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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:540.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Nikolaus Marx; Daniel Walcher; Claudia Raichle; Milos Aleksic; Helga Bach; Miriam Grüb; Vinzenz Hombach; Peter Libby; Arthur Zieske; Satoki Homma; Jack Strong

From the Department of Internal Medicine II–Cardiology (N.M., D.W., C.R., M.A., H.B., M.G., V.H.), University of Ulm, Germany; the Department of Medicine (P.L.), Leducq Center for Cardiovascular Research, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; and the Health Sciences Center (A.Z., S.H., J.S.), Louisiana State University, New Orleans, LA.

Correspondence to Nikolaus Marx, MD, Department of Internal Medicine II–Cardiology, University of Ulm, Robert-Koch-Str. 8, D-89081 Ulm, Germany. E-Mail nikolaus.marx{at}medizin.uni-ulm.de

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 2.3±0.4-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.

Key Words: C-peptide • monocytes • diabetes • arteriosclerosis

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