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
beta-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.