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01.02.2019 | ORIGINAL ARTICLE | Ausgabe 2/2019

Inflammation 2/2019

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

Zeitschrift:
Inflammation > Ausgabe 2/2019
Autoren:
Mariana Rodrigues Davanso, 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
Wichtige Hinweise

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.
Júlio César Voltarelli is deceased.

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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.

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Zusatzmaterial
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_MOESM1_ESM.pdf
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_MOESM2_ESM.pdf
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)
10753_2018_954_MOESM3_ESM.docx
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