 (Laron- and Ames- dwarfs) as well as in short living mice with high levels of circulating IGF-1 (e.g., transgenic mice that overexpress bovine growth hormone; bGH) was evaluated by FACS. VSELs were isolated and epigenetic status of genes regulating pluripotency (e.g., Oct-4) as well as imprinted genes regulating IIS was evaluated by employing bisulfate modification of DNA followed by sequencing and by COBRE assay. We also challenged long living mice with low IGF-1 plasma level by daily injections of recombinant GH or IGF-1. Results:We found that the number of VSELs and HSCs residing in BM inversely correlates with plasma GH/IGF-1 level. To support this, mice with low circulating plasma IGF-1 levels (Laron- and Ames-dwarf mice) have higher numbers of VSELs and HSCs in BM that, in contrast to aged-matched normal littermates, are maintained at high levels even into advanced age. The analysis of molecular signature of VSELs in these animals revealed prolonged retention of hypomethylation in the DMRs within the Igf2-H19 and RasGRF1 loci, which attenuates IIS signaling in these cells. The number of VSELs, however, decreased in these animals after prolonged treatment with GH or recombinant IGF-I. Conversely, mice with elevated IGF-I level in plasma due to expression of the GH transgene or normal wild type mice injected for a sustained period with recombinant GH both exhibit significant decreases in the number of VSELs and HSCs in BM compared to control animals. These decreases were paralleled by epigenetic changes in Igf2-H19 and RasGRF1 loci in which DMRs became hypermethylated over time. These changes in methylation lead to increases in IGF-2 and RasGRF1 expression and may explain why GH transgenic mice have an increase in IIS that leads to shortening of life span in these animals. Conclusions:Our data shed new light on the relationships between senescence, GH/IGF-1 level, prolonged IIS, and number of VSELs and LT-HSCs. Accordingly, we propose a new paradigm in which a decrease in IIS (e.g., due to caloric restriction that lowers plasma IGF-1 level) may delay the age-dependent elimination of VSELs from adult tissues. By contrast, chronic IIS (e.g., due to chronic high caloric intake and the resulting elevated GH and IGF-1 levels) prematurely depletes VSELs residing in adult organs, which for example in BM leads to a decrease in the number of LT-HSCs. This study also indicates that GH-based anti-aging therapies need careful re-evaluation of their potentially uncontrolled stimulation of VSELs in BM that may lead to development of hematological malignancies. In support of this, elevated GH and IIS lead to hematological malignancies, while, by contrast, Laron dwarf mice and Laron dwarf patients, which have a low plasma IGF-1 levels, do not develop leukemias. Disclosures:Ratajczak:Neostem Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Novel View on Stem Cell Compartment and Aging - a Number of Pluripotent Very Small Embryonic Like Stem Cells and Hematopoietic Stem Cells in Murine Bone Marrow Is High in Several Long-Living and Reduced in Short-Living Murine Strains and Unexpectedly Inversely Correlates in These Animals with Plasma Growth Hormone/Insulin-Like Growth Factor-1 Level

