Abstract
Background:
Considerable evidence suggests that oxidative stress affects diabetes mellitus (DM) and contributes to its complications. Vitamin D has been shown to possess antioxidant properties. The aim of this study was to determine the association between serum levels of calcifediol (25-OH-D), an indicator of vitamin D status, and lipid profiles with oxidative stress in patients with type 2 diabetes mellitus (T2DM).
Methods:
In this case-control study, 57 T2DM patients with low vitamin D status (< 30 ng/mL) and 48 T2DM patients with normal vitamin D status (> 30 ng/mL) were enrolled. Fasting concentrations of 25-OH-D, calcium, phosphorus, parathyroid hormone (PTH), lipid profiles, fasting blood sugar (FBS), glycosylated hemoglobin (HbA1c), F2-isoprostane, and oxidized-low-density lipoprotein (ox-LDL) were measured.
Results:
The mean fasting serum concentrations of 25-OH-D, calcium, and phosphorus in patients with low vitamin D status were significantly lower than in controls (p < 0.001). The mean concentrations of ox-LDL, F2-isoprostane, total cholesterol, and LDL were significantly higher in patients with low vitamin D status than in controls. There was a negative correlation between vitamin D levels and F2-isoprostane (r = 0.647and P = 0.0001), LDL (r = -0.218 and P = 0.030), and ox-LDL (r = -0.637 and P = 0.0001).
Conclusion:
The results of present study indicated that serum concentrations of 25-OH-D were inversely correlated with F2-isoprostane, LDL, and ox-LDL. Therefore, vitamin D may have a beneficial effect on the control of lipid profiles and oxidative stress in T2DM patients.
Key Words: Diabetes mellitus type 2, F2-isoprostane, Oxidative stress, Ox-LDL, Vitamin D
Introduction
The increasing prevalence of diabetes mellitus (DM) is considered a global public health concern. According to the World Health Organization, the global prevalence of type 2 DM (T2DM) will increase from 171 million people in 2000 to 366 million in 2030 (1). Type 2 DM is more prevalent than type 1 DM, and is responsible for 90% of DM cases (2). Genetic and environmental factors play a pivotal role in the etiology and pathogenesis of DM (3). Low Vitamin D status, as an environmental risk factor, is associated with many non-skeletal diseases, including DM (4), hypertension (5), pemphigus (6), cardiovascular disease (7), and autoimmune diseases (8). Vitamin D deficiency is associated with decreased insulin synthesis and secretion (4). Many studies have shown that diabetic patients are likely to be vitamin D deficient, suggesting that vitamin D participates in the development of diabetes (9, 10). In addition, in diabetic patients with vitamin D deficiencies, serum levels of total cholesterol, triglycerides (TGs), and LDL were greater and HDL was less than in patients with vitamin D sufficiency (11).
The imbalance between reactive oxygen species (ROS) generation and the antioxidant system results in oxidative stress and cell damage, which is involved in the pathogenesis of many diseases (12). Type 2 DM is associated with excess generation of highly reactive free radicals, largely due to hyperglycemia, which causes oxidative stress (13).
Considerable documentation indicates that oxidative stress plays an important role in DM and its complications (14, 15). Some experimental studies showed that vitamin D can prevent oxidative damage-induced DM, possibly through its antioxidant effect (16, 17). In a cross-sectional study, it was found that vitamin D may have a beneficial effect on the control of glycemic profiles and oxidative stress in T2DM patients (18). However, other studies found no correlation between vitamin D levels and the antioxidant status of diabetic rats (19). In addition, population studies suggest that vitamin D may play a considerable role in boosting β-cell function and insulin sensitivity (4).
Because of the anti-oxidative effect of vitamin D and high prevalence of vitamin deficiencies, we aimed to compare the serum levels of vitamin D via 25-OH-D, and glycemic and lipid profiles, F2-isoprostane, and oxidized-low-density lipoprotein (ox-LDL) in vitamin D-deficient and vitamin D-sufficient T2DM patients.
