Cell Surface Expression of LDL Receptor Is Decreased in Type 2 Diabetic Patients and Is Normalized by Insulin Therapy

Abstract

OBJECTIVE -In type 2 diabetic patients with poor metabolic control, kinetic studies have demonstrated that LDL fractional catabolic rate (FCR) is slowed down, whereas it is normalized on insulin therapy. This study was designed to analyze whether variations in the expression of LDL receptors at the cell surface could explain the results observed in kinetic studies.RESEARCH DESIGN AND METHODS -LDL receptors were quantified at the surface of mononuclear cells in fresh fasting blood samples by a flow cytometry method in 21 control subjects and 21 type 2 diabetic patients before and 3 months after the introduction of insulin therapy and concomitant removal of oral antidiabetic drugs.RESULTS -Before insulin treatment, monocyte LDL receptor expression was reduced by 41% (6,439 Ϯ 2,310 vs. 10,846 Ϯ 2,764 receptors per monocyte, P Ͻ 0.001) in type 2 diabetic patients compared with control subjects. It increased by 57% after 3 months of insulin therapy (10,096 Ϯ 5,657 vs. 6,439 Ϯ 2,310, P Ͻ 0.01) and was similar to that observed in control subjects.CONCLUSIONS -Our results suggest that insulin plays an important role in the in vivo expression of LDL receptors. Moreover, modulations in the expression of LDL receptors in type 2 diabetic patients either with poor metabolic control or on insulin therapy are likely to contribute to the variations of LDL FCR demonstrated by kinetic studies under those circumstances. Diabetes Care 26:1540 -1544, 2003C ardiovascular diseases are the most common complications observed in type 2 diabetes. The multiple abnormalities in lipoprotein metabolism frequently associated with this disorder play an important role in the premature development of atherosclerosis in type 2 diabetic patients (1-4).This dyslipidemia is characterized both by quantitative abnormalities consisting in hypertriglyceridemia and decreased plasma HDL cholesterol level and by qualitative abnormalities, mainly small LDL size and triglyceride enrichment of every lipoprotein subclass. LDL cholesterol concentration is similar to that observed in nondiabetic subjects or slightly more elevated. Despite a quite normal concentration, the metabolism of LDL particles is modified in poorly controlled type 2 diabetic patients. Indeed, in several kinetic studies, LDL fractional catabolic rate (FCR) has been found to be significantly slowed down, regardless of whether patients are on oral antidiabetic therapy (5-7). In parallel, LDL synthesis rate is normal or tends to be decreased, resulting in a normal or only moderately increased plasma LDL concentration.Recently, we demonstrated that replacing oral antidiabetic treatment with insulin therapy corrected the abnormalities of LDL metabolism in type 2 diabetic patients, both by normalizing FCR and increasing synthetic rate (8). Due to these two simultaneous changes, the concentration of circulating LDL particles remains constant.The aim of this work was to get further insight into the mechanisms responsible for the changes in LDL FCR reported by kinetic studies in type 2 diabetic patie...

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