Ceramide Synthase Isoforms and Insulin Resistance: A Molecular Perspective

The review analyzes the literature data that forms the basis for the "ceramide-centric" view of insulin resistance pathogenesis and obesity-associated diabetes mellitus type 2. The results of recent independent studies have shown that normal sphingolipid metabolism is one of the most important conditions for maintaining glucose homeostasis in the body. The lipid analysis of adipose tissue, skeletal muscles and liver in rodents with experimental obesity, as well as biopsic specimens of diabetics, indicate the high pathogenicity of specific ceramide family members. Analysis of the clinical material and the results of model experiments showed that increased expression of the isoenzyme CerS-6 positively correlated with the degree of resistance to insulin. The degree of pathogenicity is determined by the length of the acyl chain included in de novo synthesized ceramide with the involvement of one of the six ceramide synthase isoenzymes. Selective inhibition of the ceramide synthase-6 isoenzyme to reduce the tissue level of the most pathogenic C16:0-ceramide may be a promising approach for correcting insulin resistance. The creation of a specific inhibitor of CerS-6 will allow selectively to reduce the tissue content of C16:0-ceramide, which, apparently, may contribute to the development of a new direction of pathogenetically grounded pharmacological correction of obesity-associated insulin resistance.