Vitamin D in Type 2 Diabetes: Genetic Susceptibility and the Response
                    to Supplementation

Edith Klahold; Marissa Penna-Martinez; Franziska Bruns; Christian Seidl; Sabine Wicker; Klaus Badenhoop

doi:10.1055/a-1157-0026

Hormone and Metabolic Research, Inhaltsverzeichnis

CC BY-NC-ND 4.0 · Horm Metab Res 2020; 52(07): 492-499
DOI: 10.1055/a-1157-0026

Endocrine Care

Vitamin D in Type 2 Diabetes: Genetic Susceptibility and the Response to Supplementation

Edith Klahold

¹Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, Goethe-University Hospital, Frankfurt/Main, Germany

,

Marissa Penna-Martinez‡

¹Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, Goethe-University Hospital, Frankfurt/Main, Germany

,

Franziska Bruns

¹Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, Goethe-University Hospital, Frankfurt/Main, Germany

,

Christian Seidl

²German Red Cross Blood Donor Service, Institute for Transfusion Medicine and Immunohaematology, Frankfurt/Main, Germany

,

Sabine Wicker

³Occupational Health Service, Goethe-University Hospital, Frankfurt/Main, Germany

,

Klaus Badenhoop‡

¹Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, Goethe-University Hospital, Frankfurt/Main, Germany

› Institutsangaben

Abstract

Variants of vitamin D metabolism-genes may predispose to type 2 diabetes (T2D). This study investigated the impact of these variants on disease susceptibility, Vitamin D, parathyroid hormone, C-peptide and HbA1c levels before and after cholecalciferol supplementation in patients with T2D.

Twelve polymorphisms within CYP2R1, CYP27B1, DBP, VDR and CYP24A1 were genotyped in 553 T2D patients and 916 controls. In addition 65 patients receiving either cholecalciferol or placebo were analyzed during 6 months intervention and 6 months follow-up.

T2D risk alleles are VDR rs7975232 “G” (p_c=0.031), rs1544410 “G” (p_c=0.027) and CYP2R1 rs10741657 “A” (p_c=0.016). Patients with genotypes CYP27B1 rs10877012 “CC” (p_c=4x10^-5), DBP rs7041 “GG” (p_c=0.003), rs4588 “CC” (p_c = 3x10^-4), CYP24A1 rs2585426 “CG” (p_c=0.006) and rs2248137 “CG” (p_c=0.001) showed lower 25(OH)D3 and DBP rs4588 “CC” lower 1,25(OH)2D3 levels (p_c=0.005). Whereas DBP rs4588 “CC” (p_c=0.009), CYP27B1 rs10877012 “AC” (p_c=0.059), VDR rs7975323 “AG” (p_c=0.033) and rs1544410 “GG” (p_c=0.013) are associated with higher 25(OH)D3 levels at 6 months’ follow-up. Significant PTH suppression was detected for CYP2R1 “AG“ (p_c=0.002), DBP rs4588 “CC” (p_c<0.001), VDR rs110735810 “CT” (p_c<0.001) and CYP24A1 rs2248137 “GG” (p_c=0.021).

Genetic variants of the vitamin D system predispose to type 2 diabetes and regulate – partially - vitamin D metabolism, concentrations and the vitamin D status. Vitamin D insufficiency is a T2D risk factor. The response to cholecalciferol supplementation can be measured as 25(OH)D3 increment and PTH suppression. This process is regulated by genes of the vitamin D system conferring modest T2D risk.

