Impaired plasma nonesterified fatty acid tolerance is an early defect in the natural history of type 2 diabetes

Abstract

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

Objectives: Our objectives were to demonstrate whether there is a defect in insulin-mediated suppression of plasma NEFA appearance (RaNEFA) and oxidation (OxNEFA) during enhanced intravascular triacylglycerol lipolysis early 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: These are cross-sectional studies.

Setting: The studies were performed at an academic clinical research center.

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 were included in the studies.

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

Main outcome measures: RaNEFA and OxNEFA were determined.

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

Conclusions: Increased RaNEFA and OxNEFA during intravascular lipolysis at high insulin levels occur early in the natural history of type 2 diabetes.

Figure 1

Ra_glycerol (A), Ra_palmitate (B), and oxidation rate (Ox_palmitate) (C). Plasma NEFA appearance rate (Ra_NEFA) (D) and oxidation rate (Ox_NEFA) (E). †, P < 0.05 vs. INS_LOW by ANOVA with Scheffe’s test. *, P < 0.05 vs. FH− by ANOVA. FH− (open bars). FH+ (closed bars). Data are mean ± se. LBM, Lean body mass.

Figure 2

NA-mediated change (INS_LOW NA minus INS_LOW) (A), insulin-mediated change (INS_HIGH minus INS_LOW) (B), and insulin-mediated change during NA intake (INS_HIGH NA minus INS_LOW NA) (C) in Ra_palmitate. NA-mediated change (D), insulin-mediated change (E), and insulin-mediated change during NA intake (residual) (F) in plasma NEFA appearance rate (Ra_NEFA). FH− (open bars). FH+ (closed bars). P values are from comparison of the two groups of participants by ANOVA. Data are mean ± se. LBM, Lean body mass.