NEWS & VIEWS GENETICS
Vitamin D and type 2 diabetes mellitus—hype or hope? Klaus Badenhoop
Vitamin D deficiency is a global health concern, which might affect the pathogenesis of diabetes mellitus. Previous studies suggest vitamin D has some potential in the treatment of type 2 diabetes mellitus. A new combined genetic study and meta-analysis reveals conflicting results regarding the effects of circulating levels of vitamin D on type 2 diabetes mellitus risk. Badenhoop, K. Nat. Rev. Endocrinol. advance online publication 25 November 2014; doi:10.1038/nrendo.2014.206
The high and ever increasing prevalence of type 2 diabetes mellitus (T2DM) poses an enormous challenge to health-care provision and funding systems worldwide. Genome-wide association studies (GWAS) have identified a long list of genes that are moderately associated with a predisposition to T2DM, many of which are involved in pancreatic β‑cell function. However, none of these associations are sufficiently strong for these genes to be used for prediagnostic screening. Currently, a positive family history remains the best predictor of heritable risk. Although variations in genes involved in vitamin D signalling and metabolism are generally not associated with T2DM, many studies have found low circulating levels of vitamin D (as indicated by vitamin D3 levels) to be a risk factor, and possibly a target for intervention owing to the anti-inflammatory and pro-differentiation properties of this steroid hormone.1 In a high-powered meta-analysis of 22 prospective studies, Ye et al.2 confirmed that lower circulating concentrations of vita min D (by 1 SD) confer an increased risk of T2DM in people of European ancestry. However, whether low circulating levels of vitamin D are causal or a mere consequence of metabolic disease remains unclear. Pre viously, it has been shown that the genes encoding 7‑dehydrocholesterol reductase (DHCR7), vitamin D 25-hydroxylase (CYP2R1), vitamin D‑binding protein (DBP) and 1,25-dihydroxyvitamin D 3 24-hydroxylase, mitochondrial (CYP24A1) are the main loci controlling the heritable
variation in circulating levels of vitamin D.3 Common variants in three of these genes (DHCR7, CYP2R1 and CYP24A1) are known to confer risk of type 1 diabetes mellitus or islet autoimmunity.4
‘‘
…lower circulating concentrations of vitamin D … confer an increased risk of T2DM…
’’
Ye et al.2 also investigated the effects of single nucleotide polymorphisms (SNPs) in DHCR7, CYP2R1, DBP and CYP24A1. The variants were selected on the basis of GWAS and were independently associated with reduced circulating levels of vita min D (termed vitamin D lowering alleles). Following analysis of 28,144 patients with T2DM and 76,344 individuals without diabetes mellitus, a Mendelian randomizationderived analysis revealed no significant difference in risk of T2DM for carriers of the vitamin D lowering alleles. Most confusingly, results of this instrumental variable analysis point to a marginal protection, on the basis of vitamin D lowering alleles in patients with T2DM. How can we interpret this discrepancy in light of the clear message from the meta-analysis? Several interpretations of this finding are possible. For example, any vitamin D deficiency observed in patients is, to a large degree, an acquired phenomenon and is unlikely to be caused by the genetic variants. Alternatively, genetic influence exerted
NATURE REVIEWS | ENDOCRINOLOGY
by these four genes is so limited that another genetic cause (yet to be identified) or epigenetic modifications are likely to be the major contributor to vitamin D deficiency. Furthermore, the contribution of vitamin D deficiency to the pathophysiology of T2DM is complex. Thus, pooling diverse populations with differing genetic backgrounds might dilute effects that could be identified if a well-defined population with a homogeneous genetic profile and environmental exposure was investigated. Mendelian randomization is a statistical approach used to investigate genetic variation as a potential cause of a heritable disease or trait. This approach is based on the assumption that meiotic divisions occur at random and the distribution of alleles in a large sample population is not confounded by the investigated disease or traits. Humans evolve in outbred populations; therefore, this reverse-genetics approach might detect clinical effects in sufficiently large datasets. Ye et al.2 pooled data on vitamin D levels, SNPs in genes associated with