Thursday, November 30, 2023
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Vitamin D and its active metabolite, 1,25-di(OH)-vitamin D or calcitriol, have long been recognized as important regulators
of serum calcium and bone health. Production of calcitriol is dependent on adequate vitamin D. Following constitutive conversion
of vitamin D to 25(OH)-vitamin D by the liver, most circulating calcitriol (hormonal calcitriol) is made by the highly regulated
1alpha-hydroxylase (CYP27B1) present in the kidneys. Numerous other tissues also possess 1alpha-hydroxylase and appear to
produce calcitriol locally at high concentrations. The receptor for calcitriol, the vitamin D receptor (VDR), is expressed
in virtually all tissues. Thus, this latter form of calcitriol production constitutes a classic paracrine-autocrine system.
Local production of calcitriol may even be important in the classic calcitriol target tissues of bone and the parathyroid
gland because investigators have demonstrated the presence of 1alpha-hydroxylase in bone and parathyroid
cells.[1,2]
Activation of the VDR by hormonal or locally produced calcitriol generally promotes differentiation of tissues and inhibits proliferation. Some regulatory actions of VDR are even independent of calcitriol. Scientists have investigated the relationship of vitamin D deficiency to cancer, cardiovascular disease, neuromuscular function, and autoimmune diseases.
A large proportion of the population has low vitamin D levels, which are generally defined as a serum level of 25(OH)-vitamin D less than 20 or 30 ng/mL. Although sunlight stimulates skin production of vitamin D, many in modern society are dependent on ingestion of vitamin D in milk or supplements to maintain normal vitamin D levels, especially during the winter months. Vitamin D deficiency is particularly common in hospitalized individuals, those with chronic diseases, and African Americans. Over the past decade, the relationship of vitamin D deficiency to the risk of developing diabetes mellitus (DM) and the risk for diabetic complications has been of great interest to scientists.
Dialysis patients have an enormous burden of vitamin D abnormalities, and this burden also falls on diabetics, who constitute almost 50% of new dialysis patients. Due to the loss of renal function, dialysis patients are unable to produce adequate calcitriol. Consequently, these patients have very low hormonal calcitriol levels. Without supplementation with calcitriol or a calcitriol analog, they have profoundly diminished activation of the VDR in tissues throughout the body. Wolf and colleagues examined incident hemodialysis patients, and found that diabetics were more likely to be severely 25(OH)-vitamin D-deficient (< 10 ng/mL) than nondiabetics (22% vs 17%).[3] Lower 25(OH)-vitamin D levels and lower calcitriol levels strongly correlated with an increased risk for death during the first 90 days in patients not given injectable calcitriol or an analog.[3]
Several observational studies have suggested that either low vitamin D levels or low vitamin D intake may predispose to the development of both type 1 and type 2 DM. The Nurses' Health Study found that vitamin D intake above 800 IU/day and more than 1200 mg of calcium per day were associated with a 33% reduction in the risk of developing type 2 DM compared with an intake of < 600 mg of calcium and < 400 IU of vitamin D.[4] A meta-analysis of largely observational studies concluded that there was "a relatively consistent association between low vitamin D status, calcium or dairy intake, and prevalent type 2 DM or metabolic syndrome.[5]" Evidence from interventional trials suggests that combined vitamin D and calcium supplementation may help prevent type 2 DM in only some populations at high risk for diabetes.[5]
Low vitamin D levels, low sun exposure, and low intake of vitamin D have each been associated with an increased risk for the development of type 1 DM. In animal models, induction of type 1 DM by streptozocin induces a marked fall in calcitriol levels, whereas 25(OH)-vitamin D levels remain normal. Treatment with insulin restores calcitriol levels to normal. Calcitriol has an immunomodulatory effect. In a nonobese diabetic mouse model, administration of calcitriol or 1alpha-(OH)-vitamin D (a precursor of calcitriol) has been shown to significantly reduce the likelihood of development of type 1 DM.[6]
A report from Martins and colleagues on data from over 15,000 adults in the Third National Health and Nutrition Examination Survey is perhaps the best recent evidence on vitamin D and the general population.[7] The 25(OH)-vitamin D levels were lower in diabetics, women, the elderly, and racial minorities, groups that are at increased risk of having chronic kidney disease (CKD).[7] Scragg and colleagues reported in 1995 the association of low 25(OH)-vitamin D levels with the presence of DM or glucose intolerance.[8] Consistent with these findings, low vitamin D levels are associated with obesity, as assessed by body mass index or waist circumference, and weakly with elevated glycated hemoglobin (A1C) levels.[9]
Wang and colleagues studied 1739 Framingham offspring participants without prior cardiovascular disease, and found that low 25(OH)-vitamin D levels (< 15 ng/mL) were significantly associated with an increased incidence of a first cardiovascular event during the mean 5.4 years of follow-up.[10] Among diabetics in this cohort, low 25(OH)-vitamin D levels were significantly more common than nondiabetics (11% vs 7%), but the association of low vitamin D levels to first cardiovascular event remained after adjustment for diabetics and other known risk factors.
Low 25(OH)-vitamin D levels have been shown to correlate with the presence of cardiovascular disease in diabetics.[11] Similarly, hypovitaminosis D has been independently associated with carotid artery intimal-medial thickening, a harbinger of cerebrovascular and cardiovascular events.[12] Suzuki and colleagues found that microvascular complications were more frequent when vitamin D levels were low, despite similar duration of disease and other clinical characteristics compared with control patients without complications.[13]
These data suggest that diabetic patients are at greater risk of being vitamin D-deficient and harmed by this deficiency. The presence of CKD will compromise the production of calcitriol, and potentially further contribute to inadequate vitamin D signaling. Consistent with this, among 463 diabetics with CKD, low vitamin D levels were independently associated with the presence of cardiovascular disease.[14]
Vitamin D receptor activators (VDRAs) are calcitriol or related analogs capable of binding to the VDR and activating it. Use of a VDRA is common in patients with CKD and dialysis for the treatment of secondary hyperparathyroidism. In nephrology, the first suggestion that use of a VDRA may be related to survival was the sentinel study in 2003 by Teng and colleagues reporting an association of improved survival in hemodialysis patients given paricalcitol, a VDRA and analog of calcitriol, compared with native calcitriol.[15] Critics of that study suggested that either agent may be worse than no VDRA therapy. These critics noted that both paricalcitol and calcitriol increase serum calcium and phosphorus, which are associated with lower survival in some observational studies of the dialysis population.
A subsequent observational study by Teng and colleagues found that use of either paricalcitol or calcitriol in dialysis patients was associated with improved survival compared with no VDRA therapy.[16] The strength and consistency of the association of VDRA use with improved survival has increased over the succeeding years, with diverse studies of CKD and dialysis populations confirming the associations.[17-19]
Most of the data outlined above show associations of vitamin D, calcitriol, or calcitriol analogs with cardiovascular burden and survival in diabetic patients. The potential mechanisms by which treatment of vitamin D and calcitriol deficiency can lead to improved survival and lower cardiovascular events reflect the diverse actions of vitamin D in the body. Studies are ongoing to determine through randomized trials whether use of vitamin D can lower inflammation, moderate cardiac and vascular disease, and lower proteinuria. Significant work is still required to determine whether this decade of associating vitamin D deficiency with diabetics and their complications will be followed by results showing that treatment can mitigate those complications, and even lower the prevalence of diabetes.
This activity is supported by an independent educational grant from Abbott.