Key words

CYP2R1 - CYP27B1 - DBP - VDR - CYP24A1 - GC

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Referenzen

References

1 Mezza T, Muscogiuri G, Sorice GP. et al. Vitamin D deficiency: A new risk factor for type 2 diabetes?. Ann Nutr Metab 2012; 61: 337-348
2 Lopez ER, Regulla K, Pani MA et al. CYP27B1 polymorphisms variants are associated with type 1 diabetes mellitus in Germans. J Steroid Biochem Mol Biol. 2004; 89–90 155–157
3 Cheng JB, Levine MA, Bell NH. et al. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci USA 2004; 101: 7711-7715
4 Zehnder D, Bland R, Walker EA. et al. Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in the human kidney. J Am Soc Nephrol 1999; 10: 2465-2473
5 Lips P. Vitamin D physiology. Prog Biophys Mol Biol 2006; 92: 4-8
6 Sakaki T, Sawada N, Nonaka Y. et al. Metabolic studies using recombinant escherichia coli cells producing rat mitochondrial CYP24 CYP24 can convert 1alpha,25-dihydroxyvitamin D3 to calcitroic acid. Eur J Biochem 1999; 262: 43-48
7 Kurylowicz A, Ramos-Lopez E, Bednarczuk T. et al. Vitamin D-binding protein (DBP) gene polymorphism is associated with Graves' disease and the vitamin D status in a Polish population study. Exp Clin Endocrinol Diabetes 2006; 114: 329-335
8 Strobel F, Reusch J, Penna-Martinez M. 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 2014; 46: 54-58
9 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215
10 Ross AC, Manson AE, Abrams SA. et al. The 2011 report on dietary reference intakes for calcium and vitamin D. Public Health Nutr 2011; 14: 938-939
11 Xue A, Wu Y, Zhu Z. et al. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat Commun 2018; 9: 2941
12 Jorde R, Schirmer H, Wilsgaard T. et al. Polymorphisms related to the serum 25-hydroxyvitamin D level and risk of myocardial infarction, diabetes, cancer and mortality. The Tromso Study. PLoS One 2012; 7: e37295
13 Yuan S, Jiang X, Michaëlsson K. et al. Genetic prediction of serum 25-hydroxyvitamin D, calcium, and parathyroid hormone levels in relation to development of type 2 diabetes: A mendelian randomization study. Diabetes Care 2019; 42: 2197-2203
14 Wang TJ, Zhang F, Richards JB. et al. Common genetic determinants of vitamin D insufficiency: A genome-wide association study. Lancet 2010; 376: 180-188
15 Ye 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 2015; 3: 35-42
16 Ramos-Lopez E, Bruck P, Jansen T. et al. CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans. Diabetes Metab Res Rev 2007; 23: 631-636
17 Ortlepp JR, Lauscher J, Hoffmann R. et al. The vitamin D receptor gene variant is associated with the prevalence of type 2 diabetes mellitus and coronary artery disease. Diabet Med 2001; 18: 842-845
18 Bid HK, Konwar R, Aggarwal CG. et al Vitamin D receptor (FokI, BsmI and TaqI) gene polymorphisms and type 2 diabetes mellitus: a North Indian study. Indian J Med Sci 2009; 63: 187-194
19 Mukhopadhyaya PN, Acharya A, Chavan Y. et al. Metagenomic study of single-nucleotide polymorphism within candidate genes associated with type 2 diabetes in an Indian population. Genet Mol Res 2010; 9: 2060-2068
20 Li L, Wu B, Liu JY. et al. Vitamin D receptor gene polymorphisms and type 2 diabetes: A meta-analysis. Arch Med Res 2013; 44: 235-241
21 Ogunkolade BW, Boucher BJ, Prahl JM. et al. Vitamin D receptor (VDR) mRNA and VDR protein levels in relation to vitamin D status, insulin secretory capacity, and VDR genotype in Bangladeshi Asians. Diabetes 2002; 51: 2294-2300
22 Malecki MT, Frey J, Moczulski D. et al. Vitamin D receptor gene polymorphisms and association with type 2 diabetes mellitus in a Polish population. Exp Clin Endocrinol Diabetes 2003; 111: 505-509
23 Dilmec F, Uzer E, Akkafa F. et al. Detection of VDR gene ApaI and TaqI polymorphisms in patients with type 2 diabetes mellitus using PCR-RFLP method in a Turkish population. J Diabetes Complicat 2010; 24: 186-191
24 Wang Q, Xi B, Reilly KH. et al. Quantitative assessment of the associations between four polymorphisms (FokI, ApaI, BsmI, TaqI) of vitamin D receptor gene and risk of diabetes mellitus. Mol Biol Rep 2012; 39: 9405-9414
25 Neyestani TR, Djazayery A, Shab-Bidar S. et al. Vitamin D receptor Fok-I polymorphism modulates diabetic host response to vitamin D intake: Need for a nutrigenetic approach. Diabetes Care 2013; 36: 550-556
