Highlights
•
Vitamin D dosage ≤1000 IU/day significantly increased IGF-1 levels. •
Intervention duration ≤12 weeks significantly increased IGF-1 levels. •
In cohort study, under 60 years subjects with a higher dietary vitamin D intake had significantly higher IGF-1 levels.
Abstract
Background
Inconsistencies exist with regard to influence of vitamin D supplementation on IGF-1 levels. The inconsistencies could be attributed to several factors, such as dosage and duration of intervention, among others. To address these inconsistencies, this study was conducted to determine the impact of vitamin D supplementation on IGF-1 levels through a systematic review and meta-analysis of randomized controlled trials (RCTs).
Methods
A comprehensive systematic search was carried out in PubMed/MEDLINE, Web of Science, SCOPUS and Embase for RCTs that investigated the impact of vitamin D intake on circulating IGF-1 levels from inception until June 2019. Weighted mean difference (WMD) with the 95 % CI were applied for estimating combined effect size. Subgroup analysis was performed to specify the source of heterogeneity among studies.
Results
Pooled results from eight studies demonstrated an overall non-significant increase in IGF-1 following vitamin D supplementation (WMD: 4 ng/ml, 95 % CI: −4 to 11). However, a significant degree of heterogeneity among studies was observed (I2 = 66 %). The subgroup analyses showed that vitamin D dosage of ≤1000 IU/day (WMD: 10 ng/ml) significantly increased IGF-1 compared to the vitamin D dosage of <1000 IU/day (WMD: −1 ng/ml). Moreover, intervention duration ≤12 weeks (WMD: 11 ng/ml) significantly increased IGF-1 compared to intervention duration <12 weeks (WMD: −3 ng/ml). In the epidemiological cohort study, participants under 60 years of age with a higher dietary vitamin D intake had significantly higher IGF-1 levels when compared to those with lower dietary vitamin D intake in second categories.
Conclusion
The main results indicate a non-significant increase in IGF-1 following vitamin D supplementation. Additionally, vitamin D dosages of <1000 IU/day and intervention durations of <12 weeks significantly raised IGF-1 levels.
Introduction
Insulin-like growth factor 1 (IGF-1) is a main regulator of various biological activities related to growth hormone (GH). Thus, IGF-1 signaling pathway has been unequivocally linked to cell proliferation, differentiation and apoptosis, as well as the aging process. Disruption to the IGF-1/GH pathway has been shown to improve the longevity and reduce the occurrence of age-related diseases in animal models (Sriram Gubbi et al., 2018). Knockout of GH receptor in mice, which resulted in IGF-1 deficiency, has also been known to result in prolonged longevity (Coschigano et al., 2000). Likewise, in humans, genetic alterations in IGF1R, which dampen the IGF-1 signaling, have been found to confer an increased longevity (Milman et al., 2014; Suh et al., 2008; Tazearslan et al., 2011). In addition, low levels of circulating IGF1 has been demonstrated to be associated with a better cognitive function in elderly women (Perice et al., 2016). Besides aging processes, IGF1 levels have also been implicated with musculoskeletal disorders, cardiovascular diseases, metabolic syndromes and cancers (Colao, 2008; Hyppönen et al., 2008; Locatelli and Bianchi, 2014; Shanmugalingam et al., 2016). These observations suggest that a proper regulation of IGF-1 level is crucial for health.
Several studies have suggested that production of IGF-1 in the liver could be stimulated by vitamin D (Ameri et al., 2013b). Thus, it has been proposed that supplementation of vitamin D could influence IGF-1 levels (Locatelli and Bianchi, 2014). In mice models, knockout of vitamin D receptor (VDR) has been found to reduce the IGF-1 concentrations (Song et al., 2003). In humans, a few observational studies have demonstrated a correlation between serum concentrations of IGF-1 with vitamin D levels (Forouhi et al., 2008; Hyppönen et al., 2008). Nonetheless, inconsistencies exist with regard to influence of vitamin D supplementation on IGF-1 levels. The inconsistencies could be attributed to several factors, such as dosage and duration of intervention, among others. For example, while Ameri et al. (Ameri et al., 2013a) reported that supplementation of 5000 or 7000 IU/week of vitamin D for a duration of 12 weeks increased circulating IGF-1 levels in adults, Trummer et al. (Trummer et al., 2017) showed that supplementation of 2800 IU/day of vitamin D for eight weeks did not have a significant effect on IGF-1 concentrations. To address these inconsistencies, this study was conducted to determine the impact of vitamin D supplementation on IGF-1 levels through a systematic review and meta-analysis of randomized controlled trials (RCTs).