vitamin D signalling and metabolism and metabolic traits from several consortia. These consortia integrate data from European centres with a strong UK contribution. Thus, to interpret their findings, one needs to know the magnitude of the contribution of each SNP to the overall variation in circulating levels of vitamin D. The presence of the vitamin D lowering allele of each gene separately (0.4–2.0%) or all four combined (3.6%) accounted for substantially less variation in circulating levels of vitamin D than that expected from seasonal variation, geographic latitude or dietary intake (about 25%), and only a fraction of the estimated heritability in vitamin D variation from twin studies (28.8%).5 These investigations also raise questions regarding the stage of the pathogenesis at which addressing vitamin D deficiency would be most effective. One intervention study of vitamin D and calcium supplementation detected an improvement in insulin sensitivity in patients with prediabetes after 6 months of treatment.6 This finding suggests that vitamin D supplementation might be most effective in individuals who are at risk of T2DM, but have not yet developed the disorder. ADVANCE ONLINE PUBLICATION | 1
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS O t he r Mend eli an r andom i z at i on approaches addressing T2DM-related traits detected strong associations between variant genes involved in vitamin D signalling and metabolism and circulating levels of vitamin D.7 In a large meta-analysis of patients with hypertension, the presence of vitamin D lowering alleles of DHCR7 and CYP2R1 was combined to produce a synthesis score. Hypertension was found to be significantly associated with this score, in that low vitamin D synthesis resulted in increased risk of hypertension. 7 Hyper tension complicates the course of T2DM; for this reason, large-scale controlled studies investigating the effects of vita min D supplementation on the cardiovas cular system will be of interest. Such studies need to be sufficiently powered to address whether variations in genes associated with vitamin D signalling and metabolism can influence the occurrence, or size, of these effects. Small-scale studies suggest potential benefits of vitamin D as an intervention, in particular relating to metabolism and improved insulin sensitivity in patients with T2DM.6,8 T2DM is also regarded as a vascular metabolic disease and the vascular system could be considered a novel therapeutic target. Howe ver, targeting the vascular system would require a better understanding of the interplay of cellular and tissue targets for vitamin D-related interventions. Evidence from a clinical Mendelian randomization study investigating the association of vitamin D status and presence of atherosclerosis (as indicated by carotid intima– media thickness) showed that the presence of the vitamin D lowering allele in DHCR7
accelerates the progression of subclinical atherosclerosis in patients with T2DM.9 Furthermore, in a translational study using both experimental animals and humans, vitamin D was shown to promote vascular repair mechanisms.10 The authors reported that vitamin D can stimulate hypoxia-inducible-factor 1α, which regulates several regenerative tissue factors, demonstrating a new mechanism of vita min D action. Many patients with T2DM have vascular disease; therefore, early treatment with vitamin D might reduce the occurrence of diabetic complications. In conclusion, genetic studies of T2DM can identify biochemical pathways, but have so far failed, with the exception of rare monogenic forms of the disease, to establish causality. More measurable effect sizes are required to identify vitamin D signalling and metabolism gene variations associated with heritable risk of T2DM. Prospective controlled studies with sufficient vitamin D doses are needed that monitor metabolic, immune and vascular health. Such intervention studies combining genetics with the investigation of new mechanisms will hopefully reveal new therapeutic opportunities and lead to the development of more precise medications. Division of Endocrinology & Diabetes, Medical Department 1, University Hospital, Goethe‑University, D‑60590 Frankfurt/M, Germany. [email protected] Acknowledgements K.B. is supported by the European Community Health Seventh Framework Programme (FP7/2009–2014 under grant agreement 241447 with acronym NAIMIT) and the Else-Kröner-Fresenius Foundation–postgraduate program (TRIP).
