📘 Vitamin D and the risk for type 1 diabetes

Vitamin D functions as a hormone that guides the immune system, not merely as a simple nutrient. Its active form (calcitriol) is able to bind to the vitamin D receptor present in almost all cells of the immune system (T and B lymphocytes, macrophages, dendritic cells, natural killer cells and neutrophils). Once activated, this receptor 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 toward one's own body [1].

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

Beta cells in the pancreatic islets have vitamin D receptors on them. 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. In the absence of an adequate intake of vitamin D, the insulin secretion of beta cells stimulated by rising blood glucose is diminished, and the beta cells' response to glycemic increases becomes slower and ultimately insufficient [2].

Vitamin D protects the survival of beta cells. In addition, calcitriol reduces the self-determined cell death (apoptosis) of beta cells, as a self-defense response (to protect the rest of the still-unaffected cells) to the accumulation of toxic residues in the insulin-production machinery (endoplasmic reticulum stress). 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, well-behaved T lymphocytes, which maintain tolerance toward beta cells [4].

At the pancreatic level, these changes translate into a reduction of local inflammation, with protection of beta cells from the attack of cytotoxic T lymphocytes. Vitamin D diminishes the expression on the surface of beta cells of those 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 compared to those who have none of these autoantibodies [5]. It is important to note, however, that vitamin D supplementation does not decrease the titer of these antibodies. Vitamin D is not recommended as a specific preventive intervention for type 1 diabetes mellitus [6].

The vitamin D receptor (VDR) is a protein located in the nucleus. In order to bind to its receptor, vitamin D must first reach it, that is, enter the nucleus. Once VDR is activated, being already in the nucleus it is very easy for it to access DNA and stimulate the expression of target genes [7].

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. We thus understand why vitamin D has so many effects in the body [7].

Higher vitamin D levels in childhood are associated with a lower risk of developing autoantibodies against the pancreatic islets. It is possible, however, that this is not valid in all populations [8].

At present, it is considered that there is an association between vitamin D deficiency and the risk of autoimmunity, but there is insufficient evidence to establish causality [6]. As a result, we interpret things as a mere association for now. It is possible that the things that modify vitamin D levels are the ones that actually modify the risk of T1D. Maintaining an adequate vitamin D status in childhood remains a prudent measure [9].

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 register significantly lower rates [10]. 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 angle of sunlight increases, so that at latitudes above approximately 35° north or south cutaneous synthesis is minimal during the winter months [10].

This limitation of cutaneous synthesis, together with shorter time spent outdoors, with clothing that covers the skin and with atmospheric pollution, has the potential to increase the risk of T1D, possibly including through lower vitamin D generation [10]. People with darker skin synthesize vitamin D more slowly, which aggravates the situation among immigrants from equatorial to northern regions. Latitude is, however, not the only variable here. Sardinia, although located at a southern latitude, has an incidence of type 1 diabetes mellitus comparable to Finland, probably because of genetic particularities related to HLA [5] [11]. Latitude appears rather to be a population marker of vitamin D status, but since T1D is a disease with multifactorial etiology (multiple causes), several things are needed for it to appear.

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 autumn and winter, with a peak in the cold months and lower in summer [12]. This pattern is more pronounced in older children and adolescents compared to those under five years. Serum vitamin D levels also generally reach a minimum at the end of winter and the beginning of spring and a maximum at the end of summer. The coincidence between the minimum point of vitamin D concentration and the peak of T1D diagnosis has been interpreted as a seasonal reduction of protective immunomodulation [10].

However, this association is very possibly nothing more than a coincidence, because vitamin D is not the only seasonal factor involved. Enterovirus infections, especially Coxsackie B, also have a similar seasonal pattern and are a possible trigger of islet autoimmunity [10]. 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, possibly because of low maternal vitamin D status in the last trimester or perinatal viral exposures. The current model for explaining the seasonality of T1D diagnosis proposes a sum of multiple exposures, including vitamin D deficiency, viruses and dietary variations, all on a background of genetic susceptibility (especially HLA) [5] [12].

