The role of protein kinase B/Akt in insulin-induced inactivation of phosphorylase in rat hepatocytes

Aiston, Susan; Hampson, Laura J.; Arden, Catherine; Iynedjian, Patrick B.; Agius, Loranne

doi:10.1007/s00125-005-0068-4

Cited by 29 publications

(21 citation statements)

References 39 publications

(71 reference statements)

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“…2). Recent studies have shown that overexpression of a constitutively active form of Akt in rat hepatocytes induces glycogen synthase activity and inhibits glycogen phosphorylase activity (12). Our data provide in vivo evidence that increased Akt activity indeed influences both branches of glycogen metabolism, since in our study hepatic SHIP2 inhibition led to decreased phosphorylation of glycogen synthase and glycogen phosphorylase.…”

Section: Discussionsupporting

confidence: 78%

“…Second, insulin promotes glycogen accumulation by activation of glycogen synthesis, through stimulation of glycogen synthase and reduction of glycogen breakdown, via inhibition of glycogen phosphorylase. The activities of both enzymes are regulated by changes in their phosphorylation states (11), and it has been shown recently that Akt also plays an important role in mediating the inactivation of hepatic glycogen phosphorylase and activation of glycogen synthase (12).…”

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confidence: 99%

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Normalization of Prandial Blood Glucose and Improvement of Glucose Tolerance by Liver-Specific Inhibition of SH2 Domain–Containing Inositol Phosphatase 2 (SHIP2) in Diabetic KKAy Mice

et al. 2007

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Type 2 diabetes is characterized by a progressive resistance of peripheral tissues to insulin. Recent data have established the lipid phosphatase SH2 domain-containing inositol phosphatase 2 (SHIP2) as a critical negative regulator of insulin signal transduction. Mutations in the SHIP2 gene are associated with type 2 diabetes. Here, we used hyperglycemic and hyperinsulinemic KKA y mice to gain insight into the signaling events and metabolic changes triggered by SHIP2 inhibition in vivo. Liver-specific expression of a dominant-negative SHIP2 mutant in KKA y mice increased basal and insulin-stimulated Akt phosphorylation. Protein levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase were significantly reduced, and consequently the liver produced less glucose through gluconeogenesis. Furthermore, SHIP2 inhibition improved hepatic glycogen metabolism by modulating the phosphorylation states of glycogen phosphorylase and glycogen synthase, which ultimately increased hepatic glycogen content. Enhanced glucokinase and reduced pyruvate dehydrogenase kinase 4 expression, together with increased plasma triglycerides, indicate improved glycolysis. As a consequence of the insulin-mimetic effects on glycogen metabolism, gluconeogenesis, and glycolysis, the liverspecific inhibition of SHIP2 improved glucose tolerance and markedly reduced prandial blood glucose levels in KKA y mice. These results support the attractiveness of a specific inhibition of SHIP2 for the prevention and/or treatment of type 2 diabetes. Diabetes 56:2235-2241, 2007 A key event in insulin signal transduction is the increase in phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P 3 ], which recruits and activates downstream effectors at the plasma membrane (1). The lipid phosphatase SH2 domain-containing inositol phosphatase 2 (SHIP2) is expressed in insulin target tissues and dephosphorylates PI(3,4,5)P 3 at the D5 position (2,3). Activating mutations in the SHIP2 gene contribute to the genetic susceptibility to type 2 diabetes in humans (4). Mice lacking the SHIP2 gene (Inppl1 Ϫ/Ϫ mice) are viable and have normal glucose and insulin levels with normal insulin and glucose tolerances. However, Inppl1Ϫ/Ϫ mice are protected from diet-induced obesity, hyperglycemia, and insulin resistance (5). The function of SHIP2 in differentiated L6 myotubes and 3T3-L1 adipocytes was extensively studied by inhibition of the endogenous SHIP2 via overexpression of a dominantnegative SHIP2 mutant (dnSHIP2). SHIP2 inhibition increases phosphorylation of Akt (also known as protein kinase B) and glycogen synthesis in both cell lines (6,7). The liver-specific overexpression of dnSHIP2 in db/db mice results in dramatically decreased fasting glucose levels due to the reduced expression of the gluconeogenic genes glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) (8). However, the strong reduction in fasting blood glucose concentration confounds the interpretation of an improved glucose tolerance test in this model. Furthermore, an effect o...

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Section: Discussionsupporting

confidence: 78%

mentioning

confidence: 99%

Normalization of Prandial Blood Glucose and Improvement of Glucose Tolerance by Liver-Specific Inhibition of SH2 Domain–Containing Inositol Phosphatase 2 (SHIP2) in Diabetic KKAy Mice

et al. 2007

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“…The cells were extracted in gel-loading buffer containing 15% sucrose, 2% SDS, bromophenol blue and 1% mercaptoethanol, separated by 10% SDS-PAGE and transferred to nitrocellulose membranes. Membranes were blocked for 2 h in 3% BSA and incubated overnight with a phosphospecific antibody against Akt (protein kinase B) serine 473 (New England BioLabs, Beverly, MA) followed by horseradish peroxidase-linked anti-IgG (Jackson Immunoresearch, Westgrove, PA) [26]. Immunoreactive bands were detected using an enzyme chemiluminescence kit (Amersham Biosciences, Little Chalfont, UK).…”