Abstract LBA-5 Background: It is known that an increase in caloric intake leads to increase in plasma growth hormone (GH) level that subsequently induces secretion of insulin-like growth factor-1 (IGF-1) from liver, what leads to accelerated aging (Nature 2010;464:504). On the other hand, caloric restriction and a resulting decrease in plasma IGF-1 level has the opposite effect and extends lifespan. It also known that adult tissues contain a population of pluripotent very small embryonic like stem cells (VSELs) that play as postulated an important role in rejuvenation of long term hematopoietic stem cells (LT-HSCs) in bone marrow (BM) Leukemia 2011; doi:10.1038/leu.2011.73, Exp. Hematology 2011;39:225–237). As we observed previously, the number of these cells in murine BM decreases with age and VSELs are kept quiescent in BM and protected from premature depletion by erasure of the somatic imprint in differentially methylated regions (DMRs) of some paternally imprinted genes involved in insulin/insulin growth factors signaling (IIS) such as e.g., Igf2-H19 and RasGRF1 (Leukemia 2009;23:2042). Hypothesis: To explain and connect these phenomena together, we hypothesized that prolonged insulin/insulin growth factors signaling (IIS) prematurely depletes VSELs from the adult tissues and in BM may negatively impact on population of HSCs. Material and Methods: The number of VSELs and HSCs in long living murine strains with inborn low level of circulating IGF-1 (Laron- and Ames- dwarfs) as well as in short living mice with high levels of circulating IGF-1 (e.g., transgenic mice that overexpress bovine growth hormone; bGH) was evaluated by FACS. VSELs were isolated and epigenetic status of genes regulating pluripotency (e.g., Oct-4) as well as imprinted genes regulating IIS was evaluated by employing bisulfate modification of DNA followed by sequencing and by COBRE assay. We also challenged long living mice with low IGF-1 plasma level by daily injections of recombinant GH or IGF-1. Results: We found that the number of VSELs and HSCs residing in BM inversely correlates with plasma GH/IGF-1 level. To support this, mice with low circulating plasma IGF-1 levels (Laron- and Ames-dwarf mice) have higher numbers of VSELs and HSCs in BM that, in contrast to aged-matched normal littermates, are maintained at high levels even into advanced age. The analysis of molecular signature of VSELs in these animals revealed prolonged retention of hypomethylation in the DMRs within the Igf2-H19 and RasGRF1 loci, which attenuates IIS signaling in these cells. The number of VSELs, however, decreased in these animals after prolonged treatment with GH or recombinant IGF-I. Conversely, mice with elevated IGF-I level in plasma due to expression of the GH transgene or normal wild type mice injected for a sustained period with recombinant GH both exhibit significant decreases in the number of VSELs and HSCs in BM compared to control animals. These decreases were paralleled by epigenetic changes in Igf2-H19 and RasGRF1 loci in which DMRs became hypermethylated over time. These changes in methylation lead to increases in IGF-2 and RasGRF1 expression and may explain why GH transgenic mice have an increase in IIS that leads to shortening of life span in these animals. Conclusions: Our data shed new light on the relationships between senescence, GH/IGF-1 level, prolonged IIS, and number of VSELs and LT-HSCs. Accordingly, we propose a new paradigm in which a decrease in IIS (e.g., due to caloric restriction that lowers plasma IGF-1 level) may delay the age-dependent elimination of VSELs from adult tissues. By contrast, chronic IIS (e.g., due to chronic high caloric intake and the resulting elevated GH and IGF-1 levels) prematurely depletes VSELs residing in adult organs, which for example in BM leads to a decrease in the number of LT-HSCs. This study also indicates that GH-based anti-aging therapies need careful re-evaluation of their potentially uncontrolled stimulation of VSELs in BM that may lead to development of hematological malignancies. In support of this, elevated GH and IIS lead to hematological malignancies, while, by contrast, Laron dwarf mice and Laron dwarf patients, which have a low plasma IGF-1 levels, do not develop leukemias. Disclosures: Ratajczak: Neostem Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees.

A Novel Perspective on Stem Cells, Tissue Senescence and Aging: Pluripotent Very Small Embryonic-Like Stem Cells (VSELs) and Hematopoietic Stem Cells (HSCs) Are Prematurely Depleted in Adult Bone Marrow (BM) in Response to Prolonged Growth Hormone/Insulin-Like Growth Factor-1 Signaling (IIS) and Chronic Increase in Caloric Uptake

