Whatever the precise pathophysiological mechanism, it has been shown that lowering fatty acid availability by suppressing 24 h FFA levels, using short term intensive treatment with the nicotinic acid analog acipimox, induced substantial improvements in blood glucose control in patients with type 2 diabetes [9]. While this validates the pharmacodynamic principle of FFA lowering, unfortunately tachyphylaxis towards the FFA lowering effect prevents this nicotinic acid analog from providing a robust and durable therapy for improving glucose control [9, 10]. An alternative approach to reducing ectopic lipid accumulation might be to enhance local fatty acid oxidation. This could be done either by forcing FFA oxidation (e.g., by inhibiting acetyl-CoA carboxylase 2 [11]) or by increasing the capacity to oxidize fatty acids (e.g., by increasing mitochondrial mass) potentially allowing larger physiological increments in oxidation. The approach of increasing fatty acid oxidation to achieve improved glucose control is however speculative because of the potential for accelerated lipid oxidation to inhibit glucose metabolism [12], and final judgment about the usefulness of such a pharmacodynamic principal awaits critical clinical evidence.
