Reduced Serum Vitamin D–Binding Protein Levels Are Associated With Type 1 Diabetes

Department of Pathology, University of Florida, Gainesville, Florida, USA.
Diabetes (Impact Factor: 8.1). 08/2011; 60(10):2566-70. DOI: 10.2337/db11-0576
Source: PubMed


Previous studies have noted a specific association between type 1 diabetes and insufficient levels of vitamin D, as well as polymorphisms within genes related to vitamin D pathways. Here, we examined whether serum levels or genotypes of the vitamin D-binding protein (VDBP), a molecule key to the biologic actions of vitamin D, specifically associate with the disorder.
A retrospective, cross-sectional analysis of VDBP levels used samples from 472 individuals of similar age and sex distribution, including 153 control subjects, 203 patients with type 1 diabetes, and 116 first-degree relatives of type 1 diabetic patients. Single nucleotide polymorphism (SNP) typing for VDBP polymorphisms (SNP rs4588 and rs7041) was performed on this cohort to determine potential genetic correlations. In addition, SNP analysis of a second sample set of banked DNA samples from 1,502 type 1 diabetic patients and 1,880 control subjects also was used to determine genotype frequencies.
Serum VDBP levels were highest in healthy control subjects (median 423.5 µg/mL [range 193.5-4,345.0; interquartile range 354.1-]586), intermediate in first-degree relatives (402.9 µg/mL [204.7-4,850.0; 329.6-492.4]), and lowest in type 1 diabetic patients (385.3 µg/mL [99.3-1,305.0; 328.3-473.0]; P = 0.003 vs. control subjects). VDBP levels did not associate with serum vitamin D levels, age, or disease duration. However, VDBP levels were, overall, lower in male subjects (374.7 µg/mL [188.9-1,602.0; 326.9-449.9]) than female subjects (433.4 µg/mL [99.3-4,850.0; 359.4-567.8]; P < 0.0001). It is noteworthy that no differences in genotype frequencies of the VDBP polymorphisms were associated with serum VDBP levels or between type 1 diabetic patients and control subjects.
Serum VDBP levels are decreased in those with type 1 diabetes. These studies suggest that multiple components in the metabolic pathway of vitamin D may be altered in type 1 diabetes and, collectively, have the potential to influence disease pathogenesis.

