ID: 20-0484 10 1 C Cristelo et al. Vitamin D, cathelicidin and 10:1 R1–R12 type 1 diabetes REVIEW The roles of vitamin D and cathelicidin in type 1 diabetes susceptibility Cecília Cristelo1,2, Alexandra Machado2, Bruno Sarmento1,3 and Francisco Miguel Gama2 1i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal 2CEB – Centro de Engenharia Biológica, Universidade do Minho, Braga, Portugal 3CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde & Instituto Universitário de Ciências da Saúde, Gandra, Portugal Correspondence should be addressed to F M Gama: [email protected] Abstract Type 1 diabetes has an increasingly greater incidence and prevalence with no cure Key Words available. Vitamin D supplementation is well documented to reduce the risk of developing f β cell protection type 1 diabetes. Being involved in the modulation of cathelicidin expression, the question f cathelicidin whether cathelicidin may be one of the underlying cause arises. Cathelicidin has been f diabetes implicated in both the development and the protection against type 1 diabetes by f immunomodulation mediating the interplay between the gut microbiome, the immune system and β cell f vitamin D function. While its potential on type 1 diabetes treatment seems high, the understanding of its effects is still limited. This review aims to contribute to a more comprehensive understanding of the potential of vitamin D and cathelicidin as adjuvants in type 1 Endocrine Connections diabetes therapy. (2021) 10, R1–R12 Type 1 diabetes Diabetes mellitus refers to a group of metabolic diseases This is most concerning in children with less than 15 characterised by chronic hyperglycaemia due to absent years and particularly less than 5 years (8). insulin secretion, insulin action or both (1). Diabetes Type 1 diabetes is a multifactorial disease. Genetic is classically divided in type 1 and type 2 diabetes (2) factors associated with certain haplotypes from the HLA and of all individuals diagnosed with this disease, type 1 complex have been shown to decisively influence the diabetes represents up to 10%, of which 80–90% are susceptibility (9). Additionally, environmental factors children or adolescents (3). Type 1 diabetes is commonly such as the seasonal environment at birth (3), infant diet referred to as autoimmune diabetes and results from (10), viral infections (11) and the gut microbiome (12) the autoimmune destruction of pancreatic β cells. have also been suggested to play a role on type 1 diabetes On the other hand, type 2 diabetes, which accounts development. The heterogeneity and variation in the for the remaining 90% of cases, affects mostly adults, pathogenic process and phenotypic characteristics makes although its incidence in youth is increasing due to it difficult to diagnose and to treat the disease at an early changes in lifestyle and increased obesity (4). Differently stage (13). from type 1 diabetes, type 2 diabetes is characterised by insulin resistance and defective insulin secretion, Pathophysiology which may be accompanied by the destruction of β cells (5). Type 1 diabetes is a chronic disease resulting from the Type 1 diabetes is one of the most common endocrine autoimmune destruction of the insulin-producing β cells diseases in children (6); recent reports indicate a yearly in the pancreas. Not all cases of type 1 diabetes are increase from 3 to 4% on the incidence in childhood (7). autoimmune mediated. For around 10–30% of patients, https://ec.bioscientifica.com © 2021 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-20-0484 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 09/25/2021 05:33:06AM via free access -20-0484 PB–XX C Cristelo et al. Vitamin D, cathelicidin and 10:1 R2 type 1 diabetes the cause is idiopathic and the specific pathogenesis is also be looked as a multivalent strategy. Alternative unclear (14). strategies have been explored, including the use of The triggering event that leads to the autoimmune immunosuppressant therapies, which leave the patients elimination of β cells is still unknown but may be immunocompromised and susceptible to infections; related to a failure in the elimination of self-reactive the use of antigenic tolerance therapies, the protection T cells, in the thymus. This leads to the escape of T cell of β cells and selective stimulation of their proliferation populations – autoreactive against β cell proteins such as or reprograming of non-β cells into functional β cells insulin, glutamic acid decarboxylase (GAD) and protein (19). Although islets have limited regenerative capacity tyrosine phosphatase IA-2 – to the periphery (15, 16, 17). it has been found