Thus, impaired insulin secretion in response to alcohol and reduced glucose disposal may both contribute to the impaired glucose tolerance demonstrated in this study. Our data suggest that Plin2 deficiency prevents these alcohol mediated effects on glucose tolerance. Our future studies will investigate specific mechanisms by which Plin2 deficiency protects against pancreatic beta cell dysfunction and glucose intolerance. Bioactive lipid metabolites can impair insulin signaling. In ALD, ceramides accumulate in the livers of both humans and rodents with ALD and are implicated in disease severity. Ceramide biosynthesis and metabolism is complex and involves three major synthetic pathways and metabolism to other sphingolipid species. Through mechanisms that are incompletely understood, ceramide accumulation results in activation of protein phosphatase 2A and subsequent inhibition of AKT phosphorylation, thereby impairing insulin signaling. The ceramide precursor sphingomyelin is a component of the lipid droplet membrane and the production of ceramide from sphingomyelin hydrolysis is implicated in alcohol��s impairment of glucose homeostasis. Here, we show a predominance of C16, C16.1, C22, C24 and C24:1 ceramides with alcohol-feeding. Little is known about the role of specific ceramide species in ALD, but reduction of C24 in alcohol fed mice has been shown to improve hepatic steatosis. Studies in other disease states have shown that C22 may have anti-proliferative properties ; C24 and C24:1 have pro-proliferative properties ; and C16 may promote apoptosis, thus its accumulation may conceivably promote alcohol-induced hepatotoxicity. Pharmacologic inhibition of ceramide de novo synthesis with myriocin improves hepatic insulin signaling in Long-Evans rats chronically fed alcohol and we previously reported that the onset of hepatic steatosis and insulin TPPU resistance in IWP 4 experimental ALD temporally correlates with an increase in long-chain hepatic ceramides and upregulation of Plin2. Our current results show that the increases in hepatic ceramides are prevented in the absence of Plin2 suggesting that Plin2 may mediate both cellular ceramide metabolism and insulin resistance in ALD, thus making Plin2 a potential target for therapy and/or prevention of ALD. In summary, alcohol-fed Plin2KO mice are protected from hepatic steatosis, glucose intolerance and hepatic ceramide accumulation.