Systemic IGF-1 Levels Research Articles

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

The Use of Bovine Colostrum in Sport and Exercise.

There has been a great deal of interest in bovine colostrum within sports nutrition over the last 25 years. Studies have investigated the effects on body composition, physical performance, recovery, gut damage and permeability, immune function, and illness risk. This narrative review considers available evidence in each of these areas. Although some studies have shown protection against performance decrements caused by periods of intensified training, there is limited evidence for effects on body composition and physical performance. There is stronger evidence for benefit on gut permeability and damage markers and on immune function and illness risk, especially during periods of intensified training. The balance of available evidence for gut permeability and illness risk is positive, but further research is required to fully determine all mechanisms responsible for these effects. Early suggestions that supplementation with bovine colostrum products could increase systemic IGF-1 levels are not supported by the balance of available evidence examining a range of doses over both short- and long-term periods. Nevertheless, dose–response studies would be valuable for determining the minimum efficacious dose, although this is complicated by variability in bioactivity between products, making any dose–response findings applicable only to the specific products used in such studies.

Major depressive disorder and accelerated aging from a peripheral IGF-1 overexpression perspective

Over the past decades, data on the relationship between major depressive disorder (MDD) and accelerated aging processes were accumulated. Specific cognitive impairments, alterations in associated brain areas, a significant decrease in telomere length and expression of telomerase reverse transcriptase, oxidative and nitrosative stress, neuroinflammatory machinery, deficiency of growth factors (BDNF, IGF-1) in the brain of MDD patients resemble those that occur in aging. A decrease in the brain IGF-1 expression has been proven to disrupt mechanisms of neuroplasticity and promote cerebral inflammatory pathways, leading to morphological deterioration in the brain areas responsible for emotional and cognitive processing. From this point of view, the increase in systemic IGF-1 levels observed in most patients with MDD can be considered as a compensatory mechanism of enhancing the hypothalamic-pituitary-somatotropic axis activity in response to insufficient cerebral IGF-1 concentrations. Nevertheless, this compensatory mechanism may have a pathogenic value, improving the aging process in this patients population. This point of view has been confirmed by the evidence on the IGF-1-induced stimulation of the intracellular kinase-dependent pathways (Rho/ROCK kinase) involved in proliferation and telomere attrition in various organs, which can be considered as the underlying mechanism of aging. In line with these data, there is evidence that decreased IGF-1 signaling extends longevity in a wide range of biological species, including humans. Therefore, we hypothesized that systemic IGF-1 overexpression could be one of the pathological factors of accelerating aging in MDD patients. In this article, we analyzed data supporting this hypothesis.

Abstract 237: Increased NSCLC tumorigenesis in mice fed a high fat diet is associated with increased plasma IGF-1 levels and PD-1 expression in CD4+ tumor-infiltrating lymphocytes

