METABOLIC CONSEQUENCES OF SUSTAINED SUPPRESSION OF FREE FATTY-ACIDS BY ACIPIMOX IN PATIENTS WITH NIDDM

To examine whether overnight suppression of free fatty acid levels red uces hepatic glucose production, 20 NIDDM patients were given a slow-r elease formulation of the antilipolytic agent acipimox, in a double-bl ind crossover manner at bedtime for 4 wk. During acipimox treatment, s erum free fatty acid concentrations were suppressed between 2400 and 0 600 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, acip imox 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 tre atment periods. In the morning, the rise in free fatty acid concentrat ion occurred despite identical serum acipimox concentrations as those measured at midnight, when free fatty acid levels were suppressed. Alt hough energy expenditure was higher (P < 0.05) during periods of eleva ted free fatty acid levels, the sums of energy expenditure measured in the morning and in the evening were similar during the acipimox and p lacebo periods. To exclude that the free fatty acid rise was caused by administration of acipimox only once at bedtime, additional experimen ts were performed administering acipimox every 2 h for 4 days. Despite similar acipimox concentration on day 1 and day 4 of this frequent do sing regimen, the free fatty acid concentrations were significantly hi gher on day 4 compared with day 1 (P < 0.01). In conclusion, under the se circumstances overnight lowering of serum free fatty acid by antili polytic treatment does not reduce hepatic glucose production in patien ts with NIDDM. Instead, it results in a sustained daytime rise in free fatty acid, leading to unchanged 24-h free fatty acid levels. This co mpensatory free fatty acid rise may be necessary to maintain energy pr oduction unchanged. Long-term studies are required to answer the quest ion whether it is possible to inhibit the appearance of a major energy substrate as free fatty acid during chronic therapy in patients with NIDDM.