Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes

Vosseller, Keith; Wells, Lance; Lane, M. Daniel; Hart, Gerald W.

doi:10.1073/pnas.072072399

Cited by 437 publications

(428 citation statements)

References 64 publications

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“…From our data, we cannot conclude that glucosamine causes ER stress via increased protein O-GlcNAc levels, although this mechanism cannot be ruled out. In fact, data from the literature support the existence of mechanisms that are dependent on [30] and independent of [31] protein O-GlcNAc. Our results also suggest that a glucosamine intermediate is involved in ER stress induction, as inhibition of glutamine amidotransferases, including GFAT, by azaserine blocked ER stress induction by high glucose but not by glucosamine.…”

Section: Discussionmentioning

confidence: 63%

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

et al. 2011

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Aims/hypothesis Beta cell failure is caused by loss of cell mass, mostly by apoptosis, but also by simple dysfunction (decline of glucose-stimulated insulin secretion, downregulation of specific gene expression). Apoptosis and dysfunction are caused, at least in part, by lipoglucotoxicity. The mechanisms implicated are oxidative stress, increase in the hexosamine biosynthetic pathway (HBP) flux and endoplasmic reticulum (ER) stress. Oxidative stress plays a role in glucotoxicity-induced beta cell dedifferentiation, while glucotoxicity-induced ER stress has been mostly linked to beta cell apoptosis. We sought to clarify whether ER stress caused by increased HBP flux participates in a dedifferentiating response of beta cells, in the absence of relevant apoptosis. Methods We used INS-1E cells and murine islets. We analysed the unfolded protein response and the expression profile of beta cells by real-time RT-PCR and western blot. The signal transmission pathway elicited by ER stress was investigated by real-time RT-PCR and immunofluorescence. Results Glucosamine and high glucose induced ER stress, but did not decrease cell viability in INS-1E cells. ER stress caused dedifferentiation of beta cells, as shown by downregulation of beta cell markers and of the transcription factor, pancreatic and duodenal homeobox 1. Glucose-stimulated insulin secretion was inhibited. These effects were prevented by the chemical chaperone, 4-phenyl butyric acid. The extracellular signal-regulated kinase (ERK) signal transmission pathway was implicated, since its inhibition prevented the effects induced by glucosamine and high glucose. Conclusions/interpretation Glucotoxic ER stress dedifferentiates beta cells, in the absence of apoptosis, through a transcriptional response. These effects are mediated by the activation of ERK1/2.

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Section: Discussionmentioning

confidence: 63%

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

et al. 2011

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“…Hexosamines are currently believed to exert their effects by increasing the levels of enzymatic O-linked glycosylation of cytosolic and nuclear proteins by N-acetylgucosamine (43)(44)(45). For example, it has been recently demonstrated that elevated glycosylation by O-linked GlcNAc can inhibit insulin-dependent activation of Akt (43). Thus one possible explanation for insulin resistance in Mb7 hearts stems from the backup of glycolysis at PFK-1, leading to increased flux through the hexosamine pathway.…”

Section: Discussionmentioning

confidence: 99%

“…One demonstrated mechanism is increased hexosamine flux (41,42), which was indicated in this model by the 2-fold increase in levels of UDP-GlcNAc. Hexosamines are currently believed to exert their effects by increasing the levels of enzymatic O-linked glycosylation of cytosolic and nuclear proteins by N-acetylgucosamine (43)(44)(45). For example, it has been recently demonstrated that elevated glycosylation by O-linked GlcNAc can inhibit insulin-dependent activation of Akt (43).…”

Section: Discussionmentioning

confidence: 99%

Cardiac Expression of Kinase-deficient 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase Inhibits Glycolysis, Promotes Hypertrophy, Impairs Myocyte Function, and Reduces Insulin Sensitivity

Donthi

et al. 2004

Journal of Biological Chemistry

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Glycolysis is important to cardiac metabolism and reduced glycolysis may contribute to diabetic cardiomyopathy. To understand its role independent of diabetes or hypoxic injury, we modulated glycolysis by cardiacspecific overexpression of kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (kd-PFK-2). PFK-2 controls the level of fructose 2,6-bisphosphate (Fru-2,6-P 2 ), an important regulator of glycolysis. Transgenic mice had over 2-fold reduced levels of Fru-2,6-P 2 . Heart weight/body weight ratio indicated mild hypertrophy. Sirius red staining for collagen was significantly increased. We observed a 2-fold elevation in glucose 6-phosphate and fructose 6-phosphate levels, whereas fructose 1,6-bisphosphate was reduced 2-fold. Pathways branching off of glycolysis above phosphofructokinase were activated as indicated by over 2-fold elevated UDP-N-acetylglucosamine and glycogen. The kd-PFK-2 transgene significantly inhibited glycolysis in perfused hearts. Insulin stimulation of metabolism and Akt phosphorylation were sharply reduced. In addition, contractility of isolated cardiomyocytes was impaired during basal and hypoxic incubations. The present study shows that cardiac overexpression of kinase-deficient PFK-2 reduces cardiac glycolysis that produced negative consequences to the heart including hypertrophy, fibrosis, and reduced cardiomyocyte function. In addition, metabolic and signaling responses to insulin were significantly decreased.

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“…Competitive inhibition of OGA glycosidase activity using a GlcNAc analogue O-(2-acetoamido-2 deoxy-Dglucopyranosylidene)-amino-N-phenylcaramate (PUGNAc) results in elevation of global O-GlcNAc levels, and suppresses insulin-stimulated glucose uptake and Akt phosphorylation in 3T3-L1 adipocytes 42) . However, such insulin-desensitizing effects are not observed when 3T3-L1 adipocytes are treated with 1,2-dideoxy-2'-propyl-α-D-glucopyranoso-[2,1-D]-Δ2'-thiazoline (NButGT), a more potent and selective OGA inhibitor 43) , and similar results were also obtained in a rodent model 44) , indicating that non-targeted globally elevated O-GlcNAc levels do not independently cause the development of insulin resistance 43,44) .…”

Section: Ogamentioning

confidence: 99%

Effects of exercise on the hexosamine biosynthetic pathway and glycosylation

Shirato

Kizaki

Ohno

et al. 2012

JPFSM

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Minor amounts of glucose incorporated into the cells is metabolized via the hexosamine biosynthetic pathway, resulting in the production of uridine-5'-diphosphate-N-acetylglucosamine (UDP-GlcNAc), which is utilized as a donor substrate for the N-and O-linked glycosylation of extracellular and membrane proteins in the Golgi apparatus, or for the O-linked GlcNAc modification (O-GlcNAcylation) of intracellular proteins in the cytosol. In particular, O-GlcNAcylation, the addition of GlcNAc to serine/threonine residues, is reversibly regulated by the enzymatic activities of O-GlcNAc transferase (OGT) and O-GlcNAcase. Since OGT activity is sensitive to the intracellular UDP-GlcNAc level, flux via the hexosamine pathway influences O-GlcNAcylation. Actually, excess flux via the hexosamine pathway and resultant increased O-GlcNAcylation are associated with several pathophysiological conditions, including insulin resistance. To date, there are several studies addressing the effects of exercise on the hexosamine pathway and O-GlcNAcylation. Thus, this short review focuses on the relationships among exercise, the hexosamine pathway, O-GlcNAcylation, and insulin resistance.

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Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes

Cited by 437 publications

References 64 publications

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

Cardiac Expression of Kinase-deficient 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase Inhibits Glycolysis, Promotes Hypertrophy, Impairs Myocyte Function, and Reduces Insulin Sensitivity

Effects of exercise on the hexosamine biosynthetic pathway and glycosylation

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