Abstract 4818 Background.Caloric uptake elevates the plasma level of growth hormone (GH), which subsequently stimulates release of insulin-like growth factor-1 (IGF-1) from the liver. Evidence is accumulating that an increase in caloric intake, which leads to prolonged growth hormone (GH) and insulin/insulin-like growth factors signaling (IIS), accelerates aging. On the other hand, caloric restriction and a resulting decrease in IIS has the opposite effect and extends lifespan (Nature 2010;464:504). In support of this finding, mice with low circulating IGF-1 levels (Laron, Ames, and Snell dwarfs) live much longer than their normal littermates and, conversely, mice with high levels of circulating IGF-1 (e.g., transgenic mice that overexpress bovine growth hormone [bGH]) have significantly reduced life span. Aim of Hypothesis.To explain these phenomena, we hypothesized that prolonged IIS prematurely depletes adult tissues of very small embryonic-like stem cells (VSELs), which are the most developmentally primitive adult tissue-residing pluripotent stem cells (Leukemia 2006;20:857). We envision that VSELs play an important role in rejuvenation of the pool of tissue-committed stem cells and, as we observed previously, the number of these cells in murine BM decreases with age. We demonstrated that in bone marrow (BM), VSELs give rise to long-term repopulating hematopoietic stem cells (LT-HSCs) (Leukemia 2011; doi:10.1038/leu.2011.73, Exp. Hematology 2011;39:225–237). As previously reported, VSELs are kept quiescent in BM and protected from premature depletion by erasure of the somatic imprint in differentially methylated regions (DMRs) of some paternally imprinted genes involved in IIS (e.g., Igf2-H19 and RasGRF1). Results.In the current study, we provide direct evidence that the number of VSELs deposited in BM during ontogenesis is related to plasma IIS signaling, which is affected by the GH/IGF-1 level. In particular, mice with elevated IGF-I level in plasma due to expression of the bovine GH transgene and wild type mice injected for a sustained period with porcine GH both exhibit significant decreases in the number of VSELs and HSCs in BM compared to control animals. These decreases were paralleled by epigenetic changes in Igf2-H19 and RasGRF1 loci in which DMRs became hypermethylated over time. These changes in methylation lead to increases in IGF-2 and RasGRF1 expression and may explain why bovine GH transgenic mice have an increase in IIS and a significantly reduced life span. Conversely, mice with low circulating plasma IGF-1 levels (Laron and Ames dwarf mice ) have higher numbers of VSELs and HSCs in BM that, in contrast to aged-matched normal littermates, are maintained at high levels even into advanced age. The molecular signature of VSELs in these animals revealed prolonged retention of hypomethylation in the DMRs within the Igf2-H19 and RasGRF1 loci, which attenuated IIS signaling in these cells. The number of VSELs, however, decreased in these animals after prolonged treatment with porcine GH or human recombinant IGF-I. Conclusions.Our data shed new light on the relationships between senescence, high GH level, prolonged IIS, and depletion of VSELs and LT-HSCs. Accordingly, we propose a new paradigm in which chronic IIS (e.g., due to chronic high caloric intake and the resulting elevated GH and IGF-1 levels) prematurely depletes VSELs in BM, which leads to a decrease in the number of LT-HSCs. By contrast, caloric restriction and a decrease in IIS may delay the age-dependent elimination of VSELs from BM. This study also indicates that GH-based anti-aging therapies need careful re-evaluation of their potentially uncontrolled stimulation of VSELs in BM and downstream effects on hematopoiesis and the development of hematological malignancies. In support of this concern, elevated IIS may lead to hematological malignancies (uncontrolled proliferation of VSELs), while, by contrast, it is known that Laron dwarf mice and Laron dwarf patients, which have a GH-receptor deficiency and low plasma IGF-1 levels, do not develop leukemias. Disclosures:Ratajczak:Neostem Inc: Consultancy, Research Funding.

Caloric restriction promotes the reproductive capacity of female rats via modulating the level of insulin-like growth factor-1 (IGF-1)

The insulin-like growth factor-1 (IGF-1) plays an important role in the regulation of reproductive function. In the present study, we examined the effects of caloric restriction (CR) on the reproductive lifespan in rats and investigated the potential role of IGF-1. After 10 weeks of treatment, we determined the distribution of the ovarian follicles at various stages and measured the plasma level of IGF-1, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estrogen (ESG). Our results show that IGF-1 level was decreased after CR and correlated with the decrease in the levels of LH, FSH and ESG. Moreover, a higher percentage of primordial follicles and surviving follicles was observed in CR rats than in control rats ( P < 0.05). Immunohistochemical analysis showed that IGF-1 was extensively expressed in the cytoplasm of granulosa cells in the surviving follicles at different stages but not in the atretic follicles. Taken together, these results suggest that caloric restriction promotes the reproductive capacity of female rats via modulating the level of IGF-1, which then regulate pituitary gonadotrope cells to reduce the release of LH, FSH and ESG, and modulate follicular development.

