Vitamin D in type 1 diabetes: risk, supplementation and safety

Vitamin D functions as a hormone that guides the immune system, not merely as a simple nutrient. Its active form (calcitriol) binds to the vitamin D receptor. This receptor is present in almost all cells of the immune system (T and B lymphocytes, macrophages, dendritic cells, natural killer cells and neutrophils). Once activated, it controls the production of hundreds of molecules involved in the proper functioning of the immune system. When dendritic cells come into contact with vitamin D, they change their behavior and become more tolerant of one's own body [1].

The effects extend to both arms of immunity. In innate immunity, vitamin D stimulates the production of antimicrobial peptides, strengthening the general anti-infection defense, and calms inflammation. In adaptive immunity, vitamin D shifts the balance of T lymphocytes away from pro-inflammatory subtypes toward regulatory, calming subtypes that promote tolerance. This reconfiguration is essential for maintaining immune tolerance, so that we do not attack our own body. It also explains why vitamin D deficiency is frequently associated with autoimmune diseases [1].

Beta cells in the pancreatic islets have vitamin D receptors. They are also able to activate vitamin D, by transforming it into calcitriol. The calcitriol thus produced will act on the very beta cell that produced it (autocrine effect), with positive effects on insulin synthesis and its prompt release when needed. Without an adequate intake of vitamin D, beta cells secrete less insulin in response to rising blood glucose. Their response to rises in blood glucose becomes slower and ultimately insufficient [2].

Vitamin D supports beta cell survival. In addition, calcitriol reduces the programmed cell death (apoptosis) of beta cells. This death occurs when toxic residues accumulate in the insulin-production machinery (endoplasmic reticulum stress). In this way, the severely damaged cell is eliminated so that the still-unaffected cells are protected. The cost, however, is the loss of beta cells, and vitamin D limits this loss. All these mechanisms explain why prolonged vitamin D insufficiency reduces both the secretory capacity and the number of pancreatic beta cells [3].

Type 1 diabetes is an autoimmune disease in which autoreactive T lymphocytes destroy pancreatic beta cells. Vitamin D intervenes directly in this process by reconfiguring the immune response. Calcitriol (activated vitamin D) inhibits the development of special types of autoreactive T lymphocytes and reduces the production of those substances they use to attack beta cells. Simultaneously, activated vitamin D stimulates the development of regulatory T lymphocytes, which maintain tolerance toward beta cells [4].

In the pancreas, these changes reduce local inflammation and protect beta cells from attack by cytotoxic T lymphocytes. Vitamin D reduces the display, on the surface of beta cells, of the structures that help the immune system recognize them more easily. Patients with anti-GAD, anti-IA-2 or anti-ZnT8 autoantibodies generally have lower vitamin D levels than those who have none of these autoantibodies. There is no solid evidence that vitamin D supplementation lowers the titer of these antibodies, and small studies have contradictory results [4]. Vitamin D is not recommended as a specific preventive intervention for type 1 diabetes mellitus [5].

The vitamin D receptor (VDR) is a protein located in the nucleus. To bind to its receptor, vitamin D must first reach it, that is, enter the nucleus. Once VDR is activated, it is already in the nucleus, so it can easily access DNA and stimulate the expression of target genes [6].

VDR is expressed in over 30 types of tissues, including cells of the immune system, pancreatic beta cells, enterocytes, renal cells, osteoblasts, keratinocytes and muscle cells. This explains why vitamin D has so many effects in the body [6].

Higher vitamin D levels in childhood are associated with a lower risk of developing autoantibodies against the pancreatic islets. This may not hold true in all populations, however [7].

At present, an association is thought to exist between vitamin D deficiency and the risk of autoimmunity, but there is insufficient evidence to establish causality [5]. As a result, we interpret this as a mere association for now. It is possible that the factors that modify vitamin D levels are the ones that actually modify the risk of type 1 diabetes. Maintaining an adequate vitamin D status in childhood remains a prudent measure [8].

The incidence of type 1 diabetes mellitus in children varies enormously globally, and one of the clearest geographic patterns is the north-south gradient. Northern European countries (Finland, Sweden, Norway) have the highest incidence rates, while Mediterranean (with the exception of Sardinia, in Italy) and equatorial regions record significantly lower rates [9]. This distribution partially reflects cutaneous vitamin D synthesis, which depends on exposure to UV radiation in the 290–315 nm band (UVB). The amount of UVB reaching the skin drops drastically as the solar zenith angle increases, that is, when the sun is lower in the sky. Above approximately 35° north or south, cutaneous synthesis is minimal during the winter months [9].

