Ceramide impairs the insulin-dependent membrane recruitment of Protein Kinase B leading to a loss in downstream signalling in L6 skeletal muscle cells
| Autor: | Anudharan Balendran, Gary J. Litherland, Anne S. Blair, Ian H. Batty, C P Downes, Harinder S. Hundal, Eric Hajduch |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
medicine.medical_specialty
Inositol Phosphates Endocrinology Diabetes and Metabolism Protein Serine-Threonine Kinases Cell Line Phosphatidylinositol 3-Kinases Insulin resistance Sphingosine Proto-Oncogene Proteins Internal medicine Okadaic Acid Internal Medicine medicine Insulin ASK1 Phosphorylation Muscle Skeletal Glycogen synthase Protein kinase A Protein kinase B biology Akt/PKB signaling pathway Cell Membrane Biological Transport Lipid signaling Phosphoproteins medicine.disease Phosphoric Monoester Hydrolases Enzyme Activation Insulin receptor Glucose Endocrinology Insulin Receptor Substrate Proteins biology.protein Proto-Oncogene Proteins c-akt Glycogen Signal Transduction |
| Zdroj: | Diabetologia. 44:173-183 |
| ISSN: | 1432-0428 0012-186X |
| DOI: | 10.1007/s001250051596 |
| Popis: | Aims/hypothesis. Increased cellular production of ceramide has been implicated in the pathogenesis of insulin resistance and in the impaired utilisation of glucose. In this study we have used L6 muscle cells to investigate the mechanism by which the short-chain ceramide analogue, C2-ceramide, promotes a loss in insulin sensitivity leading to a reduction in insulin stimulated glucose transport and glycogen synthesis. Method. L6 muscle cells were pre-incubated with C2-ceramide and the effects of insulin on glucose transport, glycogen synthesis and the activities of key molecules involved in proximal insulin signalling determined. Results. Incubation of L6 muscle cells with ceramide (100 μmol/l) for 2 h led to a complete loss of insulin-stimulated glucose transport and glycogen synthesis. This inhibition was not due to impaired insulin receptor substrate 1 phosphorylation or a loss in phosphoinositide 3-kinase activation but was caused by a failure to activate protein kinase B. This defect could not be attributed to inhibition of 3-phosphoinositide-dependent kinase-1, or to impaired binding of phosphatidylinositol 3,4,5 triphosphate (PtdIns(3,4,5)P3) to the PH domain of protein kinase B, but results from the inability to recruit protein kinase B to the plasma membrane. Expression of a membrane-targetted protein kinase B led to its constitutive activation and an increase in glucose transport that was not inhibited by ceramide. Conclusions/interpretation. These findings suggest that a defect in protein kinase B recruitment underpins the ceramide-induced loss in insulin sensitivity of key cell responses such as glucose transport and glycogen synthesis in L6 cells. They also suggest that a stimulated rise in PtdIns(3,4,5)P3 is necessary but not sufficient for protein kinase B activation in this system. [Diabetologia (2001) 44: 173–183] |
| Databáze: | OpenAIRE |
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