Early High-Dose Vitamin D and Residual β-Cell Function in Pediatric Type 1 Diabetes

Type 1 diabetes (T1D) is a chronic autoimmune disease that is immune-mediated destruction of pancreatic β-cells. It relies on insulin therapy. The currently accepted standardized treatment is intensive insulin therapy (>3 injections per day). The incidence of T1D is increasing globally, prompting researchers to study new immune regulation strategies to stop the autoimmune process and change the progression of the disease. T1D is considered to be a multifactorial disease, where genetic susceptibility and environmental factors interact to promote the triggering of an autoimmune response against β cells. In the past few decades, in addition to the established role of vitamin D in regulating calcium homeostasis and bone metabolism, vitamin D also played an anti-inflammatory and immunomodulatory role in inflammation. In addition, the global incidence of vitamin D deficiency is also increasing sharply, providing epidemiological evidence for the involvement of T1D vitamin D deficiency in the pathogenesis. Polymorphisms in key genes involved in vitamin D metabolism have also been shown to regulate the risk of T1D.

The results of animal experiments show that vitamin D can preserve the number and function of β cells through different mechanisms, such as: (1) promoting the transition from Th1 to Th2 cytokine expression profile, (2) enhancing the clearance of autoreactive T cells and reducing pancreatic islets infiltration of Th1 cells, (3) reducing cytokine-induced β cell damage, and the major histocompatibility complex (MHC) class I and II expression in β cells, (4) promoting Tregs differentiation and inhibition ability. Different intervention studies and randomized controlled trials have shown that supplementation of cholecalciferol (vitamin D3-a safe and easy-to-implement treatment for children, with a toxic dose of 20,000 to 50,000 IU/d for infants and young children and continuously taken for several weeks) in T1D patients can protect residual β Cell function (RBCF) and improve glycemic control: Gabbay et al. found that patients with newly-onset T1D receiving oral vitamin D3 (2000 IU/day) for 18 months can effectively slow down the rate of decrease in C-peptide levels after meals. In addition, the level of glycated hemoglobin (HbA1c) decreases; vitamin D3 (3000 IU/day) treatment for 12 months can delay the decline of RBCF in children with T1D within 1-2 years of the disease course and improve glycemic control. However, some reports found that according to age groups (1-3 years old -60,000 IU, 4-8 years old -90,000 IU, 9-18 years old-1,20,000 IU), with oral vitamin D3 administered once a month for 6 consecutive months, although it can improve fasting C-peptide (FCP) levels, it did not reduce HbA1c and daily insulin requirements; Perchard et al. proved that a single oral vitamin D3 (100,000 or 160,000 IU) failed to improve HbA1c levels in children with T1D.

Based on the results of previous studies, some researchers believe that maintaining a stable serum 25(OH)D3 level at an adequate level of vitamin D (>30/mL[>75 nmol/L]) may be more meaningful than a single high-dose oral vitamin D3. The latter is likely to be unable to maintain sufficient serum 25(OH)D3 levels during long-term follow-up. Therefore, Treiber et al. gave 15 children with newly-onset T1D oral vitamin D3 (70 IU/kg/d-first month loading dose 140 IU/kg/d) for 12 consecutive months to maintain a high level of serum 25(OH)D3. Compared with the placebo group, the intervention group had better peripheral blood Treg function at 12 months, but there was no significant difference in islet function and HbA1c level between the two groups (in intervention group, the percentage of 25(OH)D3 level>50 ng/mL[> 125 nmol/L]) was 50% after 3 months while 36% after 12 months); some researchers use direct supplementation of 25(OH)D3 (calcifediol), starting at 10ug/d until the serum 25(OH)D3 50-80 ng/mL[125-200 nmol/L] level is maintained (maintained at 71±5 ng/mL[177.5±12.5 nmol/L] after 1 year on average), FCP level of the intervention group remained stable after 1 year of treatment ; some studies have used calcitriol (1,25(OH)D3, or active vitamin D) 0.25ug qod for continuous oral administration for 1 year. The insulin consumption of the intervention group decreased, but no difference was observed in islet function.

It's worth noting that an individual's response to a given dose of vitamin D is highly variable and depends on several factors, such as baseline vitamin D status, body fat percentage, gender, ethnicity, genetics, seasonal changes, medications, and vitamin D formula type. Therefore, the optimized research design is necessary to more effectively evaluate the impact of vitamin D on the research results. Cholecalciferol (vitamin D3) is still considered the most promising vitamin D dosage form due to its long half-life, large safety window, and convenience (over-the-counter medication). To sum up, this study intends to use cholecalciferol, integrated individual factors, on the basis of maintaining a high serum 25(OH)D3 level, and an optimized research plan to extend the intervention time to evaluate the effect of vitamin D on T1D pancreatic islet function.