Section: Methodsmentioning

confidence: 99%

“…Mechanism of inactivation of phosphorylase by α-methyl-5-HT Inactivation of phosphorylase by insulin in hepatocytes occurs downstream of activation of Akt and is associated with phosphorylation of serine 473 [26]. However, α-methyl-5-HT, unlike insulin, did not cause Akt phosphorylation (Fig.…”

Section: -mentioning

confidence: 97%

Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

2007

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Aims/hypothesis Intraportal infusion of serotonin (5-hydroxytryptamine, 5-HT) or inhibitors of its cellular uptake stimulate hepatic glucose uptake in vivo by either direct or indirect mechanisms. The aims of this study were to determine the direct effects of 5-HT in hepatocytes and to test the hypothesis that atypical antipsychotic drugs that predispose to type 2 diabetes counter-regulate the effects of 5-HT. Materials and methods Rat hepatocytes were studied in short-term primary culture. Results Serotonin (5-HT) stimulated glycogen synthesis at nanomolar concentrations but inhibited it at micromolar concentrations. The stimulatory effect was mimicked by α-methyl-5-HT, a mixed 5-HT1/5-HT2 receptor agonist, whereas the inhibition was counteracted by a 5-HT2B/2C receptor antagonist. α-Methyl-5-HT stimulated glycogen synthesis additively with insulin, but unlike insulin, did not stimulate glucose phosphorylation and glycolysis, nor did it cause Akt (protein kinase B) phosphorylation. Stimulation of glycogen synthesis by α-methyl-5-HT correlated with depletion of phosphorylase a. This effect could not be explained by elevated levels of glucose 6-phosphate, which causes inactivation of phosphorylase, but was explained, at least in part, by decreased phosphorylase kinase activity in situ. The antipsychotic drugs clozapine and olanzapine, which bind to 5-HT receptors, counteracted the effect of α-methyl-5-HT on phosphorylase inactivation. Conclusions/interpretation This study provides evidence for both stimulation and inhibition of glycogen synthesis in hepatocytes by serotonergic mechanisms. The former effects are associated with the inactivation of phosphorylase and are counteracted by atypical antipsychotic drugs that cause hepatic insulin resistance. Antagonism of hepatic serotonergic mechanisms may be a component of the hepatic dysregulation caused by antipsychotic drugs that predispose to type 2 diabetes.

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“…2 Akt plays a critical role in insulin-mediated activation of hepatic glycogen synthase and inactivation of glycogen phosphorylase. 3 Homocysteine is an intermediate in methionine metabolism. Elevated levels of circulating homocysteine, a condition known as hyperhomocysteinemia (HHcy), are an independent risk factor for atherosclerosis.…”

Section: Sismentioning

confidence: 99%

Inhibition of Hepatic Glycogen Synthesis by Hyperhomocysteinemia Mediated by TRB3

Liu

et al. 2011

The American Journal of Pathology

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Recently, epidemiological and experimental studies have linked hyperhomocysteinemia (HHcy) to insulin resistance. However, whether HHcy impairs glucose homeostasis by affecting glycogenesis in the liver is not clear. In the present study, we investigated the effect of HHcy on hepatic glycogen synthesis. Hyperhomocysteinemia was induced in mice by drinking water containing two percent methionine. Mice with HHcy showed an increase in the phosphorylation of glycogen synthase and a significant decrease in hepatic glycogen content and the rate of glycogen synthesis. The expression of TRB3 (tribbles-related protein 3) was up-regulated in the liver of mice with HHcy, concomitantly with the dephosphorylation of glycogen synthase kinase-3␤ and Akt. The knockdown of TRB3 by short hairpin RNA suppressed the dephosphorylation of these two kinases. Homocysteine induced an increase in the levels of hepatic cAMP and cAMP response element-binding protein phosphorylation, which in turn up-regulated the expression of peroxisome proliferator-activated receptor (PPAR)-␥ coactivator-1␣ and TRB3. The inhibition of PPAR-␣ by its inhibitor, MK886, or knockdown of PPAR-␣ by small interfering RNA significantly inhibited the expression of TRB3 induced by homocysteine. The current study demonstrates that HHcy impairs hepatic glycogen synthesis by inducing the expression of TRB3. These results provide a novel explanation for the development and progression of insulin resistance in HHcy.

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The role of protein kinase B/Akt in insulin-induced inactivation of phosphorylase in rat hepatocytes

Cited by 29 publications

References 39 publications

Normalization of Prandial Blood Glucose and Improvement of Glucose Tolerance by Liver-Specific Inhibition of SH2 Domain–Containing Inositol Phosphatase 2 (SHIP2) in Diabetic KKAy Mice

Normalization of Prandial Blood Glucose and Improvement of Glucose Tolerance by Liver-Specific Inhibition of SH2 Domain–Containing Inositol Phosphatase 2 (SHIP2) in Diabetic KKAy Mice

Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

Inhibition of Hepatic Glycogen Synthesis by Hyperhomocysteinemia Mediated by TRB3

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