26 Ramos-Lopez E, Kahles H, Weber S. et al. Gestational diabetes mellitus and vitamin D deficiency: Genetic contribution of CYP27B1 and CYP2R1 polymorphisms. Diabetes Obes Metab 2008; 10: 683-685
27 Hypponen E, Berry DJ, Wjst M. et al. Serum 25-hydroxyvitamin D and IgE - a significant but nonlinear relationship. Allergy 2009; 64: 613-620
28 Signorello LB, Shi J, Cai Q. et al. Common variation in vitamin D pathway genes predicts circulating 25-hydroxyvitamin D Levels among African Americans. PLoS One 2011; 6: e28623
29 Hussein AG, Mohamed RH, Alghobashy AA. Synergism of CYP2R1 and CYP27B1 polymorphisms and susceptibility to type 1 diabetes in Egyptian children. Cell Immunol 2012; 279: 42-45
30 Ramos-Lopez E, Bruck P, Jansen T. et al. CYP2R1-, CYP27B1- and CYP24-mRNA expression in German type 1 diabetes patients. J Steroid Biochem Mol Biol 2007; 103: 807-810
31 Simon KC, Munger KL, Kraft P. et al. Genetic predictors of 25-hydroxyvitamin D levels and risk of multiple sclerosis. J Neurol 2011; 258: 1676-1682
32 Lu L, Sheng H, Li H. et al. Associations between common variants in GC and DHCR7/NADSYN1 and vitamin D concentration in Chinese Hans. Hum Genet 2012; 131: 505-512
33 Azad AK, Bairati I, Qiu X. et al. Genetic sequence variants in vitamin D metabolism pathway genes, serum vitamin D level and outcome in head and neck cancer patients. Int J Cancer 2013; 132: 2520-2527
34 Carpenter TO, Zhang JH, Parra E. et al. Vitamin D binding protein is a key determinant of 25-hydroxyvitamin D levels in infants and toddlers. J Bone Miner Res 2013; 28: 213-221
35 Engelman CD, Meyers KJ, Iyengar SK. et al. Vitamin D intake and season modify the effects of the GC and CYP2R1 genes on 25-hydroxyvitamin D concentrations. J Nutr 2013; 143: 17-26
36 Santos BR, Mascarenhas LP, Boguszewski MC. et al. Variations in the vitamin D-binding protein (DBP) gene are related to lower 25-hydroxyvitamin D levels in healthy girls: A cross-sectional study. Horm Res Paediatr 2013; 79: 162-168
37 Coppenhaver DH, Sollenne NP, Bowman BH. Post-translational heterogeneity of the human vitamin D-binding protein (group-specific component). Arch Biochem Biophys 1983; 226: 218-223
38 Ravnsborg T, Olsen DT, Thysen AH. et al. The glycosylation and characterization of the candidate Gc macrophage activating factor. Biochim Biophys Acta 2010; 1804: 909-917
39 Testa R, Vanhooren V, Bonfigli AR. et al. N-glycomic changes in serum proteins in type 2 diabetes mellitus correlate with complications and with metabolic syndrome parameters. PLoS One 2015; 10: e0119983
40 Nimitphong H, Saetung S, Chanprasertyotin S. et al. Changes in circulating 25-hydroxyvitamin D according to vitamin D binding protein genotypes after vitamin D(3) or D(2) supplementation. Nutr J 2013; 12: 39
41 Serrano JC, De Lorenzo D, Cassanye A. et al. Vitamin D receptor BsmI polymorphism modulates soy intake and 25-hydroxyvitamin D supplementation benefits in cardiovascular disease risk factors profile. Genes Nutr 2013; 8: 561-569
42 Jones G, Prosser DE, Kaufmann M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): Its important role in the degradation of vitamin D. Arch Biochem Biophys 2012; 523: 9-18
43 Fu L, Yun F, Oczak M. et al. Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation. Clin Biochem 2009; 42: 1174-1177
44 Muindi JR, Adjei AA, Wu ZR. et al. Serum vitamin D metabolites in colorectal cancer patients receiving cholecalciferol supplementation: Correlation with polymorphisms in the vitamin D genes. Horm Cancer 2013; 4: 242-250
45 Aloia JF, Chen DG, Chen H. The 25(OH)D/PTH threshold in black women. J Clin Endocrinol Metab 2010; 95: 5069-5073
46 Yao P, Sun L, Lu L. et al. Effects of Genetic and nongenetic factors on total and bioavailable 25(OH)D responses to vitamin D supplementation. J Clin Endocrinol Metab 2017; 102: 100-110
47 Al-Daghri NM, Mohammed AK, Al-Attas OS. et al. Vitamin D receptor gene polymorphisms modify cardiometabolic response to vitamin D supplementation in T2DM Patients. Sci Rep 2017; 7: 8280
48 Eyles DW, Smith S, Kinobe R. et al. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat 2005; 29: 21-30
49 Sisley SR, Arble DM, Chambers AP. et al. Hypothalamic vitamin D improves glucose homeostasis and reduces weight. Diabetes 2016; 65: 2732-2741

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