Improvement in the regulation of cellular cholesterologenesis in diabetes: the effect of reduction in serum cholesterol by simvastatin.

Cellular cholesterol homeostasis was examined in 11 hypercholesterolaemic Type 2 diabetic patients prior to and following reduction of serum cholesterol using simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase. Following 12 weeks of treatment with simvastatin (10-40 mg day-1), serum cholesterol decreased by 30 +/- 3% from 7.8 +/- 0.2 mmol l-1 to 5.5 +/- 0.2 mmol l-1 (p less than 0.001) and LDL-cholesterol by 35 +/- 4% from 5.7 +/- 0.2 to 3.6 +/- 0.1 mmol l-1 (p less than 0.001). The esterified/free cholesterol ratio in LDL also decreased from 2.75 +/- 0.18 to 1.94 +/- 0.10 (p less than 0.01) after treatment. Cellular cholesterol synthesis, measured by [14C] acetate incorporation into mononuclear leucocytes, decreased by 39 +/- 11% from 231 +/- 13 to 140 +/- 25 mumol g-protein-1 (p less than 0.01). The degree of suppression of [14C]acetate incorporation into cholesterol in normal mononuclear cells by diabetic patients' LDL increased from 32.1 +/- 4.0% to 48.8 +/- 2.5% (p less than 0.001) following simvastatin. The activity of acyl coenzyme A:cholesterol-0-acyltransferase (ACAT) increased significantly by 55 +/- 18% (p less than 0.05) after treatment. Cholesterol synthesis in patients' mononuclear cells correlated positively (r = 0.66, p less than 0.05) with the esterified/free cholesterol ratio of their LDL, while suppression of cholesterol synthesis by patients' LDL correlated negatively (r = -0.64, p less than 0.05) with the esterified/free cholesterol ratio of the LDL following treatment.(ABSTRACT TRUNCATED AT 250 WORDS)