C‐peptide promotes lesion development in a mouse model of arteriosclerosis

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.