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Impaired Plasma Nonesterified Fatty Acid Tolerance Is an Early Defect in the Natural History of Type 2 Diabetes

Department of Medicine (P.B., F.F., F.L., A.B., J.-P.B., A.C.C.), Division of Endocrinology, Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4; Department of Pediatrics (D.C., R.D.), Division of Genetics, Université de Sherbrooke, Research Center on Aging (S.C.C.), Sherbrooke, Québec, Canada J1K 2R1; and the Center for Human Nutrition (B.W.P.), Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Dr. André Carpentier, Division of Endocrinology, Centre hospitalier universitaire de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4. E-mail: andre.carpentier{at}usherbrooke.ca.

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 (Ra_NEFA) and oxidation (Ox_NEFA) 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 ([1,1,2,3,3-²H₅]-glycerol and [U-¹³C]-palmitate or [1,2-¹³C]-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: Ra_NEFA and Ox_NEFA were determined.

Results: During heparin plus Intralipid infusion at high plasma insulin levels, and despite similar intravascular lipolytic rates, FH+ had higher Ra_NEFA and Ox_NEFA than 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_NEFA was still observed in FH–, but not in FH+.

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