C-Peptide Colocalizes with Macrophages in Early Arteriosclerotic Lesions of Diabetic Subjects and Induces Monocyte Chemotaxis In Vitro

Abstract

Objective-Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes, a high-risk population for the development of a diffuse and extensive pattern of arteriosclerosis. This study tested the hypothesis that C-peptide might participate in atherogenesis in these patients. Method and Results-We demonstrate significantly higher intimal C-peptide deposition in thoracic artery specimens from young diabetic subjects compared with matched nondiabetic controls as determined by immunohistochemical staining. C-peptide colocalized with monocytes/macrophages in the arterial intima of artery specimen from diabetic subjects. In vitro, C-peptide stimulated monocyte chemotaxis in a concentration-dependent manner with a maximal 2.3Ϯ0.4-fold increase at 1 nmol/L C-peptide. Pertussis toxin, wortmannin, and LY294002 inhibited C-peptide-induced monocyte chemotaxis, suggesting the involvement of pertussis toxin-sensitive G-proteins as well as a phosphoinositide 3-kinase (PI3K)-dependent mechanism. In addition, C-peptide treatment activated PI3K in human monocytes, as demonstrated by PI3K activity assays. Conclusion-C-peptide accumulated in the vessel wall in early atherogenesis in diabetic subjects and may promote monocyte migration into developing lesions. These data support the hypothesis that C-peptide may play an active role in atherogenesis in diabetic patients and suggest a new mechanism for accelerated arterial disease in diabetes.

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

“…In vitro cell migration assay The migration of isolated monocytes was determined as previously described [20]. Briefly, cells were cultured in serum-free media for 16 h. Monocytes (5×10 6 cells/ml) were pretreated for 30 min with GLP-1(7-36) (Sigma) at the concentrations indicated in serum-free medium and subsequently assayed for chemotaxis under serum-free conditions in a 48-well microchemotaxis chamber (Neuroprobe, Leamington Spa, Warwickshire, UK).…”

Mechanisms by which diabetes increases cardiovascular disease

“…C peptide has been shown to be expressed in atherosclerotic lesions from diabetic patients [61]. In vitro, C-peptide displayed chemotactic activity towards monocytes via a Gprotein coupled receptor and phosphatidylinositol-3 kinase-(PI3K)-dependent mechanism [61] and induced proliferation of vascular smooth muscle cells [62].…”

Serum C-peptide levels and risk of death among adults without diabetes mellitus

“…4,5 C-peptide deposition occurs in the atherosclerotic lesions of patients with diabetes. 6 Recent studies have suggested that Cpeptide may be a valuable predictor of cardiovascular events and mortality (all-cause and cardiovascular-related mortality). [6][7][8][9][10][11][12] In this study, we investigated the association between serum C-peptide level and all-cause, cardiovascular-related and coronary artery disease-related mortality among patients without diabetes.…”