title: Glucosamine induces REDD1 to suppress insulin action in retinal Müller cells.
abstract: Resistance to insulin action is a key cause of diabetic complications, yet much remains unknown about the molecular mechanisms that contribute to the defect. Glucose-induced insulin resistance in peripheral tissues such as the retina is mediated in part by the hexosamine biosynthetic pathway (HBP). Glucosamine (GAM), a leading dietary supplement marketed to relieve the discomfort of osteoarthritis, is metabolized by the HBP, and in doing so bypasses the rate-limiting enzyme of the pathway. Thus, exogenous GAM consumption potentially exacerbates the resistance to insulin action observed with diabetes-induced hyperglycemia. In the present study, we evaluated the effect of GAM on insulin action in retinal Müller cells in culture. Addition of GAM to Müller cell culture repressed insulin-induced activation of the Akt/mTORC1 signaling pathway. However, the effect was not recapitulated by chemical inhibition to promote protein O-GlcNAcylation, nor was blockade of O-GlcNAcylation sufficient to prevent the effects of GAM. Instead, GAM induced ER stress and subsequent expression of the protein Regulated in DNA Damage and Development (REDD1), which was necessary for GAM to repress insulin-stimulated phosphorylation of Akt on Thr308. Overall, the findings support a model whereby GAM promotes ER stress in retinal Müller cells, resulting in elevated REDD1 expression and thus resistance to insulin action.
authors: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.
authors: Joshua A
authors: JA
authors: Moore
authors: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.
authors: William P
authors: WP
authors: Miller
authors: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States. Electronic address: mdennis@psu.edu.
authors: Michael D
authors: MD
authors: Dennis
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D063928:Ependymoglial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005944:Glucosamine / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D007329:Insulin Antagonists / Q000494:pharmacology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C469992:Ddit4 protein, mouse; D007328:Insulin; D007329:Insulin Antagonists; D046912:Multiprotein Complexes; D014157:Transcription Factors; D013912:Threonine; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005944:Glucosamine; D000117:Acetylglucosamine
keywords: ER Stress; Glucosamine; Hexosamine biosynthetic pathway; Insulin; O-GlcNAcylation; Regulated in DNA Damage and Development 1