Abstract Lung cancer is the leading cause of cancer-related mortality worldwide, and 85% of lung cancer cases are associated with tobacco use. Activating mutations in K-ras have been identified in ~25% of tobacco-associated lung adenocarcinomas. Using mouse models of K-ras-driven lung tumorigenesis, we previously demonstrated that deletion of the IGF-1 gene or reduction of systemic IGF-1 levels using the antidiabetic drug metformin markedly reduced tumor burden. Preclinical and clinical studies suggest that diet composition is the best predictor of IGF-1 levels. Therefore, we hypothesized that diets high in fat or carbohydrate would promote lung tumorigenesis by increasing systemic IGF-1 levels. To assess the effect of diet on systemic IGF-1 levels, 9 week old C57Bl/6J and A/J mice were fed standard cereal, high-carbohydrate, or high-fat (HFD) diets for 12 weeks. Compared to cereal-fed control mice, plasma IGF-1 and insulin levels were increased in both strains of mice fed a HFD, but not in mice fed a diet high in carbohydrate. This was not due to obesity, as only the C57Bl/6J mice fed a HFD had an increase in body weight. We then investigated the effect of HFD on lung tumorigenesis using two mouse models. In the first, C57Bl/6LA2 mice, which harbor a mutation in K-ras, were fed either cereal diet or HFD for 10 weeks following weaning. Lung tumor burden in the mice fed HFD was increased 2.7-fold compared to littermates fed cereal diet. In the second model, the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK) was given by intraperitoneal injection to A/J mice beginning at 6 weeks of age. This carcinogen causes lung tumor development by inducing K-ras mutations. After 3 weekly injections of NNK, the mice were randomized to cereal diet or HFD for ten weeks. Mice fed HFD had a 60% increase in lung tumor burden. In both models, there was no relationship between the weight of the mice and lung tumor burden. Immunohistochemical analysis of the proliferation marker Ki-67 showed no significant difference in expression between tumors from mice fed a HFD or a cereal diet. Therefore, we evaluated tumor-infiltrating lymphocytes (TIL) from mice on both diets. Interestingly, both immunohistochemical analysis and flow cytometry demonstrated a 50% reduction in the number of TIL in mice fed HFD compared to mice fed a cereal diet. Additionally, HFD was associated with a 2-fold increase in PD-1+ CD4+ TIL, and the PD-1 staining intensity in these lymphocytes was significantly greater than in mice fed a cereal diet. These results may suggest that a high fat diet increases lung tumorigenesis by increasing systemic IGF-1 levels and by creating an immune-permissive tumor microenvironment. Citation Format: Regan M. Memmott, Krista Pearman, Joell Gills, Tony Tullot, Valerie Wong, Benjamin Singer, Kristin Lastwika, Franco D'Alessio, Phillip Dennis, Jeffrey William Norris. Increased NSCLC tumorigenesis in mice fed a high fat diet is associated with increased plasma IGF-1 levels and PD-1 expression in CD4+ tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 237. doi:10.1158/1538-7445.AM2017-237

Abstract 4330: A high-fat diet promotes tumorigenesis in two mouse models of K-ras-driven lung cancer

Abstract Lung cancer is the leading cause of cancer-related mortality worldwide, and 85% of lung cancer cases are associated with tobacco use. Within this group, activating mutations in K-ras have been identified in ∼25% of lung adenocarcinomas. Using a mouse model of k-ras-driven lung tumorigenesis, we previously demonstrated that deletion of the IGF-1 gene or reduction of systemic IGF-1 levels using the antidiabetic drug metformin markedly reduced tumor burden. Since preclinical and clinical studies suggest that diet composition is the best predictor of IGF-1 levels, we hypothesized that diets high in fat or carbohydrate would promote lung tumorigenesis by increasing systemic IGF-1 levels. To assess the effect of diet on systemic IGF-1 levels, 9 week old C57Bl/6J and A/J mice were fed standard cereal, high-carbohydrate, or high-fat (HFD) diets for 12 weeks. At the conclusion of the study plasma, liver, and lung samples were collected. Compared to the cereal-fed control mice, IGF-1 and insulin levels were increased in both strains of mice only with HFD. Average body weight only increased for the C57Bl/6J group that was fed HFD. We investigated the effect of HFD on lung tumorigenesis using two mouse models of lung cancer. In the first, C57Bl/6LA2 mice, which are genetically modified with a K-ras mutation present in human smokers, were fed either cereal diet or HFD for 10 weeks following weaning. Lung tumor burden in the mice fed HFD was increased 2.7-fold compared to littermates fed cereal diet. In the second model, the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK) was given by IP injection to A/J mice beginning at 6 weeks of age. This carcinogen causes lung tumor formation by inducing K-ras mutations. Following once weekly injections of NNK for 3 weeks, the mice were randomized to cereal diet or HFD. 10 weeks later, mice fed HFD were found to have a 60% increase in lung tumor burden. In both studies, there was no relationship between the final body weight of the mice and tumor burden. These studies show that HFD promotes lung tumor growth resulting from a mutation commonly observed in smokers. Therefore, dietary modification may slow the progression of tumorigenesis resulting from smoking-related genetic changes through IGF-1. Chemopreventative drugs, like metformin, may also have greater efficacy in a HFD model due to the increased insulin and IGF-1 associated with this model. Finally, understanding the molecular mechanisms by which HFD promotes tumor growth may help to identify new targets for cancer prevention. Citation Format: Jeffrey Norris, Krista Pearman, Regan Memmott, Kristin Lastwika, Joell Gills, Phillip Dennis. A high-fat diet promotes tumorigenesis in two mouse models of K-ras-driven lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4330.

