A case study was recently reported in the Immunotherapy journal, in which supplementation with calcifediol, in conjunction with insulin, resulted in an unusually long remission phase in a young man newly-diagnosed with type 1 diabetes.¹ Type 1 diabetes is an autoimmune disease characterised by progressive immunologic destruction of the insulin-producing beta islet cells of the pancreas. Over time, insulin secreting ability reduces to a critical level, and reliance on exogenous insulin is lifelong. Around two thirds of patients newly diagnosed with type 1 diabetes will enter a partial remission phase or “honeymoon phase” following the initiation of insulin therapy. During this phase, patients experience a reduction of symptoms and often an increase in endogenous insulin secretion. The exact reason for this is unclear, but is thought to be due to a reduced load on the residual pancreatic beta cells, thanks to the exogenous insulin; and possibly due to reduced autoimmune destruction of the remaining beta cells. The duration of this honeymoon phase varies, but rarely exceeds 12 months. A longer honeymoon phase has many benefits for the patient, including a significantly reduced risk of diabetic complications.¹

The causes of type 1 diabetes are multifactorial; however, vitamin D deficiency is thought to play a role. In this case, the young man had suboptimal levels of vitamin D at the time of diagnosis (28 ng/mL [70 nmol/L] ideal range >75 nmol/L). His doctor therefore prescribed calcifediol, at a dose of 0.266 mg (266 mcg) once every 20 days (equivalent daily dose 13 mcg).¹ Calcifediol is a form of vitamin D3 that is naturally produced in the body by the liver from the precursor colecalciferol. Calcifediol bypasses hydroxylation in the liver, a metabolic step required by colecalciferol. As such, calcifediol only requires one reaction to convert to active vitamin D3.² The patient was also prescribed two forms of insulin, namely rapid-acting insulin lispro three times daily plus low-dose basal insulin degludec once daily, with a total daily insulin dose of 0.7 IU/kg body weight/24 hours. He was also given nutritional counselling on following a Mediterranean diet. Over the next 30 days, his insulin dose was reduced as he experienced repeated hypoglycaemic episodes. By day 30, he was considered to be in the honeymoon phase of partial remission, and the rapid-acting insulin was ceased entirely, leaving only the low-dose basal insulin at a dose of 0.09 IU/kg body weight daily. This dose was maintained over the next two and half years, reaching a maximum dose of 0.11 IU/kg of body weight per day at 31 months. The patient retained substantial beta cell function throughout this time, as measured by serum C-peptide of 1.16 ng/mL (384 pmol/L) and insulin dose-adjusted glycated haemoglobin (IDDA1c) of <9 (actual reading 6.4 at 31 months). These outcomes remained current at the time of publishing.¹

Given the unusually prolonged honeymoon phase observed in this patient, his doctors decided to perform immunophenotyping of his peripheral blood lymphocytes to assess immunological function. The panel found that the patient had lower than expected levels of CD4+ and CD8+ memory effector cells and T helper 17 cells, which play a pathogenic role via initiation of insulitis in type 1 diabetes. He also had normal levels of T regulatory cells. These findings indicate the presence of a predominant immunoregulatory T-cell phenotype, allowing for a prolonged honeymoon phase for this patient. Calcifediol is an important modulator of T regulatory cell function, and may have played a role in the development of a more tolerogenic immune profile, and subsequently less severe β-cell autoimmune destruction.¹

As a single case report, it is not possible to infer causality; however, the outcomes in this case align with the results of a recent randomised controlled trial.³ In this trial, 38 patients with new-onset type 1 diabetes were randomised to receive colecalciferol 2000 IU per day or placebo, alongside insulin therapy, for 18 months. The vitamin D group had a slower decline of residual beta cell function compared to the placebo group, with only 18.7% progressing to undetectable serum c-peptide levels by the end of the study, versus 62.5% in the placebo group. The vitamin D group also had a more favourable immunological profile compared to the placebo group, characterised by higher T regulatory cell function.³

The results of this case study,¹ along with the results of this clinical trial,³ indicate that calcifediol may be a beneficial supplement for patients recently diagnosed with type 1 diabetes.

References

1. Infante M, Vitiello L, Fabbri A, Ricordi C, Padilla N, Pacifici F, et al. Prolonged clinical remission of type 1 diabetes sustained by calcifediol and low-dose basal insulin: a case report. Immunotherapy. 2023 Sep;15(13):1009-19. DOI: 10.2217/imt-2022-0266

2. Sosa Henríquez M, Gómez de Tejada Romero MJ. Colecalciferol or Calcifediol in the Management of Vitamin D Deficiency. Nutrients. 2020;12(6):1617. http://dx.doi.org/10.3390/nu12061617

3. Gabbay MAL, Sato MN, Finazzo C, Duarte AJS, Dib SA. Effect of Cholecalciferol as Adjunctive Therapy With Insulin on Protective Immunologic Profile and Decline of Residual β-Cell Function in New-Onset Type 1 Diabetes Mellitus. Arch Pediatr Adolesc Med. 2012 Jul 1;166(7):601-07. doi:10.1001/archpediatrics.2012.164