Plasma Ceramides Target Skeletal Muscle in Type 2 Diabetes

  1. John P. Kirwan
  1. Metabolic Translational Research Center, Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, Ohio; the Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
  2. Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio and
  3. Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
  1. Corresponding author: John P. Kirwan, kirwanj{at}

Type 2 diabetes (T2DM) is characterized by hyperglycemia, and the underlying pathophysiology includes insulin resistance and pancreatic β-cell failure. The precise cellular and molecular regulators of insulin resistance and impaired insulin secretion are under intense investigation, but a unifying theory remains elusive. The role of lipids in insulin resistance and β-cell failure has been the subject of considerable empirical investigation, and intermediates of lipid metabolism including diacylglycerols, long-chain fatty acyl-CoAs, and ceramides have all been examined to varying degrees and with varying levels of success. There is good evidence that diacylglycerols and fatty acyl-CoAs directly contribute to dysregulation of cellular insulin signaling through incomplete fatty acid oxidation and/or phosphorylation/dephosphorylation of specific serine and threonine sites on insulin receptor substrate-1 (1,2). Evidence regarding the role of ceramides in insulin resistance has been less consistent. Ceramides are members of the sphingolipid family of lipids and are integral to the structure of the lipid bilayer that makes up all cell membranes (3). They also exert biological effects through cellular proliferation, differentiation, and cell death and interact with several pathways involved in insulin resistance, oxidative stress, inflammation, and apoptosis, all of which are linked to T2DM (46). Several lines of evidence suggest that the liver is the major source of plasma ceramides in animals and humans (7,8). In a hamster model, de novo synthesis of ceramides in the liver is induced in response to …

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