The development of pancreatic beta cells and fetal immune programming take place in the uterus, which has suggested the hypothesis that maternal vitamin D status could influence the risk of type 1 diabetes mellitus in the child. A low vitamin D level in the mother in the third trimester is associated with an increased risk for the child [13], however especially in the presence of a genetic susceptibility related to the vitamin D receptor [14]. There is no demonstrated protective effect of maternal vitamin D supplementation on islet autoimmunity in the future child [6].

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. No international guideline recommends vitamin D supplementation in pregnancy specifically for the prevention of type 1 diabetes mellitus in the child [6]. Empirical supplementation above the daily recommended dose in pregnant women is recommended for other important benefits, such as reducing the risk of preeclampsia, premature birth, low birth weight and neonatal mortality. 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.

Some observational studies (of weak quality) show a small association between vitamin D supplementation in childhood and a slightly lower risk of subsequent type 1 diabetes mellitus. There are no randomized controlled intervention trials with adequate statistical power that test childhood vitamin D supplementation as a protective factor for the development of type 1 diabetes mellitus [6].

Observational studies are vulnerable to many confounders because 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. Prevention of type 1 diabetes is done through screening of autoantibodies in people at high risk and possibly teplizumab for delaying progression from stage 2 to stage 3 (very expensive). Routine vitamin D supplementation in infants and children is recommended for other proven benefits, such as prevention of rickets, normal height growth and reduction of respiratory infections [15].

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) [15].

Formula-fed infants do not require supplementation if they consume approximately one liter of fortified formula per day. If they consume less they also need to receive 400 IU/day. An alternative is vitamin D supplementation of the breastfeeding mother (with high daily doses), which increases the vitamin D content of breast milk up to levels equivalent to direct supplementation of the infant. Standard maternal doses of 400–600 IU/day are not sufficient to fortify breast milk. After the first year, the recommended intake rises to 600 IU/day for children between 1 and 18 years [15].

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). Calcemia reaches values above 11 mg/dL and is accompanied by hypercalciuria. Symptoms of vitamin D intoxication include anorexia, nausea, vomiting, constipation, polyuria, polydipsia, muscle weakness, confusion. In severe forms, renal lithiasis (kidney stones), nephrocalcinosis (diffuse calcification in the kidneys), acute renal failure, pancreatitis, arrhythmias and vascular calcifications appear [16].

Chronic vitamin D supplementation should not exceed 1000 IU/day for infants under 6 months, 1500 IU/day between 6 and 12 months, 2500 IU/day between 1 and 3 years, 3000 IU/day between 4 and 8 years and 4000 IU/day above 9 years, including in pregnancy and lactation. 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. Respecting the recommended doses by age category and avoiding the association with excessive calcium intake significantly reduces this risk [16].

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 [10]. 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, while 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. It is even recommended to avoid direct sun exposure for infants under six months, and older children should use protective clothing, hats and sunscreen with SPF of at least 15–30. Artificial tanning beds are contraindicated, being classified as group 1 carcinogens. Although the north-south gradient suggests a role of UVB exposure in the incidence of type 1 diabetes mellitus, the medical recommendation remains obtaining vitamin D through foods, possibly fortified, and supplements, not through prolonged sun exposure [15].

Calcitriol is the active hormonal form of vitamin D, and alfacalcidol is a precursor that bypasses the limiting renal step and is converted hepatically into calcitriol. Both act directly on the vitamin D receptor [7].

Calcitriol administered to patients newly diagnosed with type 1 diabetes mellitus has no effect on preserving residual beta cell function, stimulated C-peptide or reducing HbA1c. Calcitriol or alfacalcidol are for this reason not recommended for the prevention or metabolic control in type 1 diabetes mellitus [17].

The "honeymoon", or partial remission, is a transient period that can appear after diagnosis, in which residual beta cell function partially recovers, insulin requirement sometimes drops to zero and glycemic control stabilizes. Preservation of even a small amount of endogenous insulin secretion is clinically relevant, being associated with lower glycemic variability, fewer hypoglycemias 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 [18].

Unfortunately, there is no conclusive evidence regarding the benefit of vitamin D supplementation with the aim of prolonging the honeymoon. No current guideline recommends vitamin D as standard for prolonging the honeymoon [6]. Current research is exploring combinations between vitamin D and other substances, where vitamin D acts as an immunomodulatory adjuvant, without having practical conclusions at this time [4].