American Diabetes Association
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Deoxysphingolipids – atypical skeletal muscle lipids related to insulin resistance in humans that decrease insulin sensitivity in vitro

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posted on 2023-04-24, 21:09 authored by Simona Zarini, Karin A. Zemski Berry, Darcy E. Kahn, Amanda Garfield, Leigh Perreault, Anna Kerege, Bryan C. Bergman


Sphingolipids are thought to promote skeletal muscle insulin resistance. 1-Deoxysphingolipids (dSL) are atypical sphingolipids that are increased in plasma of individuals with type 2 diabetes and cause β-cell dysfunction in vitro. However, their role in human skeletal muscle in unknown. We found that dSL species are significantly elevated in muscle of individuals with obesity and type 2 diabetes compared to athletes and lean individuals and are inversely related to insulin sensitivity. Furthermore, we observed a significant reduction in muscle dSL content in individuals with obesity who completed a combined weight loss and exercise intervention. Increased dSL content in primary human myotubes caused a decrease in insulin sensitivity associated with increased inflammation, decreased AMP-activated kinase (AMPK) phosphorylation, and altered insulin signaling. Our findings reveal a central role for dSL in human muscle insulin resistance and suggest dSL as therapeutic targets for the treatment and prevention of type 2 diabetes.


This work was supported by the CCTSI 2019 CO-Pilot grant CO-M-19-74 to Simona Zarini and partially supported by the National Institutes of Health General Clinical Research Center grant RR-00036, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant to Bryan C. Bergman (R01DK089170), the Colorado Nutrition Obesity Research Center grant P30DK048520, and the American Diabetes Association grant to Bryan C. Bergman 1-14-CE-05. The Metabolomics Core Facility is supported by the Cancer Center Support Grant P30CA046934. The Antibody-Based Proteomics Core is supported by the CPRIT Core Facility Support Award (RP210227), NCI Cancer Center Support Grant (P30CA125123), and NIH S10 Instrument Award (S10OD028648, SH).