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    • "Glycosylation can increase the solubility of glycoproteins due to the hydrophilic nature of carbohydrates and could stimulate glomerular clearance and/or reduced proximal tubular endocytic uptake of VDBP. Previous studies have reported an enhanced excretion of urinary VDBP in patients associated with progressive renal tubular dysfunction and in patients with diabetic nephropathy [39] [45]. In our study, the three patients whose urinary VDBP excretion was measured showed normal renal function. "
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    ABSTRACT: Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disorder caused by a deficiency of hepatic porphobilinogen deaminase (PBGD). The disease is characterized by life threatening acute neurovisceral attacks. The aim of this study was to identify metabolites secreted by the hepatocytes that reflect differential metabolic status in the liver and that may predict response to the acute attack treatment. Plasma vitamin D binding protein (VDBP) from a mouse model of AIP displayed an abnormal migration in 2D-electrophoresis that is efficiently recovered upon gene therapy leading to liver specific over-expression of the PBGD protein. The change in VDBP mobility results from a differential isoelectric point suggesting a post-translational modification that takes place preferably in the liver. Liquid chromatography-massspectrometry (LC-MS) analysis of human samples before and after glycosidase treatment revealed glycosylated plasma VDBP specifically in patients with recurrent attacks of AIP. Glycosylated VDBP recovered normal values in three severely afflicted AIP patients submitted to therapeutic liver transplantation. Our findings suggest that post-translational modification of VDBP might be considered as a promising biomarker to study and monitor the liver metabolic status in patients with AIP. We describe an increased glycosylation of VDBP in porphyric livers. Normal glycosylation was recovered upon liver gene therapy in a mouse model of porphyria or after liver transplantation in severely afflicted patients with AIP. Moreover, quantification of glycosylated VDBP by our ELISA immunoassay or LC-MS protocol in patients undergoing PBGD gene therapy ( may be used as a marker indicating improvement or normalization of the patient's hepatic metabolism. Copyright © 2015. Published by Elsevier B.V.
    Journal of proteomics 05/2015; 127. DOI:10.1016/j.jprot.2015.05.004 · 3.89 Impact Factor
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    • "Alternatively, the bioavailable and DBP-bound 25(OH)D can be calculated using equations adapted from Vermeulen et al. [7] and is currently being used in clinical practice [8]. Recent studies have found that serum DBP and vitamin D levels are decreased in type 1 diabetes mellitus (T1DM) [9], chronic liver [10], and renal diseases [11], while pregnancy and oral contraceptive pills (OCP) increase DBP and vitamin D levels [12, 13]. On the other hand, in a large cohort of healthy adults with sufficient vitamin D levels, the biological effects of vitamin D on PTH levels are mainly independent of DBP concentration [14]. "
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    ABSTRACT: There is a high prevalence of vitamin D deficiency worldwide, but how to define vitamin D deficiency is controversial. Currently, the plasma concentration of total 25-hydroxyvitamin D [25(OH)D] is considered an indicator of vitamin D status. The free hormone hypothesis states that protein-bound hormones are inactive while unbound hormones are free to exert biological activity. The majority of circulating 25(OH)D and 1,25(OH)2D is tightly bound to vitamin D binding protein (DBP), 10-15% is bound to albumin, and less than 1% of circulating vitamin D exists in an unbound form. While DBP is relatively stable in most healthy populations, a recent study showed that there are gene polymorphisms associated with race and ethnicity that could alter DBP levels and binding affinity. Furthermore, in some clinical situations, total vitamin D levels are altered and knowing whether DBP is also altered may have treatment implications. The aim of this review is to assess DBP concentration in different physiological and pathophysiological conditions. We suggest that DBP should be considered in the interpretation of 25(OH)D levels.
    International Journal of Endocrinology 04/2014; 2014(3):981581. DOI:10.1155/2014/981581 · 1.95 Impact Factor
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    • "Vit D levels were found to be correlated negatively with HOMA-IR and 2-h glucose levels [9]. Most of the human studies investigating the association between Vit D status and DM are either cross-sectional, which focuses on the effect of hypovitaminosis D, or supplementation trials with regular Vit D as protection against development of diabetes [10–12]. Although there are some contradictory results, higher baseline 25 (OH) D was found to predict better β-cell function in the PROMISE study, and diabetes was also found to be associated with low levels of 25(OH)D, but there was no conclusion about the exact mechanism related to Vit D and diabetes [13–16]. "
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    ABSTRACT: Background Hyperglycemia is a common complication of diabetes melitis (DM) and in the absence of metabolic decompensation is a common finding in the Emergency Department (ED). We aimed to evaluate the 25 OH Vit D [25(OH)D] and procalcitonin (PCT) levels during hyperglycemia and after normalization of blood glucose. Material/Methods The study included 88 patients over the age of 18 years who presented with acute hyperglycemia at the Hacettepe University Department of Emergency Medicine. Euglycemia was obtained within 6–12 hours and serum samples were taken from patients on admission and 6 hours after normalization of blood glucose. Along with plasma glucose, plasma 25(OH)D and PCT levels were measured using ELISA. Results There were 88 (45 males) patients, with a median age of 60.0±13.9 years. Serum 25(OH)D levels increased in all patients after normalization of blood glucose, and serum PCT levels decreased in the whole group. This decrease was independent of type of diabetes or presence of infection. Conclusions We demonstrated an increase in 25(OH)D after normalization of blood glucose, and a decrease in PCT in patients with hyperglycemia. This effect was independent of the type of diabetes and presence of infection. Further studies are needed to evaluate the faster link between metabolic abnormalities, vitamin D, PCT, and inflammation.
    Medical science monitor: international medical journal of experimental and clinical research 04/2013; 19(1):264-8. DOI:10.12659/MSM.883880 · 1.43 Impact Factor
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