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Section snippets
Search strategy
This systematic review and meta-analysis was performed based on the PRISMA [Preferred Reporting Items for Systematic Review and Meta-analysis] protocols (Moher et al., 2015). A comprehensive systematic search was carried out in PubMed/MEDLINE, Web of Science, SCOPUS and Embase by two independent reviewers (JR and HKV) from inception until June 2019 without using time or language restrictions. We considered randomized controlled trials (RCTs) that measured the effects of vitamin D
Results
Primary systematic search identified 850 studies from PubMed/MEDLINE, Web of Science, Scopus, and Embase (Supplementary Fig. S1). Duplicated studies were removed and 615 studies remained. During the primary screening, which was based on review of study titles and abstracts,
570 studies were excluded and 45 studies remained for full text extraction. During the secondary screening, 40 studies were excluded for the following reasons: 1) non-RCT design, 2) and studies included no data of interest.
Discussion
IGF-1 is an insulin related peptide hormone which contributes to the stimulation of the anabolic and mitotic activity of growth hormone (Laron, 2001). Raised IGF-1 levels have been associated with certain adverse health outcomes, such as, increased metastatic potential of various human cancers, through increased cell proliferation and down regulation of apoptosis (Christopoulos et al., 2015; Kaaks, 2004; Setya et al., 2004). Similarly, congenital deficiencies of IGF-1 have been associated with
Funding
The authors sincerely thank Shahid Beheshti University of Medical Sciences for all moral and material supports. This study was supported by grants from the Student Research Committee, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran (Grant’s ID: 1398/3995).
Declaration of Competing Interest
All the authors declared that they have no conflicts of interest.
References (50)
et al.
A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response
Cell
(2013) M.E. Levine et al.
Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population
Cell Metab.
(2014) R. Pérez-Fernandez et al.
Vitamin D receptor gene expression in human pituitary gland
Life Sci.
(1996) O. Shevah et al.
Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report
Growth Horm. Igf Res.
(2007) Y. Song et al.
Vitamin D receptor (VDR) knockout mice reveal VDR-independent regulation of intestinal calcium absorption and ECaC2 and calbindin D9k mRNA
J. Nutr.
(2003) S.P. Xie et al.
Vitamin D analogues suppress IGF-I signalling and promote apoptosis in breast cancer cells
Eur. J. Cancer (Oxford, England: 1990)
(1999) S. Zúñiga et al.
Vitamin D and the vitamin D receptor in liver pathophysiology
Clin. Res. Hepatol. Gastroenterol.
(2011) N.M. Al-Daghri et al.
IGF and IGFBP as an index for discrimination between vitamin D supplementation responders and nonresponders in overweight Saudi subjects
Medicine (Baltimore)
(2018) N.S. Alharbi et al.
Impact of information technology–based interventions for type 2 diabetes mellitus on glycemic control: a systematic review and meta-analysis
J. Med. Internet Res.
(2016) P. Ameri et al.
Vitamin D increases circulating IGF1 in adults: potential implication for the treatment of GH deficiency
Eur. J. Endocrinol.
(2013) P. Ameri et al.
Interactions between vitamin D and IGF‐I: from physiology to clinical practice
Clin. Endocrinol.
(2013) F.J. Barrat et al.
In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines
J. Exp. Med.
(2002) F. Bogazzi et al.
Vitamin D status may contribute to serum insulin-like growth factor I concentrations in healthy subjects
J. Endocrinol. Invest.
(2011) M. Borenstein et al.
References
(2009) P.F. Christopoulos et al.
The role of the insulin-like growth factor-1 system in breast cancer
Mol. Cancer
(2015) A. Colao
The GH-IGF-I axis and the cardiovascular system: clinical implications
Clin. Endocrinol.
(2008) K.T. Coschigano et al.
Assessment of growth parameters and life span of GHR/BP gene-disrupted mice
Endocrinology
(2000) K.D. Crew et al.
Randomized Double-blind Placebo-Controlled Biomarker Modulation Study of Vitamin D in Premenopausal Women at High Risk for Breast Cancer (SWOG S0812). Cancer prevention Research (Philadelphia, Pa.)
(2019) C. Del Puerto et al.
Vitamin D axis and its role in skin carcinogenesis: a comprehensive review
Appl. Cancer Res.
(2016) K.N. Drake et al.
Protein intake is associated with plasma insulin-like growth factor (IGF) 1 in postmenopausal women but not in premenopausal women
FASEB J.
(2016) S. Esposito et al.
Vitamin D and growth hormone in children: a review of the current scientific knowledge
J. Transl. Med.
(2019) N.G. Forouhi et al.
Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990–2000
Diabetes
(2008) E. Giovannucci et al.
Nutritional predictors of insulin-like growth factor I and their relationships to cancer in men
Cancer Epidemiol. Biomark. Prev.
(2003) J. Gomez et al.
Relationship between 25-(OH) D3, the IGF-I system, leptin, anthropometric and body composition variables in a healthy, randomly selected population
Horm. Metab. Res.
(2004) J. Gubatan et al.
Vitamin D in inflammatory bowel disease: more than just a supplement
Curr. Opin. Gastroenterol.
(2018)View full text
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