The association between vitamin D, vitamin D Binding proteins and VDR polymorphisms in diabetic and non-diabetic patients

Maepa, Setjie Welcome (2019-03)

Thesis (MSc)--Stellenbosch University, 2019.

Thesis

ENGLISH ABSTRACT: Introduction: Type 2 diabetes mellitus (T2DM) is by far the most prevalent form of diabetes manifesting with insulin resistance (IR), abnormal pancreatic β-cell function and hyperglycaemia. Evidence from epidemiological and observational studies have shown that vitamin D deficiency is associated with increased risk for T2DM although the findings are inconsistent and inconclusive. In the circulation vitamin D is transported bound to vitamin D binding protein (VDBP), evidence showed that vitamin D levels are positively associated with VDBP levels. Several genes such as vitamin D receptor gene (VDR), involved in the metabolic pathway of T2DM have been considered good candidate for susceptibility to T2DM. The present study aimed to investigate the association between vitamin D, vitamin D binding proteins (VDBP) and vitamin D receptor (VDR) polymorphisms in T2DM and non-diabetic patients in the mixed ancestry population. Materials and methods: The current study comprised of 1603 participants (387 males and 1216 females). Vitamin D levels were measured using the paramagnetic particle chemiluminescence test on a Beckman DXI. Vitamin D binding protein (VDBP) in serum samples was measured using the Human Vitamin D BP Quantikine ELISA kit. Fok1 (rs2228570), Apa1 (rs7975232) and Taq1 (rs731236) single nucleotide polymorphisms (SNPs) of the VDR gene were genotyped from a genomic DNA using the TaqMan SNP Genotyping Assays and were confirmed by direct sequencing. Results: Vitamin D deficiency (44%) and insufficiency (42.6%) were highly prevalent and optimal 25(OH)D levels were very low with only 13% having optimal levels. The overall vitamin D status of the whole population group was insufficient (22.0±7.6 ng/mL). 25(OH)D levels and serum VDBP varied according to gender with males having higher 25(OH)D levels (23.6±7 vs 21.5±7.5ng/mL, P=0.0006) and females with significantly higher serum VDBP levels (299.1±71.2 vs 315.9±76.1 µg/mL, P<0.0001). 25(OH)D levels were generally significantly decreased in the hyper-glycemic subgroups. Screen-detected DM males had low 25(OH)D levels compared to normoglycaemic group (17.0±6.1vs 24.2±8.2, P=0.0214). A similar trend was observed in the female groups (21.1±6.0 vs 22.4±7.9, P=0007). Anthropometric measurements including the BMI (kg/m2), Waist C (cm) and Hip C (cm) were significantly higher in hyper-glycaemic group than in normo-glycaemic males and females (All, P<0.0001). In contrast, there were no significant differences in serum VDBP (µg/mL) between the glycaemic sub-groups in either male (P=0.5614) or females (P= 0.4813). The glycaemic parameters, as expected, were significantly increased in the hyperglycaemic sub-groups in both genders, including FBG (mmol/L), 2 hr BG (mmol/L), HbA1c (%), FBI (mIU/L), 2 hr BI (mIU/L) and HOMA-IR (All, both males and females P<0.0001). In general, the lipids, including the triglycerides (mmol/L), LDL-C (mmol/L) and Cholesterol (mmol/L) were also significantly increased in both genders in the hyper-glycaemic sub-groups (All, males P≤0.0300, females P<0.0001), while HDL-C (mmol/L) was significantly decreased in both males and females in the hyperglycaemic sub-groups (All, P≤0.0308). The variant genotype GG of the Fok1, AA of Apa1 and GG of the Taq1 SNPs were not significantly different in hyper-glycaemic patients compared to normo-glycaemic group (58.5% vs 55.1%, P-value, 40.1% vs 38.0%, P-value and 6.9% vs 8.5%, Pvalue,) respectively. Similarly, there was no significant difference in the alleles frequency distribution of these SNPs between the groups. Results also demonstrated no significance difference in the genotype or allele frequency distribution of Fok1 (rs2228570), Apa1 (rs7975232) and Taq1 (rs731236) SNPs between subjects with optimal Vitamin D (25(OH)D ng/mL) levels and those with insufficient/deficient levels (P≥0.2036 and P≥0.6347 respectively). These trends were also observed when serum VDBP levels were evaluated against Fok1, Apa1 and Taq1 genotypes. Multiple linear regression showed that low 25(OH)D was associated with increased LDL-C and PTH in both male and females irrespective of T2DM, but serum VDBP was associated with low 25(OH)D in hyper-glycaemic females only. In normo-glycaemic males 19.5% of the variation in 25(OH)D was attributed to increased LDL-C and in the hyper-glycaemic group 15.5% it was attributed to PTH and CRP. In normo-glycaemic females 12.8% variation in 25(OH)D was attributed to LDL-C, serum creatinine and PTH, whereas in hyper-glycaemic group 16.1% was attributed to increased age, serum VDBP, triglycerides, LDL-C, creatinine and PTH. Conclusion: This study showed prevalence of vitamin D deficiency/insufficiency in the mixed ancestry population group. There was no association between vitamin D (25(OH)D), vitamin D binding proteins (serum VDBP) and VDR polymorphisms in T2DM patients. Serum VDBP levels were associated with low vitamin D levels in hyper-glycaemic females only. Increased LDL-C, PTH and CRP were predictors of low vitamin D levels.

AFRIKAANSE OPSOMMING: Geen opsomming

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