2 | ADVANCE ONLINE PUBLICATION
Competing interests The author declares no competing interests. 1.
Muscogiuri, G. et al. Mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease. Eur. J. Endocrinol. 171, R101–R110 (2014). 2. Ye, Z. et al. Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a Mendelian randomisation study. Lancet Diabetes Endocrinol. http://dx.doi.org/ 10.1016/S2213-8587(14)70184-6. 3. Wang, T. J. et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376, 180–188 (2010). 4. Cooper, J. D. et al. Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes 60, 1624–1631 (2011). 5. Shea, M. K. et al. Genetic and non-genetic correlates of vitamins K and D. Eur. J. Clin. Nutr. 63, 458–464 (2009). 6. Gagnon, C. et al. Effects of combined calcium and vitamin D supplementation on insulin secretion, insulin sensitivity and β-cell function in multi-ethnic vitamin D‑deficient adults at risk for type 2 diabetes: a pilot randomized, placebo-controlled trial. PLoS ONE 9, e109607 (2014). 7. Vimaleswaran, K. S. et al. Association of vitamin D status with arterial blood pressure and hypertension risk: a Mendelian randomisation study. Lancet Diabetes Endocrinol. 2, 719–729 (2014). 8. Strobel, F. et al. Effect of a randomised controlled vitamin D trial on insulin resistance and glucose metabolism in patients with type 2 diabetes mellitus. Horm. Metab. Res. 46, 54–58 (2014). 9. Strawbridge, R. J. et al. A serum 25hydroxyvitamin D concentration-associated genetic variant in DHCR7 interacts with type 2 diabetes status to influence subclinical atherosclerosis (measured by carotid intimamedia thickness). Diabetologia 57, 1159–1172 (2014). 10. Wong, M. S. et al. Vitamin D promotes vascular regeneration. Circulation 130, 976–986 (2014).
www.nature.com/nrendo © 2014 Macmillan Publishers Limited. All rights reserved
Vitamin D and type 2 diabetes mellitus—hype or hope? Klaus Badenhoop
Vitamin D deficiency is a global health concern, which might affect the pathogenesis of diabetes mellitus. Previous studies suggest vitamin D has some potential in the treatment of type 2 diabetes mellitus. A new combined genetic study and meta-analysis reveals conflicting results regarding the effects of circulating levels of vitamin D on type 2 diabetes mellitus risk. Badenhoop, K. Nat. Rev. Endocrinol. advance online publication 25 November 2014; doi:10.1038/nrendo.2014.206
The high and ever increasing prevalence of type 2 diabetes mellitus (T2DM) poses an enormous challenge to health-care provision and funding systems worldwide. Genome-wide association studies (GWAS) have identified a long list of genes that are moderately associated with a predisposition to T2DM, many of which are involved in pancreatic β‑cell function. However, none of these associations are sufficiently strong for these genes to be used for prediagnostic screening. Currently, a positive family history remains the best predictor of heritable risk. Although variations in genes involved in vitamin D signalling and metabolism are generally not associated with T2DM, many studies have found low circulating levels of vitamin D (as indicated by vitamin D3 levels) to be a risk factor, and possibly a target for intervention owing to the anti-inflammatory and pro-differentiation properties of this steroid hormone.1 In a high-powered meta-analysis of 22 prospective studies, Ye et al.2 confirmed that lower circulating concentrations of vita min D (by 1 SD) confer an increased risk of T2DM in people of European ancestry. However, whether low circulating levels of vitamin D are causal or a mere consequence of metabolic disease remains unclear. Pre viously, it has been shown that the genes encoding 7‑dehydrocholesterol reductase (DHCR7), vitamin D 25-hydroxylase (CYP2R1), vitamin D‑binding protein (DBP) and 1,25-dihydroxyvitamin D 3 24-hydroxylase, mitochondrial (CYP24A1) are the main loci controlling the heritable
variation in circulating levels of vitamin D.3 Common variants in three of these genes (DHCR7, CYP2R1 and CYP24A1) are known to confer risk of type 1 diabetes mellitus or islet autoimmunity.4
‘‘
…lower circulating concentrations of vitamin D … confer an increased risk of T2DM…
’’
