Macrophage cholesterol efflux in type 2 diabetes mellitus.

Abstract

Accumulation of cholesterol in macrophage and foam cell formation is partly influenced by the cell’s capacity to efflux cholesterol. Cholesterol efflux from cells is an early step of reverse cholesterol transport and is predominantly mediated by cholesterol transport proteins with plasma HDL and apolipoprotein (apo) A1 being the major extracellular cholesterol acceptors. We had determined whether macrophage cholesterol efflux was abnormal in type 2 diabetic patients with and without nephropathy. Fifty-eight non-diabetic controls (C), 34 type 2 diabetic patients without nephropathy (D) and 20 type 2 diabetic patients with nephropathy (DN) (eGFR<60 mL/min/1.73m2) were recruited. Macrophage cholesterol efflux was evaluated by measuring the percentage of [3H]cholesterol transferred from individual subject’s monocyte-derived macrophages to a fixed concentration of exogenous apo A1 or HDL as cholesterol acceptors. HbA1c was similar in patients with (8.5 ± 1.2%) or without nephropathy (8.4 ± 0.9%). Macrophage cholesterol efflux to apo A1 (C: 25.3 ±10.0%, D: 18.9 ± 9.2%, DN: 12.1 ± 7.0%, ANOVA p<0.01) and to HDL (C: 42.8 ± 8.8%, D: 35.5 ± 10.2%, DN: 29.6 ± 12.1%, ANOVA p<0.01) was significantly decreased in the diabetic patients and the magnitude of reduction was greatest in those with nephropathy. These differences remained significant even after adjusting for age, gender, and BMI. Macrophage cholesterol efflux to apo A1 and to HDL correlated with HbA1c (r = -0.37 and -0.35 respectively, p<0.01) and with eGFR (r = 0.36 and r = 0.30 respectively, p<0.01). Linear regression analysis including age, sex, BMI, smoking, HbA1c, eGFR and the use of insulin, renin angiotensin aldosterone system inhibitor and/or statin therapy showed that only HbA1c and eGFR were significant independent determinants of macrophage cholesterol efflux to apo A1 or to HDL. In conclusion, macrophage cholesterol efflux was significantly impaired in patients with type 2 diabetes mellitus and the reduction was particularly pronounced in those with nephropathy. These changes in macrophage cholesterol efflux might partly contribute to the high risk of developing cardiovascular diseases in diabetic patients. The mechanism(s) whereby the presence of nephropathy further impairs macrophage ability to efflux cholesterol in diabetes warrants further investigations. - See more at: http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2016.CE.5.SUN-595#sthash.qURhyonQ.dpuf