Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp Preliminary report Dipeptidyl peptidase-4 inhibitors (DPP-4i) combined with vitamin D3: An exploration to treat new-onset type 1 diabetes mellitus and latent autoimmune diabetes in adults in the future Marcelo Maia Pinheiro a, ⁎ , Felipe Moura Maia Pinheiro b , Maria Luisa Trabachin c a Univag – University Center, Faculty of Medicine, Av. Dom Orlando Chaves, 2655 - Cristo Rei, CEP:78118-000 Várzea Grande, Mato Grosso, Brazil b Cuiabá University (UNIC), Faculty of Medicine, Rua: Manoel Jose de Arruda, 3.100, Jardim Europa, CEP:78065-900 Cuiabá, Mato Grosso, Brazil c Post-graduation in Health Sciences, Faculty of Medicine, Federal University of Mato Grosso(UFMT), Av. Fernando Corrêa da Costa, 2367, Boa Esperança, CEP:78060- 900 Cuiabá, Mato Grosso, Brazil ARTICLE INFO Keywords: Type 1 diabetes mellitus LADA DPP-4 inhibitor Vitamin D3 ABSTRACT Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by destruction of pancreatic beta cells through cell injury caused primarily by cytotoxic T lymphocytes (CD8 + ). The pathophysiological basis of T1DM seems to be an imbalance between a reduced function of T regulatory lymphocytes and an increased inflammatory activity of Th17 lymphocytes caused by increased production of inflammatory cytokines, as IL-1β, IL-6, IL-17 and IFN-gamma due to environmental factors and genetic predisposition. The preservation of the reserve of beta cells in new-onset T1DM and latent autoimmune diabetes in adults (LADA) by im- munomodulation in addition to the incretin effect seems to be possible with an association of DPP-4 inhibitors and vitamin D3. In this review, we discuss the effects of both drugs on the immune system and on beta cell function and their eventual additive effects in preserving the residual function of beta cells in new-onset T1DM and LADA. 1. Introduction Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by injury to and destruction of pancreatic beta cells secondary to activation of dendritic cells and macrophages, CD4 + and CD8 + T lymphocytes, and B lymphocytes. These cells interact to gen- erate an inflammatory response, leading to insulitis with a pre- dominance of CD8 + T lymphocytes [1]. The exact trigger of the auto- immune process is not fully understood but may involve genetic predisposition, viral infections, changes in the intestinal flora, and low vitamin D levels [2–5]. The continuous destruction of beta cells promotes loss of secretory reserve of insulin, leading to clinical diabetes when the mass of beta cells reduces to less to 20% of the total amount present before the disease [6]. Beta cells are known to be able to replicate after birth, and even patients with long-standing T1DM have residual beta cells pro- ducing insulin [7]. Preservation of residual pancreatic insulin function in patients with T1DM is fundamental to reduce blood glucose fluc- tuations, decrease insulin requirement and improve metabolic control, thereby reducing the occurrence of complications related to hypergly- cemia [8,9]. One of the goals of treatment in T1DM is to preserve/ regenerate the mass of pancreatic beta cells through intensive insulin therapy [10], reducing glucotoxicity on these cells, or through therapies that regulate the immune system, reducing the inflammatory response and cell apoptosis and improving the function of beta cells [11–14]. In T1DM, there is an imbalance between regulatory T cells (Treg), which have reduced suppressive function [15,16], and increased activity of inflammatory Th17 cells, which are responsible for the autoimmune process against beta cells [17,18]. IL-17 + CD8 + T cells (also known as Tc17 cells) [19] and IL-17 + CD4 + are increased in children with new- onset type I diabetes compared to age-matched healthy controls [20]. This imbalance seems to be generated by increased serum IL-6 levels [21] and other cytokines as IL-1β, IL-17 and INF- < gamma > [22,23]. However, it is important to emphasize the importance of IL-6 levels to control the Treg/Th17 cells differentiation and programmation [24]. Thus, therapies correcting this imbalance between Treg and Th17 cells could assist in preserving the secretory function of beta cells in T1DM. In fact, other authors and we have reported cases of prolonged clinical remission and preservation of secretory beta cell reserves with di- peptidyl peptidase-4 (DPP-4) inhibitors and/or vitamin D3 in patients with T1DM and latent autoimmune diabetes in adults (LADA) [25–31]. Based on the above, the aim of this review is to discuss the https://doi.org/10.1016/j.intimp.2018.02.003 Received 8 October 2017; Received in revised form 3 February 2018; Accepted 9 February 2018 ⁎ Corresponding author. E-mail address: marcelo.pinheiro@univag.edu.br (M.M. Pinheiro). International Immunopharmacology 57 (2018) 11–17 1567-5769/ © 2018 Elsevier B.V. All rights reserved. T