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Inflammation

pp 1–14 | Cite as

DPP-4 Inhibition Leads to Decreased Pancreatic Inflammatory Profile and Increased Frequency of Regulatory T Cells in Experimental Type 1 Diabetes

  • Mariana Rodrigues DavansoEmail author
  • Carolina Caliari-Oliveira
  • Carlos Eduardo Barra Couri
  • Dimas Tadeu Covas
  • Angela Merice de Oliveira Leal
  • Júlio César Voltarelli
  • Kelen Cristina Ribeiro Malmegrim
  • Juliana Navarro Ueda Yaochite
ORIGINAL ARTICLE

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 

Notes

Acknowledgements

The authors would like to thank and honor the memory of Prof. Júlio César Voltarelli, mastermind of stem cell transplantation studies for autoimmune diseases in Brazil. The authors are grateful to Patricia V. B. Palma and Camila C.B.O. Menezes for flow cytometry analysis, to the staff of the Regional Blood Center of Ribeirão Preto, to Rosane Bolzoni, Maria Isabel da Matta, and Giuliana M. Bertolino for their assistance with routine laboratory procedures.

Author’s Contribution

MRD participated in the design of the study, performed experiments and sample collection, analyzed all results, and wrote the manuscript. CCO participated in the experiments, sample collection, and reviewed the manuscript. DTC provided infrastructure and administrative supports. JCV (in memoriam) participated in the conception and coordination of the study, provided financial support, and discussed the experimental plans and results. AMOL, KCRM, and CEBC supervised the work, discussed the experimental plans and results, and reviewed the manuscript. JNUY supervised the work, provided financial support, discussed the experimental plans and results, and reviewed the manuscript.

Funding

This study is financially supported by the Brazilian research financial agencies São Paulo Research Foundation (FAPESP; grants 2010/02074-3 and INCTC-2008/57877-3) and CNPq (INCTC-573754/2008–0).

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.

Supplementary material

10753_2018_954_MOESM1_ESM.pdf (43 kb)
Supplemental Table 1 Levels of cytokines in pancreatic homogenate of untreated diabetic animals and treated with the DPP-4 inhibitor after 30 and 90 days of treatment. IFN-γ, TNF-α, IL-17 and IL-10 were measured in of diabetic group and diabetic group treated with iDPP-4 after 30 and 90 days of treatment. After the treatment with iDDP-4, the animals had their pancreas collected and processed in the presence of protease inhibitor. Cytokines were quantified by ELISA and its concentration represented by the ratio of pictogram of cytokine per gram of pancreatic tissue. *P < 0.05 diabetic group compared to the diabetic group treated with iDPP-4 in the same period. (PDF 42 kb)
10753_2018_954_MOESM2_ESM.pdf (66 kb)
Supplemental Table 2 iDPP-4 treatment ameliorated metabolic, systemic and local immunological parameters of type 1 diabetic mice. Diabetic animals treated and untreated with DPP-4 inhibitor incorporated into the diet ad libitum for 30 and 90 days. After being considered diabetic, the animals received control diet (AIN-93 M Purified) or diet containing MK0431 (MK0431 4 g/kg added to AIN-93 M diet Purified) ad libitum. (A) Active GLP-1, insulin and glucagon serum levels of untreated diabetic mice and treated with DPP-4 inhibitor after treatment were determined by ELISA. Glucose tolerance oral test (GTOT) was performed after iDPP-4. At the end of treatment and after 12 h of fasting, glucose solution (1.5 mg/g animal) was administered by gavage (oral) and blood glucose levels were monitored before glucose administration, 15, 30, 60, 90, 120 and 180 min after. (B) Pancreas morphology was performed by hematoxylin-eosin staining and glucagon staining. After the treatment with iDDP-4, the animals had their pancreas collected, embedded in paraffin, cut into sections of 5 μm, to perform the immunohistochemical reactions to hematoxylin-eosin and glucagon, viewed by optic microscopy. Staining for glucagon was performed for to evaluate the numbers and size of pancreatic islet. Quantitative analysis for all staining was performed in a blinded manner with imaging software. (C) CD3 + CD4+, CD3 + CD8+, CD3 + CD4 + CD26+ and CD3 + CD8 + CD26+ T cells, CD4 + CD25 + Foxp3+ and CD4 + CD25hiFoxp3+ regulatory T cells were quantified in the spleen of diabetic group and diabetic group treated with iDPP-4 after of treatment by flux cytometry. (D) CD3 + CD4+ and CD3 + CD8+ T cells and CD11b + macrophages in pancreatic lymph nodes. IFN-γ, TNF-α, IL-17 and IL-10 were quantified by ELISA and its concentration represented by the ratio of pictogram of cytokine per gram of pancreatic tissue. All parameters described above were evaluated 30 and 90 days after iDPP4 treatment. (PDF 65 kb)
10753_2018_954_MOESM3_ESM.docx (152 kb)
Supplemental Figure 1 Analysis of chow and iDPP-4 intake between different cages of diabetic mice (D) and diabetic mice treated with iDPP-4 (D + iDPP-4). Diabetic mice and diabetic mice treated with DPP-4 inhibitor incorporated into the diet ad libitum for 30 and 90 days. After being considered diabetic, the animals received control diet (AIN-93 M Purified) or diet containing MK0431 (MK0431 4 g/kg added to AIN-93 M diet Purified) ad libitum. (A) The amount of chow consumed by the groups was analyzed. (B) The amount of iDPP-4 consumed by the groups was calculated based on chow consumed. Since between cages mice could ingest different amounts of DPP-4 inhibitor, two different cages were analyzed. (DOCX 151 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mariana Rodrigues Davanso
    • 1
    • 2
    Email author
  • 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
  • Juliana Navarro Ueda Yaochite
    • 7
  1. 1.Centro de Terapia Celular, Centro Regional de Hemoterapia do Hospital das Clínicas, Faculdade de Medicina de Ribeirão PretoUniversidade de São PauloRibeirão PretoBrazil
  2. 2.Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão PretoUniversidade de São PauloRibeirão PretoBrazil
  3. 3.In Situ Cell Therapy, Supera Innovation Technology ParkRibeirão PretoBrazil
  4. 4.Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão PretoUniversidade de São PauloRibeirão PretoBrazil
  5. 5.Departamento de MedicinaUniversidade Federal de São CarlosSão CarlosBrazil
  6. 6.Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão PretoUniversidade de São PauloRibeirão PretoBrazil
  7. 7.Departmento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Odontologia e EnfermagemUniversidade Federal do CearáFortalezaBrazil

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