Vitamin D for prevention of type 2 diabetes: a clouded forecast for the sunshine vitamin
Authors: Brian Buijsse
Journal: The Lancet Diabetes & Endocrinology (2014)

Type 2 diabetes can be prevented by adoption of a healthy diet and lifestyle. However, many people have difficulties complying with dietary and lifestyle changes, so the quest for more convenient ways to reduce diabetes risk continues. Vitamin D has been the focus of much interest in this regard.1Muscogiuri G Mitri J Mathieu C et al.Mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease.Eur J Endocrinol. 2014; 171: R101-R110Crossref PubMed Scopus (113) Google Scholar Epidemiological studies in human beings consistently show that low blood concentrations of 25-hydroxyvitamin D (25[OH]D, a marker of vitamin D status) are associated with an increased risk of type 2 diabetes.2Forouhi NG Ye Z Rickard AP et al.Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies.Diabetologia. 2012; 55: 2173-2182Crossref PubMed Scopus (195) Google Scholar These studies, however, cannot distinguish causation from association because of possible uncontrolled confounding and reverse causation. In The Lancet Diabetes & Endocrinology, Zheng Ye and colleagues3Ye Z Sharp SJ Burgess S et al.Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study.Lancet Diabetes Endocrinol. 2014; (published online Oct 1.)http://dx.doi.org/10.1016/S2213-8587(14)70184-6Google Scholar make an important contribution by reporting the results of a mendelian randomisation study, which makes use of the interindividual variability in circulating 25(OH)D concentrations caused by common genetic variants. Because allocation of genetic variants at conception is independent of behavioural and environmental factors, their associations with disease are less likely to be affected by confounding or reverse causation.4Sheehan NA Didelez V Burton PR Tobin MD Mendelian randomisation and causal inference in observational epidemiology.PLoS Med. 2008; 5: e177Crossref PubMed Scopus (254) Google Scholar, 5Smith GD Lawlor DA Harbord R Timpson N Day I Ebrahim S Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology.PLoS Med. 2008; 4: e352Crossref Scopus (354) Google Scholar On the basis of the expression of four genetic variants that affect plasma 25(OH)D concentrations (single nucleotide polymorphisms of DHCR7, CYP2R1, DBP [also known as GC], and CYP24A1), Ye and colleagues report that for each 25 nmol/L reduction in genetically determined 25(OH)D concentration, the odds ratio for type 2 diabetes was 1·01 (95% CI 0·75–1·36; p=0·94). This null result is in notable contrast to the association noted in observational studies: in their study, Ye and colleagues also meta-analysed 22 prospective observational studies and report a pooled relative risk of 1·21 (95% CI 1·16–1·27; p=7·3 × 10−19). Taken together, these findings suggest that the inverse association for 25(OH)D concentration and type 2 diabetes is not causal. Ye and colleagues' study is impressive in many ways. First and foremost is its sample size, with 104 488 people included in the mendelian randomisation analysis. Second, the null result with respect to risk of type 2 diabetes was also seen for four glycaemic traits, which strengthens the credibility of the findings. Third, the authors updated their earlier meta-analysis of conventional epidemiological studies2Forouhi NG Ye Z Rickard AP et al.Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies.Diabetologia. 2012; 55: 2173-2182Crossref PubMed Scopus (195) Google Scholar by adding 11 more studies. What accounts for the discrepancy between observational and mendelian randomisation studies? As the investigators state, uncontrolled confounding and reverse causation in observational studies are prime suspects. My group6Kühn T Kaaks R Teucher B et al.Dietary, lifestyle, and genetic determinants of vitamin D status: a cross-sectional analysis from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Germany study.Eur J Nutr. 2014; 53: 731-741Crossref PubMed Scopus (48) Google Scholar and others7Sohl E Heymans MW de Jongh RT et al.Prediction of vitamin D deficiency by simple patient characteristics.Am J Clin Nutr. 2014; 99: 1089-1095Crossref PubMed Scopus (42) Google Scholar have shown that low circulating 25(OH)D concentrations are associated with general and central adiposity, physical inactivity, smoking, and low consumption of fish and alcohol. Adiposity and physical inactivity are strong risk factors of type 2 diabetes. Physical activity is usually self-reported, but its accurate assessment is notoriously difficult. So, the question is not whether there is measurement error, but how large it is. Adiposity is usually estimated with BMI, which does not include sufficient information about fat distribution. This issue could be important because low 25(OH)D concentration might be especially associated with central adiposity.6Kühn T Kaaks R Teucher B et al.Dietary, lifestyle, and genetic determinants of vitamin D status: a cross-sectional analysis from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Germany study.Eur J Nutr. 2014; 53: 731-741Crossref PubMed Scopus (48) Google Scholar However, the case of adiposity is special, because it might causally reduce circulating 25(OH)D concentration.8Vimaleswaran KS Berry DJ Lu C et al.Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts.PLoS Med. 2013; 10: e1001383Crossref PubMed Scopus (701) Google Scholar Therefore, adjustment for adiposity could be inappropriate because it removes the mediating effect of adiposity on 25(OH)D concentration. Finally, uncontrolled confounding might also occur by yet undiscovered metabolic processes that both contribute to type 2 diabetes and affect 25(OH)D concentration. It is difficult to address reverse causation in prospective observational studies. One method is to lag the statistical analysis by omitting cases that occur early during follow-up: attenuation of the association suggests reverse causation is possible. A better method is to repeatedly measure 25(OH)D concentration during follow-up to assess any variation in association over time. However, many studies do not include such analyses. Another approach is to investigate potential mechanisms of reverse causation. Reduced 25(OH)D concentration could result from pathophysiological processes leading to type 2 diabetes, perhaps via liver dysfunction, as suggested up by Ye and colleagues.3Ye Z Sharp SJ Burgess S et al.Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study.Lancet Diabetes Endocrinol. 2014; (published online Oct 1.)http://dx.doi.org/10.1016/S2213-8587(14)70184-6Google Scholar If so, then stratifying the analysis for parameters of liver function might be worthwhile. Whether genetic variants that affect concentrations of liver enzymes9Chambers JC Zhang W Sehmi J et al.Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.Nat Genet. 2011; 43: 1131-1138Crossref PubMed Scopus (418) Google Scholar predict 25(OH)D concentration is also currently unknown. Mendelian randomisation studies hinge upon some partly unverifiable assumptions.4Sheehan NA Didelez V Burton PR Tobin MD Mendelian randomisation and causal inference in observational epidemiology.PLoS Med. 2008; 5: e177Crossref PubMed Scopus (254) Google Scholar, 5Smith GD Lawlor DA Harbord R Timpson N Day I Ebrahim S Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology.PLoS Med. 2008; 4: e352Crossref Scopus (354) Google Scholar For example, the genetic variants should exclusively affect the variable in question, in this case 25(OH)D concentration, without directly affecting other vitamin D metabolites or other biological risk factors of diabetes. This assumption might not hold for all of the genetic variants used by Ye and colleagues.2Forouhi NG Ye Z Rickard AP et al.Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies.Diabetologia. 2012; 55: 2173-2182Crossref PubMed Scopus (195) Google Scholar Vitamin D-binding protein (DBP), for example, binds not only to 25(OH)D, but also to other vitamin D metabolites and to fatty acids,10Speeckaert M Huang G Delanghe JR Taes YE Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism.Clin Chim Acta. 2006; 372: 33-42Crossref PubMed Scopus (395) Google Scholar and might also have anti-inflammatory properties independent of vitamin D.11White P Cooke N The multifunctional properties and characteristics of vitamin D-binding protein.Trends Endocrinol Metab. 2000; 11: 320-327Summary Full Text Full Text PDF PubMed Scopus (327) Google Scholar DHCR7 also affects cholesterol metabolism, and CYP24A1 inactivates not only 25(OH)D, but also hormonally active vitamin D. Because of these possible pleiotropic effects, the results of mendelian randomisation studies need careful interpretation, and long-term randomised trials of vitamin D supplementation, which are underway,1Muscogiuri G Mitri J Mathieu C et al.Mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease.Eur J Endocrinol. 2014; 171: R101-R110Crossref PubMed Scopus (113) Google Scholar remain important. The results of a meta-analysis12Seida JC Mitri J Colmers IN et al.Effect of vitamin D3 supplementation on improving glucose homeostasis and preventing diabetes: a systematic review and meta-analysis.J Clin Endocrinol Metab. 2014; (published online July 25.)https://doi.org/10.1210/jc.2014-2136Crossref PubMed Scopus (188) Google Scholar of 35 short-term trials, however, do not offer much hope that vitamin D supplementation can be used to prevent type 2 diabetes. Together with Ye and colleagues' study, the sky is becoming rather clouded for vitamin D in the context of preventing type 2 diabetes. This online publication has been corrected. The corrected version first appeared at thelancet.com/diabetes-endocrinology on December 11, 2014 This online publication has been corrected. The corrected version first appeared at thelancet.com/diabetes-endocrinology on December 11, 2014 I declare no competing interests. Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation studyThe association between 25(OH)D concentration and type 2 diabetes is unlikely to be causal. Efforts to increase 25(OH)D concentrations might not reduce the risk of type 2 diabetes as would be expected on the basis of observational evidence. These findings warrant further investigations to identify causal factors that might increase 25(OH)D concentration and also reduce the risk of type 2 diabetes. Full-Text PDF Open AccessCorrection to Lancet Diabetes Endocrinol 2014; published online Oct 1Buijsse B. Vitamin D for prevention of type 2 diabetes: a clouded forecast for the sunshine vitamin. Lancet Diabetes Endocrinol 2014; published online Oct 1. http://dx.doi.org/10.1016/S2213-8587(14)70202-5—In this Comment, two corrections have been made to match corrections made to the linked Article. First, the odds ratio for type 2 diabetes reported in the fourth paragraph should be 1·01 (95% CI 0·75–1·36; p=0·94). Second, the pooled relative risk reported in the same paragraph should be 1·21 (1·16–1·27; p=7·3 × 10−19). Full-Text PDF