Clinical and Prognostic Implications of Plasma Insulin-Like Growth Factor-1 and Vascular Endothelial Growth Factor in Patients With Hepatocellular Carcinoma

Cirrhosis and hepatocellular carcinoma (HCC) together form a two-disease state that affects survival of patients with HCC and dictates treatment decisions and prognostic stratification of patients in clinical trials. The study objective was to improve prognostic stratification of patients with HCC. We prospectively collected plasma samples and baseline clinicopathologic features from 288 new patients with HCC, and plasma insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) levels were tested. We applied Cox regression and log-rank tests to assess association of IGF-1 and VEGF with overall survival (OS), Kaplan-Meier curves to estimate OS, and recursive partitioning to determine optimal cutoff points for IGF-1 and VEGF. Prognostic ability of conventional and molecular Barcelona Clinic Liver Cancer classifications was compared using the c-index. Lower plasma IGF-1 and higher plasma VEGF levels significantly correlated with advanced clinicopathologic parameters and poor OS, with optimal cut points of 26 ng/mL and 450 pg/mL, respectively. The combination of low IGF-1 and high VEGF predicted median OS of 2.7 months compared with 19 months for patients with high IGF-1 and low VEGF (P < .001), further refining the prognostic ability of conventional HCC staging (P < .001). Baseline levels of plasma IGF-1 and VEGF correlated significantly with survival in patients with HCC. Integrating IGF-1 and VEGF into HCC staging significantly enhanced prognostic stratification of patients. If validated, these results may prove to be useful in designing strategies to personalize management approaches among these patients.

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.

Plasma insulin-like growth factor-1 level and risk of incident hypertension in nondiabetic women

Insulin-like growth factor-1 may be involved in regulation of blood pressure through multiple pathways; however, the prospective association between plasma insulin-like growth factor-1 level and risk of hypertension has never been explored. We prospectively examined the association between plasma insulin-like growth factor-1 level and the risk of incident hypertension among 2046 women without a history of hypertension or diabetes. Cox proportional hazards regression models were used to adjust for potential confounders. We identified 181 incident cases of hypertension during 4 years of follow-up. After adjusting for plasma insulin-like growth factor binding protein-3 level and other potential confounders, women in the top tertile of insulin-like growth factor-1 had decreased risk of incident hypertension (relative risk 0.56, 95% confidence interval 0.35-0.91) compared with women in the bottom tertile. After further adjusting for C-peptide level and C-reactive protein level in subsets of participants who also had those markers measured, the association between insulin-like growth factor-1 and risk of incident hypertension remained robust. Higher circulating insulin-like growth factor-1 level is associated with a decreased risk of incident hypertension among nondiabetic women.

IV-HCC: Clinical and prognostic implications of plasma IGF-1 and VEGF in patients with hepatocellular carcinoma.

155 Background: Hepatocellular carcinoma (HCC) is a vascular tumor, derived mainly by vascular endothelial growth factor (VEGF)-mediated angiogenesis. It is always associated with chronic liver disease (CLD) and cirrhosis, which directly affect survival of HCC patients. Insulin-like growth factor-1 (IGF-1) is produced predominantly in the liver, and therefore, CLD is associated with low levels of IGF-1. Methods: 288 new consecutive patients with HCC were eligible for the study between 2001 and 2008 at M. D. Anderson Cancer Center. Baseline clinicopathologic features, CLIP and BCLC staging, plasma IGF-1 and VEGF levels were available and multivariate Cox regression models and median survival were calculated. Kaplan-Meier curves were used to estimate overall survival and the log-rank test was used to compare survival probabilities in patients with different IGF-1 and VEGF levels. Recursive partitioning was used to determine the optimal cut point for IGF-1 and VEGF, using repeated training/validation samples, each using 2/3 of the data to determine the best cut point and the remaining 1/3 to validate it. Prognostic ability of different molecular staging systems was compared using C-index. Results: Lower plasma IGF-1 and higher plasma VEGF levels significantly correlated with advanced clinicopathologic parameters and poor overall survival, with an optimal cut point of 26 pg/mL and 450 pg/mL respectively. The combination of low IGF-1 and high VEGF predicts median OS of 2.7 months compared with 19 month for patients with high IGF-1 and low VEGF (p-value=&lt;0.0001), and further refines the prognostic ability of BCLC and CLIP HCC staging systems (p&lt;0.0001). Conclusions: Molecular classification of HCC using baseline plasma IGF-1 and VEGF significantly correlated with clinical features and survival of HCC patients. Furthermore, integrating IGF-1 and VEGF into HCC staging systems, CLIP and BCLC, significantly enhanced their ability to predict prognosis. It may prove to be useful in designing strategies to personalize treatment approaches to these patients. No significant financial relationships to disclose.

