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To the Editor: We read with interest this recent review [1]on an important aspect of glucose and lipid metabolism. Itis agreed that there is evidence of metabolic dialogueinvolving liver, skeletal muscle and adipose tissue within acomplex regulatory network. However, we question theassertion that peroxisome proliferator activator receptor α(PPARα) agonists, such as fibrates, increase insulinsensitivity. This assertion was supported by one of thestudies quoted [2], which used fenofibrate, ciprofibrate anda high-affinity PPARα agonist, GW9578, in a rat model invivo. However, due to the doses and model used, the studycannot be directly extrapolated to human subjects. Incontrast to the animal model evidence, in vivo studies inman show no consistent effect of PPARα agonists oninsulin sensitivity. Using surrogate measures, such as theoral glucose tolerance test [3, 4], fasting insulin [5, 6] andthe frequently sampled intravenous glucose tolerance test[7, 8], variable results have been obtained. With the refer-ence-standard method of assessment, the euglycaemic–hyperinsulinaemic clamp, a well-designed study in subjectswith type 2 diabetes showed no effect of gemfibrozil com-pared with placebo [9]. In a further study comparing simva-statin and gemfibrozil in a parallel design, insulin sensitivitydecreased in both groups [10]. This parallel effect mayrelate to lifestyle or other factors not assessed in the trialand thus ascribed to a general trial, rather than pharmaco-logical mechanism.As discussed by Weickert and Pfeiffer [1], liver andskeletal muscle fat deposition both seem to cause and beaffected by insulin resistance. Agents that improve fattyacid oxidation and disposal would therefore seem likely toaffect insulin resistance. However plausible this assertionmay be, and despite the fact that animal models suggest aneffect, well-designed in vivo studies in human subjectsshow no significant improvement in insulin sensitivityusing PPARα agonists at doses which are currentlyrecommended for therapy in man [9, 10]. As recognisedby Guerre-Millo et al. [2], fibrates are low-affinity ligandsfor PPARα, and agents with higher affinity may be requiredto elicit a significant effect. Recent reviews such as thedetailed, considered article in question [1] should recognisethat this effect is not seen with these agents in man.References

Comment on: Weickert MO, Pfeiffer AFH (2006) Signalling mechanisms linking hepatic glucose and lipid metabolism. Diabetologia 49:1732–1741