Combined Use of Vitamin D and DPP-4 Inhibitors as a Potential Adjuvant Treatment Strategy to Enhance the Efficacy of Novel Beta-Cell Replacement Therapies for Type 1 Diabetes

Abstract

Emerging evidence suggests that vitamin D and dipeptidyl peptidase-4 (DPP-4) inhibitors exert synergistic immunomodulatory, anti-inflammatory and antioxidant actions. Moreover, intervention studies showed that combination therapy based on the concomitant use of vitamin D and DPP-4 inhibitors (VIDPP-4i) may preserve beta-cell function in patients with type 1 diabetes mellitus (T1D) and latent autoimmune diabetes in adults (LADA). These effects are particularly relevant in the context of beta-cell replacement strategies, whose long-term efficacy can be hampered by various factors, such as immune-mediated graft rejection, inadequate vascularization, hypoxia, trauma-induced cell apoptosis, fibrosis, host immune response, and recurrence of autoimmunity. Based on preclinical and clinical studies conducted in the fields of autoimmune diabetes and solid organ/cell transplantation, the present narrative review aims to describe the rationale behind the investigation of VIDPP-4i combination therapy as an adjuvant treatment strategy to enhance the efficacy of novel beta-cell replacement therapies for T1D. In this regard, we discuss the potential immune and metabolic mechanisms through which vitamin D and DPP-4 inhibitors can promote the long-term function and survival of transplanted islets in patients with T1D receiving various types of beta-cell replacement therapies, including therapeutic approaches using encapsulated stem cell-derived beta cells.

Keywords: CD26; DPP-4 inhibitors; T1D; VIDPP-4i; beta-cell replacement; dipeptidyl peptidase-4; islet encapsulation; islet transplantation; type 1 diabetes; vitamin D.

Figure 1

Potential mechanisms of actions through which vitamin D and DPP-4 inhibitor (VIDPP-4i) adjuvant combination therapy may promote successful outcomes of novel beta-cell replacement therapies for type 1 diabetes (particularly long-term islet graft survival and prevention of autoimmunity recurrence and allograft rejection). Figure 1 was created with images adapted from Servier Medical Art licensed under the Creative Commons Attribution 4.0 International License (CC BY 4.0) [URL: https://smart.servier.com/—accessed on 8 July 2025]. The main references for the information presented in the figure are the following: [34,35,36,37,38,39,40,41,42,43,48,49,50,51,56,64,65,66,67,68,79,80,81,82,84,85,88,89,90,91,115,116,117,118,119,120,121,122,125,126,127,128,129,131,151]. Abbreviations: DPP-4i, dipeptidyl peptidase-4 inhibitors; VIDPP-4i, vitamin D and DPP-4 inhibitor combination therapy.