Suitability of Insulin‐Like Growth Factor 1 (IGF1) as a Measure of Relative Growth Rates in Lingcod

AbstractThe effectiveness of spatial management strategies is typically evaluated through traditional biological measurements of size, density, biomass, and the diversity of species inside and outside management boundaries. However, there have been relatively few attempts to evaluate the processes underlying these biological patterns. In this study, we take the first step toward developing a relative index of body growth for lingcod Ophiodon elongatus using plasma insulin‐like growth factor 1 (IGF1) with the ultimate goal of measuring spatial differences in relative growth rates. Insulin‐like growth factor 1 is one of the principal hormones that stimulates growth at the cellular level in all vertebrates and shows significant relationships with body growth in many fishes. In the laboratory, we found that the level of IGF1 was related to the instantaneous growth of juvenile lingcod. In the field, we measured size, condition, and plasma IGF1 level in 149 lingcod from eight locations inside and outside marine protected areas in the San Juan Islands, Washington. The IGF1 levels in wild lingcod were highly variable from site to site for both genders, and we were able to detect differences in IGF1 across space in males. Multivariate analyses showed that the spatial patterns of IGF1 differed from those of traditional biological measurements. More work is needed to validate the relationship between IGF1 and growth in larger individuals, but our research shows the potential for IGF1 to be used as an ecological indicator.

Modulatory effects of vitamin E, acetyl-l-carnitine and α-lipoic acid on new potential biomarkers for Alzheimer's disease in rat model

Alzheimer's disease (AD) is the most common chronic neurodegenerative disorder associated with aging. This study aimed to explore new markers for AD as total homocysteine (tHcy), insulin, insulin like growth factor-1 (IGF-1), interlukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α); to determine the modulatory effects of vitamin E (VE), acetyl-L-carnitine (ALC) and α-lipoic acid (LA) on the investigated parameters and to evaluate the possible therapeutic role of these nutraceutical in AD-induced in rats. Our results revealed that brain acetylcholine esterase (AChE) activity and tHcy levels were significantly increased in AD model. Folic acid, vitamin B(12) levels and Na(+)/K(+) ATPase activity were markedly reduced. Plasma insulin and IGF-1 levels were noticeably decreased but plasma TNF-α and IL-1β concentrations were significantly increased, confirming that abnormal inflammatory response is associated with AD. Treatment by VE, ALC and LA restored the above mentioned parameters to about normal levels comparable to those of donepezil, indicating that tHcy, insulin, IGF-1, IL-1β and TNF-α may be considered as new biomarkers for AD. The study points to the potential restoring effects of VE, ALC and LA in AD model. Our study provides evidence for the importance of dietary supplementation in delaying the progression of age-related neurodegenerative diseases.

MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: A multicenter, randomized, placebo-controlled phase IIb study

Most elderly patients admitted for hip fracture suffer functional decline. Previous studies with MK-0677 in hip fracture patients suggested possible benefits to functional recovery. This is a randomized, double-blind study of 123 elderly hip fracture patients assigned to receive 25 mg/day of MK-0677 ( n = 62) or placebo ( n = 61). Primary outcomes were a rank analysis of change during the study in objective functional performance measurements and insulin-like growth factor-1 (IGF-1) levels in blood. At 24-weeks, the mean stair climbing power increased by 12.5 W in the MK-0677 group (95% confidence interval (CI) = −10.95–35.88; p = 0.292) compared with placebo. Gait speed increased by a 0.7-score difference in the means (95% CI = 0.17–1.28; p = 0.011). There was no improvement in MK-0677 treated patients in several other functional performance measures. The MK-0677 group experienced fewer falls during the study compared to placebo and smaller number of patients who had any falls ( p = 0.096). Levels of IGF-1 in treated patients increased by 51.4 ng/ml (95% CI = 34.42–68.44; p < 0.001) compared to placebo. Trial was terminated early due to a safety signal of congestive heart failure in a limited number of patients. In hip fracture patients treated with 25 mg/day MK-0677, the increase in plasma IGF-1 levels was not paralleled by improvement in most functional performance measures. MK-0677 has an unfavorable safety profile in this patient population.

Growth hormone response to arginine test differentiates between two subgroups of Huntington's disease patients

ObjectiveHuntington's disease (HD) is an autosomal dominant disorder characterised by motor, cognitive and psychiatric disturbances. Several studies have demonstrated that hypothalamic dysfunction is part of the phenotypic spectrum. The aim...