Ye et al.2 also investigated the effects of single nucleotide polymorphisms (SNPs) in DHCR7, CYP2R1, DBP and CYP24A1. The variants were selected on the basis of GWAS and were independently associated with reduced circulating levels of vita min D (termed vitamin D lowering alleles). Following analysis of 28,144 patients with T2DM and 76,344 individuals without diabetes mellitus, a Mendelian randomizationderived analysis revealed no significant difference in risk of T2DM for carriers of the vitamin D lowering alleles. Most confusingly, results of this instrumental variable analysis point to a marginal protection, on the basis of vitamin D lowering alleles in patients with T2DM. How can we interpret this discrepancy in light of the clear message from the meta-analysis? Several interpretations of this finding are possible. For example, any vitamin D deficiency observed in patients is, to a large degree, an acquired phenomenon and is unlikely to be caused by the genetic variants. Alternatively, genetic influence exerted
NATURE REVIEWS | ENDOCRINOLOGY
by these four genes is so limited that another genetic cause (yet to be identified) or epigenetic modifications are likely to be the major contributor to vitamin D deficiency. Furthermore, the contribution of vitamin D deficiency to the pathophysiology of T2DM is complex. Thus, pooling diverse populations with differing genetic backgrounds might dilute effects that could be identified if a well-defined population with a homogeneous genetic profile and environmental exposure was investigated. Mendelian randomization is a statistical approach used to investigate genetic variation as a potential cause of a heritable disease or trait. This approach is based on the assumption that meiotic divisions occur at random and the distribution of alleles in a large sample population is not confounded by the investigated disease or traits. Humans evolve in outbred populations; therefore, this reverse-genetics approach might detect clinical effects in sufficiently large datasets. Ye et al.2 pooled data on vitamin D levels, SNPs in genes associated with vitamin D signalling and metabolism and metabolic traits from several consortia. These consortia integrate data from European centres with a strong UK contribution. Thus, to interpret their findings, one needs to know the magnitude of the contribution of each SNP to the overall variation in circulating levels of vitamin D. The presence of the vitamin D lowering allele of each gene separately (0.4–2.0%) or all four combined (3.6%) accounted for substantially less variation in circulating levels of vitamin D than that expected from seasonal variation, geographic latitude or dietary intake (about 25%), and only a fraction of the estimated heritability in vitamin D variation from twin studies (28.8%).5 These investigations also raise questions regarding the stage of the pathogenesis at which addressing vitamin D deficiency would be most effective. One intervention study of vitamin D and calcium supplementation detected an improvement in insulin sensitivity in patients with prediabetes after 6 months of treatment.6 This finding suggests that vitamin D supplementation might be most effective in individuals who are at risk of T2DM, but have not yet developed the disorder. ADVANCE ONLINE PUBLICATION | 1
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS O t he r Mend eli an r andom i z at i on approaches addressing T2DM-related traits detected strong associations between variant genes involved in vitamin D signalling and metabolism and circulating levels of vitamin D.7 In a large meta-analysis of patients with hypertension, the presence of vitamin D lowering alleles of DHCR7 and CYP2R1 was combined to produce a synthesis score. Hypertension was found to be significantly associated with this score, in that low vitamin D synthesis resulted in increased risk of hypertension. 