Materials and Methods
Study Subjects
In this case-control study, we studied 57 T2DM patients with low vitamin D status (< 30 ng/mL) and 48 T2DM patients with normal vitamin D status (> 30 ng/mL) (controls) from the Iranian Diabetes Association. Exclusion criteria included pregnancy, lactation, chronic liver or kidney disorders, endocrinology disorders such as hypo-or hyper-thyroidism and hyper-parathyroidism, smoking, use of anti-convulsion drugs, and use of mineral or vitamin supplements
All subjects were informed about the purposes and procedures of the study and all signed written consent forms before entering the study. The research protocol was approved by the Ethics Committee of Tehran University of Medical Sciences.
Anthropometric Measurements
Body weight (with minimal clothing) and height (without shoes and standing upright) were measured using a scale (Seca GmbH & co KG, Hamburg, Germany) with accuracies of 0.1 kg and 0.5 cm, respectively.
Dietary Assessment
The dietary data of the subjects were collected by three 24-h dietary recalls for one weekend and two weekdays. The average daily nutrient intake was calculated by modified Nutritionist IV software (version 3.5.2, First Data Bank; Hearst Corp, San Bruno, California).
Blood Collection
After receiving written consent from all subjects, blood samples were collected from the antecubital vein in the morning after 12-14 hour fasts, and centrifuged at 1000 RCF for 10 min at 4 °C. The blood samples were collected in two trace element-free tubes, one for serum separation, and one with ethylene diamine tetra acetic acid (EDTA) for plasma separation and hemoglobin A1C (HbA1C) measurement. The separated plasma was immediately stored at -80 °C until biochemical analysis.
Laboratory Analysis
Fasting plasma glucose was measured using glucose-oxidase with a ZistShimi Kit (ZistShimi Co., Iran). HbA1C was determined using a Nyco Card Reader II analyzer according the procedure provided (20). Calcium, phosphorus, TGs, cholesterol, high-density lipoprotein (HDL), and LDL were measured by a colorimetric method using biochemical kits (ZistShimi CO., Tehran, Iran). The serum concentration of 25-OH-D was measured using chemiluminescence. Normal ranges of calcium and phosphorous were defined as 8.6-10.3 mg/dL and 2.5-5 mg/dL, respectively. The ox-LDL was measured by a sandwich ELISA using a commercial kit (Mercodia-Sweden). F2-isoprostane levels were measured with an ELISA kit (Cusabio Biotech Co., China). Vitamin D sufficiency was defined as a serum 25-OH-D concentration > 75 nmol/L (30 ng/mL) and vitamin D deficiency was defined as serum 25-OH-D concentration < 75 nmol/L (30 ng/mL).
Statistical Analysis
All data were expressed as means ± standard deviations (SD). Normality of data distribution was analyzed by the Kolmogorov-Smirnov test. Groups were compared with independent sample t or chi square tests for continuous and categorical data, respectively. Correlations between vitamin D levels and lipid profiles, F2-isoprostane, and ox-LDL of diabetic patients were determined using Spearman’s rho. P values < 0.05 were considered to be statistically significant. Data were analyzed using the Statistical Package for the Social Sciences (Version 11.5, SPSS Inc, Chicago, IL, USA).
Results
A total of 105 diabetic patients participated in this study. Fifty-six subjects (53%) were females, and 49 (47%) were males. The greatest duration of diabetes was 16 years. The mean age of the patients was 56.34 ± 8.16 years. Their mean BMI was 29.68 ± 5.89. Demographic and biochemical characteristics among case and control groups are shown in Table 1. No significant differences were observed in mean scores for ages, weights, or BMIs between groups. The mean fasting serum concentration of 25-OH-D, calcium, and phosphorus in patients with low vitamin D status was significantly less than that of controls (p < 0.001). The mean total cholesterol and LDL were significantly greater in patients with low vitamin D status than in controls (p < 0.01). However, the mean TG and HDL were not significantly different between the two groups (table 1). The mean serum ox-LDL and F2-isoprostane were significantly greater in patients with low vitamin D status than in controls (p < 0.001).
Table 1.
