Targeting Ceramide Synthesis to Reverse Insulin Resistance

Insulin resistance is a key feature of type 2 diabetes, and the strong association between fat oversupply and defective insulin action in target tissues, especially skeletal muscle and liver, has motivated the search for intracellular lipid mediators that can interfere with insulin signaling and glucose homeostasis. Two of the best-studied candidates are diacylglycerol (DAG) and ceramide (1–3), to the extent that the tissue levels of these intermediate species are now routinely measured in models of insulin resistance and in human studies. Correlative evidence for their roles has accumulated over the last 10–15 years, but unfortunately, there are now several conflicting reports concerning the relative importance of these molecules (4–7). To resolve this situation, it is necessary to go beyond descriptive studies in order to address causation and elucidate the mechanisms involved. In the case of ceramide, the inhibitor myriocin is proving to be a useful tool. This fungal metabolite is a potent and specific blocker of serine palmitoyltransferase (SPT), the first enzyme in the pathway of de novo ceramide synthesis (8). By reducing the condensation of serine with palmitoyl-CoA to form 3-ketosphinganine (Fig. 1), the inhibitor is able to decrease ceramide synthesis without elevating intermediates such as sphinganine, which are upstream of ceramide formation and also have biological effects (9). Myriocin treatment of rats infused with different lipid cocktails for 6 h to induce insulin resistance in an acute fashion demonstrated that a reduction in ceramide accumulation in skeletal muscle could prevent defects in glucose disposal (10). Longer-term administration of the inhibitor was also able to improve glucose tolerance in genetically obese Zucker diabetic fatty (ZDF) rats and fat-fed mice. Finally, this study also supported the conclusion, drawn from in vitro work (11), that saturated fatty acids contribute to ceramide accumulation, whereas unsaturated fatty acids induce …