Abstract B23: A high-fat diet, but not obesity, promotes tumorigenesis in two mouse models of k-ras-driven lung cancer

Abstract Lung cancer is the leading cause of cancer-related mortality worldwide, and 85% of lung cancers are associated with tobacco use. Activating mutations in K-ras have been identified in ~25% of lung adenocarcinomas and are found predominantly in smokers. We previously demonstrated that reducing systemic IGF-1 levels, by treatment with the anti-diabetic drug metformin or by liver-specific ablation of the IGF-1 gene, decreases tumorigenesis in mouse models of k-ras-driven lung cancer. Since preclinical and clinical studies suggest that diet composition is the best predictor of systemic IGF-1 levels, we hypothesized that diets high in fat or carbohydrates might increase systemic IGF-1 levels and promote lung tumorigenesis. To assess the effect of diet, C57Bl/6J and A/J mice were fed standard cereal diet, high-carbohydrate diet, or high-fat diet (HFD) for 12 weeks starting at nine weeks of age, after which plasma and tissue samples were collected. The HFD increased levels of IGF-1 and insulin in both strains of mice, and increased the weights of C57BL/6J, but not A/J mice. In contrast, the high-carbohydrate diet did not increase the weights or circulating levels of IGF-1/insulin in either strain of mice. Since insulin and IGF-I were induced more with HFD, we investigated the impact of HFD on lung tumorigenesis using two mouse models of Kras-mutant lung cancer. In the first, genetically engineered C57BL/6LA2 mice were fed a cereal diet or HFD for 10 weeks starting at weaning. Lung tumor multiplicity and tumor burden increased 2.7-fold compared to littermates fed a cereal diet. In the second model, lung tumorigenesis was initiated in 6 week old A/J mice by three weekly IP injections of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) that invariably causes Kras mutations. . One week after the last NNK injection, mice were randomized to cereal or HFD for 10 weeks. Mice on HFD had a 40% increase in lung tumor multiplicity and a 60% increase in lung tumor burden. These studies show that a HFD promotes lung tumor growth caused by a mutation commonly observed in smokers. Conversely, the results imply that dietary modification could slow the progression of tumorigensis due to smoking related genetic changes in lung epithelium. Further, chemopreventative drugs, such as metformin, may have enhanced efficacy in a HFD model due to the associated increases in levels of insulin and/or IGF-I. Finally, understanding the long term effects of HFD could identify new targets for cancer prevention. Citation Format: Jeffrey W. Norris, Regan M. Memmott, Kristin Lastwika, Phillip Dennis. A high-fat diet, but not obesity, promotes tumorigenesis in two mouse models of k-ras-driven lung cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B23.

Effects of growth hormone therapeutic supplementation on hematopoietic stem/progenitor cells in children with growth hormone deficiency: focus on proliferation and differentiation capabilities.

We investigated the direct effects of growth hormone (GH) replacement therapy (GH-RT) on hematopoiesis in children with GH deficiency (GHD) with the special emphasis on proliferation and cell cycle regulation. Peripheral blood (PB) was collected from sixty control individuals and forty GHD children before GH-RT and in 3rd and 6th month of GH-RT to measure hematological parameters and isolate CD34+-enriched hematopoietic progenitor cells (HPCs). Selected parameters of PB were analyzed by hematological analyzer. Moreover, collected HPCs were used to analyze GH receptor (GHR) and IGF1 expression, clonogenicity, and cell cycle activity. Finally, global gene expression profile of collected HPCs was analyzed using genome-wide RNA microarrays. GHD resulted in a decrease in several hematological parameters related to RBCs and significantly diminished clonogenicity of erythroid progenies. In contrast, GH-RT stimulated increases in clonogenic growth of erythroid lineage and RBC counts as well as significant up-regulation of cell cycle-propagating genes, including MAP2K1, cyclins D1/E1, PCNA, and IGF1. Likewise, GH-RT significantly modified GHR expression in isolated HPCs and augmented systemic IGF1 levels. Global gene expression analysis revealed significantly higher expression of genes associated with cell cycle, proliferation, and differentiation in HPCs from GH-treated subjects. (i) GH-RT significantly augments cell cycle progression in HPCs and increases clonogenicity of erythroid progenitors; (ii) GHR expression in HPCs is modulated by GH status; (iii) molecular mechanisms by which GH influences hematopoiesis might provide a basis for designing therapeutic interventions for hematological complications related to GHD.Electronic supplementary materialThe online version of this article (doi:10.1007/s12020-015-0591-0) contains supplementary material, which is available to authorized users.

