O-GlcNAc-Selective-N-Acetyl-β-&lt;i&gt;D&lt;/i&gt;-Glucosaminidase Activity and mRNA Expression in Muscle Is Related to Glucosamine-Induced Insulin Resistance

Durán‐Reyes, Genoveva; Pascoe-Lira, Dalila; García‐Macedo, Rebeca; Medina-Navarro, Rafael; Rosales‐Torres, Ana María; Vergara‐Onofre, Marcela; Foyo-Niembro, Enrique; Gutiérrez-Rodríguez, Margarita Eugenia; García-Gutiérrez, María Trinidad Adriana; Valladares‐Salgado, Adán; Kumate, J; Crúz, Miguel A.

doi:10.1159/000279329

Cited by 1 publication

(1 citation statement)

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“…Since O-GlcNAc is inducible and reversible, it is poised as a nutrient sensor downstream of the HBP (Wells et al 2003). Following the seminal findings for the link between excessive HBP flux and the development of insulin resistance (Marshall et al 1991;Virkamaki et al 1997;Nelson et al 2000;Nakamura et al 2001;Buse et al 2002), many studies have proceeded to demonstrate increased O-GlcNAc levels as the bridge between the two events (Hebert et al 1996;Buse et al 2002;McClain et al 2002;Vosseller et al 2002;Clark et al 2003;Hanover et al 2005;Hu et al 2005;Forsythe et al 2006;Dentin et al 2008;D'Apolito et al 2010;Duran-Reyes et al 2010;Lee et al 2010;Love et al 2010;Rahman et al 2010;Sekine et al 2010;Mondoux et al 2011). The first direct study on O-GlcNAc was established in an immortal murine adipocyte cell line (3T3-L1), whereby using PUGNAc (PUGNAc, the first generation of OGA inhibitors; Dong and Hart 1994;Haltiwanger et al 1998) to elevate global O-GlcNAc levels lead to an impairment of acute insulin-stimulated glucose uptake and signal transmission through the IRS/PI3K/Akt cascade (Vosseller et al 2002).…”

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confidence: 99%

Dissecting PUGNAc-mediated inhibition of the pro-survival action of insulin

Teo¹,

El-Karim

Wells³

2016

Glycobiology

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Previous studies utilizing PUGNAc, the most widely used β-N-acetylglucosaminidase (OGA) inhibitor to increase global O-N-acetylglucosamine (GlcNAc) levels, have reported a variety of effects including insulin resistance as a direct result of elevated O-GlcNAc levels. The notion of OGA inhibition causing insulin resistance was not replicated in studies in which elevated global O-GlcNAc levels were achieved using two other OGA inhibitors. Related to insulin action, work by others has suggested that O-GlcNAc elevation may inhibit the anti-apoptotic action of insulin. Thus, we examined the pro-survival action of insulin upon serum deprivation in the presence of PUGNAc as well as two selective OGA inhibitors (GlcNAcstatin-g and Thiamet-G), and a selective lysosomal hexosaminidase inhibitor (INJ2). We established that PUGNAc inhibits the pro-survival action of insulin but this effect is not recapitulated by the selective OGA inhibitors suggesting that elevation in O-GlcNAc levels alone is not responsible for PUGNAc's effect on the anti-apoptotic action of insulin. Further, we demonstrate that a selective hexosaminidase A/B (HexA/B) inhibitor does not impact insulin action suggesting that PUGNAc's effect is not due to inhibition of lysosomal hexosaminidase. Finally, we tested a combination of selective OGA and lysosomal hexosaminidase inhibitors but were not able to recapitulate the inhibition of insulin action generated by PUGNAc alone. These results strongly suggest that the defect in insulin action upon PUGNAc treatment does not derive from its inhibition of OGA or HexA/B, and that there is an unknown target of PUGNAc that is the likely culprit in inhibiting the protective effect of insulin from apoptosis.

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