Added to this limitation of cutaneous synthesis are shorter time spent outdoors, clothing that covers the skin and atmospheric pollution. Together, these have the potential to increase the risk of type 1 diabetes, possibly in part through lower vitamin D production [9]. People with darker skin synthesize vitamin D more slowly, which worsens the situation among immigrants from equatorial to northern regions. Latitude is, however, not the only variable here. Sardinia, although located much further south, has an incidence of type 1 diabetes mellitus comparable to Finland, probably because of genetic features related to HLA (human leukocyte antigen) [10]. Latitude appears to be more of a population marker of vitamin D status. Type 1 diabetes has a multifactorial etiology (multiple causes), so several things are needed for it to appear.

Yes, the seasonal pattern exists. Epidemiological registries from the northern and southern hemispheres consistently confirm a seasonal pattern of type 1 diabetes mellitus diagnosis. The incidence of newly diagnosed cases is higher in the fall and winter, peaking in the cold months, and lower in summer [11]. This pattern is more pronounced in older children and adolescents than in those under five years. Serum vitamin D levels also generally reach a minimum at the end of winter and the beginning of spring. The maximum comes at the end of summer, as the figure below shows. The coincidence between the minimum point of vitamin D concentration and the peak of type 1 diabetes diagnosis has been interpreted as a seasonal reduction of protective immunomodulation [9].

However, this association is very possibly nothing more than a coincidence, because vitamin D is not the only seasonal factor involved. Respiratory viral infections, which are more common in winter, are another seasonal factor [12]. Enterovirus infections, especially Coxsackie B, are a possible trigger of islet autoimmunity, but they peak in summer and early autumn [9] [13]. Another observed phenomenon is the season-of-birth effect. Children born in spring appear to have a slightly higher risk of developing type 1 diabetes mellitus. Possible explanations are a low maternal vitamin D status in the last trimester or perinatal viral exposures. The current model explains this seasonality as a sum of multiple exposures. They include vitamin D deficiency, viruses and dietary variations, all on a background of genetic susceptibility (especially HLA) [11] [14].

Yes, an association exists. The development of pancreatic beta cells and fetal immune programming take place in the uterus. This gave rise to the hypothesis that maternal vitamin D status could influence the risk of type 1 diabetes mellitus in the child. In the mother, a low third-trimester vitamin D level is associated with an increased risk for the child. The association appears above all in the presence of a genetic susceptibility related to the vitamin D receptor [15] [16]. There is no demonstrated protective effect of maternal vitamin D supplementation on islet autoimmunity in the future child [5].

The proposed critical window is the second and third trimesters, when the thymus and the pancreatic endocrine cells develop and the neonatal immune system is calibrated. Vitamin D supplementation in pregnancy is not recommended specifically for the prevention of type 1 diabetes mellitus in the child [5]. In pregnancy, supplementation may be used above the usual intake of 600 IU/day, without exceeding 4000 IU/day, the tolerable upper limit [17] [18]. The possible benefits are a lower risk of preeclampsia, intrauterine death, preterm birth, a baby small for gestational age and neonatal death [17]. The dose should, however, be decided together with the doctor who is monitoring your pregnancy. Maintaining an adequate vitamin D status in pregnancy (ideally through a healthy lifestyle) is a good recommendation, with benefits for both maternal and fetal health.

Vitamin D supplementation in childhood has been linked to a slightly lower risk of later type 1 diabetes mellitus. The association is, however, small and comes from low-quality observational studies. There are no randomized controlled intervention trials with adequate statistical power on this question. They would need to test childhood vitamin D supplementation as a protective factor for the development of type 1 diabetes mellitus [5]. Observational studies are vulnerable to many confounders (other differences between the groups being compared, which can explain the result on their own).

Families in which vitamin D is supplemented at higher doses generally differ from those that use lower doses or none at all. Currently, vitamin D supplementation is not recommended for the prevention of type 1 diabetes mellitus. Early detection relies on screening for autoantibodies in people at high risk. The testing itself does not lower the risk of developing the disease, but rather reveals it before symptoms appear. Teplizumab, a very expensive treatment, may also be used to delay progression from stage 2 to stage 3. Routine vitamin D supplementation in infants and children is recommended to prevent rickets [19]. Supplementation may also reduce the risk of respiratory infections, but the evidence for this effect is weaker [17].

Breast milk contains very low amounts of vitamin D, insufficient for the infant's needs. Exclusively breastfed infants who do not receive a vitamin D supplement are at risk of developing (mild) vitamin D insufficiency, especially in winter and at northern latitudes. All breastfed or partially breastfed infants must receive 400 IU/day of vitamin D starting from the first days of life, with higher doses in premature infants (adjusted to weight) [19]. Formula-fed infants do not require supplementation if they consume approximately one liter of fortified formula per day.