7 Hyper tension complicates the course of T2DM; for this reason, large-scale controlled studies investigating the effects of vita min D supplementation on the cardiovas cular system will be of interest. Such studies need to be sufficiently powered to address whether variations in genes associated with vitamin D signalling and metabolism can influence the occurrence, or size, of these effects. Small-scale studies suggest potential benefits of vitamin D as an intervention, in particular relating to metabolism and improved insulin sensitivity in patients with T2DM.6,8 T2DM is also regarded as a vascular metabolic disease and the vascular system could be considered a novel therapeutic target. Howe ver, targeting the vascular system would require a better understanding of the interplay of cellular and tissue targets for vitamin D-related interventions. Evidence from a clinical Mendelian randomization study investigating the association of vitamin D status and presence of atherosclerosis (as indicated by carotid intima– media thickness) showed that the presence of the vitamin D lowering allele in DHCR7
accelerates the progression of subclinical atherosclerosis in patients with T2DM.9 Furthermore, in a translational study using both experimental animals and humans, vitamin D was shown to promote vascular repair mechanisms.10 The authors reported that vitamin D can stimulate hypoxia-inducible-factor 1α, which regulates several regenerative tissue factors, demonstrating a new mechanism of vita min D action. Many patients with T2DM have vascular disease; therefore, early treatment with vitamin D might reduce the occurrence of diabetic complications. In conclusion, genetic studies of T2DM can identify biochemical pathways, but have so far failed, with the exception of rare monogenic forms of the disease, to establish causality. More measurable effect sizes are required to identify vitamin D signalling and metabolism gene variations associated with heritable risk of T2DM. Prospective controlled studies with sufficient vitamin D doses are needed that monitor metabolic, immune and vascular health. Such intervention studies combining genetics with the investigation of new mechanisms will hopefully reveal new therapeutic opportunities and lead to the development of more precise medications. Division of Endocrinology & Diabetes, Medical Department 1, University Hospital, Goethe‑University, D‑60590 Frankfurt/M, Germany. [email protected] Acknowledgements K.B. is supported by the European Community Health Seventh Framework Programme (FP7/2009–2014 under grant agreement 241447 with acronym NAIMIT) and the Else-Kröner-Fresenius Foundation–postgraduate program (TRIP).
2 | ADVANCE ONLINE PUBLICATION
Competing interests The author declares no competing interests. 1.
Muscogiuri, G. et al. Mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease. Eur. J. Endocrinol. 171, R101–R110 (2014). 2. Ye, Z. et al. Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a Mendelian randomisation study. Lancet Diabetes Endocrinol. http://dx.doi.org/ 10.1016/S2213-8587(14)70184-6. 3. Wang, T. J. et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376, 180–188 (2010). 4. Cooper, J. D. et al. Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes 60, 1624–1631 (2011). 5. Shea, M. K. et al. Genetic and non-genetic correlates of vitamins K and D. Eur. J. Clin. Nutr. 63, 458–464 (2009). 6. Gagnon, C. et al. Effects of combined calcium and vitamin D supplementation on insulin secretion, insulin sensitivity and β-cell function in multi-ethnic vitamin D‑deficient adults at risk for type 2 diabetes: a pilot randomized, placebo-controlled trial. PLoS ONE 9, e109607 (2014). 7. Vimaleswaran, K. S. et al. Association of vitamin D status with arterial blood pressure and hypertension risk: a Mendelian randomisation study. Lancet Diabetes Endocrinol. 2, 719–729 (2014). 8. Strobel, F. et al. Effect of a randomised controlled vitamin D trial on insulin resistance and glucose metabolism in patients with type 2 diabetes mellitus. Horm. Metab. Res. 46, 54–58 (2014). 9. Strawbridge, R. J. et al. A serum 25hydroxyvitamin D concentration-associated genetic variant in DHCR7 interacts with type 2 diabetes status to influence subclinical atherosclerosis (measured by carotid intimamedia thickness). Diabetologia 57, 1159–1172 (2014). 10. Wong, M. S. et al. Vitamin D promotes vascular regeneration. Circulation 130, 976–986 (2014).
www.nature.com/nrendo © 2014 Macmillan Publishers Limited. All rights reserved
