Sitagliptin (MK0431) Inhibition of Dipeptidyl Peptidase IV Decreases Nonobese Diabetic Mouse CD4+ T-Cell Migration Through Incretin-Dependent and -Independent Pathways

Kim, Su Jin; Nian, Cuilan; McIntosh, Christopher H.S.

doi:10.2337/db09-1618

Cited by 51 publications

(42 citation statements)

References 53 publications

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“…DPP IV (CD26) is known to modulate immune function, T cell proliferation, and macrophage migration (28,45), and DPP IV inhibition reportedly reduced inflammatory cytokine production by the T cells and inhibited transendothelial migration of the latter (27,45). Interestingly, a recent study showed that sitagliptin decreases NOD mice CD4ϩ T cell migration through incretin-dependent and -independent pathways (30). We showed that sitagliptin reduced macrophage infiltration in adipose tissue.…”

Section: Discussionmentioning

confidence: 82%

“…Immune cell infiltration, notably of different subpopulations of macrophages and T cells, was recently shown to correlate with the development and maintenance of insulin resistance and diabetes in obesity (8,26,41,56). Recently, sitagliptin treatment in nonobese diabetic mice was shown to decrease CD4ϩ T cell migration through incretindependent and -independent mechanisms (30). Also, DPP IV is increased in blood monocytes of obese human subjects (35).…”

mentioning

confidence: 99%

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Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

Dobrian¹,

Ma²,

Lindsay³

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

146

100

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Adipose tissue inflammation and reduced pancreatic β-cell function are key issues in the development of cardiovascular disease and progressive metabolic dysfunction in type 2 diabetes mellitus. The aim of this study was to determine the effect of the DPP IV inhibitor sitagliptin on adipose tissue and pancreatic islet inflammation in a diet-induced obesity model. C57Bl/6J mice were placed on a high-fat (60% kcal fat) diet for 12 wk, with or without sitagliptin (4 g/kg) as a food admix. Sitagliptin significantly reduced fasting blood glucose by 21% as well as insulin by ∼25%. Sitagliptin treatment reduced body weight without changes in overall body mass index or in the epididymal and retroperitoneal fat mass. However, sitagliptin treatment led to triple the number of small adipocytes despite reducing the number of the very large adipocytes. Sitagliptin significantly reduced inflammation in the adipose tissue and pancreatic islet. Macrophage infiltration in adipose tissue evaluated by immunostaining for Mac2 was reduced by sitagliptin ( P < 0.01), as was the percentage of CD11b+/F4/80+ cells in the stromal vascular fraction ( P < 0.02). Sitagliptin also reduced adipocyte mRNA expression of inflammatory genes, including IL-6, TNFα, IL-12(p35), and IL-12(p40), 2.5- to fivefold as well as 12-lipoxygenase protein expression. Pancreatic islets were isolated from animals after treatments. Sitagliptin significantly reduced mRNA expression of the following inflammatory cytokines: MCP-1 (3.3-fold), IL-6 (2-fold), IL-12(p40) (2.2-fold), IL-12(p35) (5-fold, P < 0.01), and IP-10 (2-fold). Collectively, the results indicate that sitagliptin has anti-inflammatory effects in adipose tissue and in pancreatic islets that accompany the insulinotropic effect.

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

Dobrian¹,

Ma²,

Lindsay³

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

146

100

View full text Add to dashboard Cite

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“…GLP1 receptor activation has been shown to directly reduce apoptotic cell death after exposure to a diverse number of toxins and cytokines that are likely to contribute to b-cell destruction (Buteau et al 2004). In addition, lymphocytes contain significant amounts of membrane-bound DPP4 (Engel et al 2003), and both splenic DPP4 responsive and lymph node incretin non-responsive T-cell lymphocytes have been shown to infiltrate islets of diabetic NOD mice leading to b-cell destruction (Kim et al 2010). Thus, DPP4 inhibition may exert anti-inflammatory effects in the pancreatic islets in addition to an insulinotropic effect.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, Kutoh (2011) reported beneficial effects of the DPP4 inhibitor sitagliptin as add-on therapy to insulin in reducing BG levels in a small sample of patients with T1D. In addition, sitagliptin was shown to preserve islet transplants in non-obese diabetic (NOD) mice (Kim et al 2009(Kim et al , 2010). This mouse model spontaneously develops a form of insulin-dependent diabetes similar to the human disease (Delovitch & Singh 1997, Anderson & Bluestone 2005.…”

