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.

Patients with insulin resistance and early type 2 diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. Typically, these patients show elevated serum levels of the proinsulin cleavage product C-peptide and immunohistochemical data from our group revealed C-peptide deposition in early lesions of these individuals. Moreover, in vitro studies suggest that C-peptide could promote atherogenesis. This study examined whether C-peptide promotes vascular inflammation and lesion development in a mouse model of arteriosclerosis. ApoE-deficient mice on a high fat diet were treated with C-peptide or control injections for 12 weeks and the effect on lesion size and plaque composition was analysed. C-peptide treatment significantly increased C-peptide blood levels by 4.8-fold without having an effect on glucose or insulin levels, nor on the lipid profile. In these mice, C-peptide deposition in atherosclerotic plaques was significantly increased compared with controls. Moreover, lesions of C-peptide–treated mice contained significantly more macrophages (1.6 ± 0.3% versus 0.7 ± 0.2% positive area; P < 0.01) and more vascular smooth muscle cells (4.8 ± 0.6% versus 2.4 ± 0.3% positive area; P < 0.01). Finally, lipid deposition measured by Oil-red-O staining in the aortic arch was significantly higher in the C-peptide group compared with controls. Our results demonstrate that elevated C-peptide levels promote inflammatory cell infiltration and lesion development in ApoE-deficient mice without having metabolic effects. These data obtained in a mouse model of arteriosclerosis support the hypothesis that C-peptide may have an active role in atherogenesis in patients with diabetes and insulin resistance.

Abstract-Migration of CD4-positive lymphocytes into the vessel wall represents an important step in early atherogenesis.Telmisartan is an angiotensin type 1 receptor (AT1R) blocker with peroxisome proliferator-activated receptor (PPAR)-␥-activating properties. The present study examined the effect of telmisartan on CD4-positive cell migration and the role of PPAR␥ in this context. CD4-positive lymphocytes express both the AT1R and PPAR␥. Stimulation of CD4-positive lymphocytes with stromal cell-derived factor (SDF)-1 leads to a 4.1Ϯ3.1-fold increase in cell migration. Pretreatment of cells with telmisartan reduces this effect in a concentration-dependent manner to a maximal 1.6Ϯ0.7-fold induction at 10 mol/L of telmisartan (PϽ0.01 compared with SDF-1-treated cells; nϭ22). Three different PPAR␥ activators, rosiglitazone, pioglitazone, and GW1929, had similar effects, whereas eprosartan, a non-PPAR␥-activating AT1R blocker, did not affect chemokine-induced lymphocyte migration. Telmisartan's effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced phosphatidylinositol 3-kinase activity. Downstream, telmisartan inhibited F-actin formation, as well as intercellular adhesion molecule-3 translocation. Transfection of CD4-positive lymphocytes with PPAR␥ small interfering RNA abolished telmisartan's effect on migration, whereas blockade of the AT1R had no such effect. Telmisartan inhibits chemokine-induced CD4-positive cell migration independent of the AT1R via PPAR␥. These data provide a novel mechanism to explain how telmisartan modulates lymphocyte activation by its PPAR␥-activating properties. Key Words: telmisartan Ⅲ PPAR␥ Ⅲ angiotensin type 1 receptor blocker Ⅲ CD4-positive lymphocytes Ⅲ migration A therogenesis is an inflammatory process in the vessel wall involving inflammatory cells like monocytes, macrophages, and CD4-positive lymphocytes. 1 In early atherogenesis, CD4-positive lymphocytes are attracted by chemotactic proteins, such as regulated upon activation, normal T-cell expressed, and secreted (RANTES) and stromal cellderived factor (SDF)-1 and enter the vessel wall as naïve T-helper 0 cells. In the subendothelium, these cells then encounter antigens like oxidized low-density lipoprotein and differentiate into T-helper 1 cells, subsequently releasing proinflammatory mediators like tumor necrosis factor-␣ and interferon-␥. These cytokines then govern the inflammatory response in the vessel wall by activating other cells, such as endothelial cells, macrophages, and vascular smooth muscle cells, thus promoting the inflammatory process in atherogenesis. It is unclear whether an inhibition of cell migration itself modulates vascular disease, but various experimental studies have shown that a reduction in CD4-positive lymphocyte recruitment hampers lesion development and plaque formation. 2,3 Still, most of these studies targeted the effect of T-cell-specific chemokines, but hitherto little is known about modulatory effects on CD4-positive lymphocyte migration.T...

Diabetes type 2 and insulin resistance are the risk factors for cardiovascular disease. It is already known that atherosclerosis is an inflammatory disease, and a lot of different factors are involved in its onset. C-peptide is a cleavage product of proinsulin, an active substance with a number of effects within different complications of diabetes. In this paper we discuss the role of C-peptide and its effects in the development of atherosclerosis in type 2 diabetic patients.