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.

Role of glucosamine in development of diabetic neuropathy independent of the aldose reductase pathway

“…6 ). Consistent with our results, independence of O-GlcNAcylation from tissue injury was also shown in retinal neurons ( Nakamura et al , 2001 ) as well as retinal Mueller cells ( Moore et al , 2016 ) when they were exposed to GlcN.…”

“…In contrast, although GlcN was found to be toxic to cultured motor neurons ( Lim et al , 2010 ), its relationship to diabetic neuropathy has not been adequately addressed. Interestingly, some studies have connected endoplasmic reticulum (ER) stress with HBP and the genesis of diabetic complications ( Werstuck et al , 2006 ; Moore et al , 2016 ). A role for ER stress in the development of neuropathy was confirmed by several laboratories using streptozotocin-induced diabetic rats and CCAT-enhancer-binding protein-beta CCAT-enhancer-binding homologous protein (CHOP)-deficient mice ( Lupachyk et al ., 2013 ; Wu et al ., 2013 ).…”

Is REDD1 a Metabolic Éminence Grise ?

“…This suggests that REDD1 acts to modulate site-specific activity of PP2A, although how it does so remains unclear. It is noteworthy that recent work by Moore and coworkers demonstrated the ability of glucosamine to repress insulin-stimulated PKB/Akt Thr308 phosphorylation and downstream mTORC1 signalling in retinal Müller cells by increasing ER stress and REDD1 protein expression [29]. However, the potential involvement of PP2A in mediating the insulin-desensitising action of glucosamine was not determined in this study.…”

Glucosamine inhibits IL-1β expression by preserving mitochondrial integrity and disrupting assembly of the NLRP3 inflammasome

“…However, there are little data regarding the side effects of GlcN supplementation on metabolic or vascular systems. It was reported that GlcN promotes endoplasmic reticulum stress in retinal Müller cells and leads to the resistance to insulin action, suggesting that GlcN potentially exacerbates diabetes-induced hyperglycaemia 40 . Another study also indicated that GlcN enhanced insulin resistance in mice fed a normal diet but ameliorated obesity and insulin resistance in mice fed a high-fat diet 41 .…”