To examine whether overnight suppression of free fatty acid levels reduces hepatic glucose production, 20 NIDDM patients were given a slow-release formulation of the antilipolytic agent acipimox, in a double-blind crossover manner at bedtime for 4 wk. During acipimox treatment, serum free fatty acid concentrations were suppressed between 2400 and 0600 by 64% (P < 0.001), but no reduction in hepatic glucose production was observed (2.16 ± 0.16 vs. 2.23 ± 0.16 mg · kg−1 · min−1, acipimox vs. placebo). In contrast, from 0800 to 2000 a sustained 50% rise occurred in serum free fatty acids (P < 0.001). As a consequence, the 24-h area under the free fatty acid curve was similar during both treatment periods. In the morning, the rise in free fatty acid concentration occurred despite identical serum acipimox concentrations as those measured at midnight, when free fatty acid levels were suppressed. Although energy expenditure was higher (P < 0.05) during periods of elevated free fatty acid levels, the sums of energy expenditure measured in the morning and in the evening were similar during the acipimox and placebo periods. To exclude that the free fatty acid rise was caused by administration of acipimox only once at bedtime, additional experiments were performed administering acipimox every 2 h for 4 days. Despite similar acipimox concentration on day 1 and day 4 of this frequent dosing regimen, the free fatty acid concentrations were significantly higher on day 4 compared with day 1 (P < 0.01). In conclusion, under these circumstances overnight lowering of serum free fatty acid by antilipolytic treatment does not reduce hepatic glucose production in patients with NIDDM. Instead, it results in a sustained daytime rise in free fatty acid, leading to unchanged 24-h free fatty acid levels. This compensatory free fatty acid rise may be necessary to maintain energy production unchanged. Long-term studies are required to answer the question whether it is possible to inhibit the appearance of a major energy substrate as free fatty acid during chronic therapy in patients with NIDDM.

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