Diabetes accelerates smooth muscle accumulation in lesions of atherosclerosis - Lack of direct growth-promoting effects of high glucose levels

In combination with other factors, hyperglycemia may cause the accelerated progression of atherosclerosis in people with diabetes. Arterial smooth mus cle cell (SMC) proliferation and accumulation contribute to formation of ad vanced atherosclerotic lesions. Therefore, we investigated the effects of h yperglycemia on SMC proliferation and accumulation in vivo and in isolated arteries and SMCs by taking advantage of a new porcine model of diabetes-ac celerated atherosclerosis, in which diabetic animals are hyperglycemic with out receiving exogenous insulin. We show that diabetic animals fed a choles terol-rich diet, like humans, develop severe lesions of atherosclerosis cha racterized by SMC accumulation and proliferation, whereas lesions in nondia betic animals contain fewer SMCs after 20 weeks. However, high glucose (25 mmol/l) does not directly stimulate the proliferation of SMCs in isolated a rterial tissue from diabetic or nondiabetic animals, or of cultured SMCs fr om these animals or from humans. Furthermore, the mitogenic actions of plat elet-derived growth factor, IGF-I, or serum are not enhanced by high glucos e. High glucose increases SMC glucose metabolism through the citric acid cy cle and the pentose phosphate pathway by 240 and 90%, respectively, but <10 % of consumed glucose is metabolized through these pathways. Instead, most of the consumed glucose is converted into lactate and secreted by the SMCs. Thus, diabetes markedly accelerates SMC proliferation and accumulation in atherosclerotic lesions. The stimulatory effect of diabetes on SMCs is like ly to be mediated by effects secondary to the hyperglycemic state.