that, within islets, α cells and δ cells Upon encounter with the self-antigens, T cells undergo can undergo transdifferentiation to functional β cells or activation and expansion, releasing proinflammatory β-like cells (25, 26). Pancreatic β cells replicate at a high cytokines. This promotes pancreatic infiltration of more rate during the foetal and neonatal stages, a process that T cells, macrophages, B lymphocytes and plasma cells, with rapidly declines with age (27). Inducing β cells to undergo resultant autoimmune destruction of the insulin-secreting mitosis using harmine and 5-iodotubercidin, inhibitors of β cells (18). The symptoms are observed only when around the dual-specificity tyrosine phosphorylation-regulated two-thirds of the β cell mass is lost (19). During the pre- kinase 1A (DYRK1A), has shown promising to the recovery symptomatic stage, markers of autoimmunity, presence of of β cell mass (28, 29). However, the limited potency islet autoantibodies in circulation, as well as dysregulation and lack of β cell specificity, with undesirable off-target of blood glucose start to arise due to the loss of β cells. effects, limit their applicability. A drug able to stimulate With the continuous decline in β cells, the symptomatic β cell regeneration while simultaneously shifting the stage is reached and signs of diabetes, polyuria, polydipsia, proinflammatory autoimmune islet milieu to an anti- weight loss, fatigue, diabetic ketoacidosis (DKA) are inflammatory one, to prevent future insulitis, would be identified (20). The rate of progression to the symptomatic the ideal candidate for type 1 diabetes cure (19). stage can vary from months to decades, in both children Vitamin D and the antimicrobial peptide cathelicidin and adults (13). have been proposed as promising candidates for this endeavour. On one hand, both pre-clinical and clinical research demonstrated vitamin D has a well-established Type 1 diabetes management strategies role in the protection from type 1 diabetes development. Given the absence or reduced insulin secretion, an On the other hand, although cathelicidin expression is obvious strategy for type 1 diabetes management involves directly induced by vitamin D, the mechanistic effects of its exogenous administration (21). Since the discovery of cathelicidin in type 1 diabetes susceptibility and therapy insulin in 1922, much advances in health care has been are still poorly understood. achieved, such that the previously terminal disease is now treatable. Nowadays, the availability of new insulin analogues, with varying duration of activity, allows for Vitamin D a multiple-dose insulin therapy that better resembles the physiologic insulin release (22). The combination of Vitamin D3 (cholecalciferol, hereafter mentioned as D3) the rigorous monitoring of blood glucose levels with the is a liposoluble molecule precursor of human steroid multifunctional insulin therapy enables the glycaemic hormones, which can be obtained through diet or control, and to prevent, or delay, the complications of exposure to UV-B sunlight. After production, D3 is partially type 1 diabetes (23). stored in adipose tissues in a few hours, while other Despite these advances, type 1 diabetes is still part is converted to 25-hydroxyvitamin D3 (25(OH)D3) associated with a high medical, psychological and by the liver. 25(OH)D3 is further hydroxylated into the financial burden. Hypoglycaemia and ketoacidosis remain active form 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) life-threatening complications, as well as an increased risk in the kidneys (30), which then acts to maintain serum of co-morbidities (cardiovascular disease, retinopathy and calcium levels, although its activities go beyond calcium nephropathy) and premature death (22, 24). homeostasis and bone metabolism (31). Efforts to manage the disease are not able to reach The vitamin D receptor (VDR) has been identified in a cure but only a control of the symptoms. Given the practically all immune cell types (32). After intracellular heterogeneity of type 1 diabetes, treatment should enzymatic activation of vitamin D and subsequent VDR https://ec.bioscientifica.com © 2021 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-20-0484 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 09/25/2021 05:33:06AM via free access C Cristelo et al. Vitamin D, cathelicidin and 10:1 R3 type 1 diabetes Figure 1 Classic vitamin D signalling pathway. Serum 25(OH)D3 is converted to 1,25(OH)2D3 by mitochondrial 1α-hydroxylase, initiating the signalling cascade by binding to VDR, which dimers with RXR, and binds to specific DNA sequences, VDREs,