Direct stimulation of bone mass by increased GH signalling in the osteoblasts of Socs2-/- mice.

The suppressor of cytokine signalling (Socs2 −/−)-knockout mouse is characterised by an overgrowth phenotype due to enhanced GH signalling. The objective of this study was to define the Socs2 −/− bone phenotype and determine whether GH promotes bone mass via IGF1-dependent mechanisms. Despite no elevation in systemic IGF1 levels, increased body weight in 4-week-old Socs2 −/− mice following GH treatment was associated with increased cortical bone area (Ct.Ar) (P<0.01). Furthermore, detailed bone analysis of male and female juvenile and adult Socs2 −/− mice revealed an altered cortical and trabecular phenotype consistent with the known anabolic effects of GH. Indeed, male Socs2 −/− mice had increased Ct.Ar (P<0.05) and thickness associated with increased strength. Despite this, there was no elevation in hepatic Igf1 expression, suggesting that the anabolic bone phenotype was the result of increased local GH action. Mechanistic studies showed that in osteoblasts and bone of Socs2 −/− mice, STAT5 phosphorylation was significantly increased in response to GH. Conversely, overexpression of SOCS2 decreased GH-induced STAT5 signalling. Although an increase in Igf1 expression was observed in Socs2 −/− osteoblasts following GH, it was not evident in vivo. Igf1 expression levels were not elevated in response to GH in 4-week-old mice and no alterations in expression was observed in bone samples of 6-week-old Socs2 −/− mice. These studies emphasise the critical role of SOCS2 in controlling the local GH anabolic bone effects. We provide compelling evidence implicating SOCS2 in the regulation of GH osteoblast signalling and ultimately bone accrual, which maybe via mechanisms that are independent of IGF1 production in vivo.

Heart Smart Insulin-Like Growth Factor 1

See related article, pp 680–693 The prevalence of obesity, metabolic syndrome, and type 2 diabetes mellitus, and the associated cardiac pathologies are rising to alarming levels. Conventional medical therapies for the prevention and treatment of cardiomyopathy are less effective in patients with these metabolic disorders, and this is attributed, at least in part, to a limited understanding of the cellular and genetic mechanisms responsible for the pathology in the heart. The cause(s) underlying the development of obesity and metabolic syndrome have been attributed to several factors including, but not limited to, consumption of a high-fat diet and are often associated with myocardial contractile and metabolic dysfunction.1 The detrimental effects of high-fat diets on the heart are likely to be multifactorial and include lipotoxicity, abnormal fatty acid metabolism, endothelial dysfunction, impaired calcium handling, mitochondrial dysfunction, and disruption of the insulin signaling pathway. Recent evidence also suggests that a high-fat diet induces epigenetic defects in the heart,2 which could potentially result in an increased risk of cardiac pathologies in offspring. A better understanding of the mechanisms underlying the increased propensity for high-fat diets to induce cardiac dysfunction is necessary to develop treatment strategies. Insulin-like growth factor-1 (IGF-1) plays a role in regulating cell proliferation, differentiation, survival, and metabolism and is produced in many tissues, including the heart. Reduced IGF-1 levels are associated with obesity, cardiovascular disease, atherosclerosis, and diabetes mellitus, whereas elevated IGF-1 has been associated with longevity in humans.3 …

P4-02-02: The Natural Fetal Estrogen Estetrol (E4), Causes Anti-Estrogenic Effects in Women with Endocrine-Responsive Positive Early Breast Cancer.