Demographic and biochemical characteristics among case and control groupsa
| Variables | Patients with low vitamin d status | Patients with normal vitamin d status | P value |
|---|---|---|---|
| Age (year) | 55.63±8.3 | 57.17±8.15 | 0.34 |
| Weight (kg) | 80.08±14.15 | 76.63±12.8 | 0.2 |
| BMI (kg/m2) | 30±5.92 | 29.6±5.8 | 0.73 |
| FBG | 136.81±36.98 | 150.54±92.45 | 0.32 |
| HbA1c | 9.33±1.55 | 8.98±1.16 | 0.26 |
| 25-OH-D (ng/mL) | 13.03±5.24 | 47.74±15.35 | <0.001 |
| Calcium (mg/dL) | 8.15±0.62 | 9.59±0.84 | <0.001 |
| Phosphorous (mg/dL) | 3.21±0.56 | 4.04±0.47 | <0.001 |
| TG (mg/dL) | 146.08±54.96 | 147.2±75.96 | 0.93 |
| LDL-C (mg/dL) | 140.57±54.88 | 114.43±64.04 | 0.01 |
| HDL-C (mg/dL) | 41.43±5 | 39.33±8.25 | 0.12 |
| TC (mg/dL) | 211.28±56.73 | 188.45±49.99 | 0.03 |
| OX-LDL (IU/L) | 88.80±21.16 | 47.92±16.91 | <0.001 |
| F2-isoprostane (pg/mL) | 283.9±111.38 | 93.23±42.02 | <0.001 |
Data were expressed as mean±SD, P value was resulted from independent sample t-test, FBG: fasting blood glucose, HbA1c: glycosylated hemoglobin, TG: Triglyceride, LDL-C: Low-density lipoprotein cholesterol, HDL-C: High-density lipoprotein cholesterol, TC: Total cholesterol,Oxidized Low-Density Lipoprotein
Table 2 shows the dietary intakes of diabetic patients with low and normal vitamin D status. The mean energy, protein, fat, and carbohydrate intake in patients with low vitamin D status were not significantly different from those in controls. Because the distribution of the data was not normal, we transformed the data into vitamin D logarithms. The vitamin D logarithms between the two groups were significantly different (P = 0.004). Interestingly, a negative correlation was observed between the vitamin D level and F2-isoprostane (r = 0.647and P = 0.0001), LDL (r = -0.218 and P = 0.030), and ox-LDL (r = -0.637 and P = 0.0001). However, no statistically significant correlation was seen between vitamin D and TG, cholesterol, or HDL (Table 3).
Table 3.
Correlations of vitamin D with lipid profiles, F2-isoprostane and ox-LDL in diabetic patients
| Variables | F2-isoprostane | ox-LDL | TG | TC | LDL-C | HDL-C | |
|---|---|---|---|---|---|---|---|
| Serum vitamin (ng/mL) | r | -0.647 | -0.637 | -0.033 | -0.107 | -0.218 | 0.87 |
| p-value | 0.0001 | 0.0001 | 0.734 | 0.274 | 0.030 | 0.373 |
r=correlation coefficient, P-value was resulted from Spearman correlation, TG: Triglyceride, LDL-C: Low-density lipoprotein cholesterol, HDL-C: High-density lipoprotein cholesterol, TC: Total cholesterol, ox-LDL: Oxidized Low-Density Lipoprotein
Table 2.
Dietary Intake Among the patients with low vitamin D status, and Control Groupsa
| Variables | Patients with low vitamin D status | Patients with normal vitamin D status | P value |
|---|---|---|---|
| Energy(kcal/day) | 1309.66±81.30 | 1310.03±72.23 | 0.99 |
| Protein (g/day) | 53.79±3.68 | 63.43±4.78 | 0.12 |
| Fat (g/day) | 139.03±15.96 | 210.32±18.09 | 0.86 |
| Carbohydrate(g/day) | 36.90±4.84 | 35.02±3.21 | 0.65 |
| Vitamin D (mg/day) | 0.59±0.22 | 1.35±0.70 | 0.76 |
| Calcium (mg/day) | 617.46±50.26 | 688.26±66.12 | 0.39 |
| Phosphorus (mg/day) | 837.63±77.15 | 833.76±63.11 | 0.97 |
aData are expressed as mean ± SD, P value was resulted from independent sample t tests
Discussion
Evidence obtained from many studies indicates that insufficient vitamin D can be considered an environmental factor that contributes to the pathophysiology of the disease. The key immunomodulatory role of vitamin D is well known. Low serum vitamin D has been observed in several autoimmune diseases including systemic lupus erythematosus (SLE) (21-23), insulin-dependent DM (IDDM) (24), rheumatoid arthritis (RA) (25), and multiple sclerosis (MS) (26).
