Context: Abnormal plasma non-esterified fatty acid (NEFA) metabolism may play a role in the development of type 2 diabetes.

Objectives: To demonstrate whether there is a defect in insulin-mediated suppression of plasma NEFA appearance (Ra_NEFA) and oxidation (Ox_NEFA) during enhanced intravascular triacylglycerols lipolysis early occurrence in the natural history of type 2 diabetes, and if so, to determine whether other mechanisms than reduced insulin-mediated suppression of intracellular lipolysis are involved.

Design: Cross-sectional studies.

Setting: An academic clinical research centre.

Participants: Nine healthy subjects with both parents with type 2 diabetes (FH+), and nine healthy subjects with no first-degree relatives with type 2 diabetes (FH-) with similar anthropometric features.

Interventions: Pancreatic clamps and intravenous infusion of stable isotopic tracers ([1,1,2,3,3-²H₅]-glycerol and [U-¹³C]-palmitate or [1,2-¹³C]-acetate) were performed while intravascular triacylglycerol lipolysis was simultaneously clamped by intravenous infusion of heparin+Intralipid at low (fasting) and high insulin levels. Oral nicotinic acid (NA) was used to inhibit intracellular lipolysis.

Main Outcome Measures: Ra_NEFAand Ox_NEFA.

Results: During heparin+Intralipid infusion at high plasma insulin levels, and despite similar intravascular lipolytic rates, FH+ had higher Ra_NEFAand Ox_NEFAthan FH- (Ra_NEFA: 17.4 ± 6.3 vs. 9.2 ± 4.2; Ox_NEFA: 4.5 ± 1.8 vs. 2.3 ± 1.5 µmol/kg lean body mass/min) independent of NA intake, gender, age and body composition. In the presence of NA, insulin-mediated suppression of Ra_NEFAwas still observed in FH- but not in FH+.

Conclusions: Increased Ra_NEFAand Ox_NEFAduring intravascular lipolysis at high insulin levels occur early in the natural history of type 2 diabetes.