If they drink less, they also need to receive 400 IU/day. An alternative that has been studied is supplementing the breastfeeding mother with 6400 IU/day [20]. This dose provides, through breast milk, the vitamin D the infant needs. Lower maternal doses, even 2400 IU/day, were not sufficient [20]. The 6400 IU/day dose does, however, exceed the usual limit of 4000 IU/day, so it is used only on medical advice and under medical supervision. After the first year, the recommended intake rises to 600 IU/day for children between 1 and 18 years.

Yes, at high doses. Vitamin D toxicity is rare and occurs at high doses administered chronically. The main manifestation is hypercalcemia and hypercalciuria (too much calcium in the urine), as a result of excessive intestinal absorption of calcium. The classical biochemical threshold for toxicity is a serum vitamin D level above 150 ng/mL (375 nmol/L), usually accompanied by a very low parathyroid hormone level (suppressed PTH). Blood calcium rises above 11 mg/dL (2.75 mmol/L) and is accompanied by hypercalciuria. Symptoms of vitamin D intoxication include anorexia, nausea, vomiting, constipation, polyuria, polydipsia, muscle weakness and confusion. Severe forms can lead to kidney stones (renal lithiasis), nephrocalcinosis (diffuse calcification in the kidneys), acute kidney failure, pancreatitis, arrhythmias and vascular calcifications [21].

Over the long term, total daily vitamin D intake, from food and supplements, should not exceed the following limits, by age category [22] [23]:

• 1000 IU/day (25 µg) — infants under 6 months;
• 1400 IU/day (35 µg) — between 6 and 12 months;
• 2000 IU/day (50 µg) — between 1 and 10 years;
• 4000 IU/day (100 µg) — from age 11 and in adults, including in pregnancy and lactation.

In the USA, the limits for children aged 1–10 years are higher, at 2500–4000 IU/day [18]. The limits apply to long-term daily intake, not to a dose given for a short time, and your doctor's recommendation takes precedence. Clinical toxicity usually requires a chronic intake above 10000 IU/day for several months. In infants and children, toxicity almost always occurs through dosing errors. Following the recommended doses for each age category and avoiding excessive calcium intake at the same time significantly reduce this risk [21].

Cutaneous vitamin D synthesis is triggered exclusively by UV radiation in the 290–315 nm band (UVB). Only about 1% of UVB coming from the sun reaches the ground surface. The amount that reaches the skin depends on the solar zenith angle, thus on latitude, season and time of day. At latitudes above 35°, cutaneous synthesis is minimal or absent in winter [9]. The skin phototype also modifies the efficiency of cutaneous vitamin D synthesis. People with very fair skin (Fitzpatrick type I) synthesize significant amounts of vitamin D in 10–15 minutes of face and arm exposure to summer sunlight. People with dark skin (types V–VI) need much longer exposures.

Sun exposure is not recommended as a main strategy for raising vitamin D levels, because UVB is the main etiological factor for skin cancers, including melanoma. Direct sun exposure should even be avoided in infants under six months. Older children should use protective clothing, hats and sunscreen with SPF of at least 30. Artificial tanning beds are contraindicated, because they are classified as group 1 carcinogens. The north-south gradient does suggest a role of UVB exposure in the incidence of type 1 diabetes mellitus. Even so, the medical recommendation remains to obtain vitamin D through foods, possibly fortified, and through supplements, not through prolonged sun exposure [19].

Calcitriol is the active hormonal form of vitamin D, and alfacalcidol is a precursor that bypasses the limiting renal step and is converted in the liver into calcitriol. Both act directly on the vitamin D receptor [6].

Calcitriol administered to patients newly diagnosed with type 1 diabetes mellitus does not preserve residual beta cell function or stimulated C-peptide and does not reduce HbA1c. For this reason, calcitriol and alfacalcidol are not recommended for prevention or for metabolic control in type 1 diabetes mellitus [24].

The "honeymoon", or partial remission, is a transient period that can appear after diagnosis. In it, residual beta cell function partially recovers, insulin requirement sometimes drops to zero and glycemic control stabilizes. Preserving even a small amount of endogenous insulin secretion is clinically relevant. It is associated with lower glycemic variability, fewer hypoglycemic episodes and lower risk of long-term microvascular complications. Vitamin D has been proposed as an adjuvant for prolonging this phase, due to its excellent safety profile and the high prevalence of its insufficiency at disease onset [25].

Unfortunately, there is no conclusive evidence regarding the benefit of vitamin D supplementation with the aim of prolonging the honeymoon [26]. Vitamin D is not recommended as a standard treatment for prolonging the honeymoon [26]. Current research is exploring combinations of vitamin D with other substances, where vitamin D acts as an immunomodulatory adjuvant, without practical conclusions at this time [4].