Our findings revealed that the serum concentration of 25-OH-D was significantly less in patients with low vitamin D status than in control subjects. In a cohort study, as a part of the Mini-Finland Health Survey, a significant inverse association was found between serum 25-OH-D and the risk of T2DM in a simple model.
However, the association was attenuated in the multivariate analysis, adjusting for potential risk factors of T2DM (9). Saedisomeolia et al. reported results similar to ours (11). Few studies have measured micronutrients other than vitamin D in diabetic patients, but our results showed that the mean fasting levels of calcium and phosphorus in patients with low vitamin D status were significantly less than in controls. In a cross-sectional study of diabetic patients, the mean serum level of calcium was significantly greater in diabetic patients with vitamin D deficiency than in patients with sufficient vitamin D, but an association was not seen between phosphorus and vitamin D. Also, serum levels of total cholesterol, TG, and LDL were greater, and HDL was less in diabetic patients with vitamin D deficiency than in patients with sufficient vitamin D levels (11).
In our study, mean total cholesterol and LDL were significantly greater in patients with low vitamin D status than in controls, and the mean TG and HDL were not significantly different between the two groups.
It is worth noting that we hypothesized that some other lipid profiles, such as ox-LDL and F2-isoprostane, are also associated with vitamin D status in diabetic patients. Hence, we initially collected data on these variables to investigate a possible association between them and vitamin D status in diabetic patients, because we found no remarkable research that assessed F2-isoprostane and ox-LDL relative to vitamin D levels in these patients. Our study indicated that in T2DM patients, TG, cholesterol, LDL, and specially, ox-LDL and F2-isoprostane, were negatively correlated with the serum vitamin D level, but a positive correlation was observed between HDL and serum vitamin D. However, in another study, an inverse, but not significant, association was seen between levels of 25-OH-D with TG and total cholesterol, and a positive correlation with HDL-C and LDL-C (11). A review of 22 cross-sectional and 10 placebo-controlled interventional studies found that serum levels of 25-OH-D are directly related to HDL cholesterol. In addition, all studies reported an inverse association between serum levels of 25-OH-D and TG. No general agreement exists regarding the effects of 25-OH-D on serum levels of TG in interventional studies with vitamin D supplementation. Although a positive association was observed in some studies, other studies showed an inverse relationship between serum levels of 25-OH-D and TG (27). These findings are consistent with our results.
Diabetes mellitus is associated with oxidative stress, defined as increased oxidative stress and simultaneous defects in the antioxidant defense system. Oxidative stress plays a key role in the onset and progression of diabetes complications, including macro/micro vascular damage. Vitamin D possesses antioxidant properties, so that vitamin D3 can inhibit the lipid peroxidation induced by iron in brain liposome; therefore, vitamin D could serve as a cellular membrane antioxidant. Anticancer activity of vitamin D is also attributable to its antioxidant properties (18, 28).
Little attention has been given to the effect of environmental and genetic factors, such as place of residence, ethnicity, and demographical characteristics on vitamin D serum levels in diabetic patients. The authors of a study of environmental factors in the etiology of Type 1 DM found that differences in the genetic predisposition between various populations may at least partly explain the conspicuous variation in incidence rates between different ethnic groups (29). Further research is needed to understand the impact of these factors on vitamin D in diabetic patients and their mechanisms of action.
The strength of this study is that it measures of micronutrients associated with 25-OH-D in diabetic patients with sufficient and insufficient vitamin D. The study was limited in that: (1) blood samples were collected only once, and this took place only in one season of the years of study; hence, 25-OH-D levels for the patients might not be fully comparable, however, adjustment for time when blood samples were collected did not notably change the results, (2) considering the case-control design in this study, recall bias should be recognized when findings from dietary intake of macronutrients are interpreted, and (3) small samples in both groups were another limitation for generalization of our findings.
