Plasma Ceramides Target Skeletal Muscle in Type 2 Diabetes
- John P. Kirwan⇓
- Metabolic Translational Research Center, Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, Ohio; the Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio and
- Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
- Corresponding author: John P. Kirwan, kirwanj{at}ccf.org.
Article Figures & Tables
Figures
- FIG. 1.
Schematic view of the proposed role of plasma ceramide in the development of skeletal muscle insulin resistance. In this model, ceramides are packaged with LDL in the liver and released into the circulation where they target skeletal muscle in two specific ways. First, LDL-ceramide is internalized in the plasma membrane where it downregulates Akt signaling and subsequent insulin-mediated glucose uptake by the tissue, leading ultimately to hyperglycemia and T2DM. Second, LDL-ceramides activate nuclear factor-κB and initiate increased cytokine production. These cytokines also target insulin signaling and impair glucose uptake, further exacerbating hyperglycemia and the likelihood of developing diabetes. IκBα, nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α; IL-1β, interleukin-1β; IL-6, interleukin-6; MCP-1, monocyte chemotactic protein-1; NF-κB, nuclear factor-κB; TLR4, toll-like receptor-4; TNF-α, tumor necrosis factor-α. Reprinted with permission from the Cleveland Clinic Foundation (CCF).
