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

Davanso, Mariana Rodrigues; Caliári-Oliveira, Carolina; Couri, Carlos Eduardo Barra; Covas, Dimas Tadeu; Leal, Ângela M. O.; Voltarelli, Júlio César; Malmegrim, Kelen Cristina Ribeiro; Yaochite, Juliana Navarro Ueda

doi:10.1007/s10753-018-00954-3

Cited by 10 publications

(9 citation statements)

References 84 publications

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“…DPP-4 inhibitor (PKF275-055) does not affect IL-2 in kidney and serum IL-6 in Sprague-Dawley (SD) rats of type 1 diabetes [34] . Sitagliptin treatment for 90 days decreased TNF-

and IL-10 in pancreatic homogenate in streptozotocin-induced type 1 diabetic mice [21] , which was different with our result. We considered it was owing to: (1) the concentrations of TNF-

and IL-10 were higher in pancreas than in serum in type 1 diabetes; (2) there were different effects of cytokines in different stages of disease.…”

Section: Discussioncontrasting

confidence: 99%

“…However, there are few studies about the immunoregulatory effect of DPP-4 inhibitors on innate immunity in type 1 diabetes. Recently, Davanso MR et al found that treatment of DPP-4 inhibitor for 90 days had no effect on CD3 + CD4+T cells and CD3 + CD8 + T cells in the spleen in streptozotocin-induced type 1 diabetic mouse [21] . However, in the present study, we found that long-term inhibition of DPP-4 (more than 8 months) significantly reduces CD4+T cells to infiltrate into islets and ameliorates insulitis.…”

Section: Discussionmentioning

confidence: 99%

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Long-term inhibition of dipeptidyl-peptidase 4 reduces islet infiltration and downregulates IL-1β and IL-12 in NOD mice

Xie

et al. 2020

International Immunopharmacology

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“…DPP-4 inhibitor (PKF275-055) does not affect IL-2 in kidney and serum IL-6 in Sprague-Dawley (SD) rats of type 1 diabetes [34] . Sitagliptin treatment for 90 days decreased TNF-

and IL-10 in pancreatic homogenate in streptozotocin-induced type 1 diabetic mice [21] , which was different with our result. We considered it was owing to: (1) the concentrations of TNF-

and IL-10 were higher in pancreas than in serum in type 1 diabetes; (2) there were different effects of cytokines in different stages of disease.…”

Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long-term inhibition of dipeptidyl-peptidase 4 reduces islet infiltration and downregulates IL-1β and IL-12 in NOD mice

Xie

et al. 2020

International Immunopharmacology

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“…of streptozotocin (STZ, Sigma-Aldrich, St. Louis, MO, USA), diluted in sodium citrate buffer (Sigma-Aldrich), pH 4.5, for five consecutive days, as described in our previous study (35).…”

Section: Mice and Ethics Protocolmentioning

confidence: 99%

Macrophage inflammatory state in Type 1 diabetes: triggered by NLRP3/iNOS pathway and attenuated by docosahexaenoic acid

et al. 2021

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Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by insulin-producing pancreatic β-cell destruction and hyperglycemia. While monocytes and NOD-like receptor family-pyrin domain containing 3 (NLRP3) are associated with T1D onset and development, the specific receptors and factors involved in NLRP3 inflammasome activation remain unknown. Herein, we evaluated the inflammatory state of resident peritoneal macrophages (PMs) from genetically modified non-obese diabetic (NOD), NLRP3-KO, wild type (WT) mice and in peripheral blood mononuclear cells (PBMCs) from human T1D patients. We also assessed the effect of docosahexaenoic acid (DHA) on the inflammatory status. Macrophages from STZ-induced T1D mice exhibited increased inflammatory cytokine/chemokine levels, nitric oxide (NO) secretion, NLRP3 and iNOS protein levels, and augmented glycolytic activity compared to control animals. In PMs from NOD and STZ-induced T1D mice, DHA reduced NO production and attenuated the inflammatory state. Furthermore, iNOS and IL-1β protein expression levels and NO production were lower in the PMs from diabetic NLRP3-KO mice than from WT mice. We also observed increased IL-1β secretion in PBMCs from T1D patients and immortalized murine macrophages treated with advanced glycation end products and palmitic acid. The present study demonstrated that the resident PMs are in a proinflammatory state characterized by increased NLRP3/iNOS pathway-mediated NO production, upregulated proinflammatory cytokine/chemokine receptor expression and altered glycolytic activity. Notably, ex-vivo treatment with DHA reverted the diabetes-induced changes and attenuated the macrophage inflammatory state. It is plausible that DHA supplementation could be employed as adjuvant therapy for treating individuals with T1D.