In summary, the results support the hypothesis that high serum 25-OH-D concentrations may be associated with a decrease in some lipid profiles, F2-isoprostane, and ox-LDL in diabetic patients with sufficient vitamin D but not in those with vitamin D deficiencies. Further research is needed to confirm the association and to distinguish between the independent role of vitamin D and the role of healthy dietary and lifestyle patterns in diabetic patients.
Acknowledgements
This study was approved by and received a grant from Tehran University of Medical Sciences (ID: 18804). The authors thank the participants for their cooperation.
References
- 1.Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes estimates for the year 2000 and projections for 2030. Diabetes care. 2004;27(5):1047–53. doi: 10.2337/diacare.27.5.1047. [DOI] [PubMed] [Google Scholar]
- 2.Hales C, Barker D. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. International journal of epidemiology. 2013;42(5):1215–22. doi: 10.1093/ije/dyt133. [DOI] [PubMed] [Google Scholar]
- 3.Åkerblom HK, Vaarala O, Hyöty H, Ilonen J, Knip M. Environmental factors in the etiology of type 1 diabetes. . American journal of medical genetics. 2002;115(1):18–29. doi: 10.1002/ajmg.10340. [DOI] [PubMed] [Google Scholar]
- 4.Takiishi T, Gysemans C, Bouillon R, Mathieu C. Vitamin D and diabetes. Endocrinology and metabolism clinics of North America. 2010;39(2):419–46. doi: 10.1016/j.ecl.2010.02.013. [DOI] [PubMed] [Google Scholar]
- 5.Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. American journal of hypertension. 2007;20(7):713–9. doi: 10.1016/j.amjhyper.2007.01.017. [DOI] [PubMed] [Google Scholar]
- 6.Zarei M, Javanbakht MH, Chams-Davatchi C, Daneshpazhooh M, Eshraghian MR, Derakhshanian H, et al. Evaluation of Vitamin D Status in Newly Diagnosed Pemphigus Vulgaris Patients. Iranian Journal of Public Health. 2014;43(11):1544–9. [PMC free article] [PubMed] [Google Scholar]
- 7.Temmerman JC. Vitamin D and cardiovascular disease. Journal of the American College of Nutrition. 2011;30(3):167–70. doi: 10.1080/07315724.2011.10719956. [DOI] [PubMed] [Google Scholar]
- 8.Cantorna MT, Mahon BD. Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Experimental biology and medicine. 2004;229(11):1136–42. doi: 10.1177/153537020422901108. [DOI] [PubMed] [Google Scholar]
- 9.Mattila C, Knekt P, Männistö S, Rissanen H, Laaksonen MA, Montonen J, et al. Serum 25-hydroxyvitamin D concentration and subsequent risk of type 2 diabetes. Diabetes care. 2007;30(10):2569–70. doi: 10.2337/dc07-0292. [DOI] [PubMed] [Google Scholar]
- 10.Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes care. 2004;27(12):2813–8. doi: 10.2337/diacare.27.12.2813. [DOI] [PubMed] [Google Scholar]
- 11.Saedisomeolia A, Taheri E, Djalali M, Moghadam AM, Qorbani M. Association between serum level of vitamin D and lipid profiles in type 2 diabetic patients in Iran. Journal of Diabetes & Metabolic Disorders. 2014;13(1):1. doi: 10.1186/2251-6581-13-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Sies H. Role of reactive oxygen species in biological processes. Klinische Wochenschrift. 1991;69(21-23):965–8. doi: 10.1007/BF01645140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Johansen JS, Harris AK, Rychly DJ, Ergul A. Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. Cardiovascular diabetology. 2005;4(1):5. doi: 10.1186/1475-2840-4-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.West I. Radicals and oxidative stress in diabetes. Diabetic Medicine. 2000;17(3):171-80;17(3):171–80. doi: 10.1046/j.1464-5491.2000.00259.x. [DOI] [PubMed] [Google Scholar]