Abstract Background: Estetrol (E4) is a natural fetal estrogen which exerts estrogenic effects on reproductive organs and on the bone, and effectively reduces menopausal smyptoms. In contrast to other estrogens, however, E4 has estrogen-antagonistic effects on breast cancer cell lines in vitro and in the rat DMBA model, which would make it a suitable Hormone Replacement Therapy (HRT) in breast cancer patients, particularly in women who are being treated with aromatase inhibitors. Patients and Methods: We have investigated the effect of 14 days preoperative treatment with 20 mg E4 per day on tumor proliferation, apoptosis, ER-receptors, PgR receptor and several endocrine parameters in a prospective, randomised, double-blind, placebo-controlled, neo-adjuvant study in 15 pre- and 14 postmenopausal women with estrogen-receptor positive early breast cancer. Results: Estetrol induced a significant increase of SHBG, a significant decrease of FSH in postmenopausal women and no increase of gonadotrophins in premenopausal women. Estetrol had no effect on Ki67 expression and on apoptosis-related Bax and Bcl-2, but the apoptosis index in tumor tissue increased significantly. Systemic IGF-1 levels decreased significantly. Surprisingly the intratumoral epithelial ER-alpha expression decreased significantly, whereas the ER-beta expression showed a trend to increase. Conclusion: Our data suggest that E4 may be suitable and safe for HRT in women with spontaneous or induced menopausal symptoms, since apoptosis increases, IGF-1 decreases and no unfavourable effects are observed on Ki67, Bax and Bcl-2. The decrease of ER-alpha and the increase of ER-beta suggest a mechanism of action, explaining why the natural fetal estrogen E4 has estrogen-antagonistic effects on breast cancer tissue. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-02.

Antiestrogenic effects of the natural fetal estrogen estetrol (E4) in women with estrogen-receptor-positive early breast cancer.

280 Background: Estetrol (E4) is a fetal estrogen which exerts estrogenic effects on vaginal epithelium, hot flushes and bone, but has estrogen-antagonistic effects on breast cancer cell lines in vitro and in the rat DMBA model. Therefore E4 may be suitable for Hormone Replacement Therapy (HRT) in women with breast cancer including women treated with aromatase inhibitors. Methods: We have investigated the effect of 14 days pre-operative treatment with 20 mg E4 per day on proliferation, apoptosis, ER-receptors and sex steroid levels in a prospective, randomised, double-blind, placebo-controlled, neo-adjuvant study in 15 pre- and 15 postmenopausal women with estrogen-receptor positive early breast cancer. Results: Estetrol induced a significant increase of SHBG, a significant decrease of FSH in postmenopausal women and no increase of gonadotrophins in premenopausal women. Estetrol had no effect on Ki67 expression and on apoptosis-related Bax and Bcl-2, but the apoptosis index in tumor tissue increased significantly. Systemic IGF-1 levels decreased significantly. Surprisingly the intratumoral epithelial ER-alpha expression decreased significantly, whereas the ER-beta expression showed a trend to increase. Conclusions: This data show that E4 has estrogenic endocrine effects. The data support the hypothesis that E4, may be suitable and safe for HRT in women with spontaneous or induced menopausal symptoms, since apoptosis increases, IGF-1 decreases and no unfavourable effects are observed on Ki67, Bax and Bcl-2. The decrease of ER-alpha and the increase of ER-beta suggest a mechanism of action, explaining why the natural fetal estrogen E4 has estrogen-antagonistic effects on breast cancer tissue.

