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Abstract
In the liver, insulin suppresses hepatic gluconeogenesis by activating Akt, which inactivates the key gluconeogenic transcription factor FoxO1 (Forkhead Box O1). Recent studies have implicated hyperactivity of the Akt phosphatase Protein Phosphatase 2A (PP2A) and impaired Akt signaling as a molecular defect underlying insulin resistance. We therefore hypothesized that PP2A inhibition would enhance insulin-stimulated Akt activity and decrease glucose production. PP2A inhibitors increased hepatic Akt phosphorylation and inhibited FoxO1in vitro and in vivo, and suppressed gluconeogenesis in hepatocytes. Paradoxically, PP2A inhibition exacerbated insulin resistance in vivo. This was explained by phosphorylation of both hepatic glycogen synthase (GS) (inactivation) and phosphorylase (activation) resulting in impairment of glycogen storage. Our findings underline the significance of GS and Phosphorylase as hepatic PP2A substrates and importance of glycogen metabolism in acute plasma glucose regulation.
Highlights
Hepatic insulin resistance is a defining feature of type 2 diabetes (T2D) but the cellular and molecular mechanisms responsible for this insulin resistance remain unknown [1]
Focus within the field of hepatic insulin action has been predominantly on the effects mediated by Akt, the assumption being that a principal effect of insulin is to activate Akt
Recent work by Lu et al [30] has, indicated that insulin-stimulated hepatic Akt activity is dispensable in the absence of FoxO1 while other studies have found that inactivation of Gsk3α plays only a minor role in insulin-stimulated glycogen synthesis [31], the implication being, that other insulin-stimulated signaling pathways are important for acute regulation of hepatic glucose production
Summary
Hepatic insulin resistance is a defining feature of type 2 diabetes (T2D) but the cellular and molecular mechanisms responsible for this insulin resistance remain unknown [1]. Insulin normally acts to suppress hepatic glucose production (HGP) by inhibiting gluconeogenesis and stimulating net glycogen synthesis, this ability is impaired in insulin resistance and T2D [2,3,4]. Insulin stimulates phosphorylation and activation of Akt that in turn acts to phosphorylate and inactivate the transcription factor FoxO1, which induces transcription of the gluconeogenic enzymes glucose-6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase 1 (Pepck) and enhances gluconeogenesis under fasting conditions [7,8,9]. Insulin-stimulated Akt activation leads to phosphorylation and inactivation of Gsk3α [10]. Since Gsk3α normally phosphorylates and inhibits GS, this results in increased GS activity and glycogen synthesis
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