- 15.Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes. 1999;48(1):1–9. doi: 10.2337/diabetes.48.1.1. [DOI] [PubMed] [Google Scholar]
- 16.Hamden K, Carreau S, Jamoussi K, Miladi S, Lajmi S, Aloulou D, et al. 1α, 25 dihydroxyvitamin D3: therapeutic and preventive effects against oxidative stress, hepatic, pancreatic and renal injury in alloxan-induced diabetes in rats. Journal of nutritional science and vitaminology. 2009;55(3):215–22. doi: 10.3177/jnsv.55.215. [DOI] [PubMed] [Google Scholar]
- 17.Hamden K, Carreau S, Jamoussi K, Ayadi F, Garmazi F, Mezgenni N, et al. Inhibitory effects of 1α, 25dihydroxyvitamin D3 and Ajuga iva extract on oxidative stress, toxicity and hypo-fertility in diabetic rat testes. Journal of physiology and biochemistry. 2008;64(3):231–9. doi: 10.1007/BF03216108. [DOI] [PubMed] [Google Scholar]
- 18.Saedisomeolia A, Taheri E, Djalali M, Djazayeri A, Qorbani M, Rajab A, et al. Vitamin D status and its association with antioxidant profiles in diabetic patients: A cross-sectional study in Iran. Indian J Med Sci. 2013;67(1):29. [PubMed] [Google Scholar]
- 19.Noyan T, Balaharoğlu R, Kömüroğlu U. The oxidant and antioxidant effects of 25-hydroxyvitamin D3 in liver, kidney and heart tissues of diabetic rats. Clinical and experimental medicine. 2005;5(1):31–6. doi: 10.1007/s10238-005-0061-8. [DOI] [PubMed] [Google Scholar]
- 20.John WG. Haemoglobin A1c: analysis and standardisation. Clinical chemistry and laboratory medicine. 2003;41(9):1199–212. doi: 10.1515/CCLM.2003.184. [DOI] [PubMed] [Google Scholar]
- 22.Kamen DL, Aranow C. The link between vitamin D deficiency and systemic lupus erythematosus. Curr Rheumatol Rep. 2008;10(4):273–80. doi: 10.1007/s11926-008-0044-3. [DOI] [PubMed] [Google Scholar]
- 22.Borba VZ, Vieira JG, Kasamatsu T, Radominski SC, Sato EI, Lazaretti-Castro M. Vitamin D deficiency in patients with active systemic lupus erythematosus. Osteoporos Int. 2009;20(3):427–33. doi: 10.1007/s00198-008-0676-1. [DOI] [PubMed] [Google Scholar]
- 23.Ruiz-Irastorza G, Egurbide MV, Olivares N, Martinez-Berriotxoa A, Aguirre C. Vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences. Rheumatology (Oxford) 2008;47(6):920–3. doi: 10.1093/rheumatology/ken121. [DOI] [PubMed] [Google Scholar]
- 24.Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358(9292):1500–3. doi: 10.1016/S0140-6736(01)06580-1. [DOI] [PubMed] [Google Scholar]
- 25.Patel S, Farragher T, Berry J, Bunn D, Silman A, Symmons D. Association between serum vitamin D metabolite levels and disease activity in patients with early inflammatory polyarthritis. Arthritis Rheum. 2007;56(7):2143–9. doi: 10.1002/art.22722. [DOI] [PubMed] [Google Scholar]
- 26.Napoli N, Carmina E, Bucchieri S, Sferrazza C, Rini GB, Di Fede G. Low serum levels of 25-hydroxy vitamin D in adults affected by thalassemia major or intermedia. Bone. 2006;38(6):888–92. doi: 10.1016/j.bone.2005.11.018. [DOI] [PubMed] [Google Scholar]
- 27.Jorde R, Grimnes G. Vitamin D and metabolic health with special reference to the effect of vitamin D on serum lipids. Prog Lipid Res. 2011;50(4):303–12. doi: 10.1016/j.plipres.2011.05.001. [DOI] [PubMed] [Google Scholar]
- 28.Deeb KK, Trump DL, Johnson CS. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer. 2007;7(9):684–700. doi: 10.1038/nrc2196. [DOI] [PubMed] [Google Scholar]
- 29.Akerblom HK, Vaarala O, Hyoty H, Ilonen J, Knip M. Environmental factors in the etiology of type 1 diabetes. Am J Med Genet. 2002;115(1):18–29. doi: 10.1002/ajmg.10340. [DOI] [PubMed] [Google Scholar]