The Estimation of GC Repeats in Promoter P1 of IGF-1 Gene and Their Influence on IGF-1 Plasma Levels in Stable Angina Patients

Increased plasma levels of insulin-like growth factor 1 (IGF-1) are observed in advanced arteriosclerosis, but the reasons for these elevated levels remain unknown. One possibility to explain them is variation in the sequences that control IGF-1 gene expression. The goal of this study was to determine the effect of molecular variants of the IGF-1 P1 promoter on IGF-1 serum levels and to determine the impact of IGF-1 levels on the severity of coronary atherosclerosis. Methods: Blood samples were collected from 101 consecutive patients undergoing routine angiography. Genomic DNA was isolated from the nucleated cells of the blood plasma as described (2). Based on the presence of conformational differences in the DNA strand and on the absence of single nucleotide polymorphisms, the DNA from 38 patients was further analyzed by the “allelic ladder” method to determine the number of repeated GC dinucleotides in the P1 promoter of the IGF-1 gene. In addition, we analyzed serum growth hormone levels in order to examine the effect on systemic IGF-1 synthesis. Results: Conformational differences in the P1 promoter of the IGF-1 gene were observed in 38 out of the 101 patients. Several genotypes, depending on the number of GC repeats, were observed (11/19,17/19,18/19,18/21,19/19,19/20,19/21). Interestingly, a family history of coronary artery disease was seen less often among individuals heterozygous for the GC repeats. A lower IGF-1 levels were seen in non-variant carriers (homozygous genotypes for 19 or 21 repeats of GC, or heterozygous genotype 19/21) when compared to the variant group (other heterozygous genotypes then 19/21) (181.6 ± 47.9 ng/mL vs. 227.7 ± 73.7, p = 0.026). A correlation between IGF-1, IGF-binding protein number 3, and growth hormone levels (p = ns) was not observed, and there were no significant differences in the growth hormone levels in the studied group of patients (p = ns).

Plasma IGF-1 is negatively correlated with body mass in a comparison of 36 mammalian species

In mammals, insulin-like growth factor-1 (IGF-1) is positively correlated with adult body mass, in comparisons made within a given species. In mice, IGF-1 deficiency is associated with dwarfism, whereas IGF-1 overproduction in transgenic animals causes gigantism. Surprisingly, the opposite is true in an inter-species context. We collected published plasma total IGF-1 data for adults of 36 mammalian species and analyzed it with respect to body mass. In contrast to the intra-species observation, this analysis revealed a significant negative correlation of plasma IGF-1 with body mass. Interestingly, IGF-1 is negatively correlated with longevity, and suppression of IGF-1 signalling in worms, flies and mice increases lifespan. Smaller mouse strains, for example, tend to have lower plasma IGF-1 levels and to be longer-lived. However, when plasma total IGF-1 was analyzed relative to the maximum lifespans of the 36 species examined here, there was no statistically significant correlation. Low plasma IGF-1 levels in larger mammalian species may be physiologically significant, considering the roles of this hormone in metabolism, tissue regeneration, and cancer incidence.

Effects of castration on insulin levels and glucose tolerance in the mouse differ from those in man

Plasma insulin concentration is increased in prostate cancer patients during androgen deprivation therapy (ADT) and hyperinsulinemia has been associated with aggressive prostate cancer behavior. To investigate the possible role of castration-induced hyperinsulinemia as a mechanism that may attenuate the beneficial effects of ADT in patients with prostate cancer, a murine model would be useful. We therefore investigated long-term metabolic effects of castration in several mouse models. We studied the long-term influence of castration on energy intake, body weight, glucose tolerance, plasma-insulin, plasma insulin-like growth factor-1 (IGF-1), plasma adiponectin, and plasma leptin in C57BL/6, Swiss nu/nu, and CB17 scid mice receiving various diets. In each case, mice were randomized to have either bilateral orchiectomy or a sham operation. Energy intake, body weight, blood glucose levels in glucose tolerance test, plasma insulin, plasma IGF-1, and plasma leptin level in all had a trend to be decreased in castrated as compared to sham operated mice. Plasma adiponectin level was increased in the castrated mice. The effects of castration on glucose, insulin, and related markers in several mouse models studied does not coincide with clinical observations; further studies in this area will require clinical research and/or the use of alternate models such as the dog.