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“…Pancreatic lymph nodes from iDPP-4-treated mice exhibited a decreased proportion of CD11b+ cells and decreased levels of inflammatory cytokines in the pancreas, especially IFN-γ. 73 A previous study reported that two young women with T1DM achieved clinical remission for 4 years after treatment with sitagliptin and vitamin D3. One patient used the oral drugs for approximately 1 month after T1DM diagnosis, while the second patient used them after 10 months.…”

Section: Experimental and Clinical Studies With Idpp-4mentioning

confidence: 99%

Emerging Roles of Dipeptidyl Peptidase-4 Inhibitors in Delaying the Progression of Type 1 Diabetes Mellitus

Penaforte-Saboia¹,

Couri²,

Albuquerque³

et al. 2021

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Type 1 diabetes mellitus (T1DM) results from the immune cell-mediated destruction of functional pancreatic β-cells. In the presymptomatic period, T1DM is characterized by the presence of two or more autoantibodies against the islet cells in patients without glycemic decompensation. Therapeutic strategies that can modify the autoimmune process could slow the progression of T1DM. Dipeptidyl peptidase-4 (DPP-4) or CD26, a multifunctional serine protease with a dual function (regulatory protease and binding protein), can modulate inflammation and immune cell-mediated β-cell destruction. CD26 is involved in T-cell costimulation, migration, memory development, thymic maturation, and emigration patterns. DPP-4 degrades the peptide hormones GLP-1 and GIP. In addition to regulating glucose metabolism, DPP-4 exerts anti-apoptotic, regenerative, and proliferative effects to promote βcell mass expansion. GLP-1 receptor signaling may regulate murine lymphocyte proliferation and maintenance of peripheral regulatory T-cells. In patients with T1DM, the serum DPP-4 activity is upregulated. Several studies have suggested that the upregulated DPP-4 activity is correlated with T1DM pathophysiology. DPP-4, which is preferentially expressed on the Th1 surface, can promote the polarization of Th1 immunity, a prerequisite for T1DM development. CD26 inhibition can suppress T-cell proliferation and Th1 cytokine production and stimulate tumor growth factor beta-1 (TGF-β1) secretion, which plays an important role in the regulation of autoimmunity in T1DM. Studies on humans or animal models of T1DM have suggested that DPP-4 inhibitors can improve β-cell function and attenuate autoimmunity in addition to decreasing insulin dependence. This review summarizes the emerging roles of DPP-4 inhibitors in potentially delaying the progression of T1DM.

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

Cited by 10 publications

References 84 publications

Long-term inhibition of dipeptidyl-peptidase 4 reduces islet infiltration and downregulates IL-1β and IL-12 in NOD mice

Long-term inhibition of dipeptidyl-peptidase 4 reduces islet infiltration and downregulates IL-1β and IL-12 in NOD mice

Macrophage inflammatory state in Type 1 diabetes: triggered by NLRP3/iNOS pathway and attenuated by docosahexaenoic acid

Emerging Roles of Dipeptidyl Peptidase-4 Inhibitors in Delaying the Progression of Type 1 Diabetes Mellitus

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