Abstract 605: Association of Apolipoprotein B with Impaired Insulin Sensitivity and Secretion Is Mediated by Reduced Fat Clearance in Obese Subjects

Abstract

OBJECTIVE: Human data from our lab and others have demonstrated that elevated concentrations of apoB-lipoproteins, measured as plasma apoB, are associated with insulin resistance (IR), hyperinsulinemia and the development of type 2 diabetes. However, the underlying mechanism to date remains unknown. We recently reported that LDL, the major form of apoB-lipoproteins, directly impairs the hydrolysis and storage of triglyceride-rich lipoproteins ex vivo in human white adipose tissue. Therefore, we hypothesized that the association between apoB and IR and compensatory increase in insulin secretion (IS) is mediated by delayed postprandial TG clearance in vivo in obese subjects. METHODS: We performed a Botnia clamp on normoglycemic obese men (N=14) and postmenopausal women (N=16) (BMI ≥ 27 kg/m2, age ≥ 45 years). First phase, 2 nd phase and total IS were measured during a 1-hour intravenous-glucose tolerance test (IVGTT) while insulin sensitivity was measured during a 3-hours hyperinsulinemic euglycemic clamp that followed. On a separate date, postprandial plasma clearance of TG was measured over 6 hours following the ingestion of a 13 C-triolein-labeled high-fat meal. RESULTS: Plasma apoB correlated positively with IR (r=0.15, p=0.037), 2 nd phase IS (r=0.15, p=0.039) and delayed TG clearance (AUC 6hrs of total plasma TG: r=0.64, p<0.001; AUC 6hrs of 13 C-plasma TG: r=0.77, p<0.001). Moreover, AUC 6hr of total plasma TG was associated with higher IR (r=0.16, p=0.042), 1 st phase IS (r=0.20, p=0.023), 2 nd phase IS (r=0.16, p=0.044) and total IS (r=0.16, p=0.046). Similarly, a positive association existed between delayed 13 C-labeled plasma TG clearance (AUC 6hrs ) and IR (r=0.41, p=0.046). A gender difference existed as TG clearance was mainly associated with IR in women (r=0.41, p=0.046) whereas it was mainly associated with 2 nd phase IS in men (r=0.41, p=0.046). As hypothesized, correcting for TG clearance eliminated the association of plasma apoB with IR and IS. CONCLUSION: The association of apoB with insulin resistance and secretion may be secondary to LDL-mediated delayed TG clearance by adipose tissue in humans.