Somatostatin Receptors in Non-Neuroendocrine Malignancies: The Potential Role of Somatostatin Analogs in Solid Tumors

Somatostatin receptors (sstrs) are G-protein-coupled receptors that mediate various physiological effects when activated by the neuropeptide somatostatin or its synthetic analogs. In addition to the well-documented antisecretory effects of sstr(2)-preferential somatostatin analogs octreotide and lanreotide, ligand binding to sstr initiates an inhibitory action on tumor growth. This effect may result from both indirect actions (suppression of growth factors and growth-promoting hormones [e.g., GH/IGF-1 axis] and inhibition of angiogenesis) and direct actions (activation of antigrowth activities [e.g., apoptosis]). As solid tumor cells express multiple sstrs, there is a rationale to evaluate the potential antitumor effects of pasireotide (SOM230), a multireceptor-targeted somatostatin analog with high binding affinity for sstr(1-3) and sstr(5). Pasireotide reduces systemic IGF-1 levels more potently than currently available somatostatin analogs and has been well tolerated in clinical trials.

Abstract B36: Induction of IL-6 by breast cancer chemotherapy mediates loss of fat-free lean body mass in tumor-free mice by decreasing systemic IGF-1

Abstract Aims: Cancer patients treated with cytotoxic chemotherapy often experience changes in body composition that occur independent of changes in food intake or physical activity. These changes may impact physical functioning and quality of life. Interleukin-6 (IL-6), an inflammatory cytokine that is up-regulated in cancer patients treated with cytotoxic chemotherapies, plays an important role in the regulation of body composition. The purpose of this study was to determine the role of IL-6 in the regulation of systemic insulin-like growth factor I (IGF-1) levels and treatment induced changes in body composition using a pre-clinical model. Methods: Changes in body composition and systemic IGF-1 levels were assessed in IL-6−/− mice and their wild type counterparts before and after 4 cycles of cytoxan-adriamycin-5-fluorouracil (CAF) a common adjuvant breast cancer chemotherapy regimen. Daily food intake and physical activity were monitored throughout treatment. Results: We found that CAF decreased systemic IGF-1 production in an IL-6-dependent manner. Similar to cancer patients, CAF treatment in WT mice led to a reduction in fat free LBM and bone mass but not fat mass (FM). These changes occurred independently of food intake and level of physical activity. In contrast, IL-6 deficient mice were protected from the treatment induced loss of fat free LBM but not bone mass. Conclusions: These preclinical findings implicate IL-6 mediated reduction in systemic IGF-1 as a possible mechanism underlying the loss of fat free LBM in cancer patients undergoing cytotoxic chemotherapy. Based upon these pre-clinical findings, examination of these relationships in the clinical setting is warranted. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B36

Comment on: Klöting et al. (2008) Autocrine IGF-1 Action in Adipocytes Controls Systemic IGF-1 Concentrations and Growth: Diabetes 57:2074–2082

The August 2008 issue of Diabetes contained a very interesting study by Kloting et al. (1) claiming that autocrine action of IGF-1 in adipocytes controls systemic IGF-1 levels. The animals generated by these investigators are of great potential importance, and the data are novel and intriguing. However, we feel that the interpretation of these findings offered by the authors ignores an important …

Plasma IGF-1 levels and cognitive dysfunction in children with obstructive sleep apnea

Background Pediatric OSA is associated with substantial morbidity in cognitive function. However, for any given OSA severity level, altered cognitive performance may or may not be present. Since IGF-1 is neuroprotective, we hypothesized that higher systemic IGF-1 levels may identify children at lower susceptibility for cognitive morbidity. Methods Consecutive habitually snoring and non-snoring children ages 5–7 years were recruited from the community, and underwent overnight polysomnography, and neurocognitive testing and a blood draw the next morning. Snoring children were divided into OSA or no OSA, and OSA children were further subdivided into those with ⩾2 abnormal cognitive subtests and into those with normal cognitive scores. Plasma levels of IGF-1 were also measured using ELISA. Results Among snoring children without OSA, circulating IGF-1 was 910 ± 110 pg/mL compared with 1070 ± 240 pg/mL in those with OSA ( p < 0.01). However, IGF-1 was 540 ± 70 pg/mL in children with OSA and cognitive deficits, compared to 1370 ± 170 μg/L in children with OSA and normal cognitive scores ( p < 0.001). Conclusions IGF-1 levels are higher in children with OSA, particularly in those who do not manifest neurocognitive deficits, suggesting that the magnitude of the IGF-1 response elicited by OSA may play a significant protective role against the neurocognitive dysfunction associated with OSA.