TY - JOUR
T1 - Glucosamine induces REDD1 to suppress insulin action in retinal Müller cells
AU - Moore, Joshua A.
AU - Miller, William P.
AU - Dennis, Michael D.
N1 - Funding Information:
This research was supported by The American Diabetes Association Pathway to Stop Diabetes Grant 1-14-INI-04 and NIH grant EY023612 (to MDD). The authors gratefully acknowledge Drs. Leonard Jefferson, Scot Kimball and Alistair Barber for critically evaluating this manuscript. The authors thank Dr. Gerald Hart and the NHLBI P01HL107153 Core C4 of Johns Hopkins University for providing Thiamet G. The authors also thank Dr. K. Hosoya for kindly providing TR-MUL cells and Dr. Leif Ellisen for providing REDD1+/+ and REDD1-/- MEF. Finally, the authors thank Chen Yang and Gina Deiter for technical assistance in performance of the studies described herein.
Funding Information:
This research was supported by The American Diabetes Association Pathway to Stop Diabetes Grant 1-14-INI-04 and NIH grant EY023612 (to MDD). The authors gratefully acknowledge Drs. Leonard Jefferson, Scot Kimball and Alistair Barber for critically evaluating this manuscript. The authors thank Dr. Gerald Hart and the NHLBI P01HL107153 Core C4 of Johns Hopkins University for providing Thiamet G. The authors also thank Dr. K. Hosoya for kindly providing TR-MUL cells and Dr. Leif Ellisen for providing REDD1 +/+ and REDD1 −/− MEF. Finally, the authors thank Chen Yang and Gina Deiter for technical assistance in performance of the studies described herein.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cellsig.2016.01.017
DO - 10.1016/j.cellsig.2016.01.017
M3 - Article
C2 - 26852666
AN - SCOPUS:84957959797
SN - 0898-6568
VL - 28
SP - 384
EP - 390
JO - Cellular Signalling
JF - Cellular Signalling
IS - 5
ER -
