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In Vivo Modulation of Plasma Free Fatty Acids in Patients with Familial Combined Hyperlipidemia Using Lipid-Lowering Medication

Department of Vascular Medicine, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands

Address all correspondence and requests for reprints to: M. Castro Cabezas, M.D., Ph.D., Department of Vascular Medicine, F02.126, University Medical Center Utrecht, P.O Box 85500, 3508 GA Utrecht, The Netherlands. E-mail: . m.castrocabezas{at}azu.nl

Abstract

One of the best studied aspects of the insulin resistance syndrome in familial combined hyperlipidemia (FCHL) is impaired insulin-mediated suppression of FFA by diminished inhibition of hormone-sensitive lipase (HSL). In vitro experiments have shown that stimulation of HSL activity by catecholamines is decreased in FCHL. The aim of this study was to investigate HSL inhibition by insulin and stimulation by endogenous catecholamines in vivo in FCHL patients. Twelve FCHL subjects using lipid-lowering medication and 12 controls underwent a mental stress test after random ingestion of either 50 g glucose or placebo. After ingestion of glucose, insulin concentrations increased from 76.8 ± 21.5 pM to a maximum of 520.2 ± 118.4 pM (P < 0.01) in FCHL and from 38.0 ± 5.0 to 221.7 ± 25.1 pM (P < 0.01) in controls. The percent decreases in plasma FFA during the first hour after glucose ingestion were similar in FCHL and controls (67 ± 5% vs. 72 ± 3%, respectively), suggesting a comparable inhibition of HSL in both. During the placebo test, FFA increased similarly in FCHL (56 ± 9%) and controls (57 ± 19%). In contrast, FFA concentrations did not change during mental stress after ingestion of glucose (from 0.17 ± 0.02 to 0.15 ± 0.02 mmol/liter in FCHL and from 0.11 ± 0.02 to 0.12 ± 0.02 mmol/liter in controls).

In conclusion, the present study provides in vivo evidence for intact insulin-mediated suppression of FFA in FCHL, although this inhibition of HSL was achieved by higher insulin levels, suggesting insulin resistance at the level of HSL. Secondly, the induction of HSL activity by endogenous catecholamines in vivo is not decreased in FCHL, in contrast to earlier in vitro findings. Finally, catecholamine-induced HSL activation can be inhibited by insulin in a similar manner in both FCHL and controls.