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Defective Liver Disposal of Free Fatty Acids in Patients with Impaired Glucose Tolerance

Turku PET Centre (P.I., V.O., J.B., T.G., P.N., J.K.), Department of Nuclear Medicine, and Department of Medicine (T.T., P.N.), University of Turku, FI-20521 Turku, Finland; PET Centre (P.I., E.F.), National Research Council, Institute of Clinical Physiology, 56100 Pisa, Italy; Department of Medicine (A.K.T.), University Hospital of Kuopio, FIN-70210 Kuopio, Finland; and Department of Internal Medicine (E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy

Address all correspondence and requests for reprints to: Patricia Iozzo, M.D., Institute of Clinical Physiology, National Research Council, Via Moruzzi 1, 56100 Pisa, Italy. E-mail: patricia.iozzo{at}ifc.cnr.it.

The liver exchanges high fluxes of glucose and free fatty acids (FFA) and is one main site of their reciprocal regulation. Acute exposure to hyperglycemia and hyperinsulinemia has been shown to reduce splanchnic ß-oxidation in healthy humans. We investigated whether a spontaneous condition of chronic mild hyperglycemia and hyperinsulinemia affects liver FFA uptake. Hepatic FFA influx rate constant (LKi) was measured after a 12–15-h fast in 10 patients with impaired glucose tolerance (IGT) and eight control subjects using positron emission tomography in combination with the long-chain FFA analog 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Compared with controls, IGT patients had higher serum insulin, glucose, and triglyceride levels (1.71 ± 0.24 vs. 0.59 ± 0.06 mmol/liter, P < 0.001), lower high-density lipoprotein (1.04 ± 0.11 vs. 1.42 ± 0.13 mmol/liter, P < 0.05), and similar FFA levels (0.59 ± 0.06 vs. 0.56 ± 0.05 mmol/liter^–1, P = not significant). LKi was significantly reduced in IGT (0.288 ± 0.014 min^–1) compared with control subjects (0.341 ± 0.014 min^–1, P < 0.02). LKi was negatively correlated with plasma glucose (r = 0.51, P < 0.03), glycosylated hemoglobin (r = 0.55, P < 0.02), and blood lactate levels (r = 0.52, P < 0.03).

We conclude that, in IGT patients, the ability of the liver to extract FFA from the circulation appears to be impaired. The reciprocal relationship between hepatic FFA extraction and glucose/lactate flux may derive from intrahepatic substrate competition.

Abbreviations: CoA, Coenzyme A; FFA, free fatty acid; [18F]FTHA, 14(R,S)- [18F]fluoro-6-thia-heptadecanoic acid; IGT, impaired glucose tolerance; LFEF, liver FFA extraction fraction; LFU, liver FFA uptake index; LKi, influx rate constant in liver.

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