Section: Introductionmentioning

confidence: 99%

The DPP4 inhibitor linagliptin delays the onset of diabetes and preserves β-cell mass in non-obese diabetic mice

Jelsing

Vrang

Witteloostuijn

et al. 2012

Journal of Endocrinology

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Recent data indicate that dipeptidyl peptidase 4 (DPP4) inhibitors have anti-inflammatory and b-cell-sparing effects in animal models of type 1 diabetes. To evaluate the effects of the DPP4 inhibitor linagliptin on b-cell mass and insulinitis, we examined the progression of diabetes (blood glucose O11 mmol/l) in non-obese diabetic (NOD) mice with terminal stereological assessment of cellular pancreatic changes. Female NOD mice were fed a normal chow diet or a diet containing linagliptin 0 . 083 g/kg chow for 60 days. At study end, the incidence of diabetes in linagliptin-treated mice was reduced by almost 50% compared with vehicle (10 of 31 mice vs 18 of 30 mice, PZ0 . 021). The total islet mass and total b-cell mass, identified by insulin immunoreactivity, were greater in non-diabetic linagliptin-treated mice compared with nondiabetic vehicle-treated mice (P!0 . 01 for both) but were greatly reduced in diabetic mice irrespective of treatment. No changes were seen in the a, d and g endocrine cell pool. Moreover, the total mass of lymphocyte insulinitis was significantly reduced in linagliptin-treated mice compared with vehicle. The data indicate that linagliptin treatment delays the onset of diabetes in NOD mice by protecting b-cell mass.

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“…DPP-IV degrades a large quantity of molecules, including multiple chemokines involved in the innate immune response, and DPP-IV inhibition has been shown to have direct inhibitory effects on CD4-positive T cell and monocyte migration, all of which are involved in atherogenesis [7][8][9][10]. In addition, clinical data suggest that DPP-IV inhibitors influence various cardiovascular risk factors associated with diabetes.…”

Section: Introductionmentioning

confidence: 99%

Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe −/− mice

et al. 2012

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Aims/hypothesis Inhibitors of dipeptidyl peptidase-IV (DPP-IV), such as sitagliptin, increase glucagon-like peptide-1 (GLP-1) concentrations and are current treatment options for patients with type 2 diabetes mellitus. As patients with diabetes exhibit a high risk of developing severe atherosclerosis, we investigated the effect of sitagliptin on atherogenesis in Apoe −/− mice. Methods Apoe−/− mice were fed a high-fat diet and treated with either sitagliptin or placebo for 12 weeks. Plaque size and plaque composition were analysed using Oil Red O staining and immunohistochemistry. Furthermore, in vitro experiments with the modified Boyden chamber and with gelatine zymography were performed to analyse the effects of GLP-1 on isolated human monocyte migration and metalloproteinase-9 (MMP-9) release.Results Treatment of Apoe −/− mice with sitagliptin significantly reduced plaque macrophage infiltration (the aortic root and aortic arch both showing a 67% decrease; p<0.05) and plaque MMP-9 levels (aortic root showing a 69% and aortic arch a 58% reduction; both p<0.01) compared with controls. Moreover, sitagliptin significantly increased plaque collagen content more than twofold (aortic root showing an increase of 58% and aortic arch an increase of 73%; both p<0.05) compared with controls but did not change overall lesion size (8.1 ± 3.5% vs 5.1 ± 2.5% for sitagliptin vs controls; p0NS). In vitro, pretreatment of isolated human monocytes with GLP-1 significantly decreased cell migration induced by both monocyte chemotactic protein-1 and by the protein known as regulated on activation, normal T cell expressed and secreted (RANTES) in a concentration-dependent manner. Furthermore, GLP-1 significantly decreased MMP-9 release from isolated human monocyte-derived macrophages. Conclusions/interpretation Sitagliptin reduces plaque inflammation and increases plaque stability, potentially by GLP-1-mediated inhibition of chemokine-induced monocyte migration and macrophage MMP-9 release. The effects observed may provide potential mechanisms for how DPP-IV inhibitors could modulate vascular disease in high-risk patients with type 2 diabetes mellitus.

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Sitagliptin (MK0431) Inhibition of Dipeptidyl Peptidase IV Decreases Nonobese Diabetic Mouse CD4+ T-Cell Migration Through Incretin-Dependent and -Independent Pathways

Cited by 51 publications

References 53 publications

Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

The DPP4 inhibitor linagliptin delays the onset of diabetes and preserves β-cell mass in non-obese diabetic mice

Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe −/− mice

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