The role of circulating ceramide in insulin resistance & inflammation

Dysregulated lipid metabolism and inflammation are linked to the development of insulin resistance in type 2 diabetes. Plasma ceramide levels are associated with insulin resistance in type 2 diabetes, although their exact role and function have not been elucidated. This thesis has defined the role of circulating ceramide on the pathogenesis of insulin resistance and inflammation using a multi-level approach consisting of several components, namely a human study examining patients with type 2 diabetes, construction of reconstituted LDL-ceramide for use in mechanistic studies, and investigation of the insulin desensitizing and inflammatory effects of LDL-ceramide in in vitro and in vivo models. This thesis found that ceramide transported in low density lipoproteins (LDL) is elevated in the plasma of obese, type 2 diabetes patients and correlated with insulin resistance, but not body mass index (BMI). Treating cultured myotubes with LDL containing ceramide promoted ceramide uptake by cells in association with reduced insulin stimulated glucose uptake, Akt phosphorylation and GLUT4 translocation compared with LDL deficient in ceramide. LDL-ceramide induced a pro-inflammatory response in cultured macrophages via toll-like receptor-dependent and independent mechanisms. Finally, infusing LDL-ceramide into lean mice reduced insulin stimulated glucose uptake and this was due to impaired insulin action, specifically in skeletal muscle. What this thesis achieved is to serve as a prospectus that clarifies the poorly investigated role of circulating ceramide in the development of insulin resistance and to show that circulating ceramides is part of the constellation of provocateurs that contribute to the pathophysiology of the disorder which is a feature in type 2 diabetes.