Hyperinsulinemia and smooth muscle cell proliferation.
Diabetic and obese subjects run a greater risk of developing atherosclerosis than the rest of the population. Several epidemiological studies suggest that hyperinsulinemia, which characterizes both obese and insulin resistant diabetic subjects, may be involved in atherosclerosis. Because insulin stimulates proliferation of arterial smooth muscle cells (SMC) in culture, it was supposed that insulin may exert an atherogenic role by promoting proliferation of SMC in the intima which is considered as one of the most important initial steps in atherogenesis. However, direct evidence of the growth-promoting effect of insulin on SMC in vivo is still lacking. Using an animal model of arterial injury with a balloon catheter (deendothelialization), we have investigated the short and long-term effect of high circulating insulin, associated or not with plasma glucose variations on aortic SMC proliferative response to endothelial denudation. SMC proliferation was appreciated by measuring the incorporation of 3H-thymidine in the DNA of intima-media layers. In a first series of experiments, we induced concomitant variations of plasma glucose and insulin concentrations by submitting rats with experimental aortic injury to fasting and refeeding. In control rats, the proliferative response to endothelial denudation was dramatically increased on day 2 after injury, remained high on day 4, and progressively declined thereafter. In fasted-refed (FR) rats, the increase on day 2 was less pronounced than in controls; concomitantly a sharp decrease in plasma glucose and insulin concentrations was observed. Refeeding was associated with a significantly less marked decline in SMC mitotic activity since day 4 after injury; at the same time, plasma glucose and insulin concentrations were sharply increased. These results suggested an involvement of variations of both glucose and insulin in SMC proliferation. However, when the surge of glucose and insulin after refeeding was prevented by adding acarbose to the diet, the SMC mitotic activity remained higher in FR rats than in controls, casting doubt as to whether hyperglycemia and hyperinsulinemia could be of importance in this process. Moreover, when deendothelialized rats were rendered either euglycemic-hyperinsulinemic or hyperglycemic-hyperinsulinemic by simultaneous infusion of glucose and insulin, no difference with controls, in the SMC proliferation, was observed. Taken together these data indicate that the acute mitotic response of SMC to endothelial denudation is not influenced by insulin associated or not with high levels of glucose. The long-term of long-lasting hyperinsulinemia was investigated using the obese Zucker rat model which is characterized especially by early spontaneous development of hyperinsulinemia and insulin resistance. Compared to controls, the SMC mitotic activity was not significantly increased from day 2 to day 7 after injury, but, from day 14 to day 30 after endothelial denudation, SMC proliferation was significantly less decreased in obese than in lean rats. Moreover, on day 30, aortic thickness, as measured by histomorphometric technique, was much higher in obese than in lean rats. This difference was entirely due to an increase in SMC number within the intima.(ABSTRACT TRUNCATED AT 400 WORDS)
Ridray
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Laboratoire de Physiopathologie de la Nutrition, Centre National de la Recherche Scientifique, Université Paris, France.
D020909:Acarbose; D000818:Animals; D001161:Arteriosclerosis / Q000453:epidemiology / Q000209:etiology / Q000473:pathology; D001786:Blood Glucose / Q000032:analysis; D002455:Cell Division / Q000502:physiology; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D005215:Fasting / Q000502:physiology; D006946:Hyperinsulinism / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D009765:Obesity / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011924:Rats, Zucker; D012307:Risk Factors; D013936:Thymidine / Q000378:metabolism; D014312:Trisaccharides / Q000494:pharmacology; D014316:Tritium
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D014312:Trisaccharides; D014316:Tritium; D007334:Insulin-Like Growth Factor I; D004247:DNA; D020909:Acarbose; D013936:Thymidine