Background: Elevated plasma concentrations of apoB-lipoproteins (i.e. hyperapoB) is an independent predictor of type 2 diabetes (T2D) in humans; however underlying mechanisms remain unclear. Chronic reduction in the function of white adipose tissue (WAT) promotes T2D. We reported that differentiation of preadipocytes and acute incubation of human WAT with LDL, the most common form of apoB-lipoproteins, induce their dysfunction, measured as decreased hydrolysis and storage of triglyceride-rich lipoproteins (TRL).
Objective: To test the hypothesis that the association of hyperapoB with risk factors for T2D, namely hypertriglyceridemia (hyperTG), insulin resistance (IR) and hyperinsulinemia, was dependent on WAT dysfunction.
Methods: Thirty normoglycemic subjects were enrolled (≥27 kg/m2, 4574 years). Fasting gynoid WAT biopsy was obtained followed by the ingestion of a 13C-triolein-labeled-high-fat meal. WAT function was measured ex vivo as the hydrolysis and storage of 3H-triolein-labeled-TRL as 3H-lipids over 4 h. Insulin secretion and sensitivity were measured using 1-h intravenous glucose tolerance test followed by 3-h hyperinsulinemia euglycermia clamp, respectively.
Results: WAT function correlated with higher insulin sensitivity (M/Iclamp r=0.60) and faster plasma clearance of chylomicrons in women (iAUC6hr apoB48 r=−0.60). Plasma apoB correlated with WAT dysfunction (r=−0.52), postprandial hyperTG (iAUC6hr TG r=0.51, 13C-TG r=0.48), IR (M/Iclamp r=−0.38) and hyperinsulinemia (2nd phase glucose-induced insulin secretion r=0.41). Co-incubation of subjects WAT with their LDL (1.2 g apoB/l) increased medium-accumulation of 3H-TRL and 3H-non-esterified fatty acids with no sex-differences. Adjusting for WAT function eliminated the association of plasma apoB with IR, independent of sex and body fat depots or gynoid adipocyte diameter. The association of plasma apoB with other risk factors was unaffected.
Conclusions: Association of hyperapoB with IR in obese subjects is dependent on gynoid WAT dysfunction. We propose that targeting hyperapoB, without increasing their uptake into non-hepatic peripheral tissues, ameliorates WAT function and reduces the risk for cardiovascular disease and T2D.