DPP-4 Inhibition Leads to Decreased Pancreatic Inflammatory Profile and Increased Frequency of Regulatory T Cells in Exp
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ORIGINAL ARTICLE
DPP-4 Inhibition Leads to Decreased Pancreatic Inflammatory Profile and Increased Frequency of Regulatory T Cells in Experimental Type 1 Diabetes Mariana Rodrigues Davanso ,1,2,8 Carolina Caliari-Oliveira,3 Carlos Eduardo Barra Couri,4 Dimas Tadeu Covas,1,4 Angela Merice de Oliveira Leal,5 Júlio César Voltarelli,1,4 Kelen Cristina Ribeiro Malmegrim,1,6 and Juliana Navarro Ueda Yaochite7
Abstract— Sitagliptin is a dipeptidyl peptidase-4 inhibitor (iDPP-4), which has been used for type 2 diabetes treatment. Recently, iDPP-4 has been described as a promising treatment of type 1 diabetes (T1D) but is still necessary to evaluate immune effects of sitagliptin. C57BL/6 mice were induced by multiple low doses of streptozotocin. Diabetes incidence, insulin, glucagon, glucagon-like peptide-1 (GLP-1) serum levels, and inflammatory cytokine levels were quantified in pancreas homogenate after 30 and 90 days of treatment. In addition, frequencies of inflammatory and regulatory T cell subsets were determined in the spleen and in the pancreatic lymph nodes. iDPP-4 decreased blood glucose level while increased GLP-1 and insulin levels. After long-term treatment, treated diabetic mice presented decreased frequency of CD4+CD26+ T cells and increased percentage of CD4+CD25hiFoxp3+ T cells in the spleen. Besides, pancreatic lymph nodes from diabetic mice treated with iDPP-4 presented lower percentage of CD11b+ cells and decreased levels of inflammatory cytokines in the pancreas. Treatment of type 1 diabetic mice with iDPP-4 improved metabolic control, decreased inflammatory profile in the pancreatic microenvironment, and increased systemic regulatory T cell frequency. Therefore, we suggest the long-term use of sitagliptin as a feasible and effective therapy for T1D. KEY WORDS: DPP-4 inhibitor; sitaglipitin; experimental type 1 diabetes; GLP-1; regulatory T cells.
Júlio César Voltarelli is deceased. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10753-018-00954-3) contains supplementary material, which is available to authorized users. 1
Centro de Terapia Celular, Centro Regional de Hemoterapia do Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Rua Tenente Catão Roxo 2501, Ribeirão Preto, São Paulo 14049-900, Brazil 2 Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo 14049-900, Brazil 3 In Situ Cell Therapy, Supera Innovation Technology Park, Av. Dra. Nadir Aguiar, 1805, prédio 2, sala 313, Ribeirão Preto, São Paulo 14056-680, Brazil
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Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo 14049-900, Brazil 5 Departamento de Medicina, Universidade Federal de São Carlos, Rodovia Washington Luís Km 235, São Carlos, São Paulo 13565-905, Brazil 6 Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciênc
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