title: 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.
  
  
  RESULTS
  We demonstrate significantly higher intimal C-peptide deposition in thoracic aorta 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine II-Cardiology, University of Ulm, Robert-Koch-Str. 8, D-89081 Ulm, Germany. nikolaus.marx@medizin.uni-ulm.de
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Marx
authors.forename: Daniel
authors.initials: D
authors.lastname: Walcher
authors.forename: Claudia
authors.initials: C
authors.lastname: Raichle
authors.forename: Milos
authors.initials: M
authors.lastname: Aleksic
authors.forename: Helga
authors.initials: H
authors.lastname: Bach
authors.forename: Miriam
authors.initials: M
authors.lastname: Grüb
authors.forename: Vinzenz
authors.initials: V
authors.lastname: Hombach
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Arthur
authors.initials: A
authors.lastname: Zieske
authors.forename: Satoki
authors.initials: S
authors.lastname: Homma
authors.forename: Jack
authors.initials: J
authors.lastname: Strong
mesh_terms: D000293:Adolescent; D000328:Adult; D000730:Androstadienes / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000378:metabolism*; D001018:Aortic Diseases / Q000209:etiology / Q000378:metabolism; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism; D002096:C-Peptide / Q000032:analysis / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications; D007333:Insulin Resistance; D008264:Macrophages / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002096:C-Peptide; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D019204:GTP-Binding Proteins; D000077191:Wortmannin