The hepatic PP1 glycogen‐targeting subunit interaction with phosphorylase <i>a</i> can be blocked by C‐terminal tyrosine deletion or an indole drug

Kelsall, Ian R.; Munro, Shonagh; Hallyburton, Irene; Treadway, Judith L.; Cohen, Patricia T.W.

doi:10.1016/j.febslet.2007.08.073

Cited by 27 publications

(26 citation statements)

References 24 publications

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“…In addition to G-6-P both glucose and glycogen are also thought to regulate the activity status of GS [51,52]. GS activity is also regulated indirectly by glycogen phosphorylase given that glycogen phosphorylase allosterically regulates PP1 activity [53]. The relative importance of each of these mechanisms affecting GS is not known although the dominance of the effects of GSK-3 inhibitors suggest, for example, that compensatory inactivation of PP1 does not occur.…”

Section: Glycogen Metabolismmentioning

confidence: 99%

Targeting glycogen synthase kinase-3 (GSK-3) in the treatment of Type 2 diabetes

MacAulay

Woodgett²

2008

Expert Opinion on Therapeutic Targets

108

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Background-In spite of its rather specific name, glycogen synthase kinase-3 (GSK-3) is an eclectic cellular regulator that modulates an array of processes from nuclear transcription, to neurological functions and metabolism. The enzyme is also a focal point for diverse signaling pathways that act to suppress its activity.Objectives-Here, we review recent evidence supporting the important role GSK-3 plays in glucose homeostasis and discuss the therapeutic potential of inhibiting this enzyme in the treatment of diabetes and insulin resistance.Results/Conclusion-Despite it's pleiotropic nature, GSK-3 has significant promise as a target for diabetes due to functional partitioning of the enzyme, tissue-selectivity and acute dosagedependency of effects of inhibition -suggesting useful therapeutic windows.

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Section: Glycogen Metabolismmentioning

confidence: 99%

Targeting glycogen synthase kinase-3 (GSK-3) in the treatment of Type 2 diabetes

MacAulay

Woodgett²

2008

Expert Opinion on Therapeutic Targets

108

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“…GP inhibitors reduce blood glucose in animal models of diabetes and improve glucose tolerance in the postprandial state. An alternative strategy has been to selectively modify the interaction between GPa and the glycogen-targeting protein G L by mutating the terminal GPa binding domain or by using small molecules that prevent the interaction of GPa with G L (12). In this way, the negative control exerted by GPa on LGS activation is released without altering the activation state of GPa.…”

mentioning

confidence: 99%

Hepatic Overexpression of a Constitutively Active Form of Liver Glycogen Synthase Improves Glucose Homeostasis

Ros

Zafra

Valles-Ortega

et al. 2010

Journal of Biological Chemistry

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In this study, we tested the efficacy of increasing liver glycogen synthase to improve blood glucose homeostasis. The overexpression of wild-type liver glycogen synthase in rats had no effect on blood glucose homeostasis in either the fed or the fasted state. In contrast, the expression of a constitutively active mutant form of the enzyme caused a significant lowering of blood glucose in the former but not the latter state. Moreover, it markedly enhanced the clearance of blood glucose when fasted rats were challenged with a glucose load. Hepatic glycogen stores in rats overexpressing the activated mutant form of liver glycogen synthase were enhanced in the fed state and in response to an oral glucose load but showed a net decline during fasting. In order to test whether these effects were maintained during long term activation of liver glycogen synthase, we generated liver-specific transgenic mice expressing the constitutively active LGS form. These mice also showed an enhanced capacity to store glycogen in the fed state and an improved glucose tolerance when challenged with a glucose load. Thus, we conclude that the activation of liver glycogen synthase improves glucose tolerance in the fed state without compromising glycogenolysis in the postabsorptive state. On the basis of these findings, we propose that the activation of liver glycogen synthase may provide a potential strategy for improvement of glucose tolerance in the postprandial state.The liver responds to an increase in blood glucose concentration in the postprandial state by net uptake of glucose and conversion to glycogen, which is subsequently mobilized in the postabsorptive state to maintain blood glucose homeostasis. Various attempts have been made to improve blood glucose homeostasis through the modulation of the expression or activity of proteins involved in the control of liver glycogen metabolism. Glucokinase (GK) 3 catalyzes the first step in hepatic glucose metabolism and exerts high control on liver glycogen synthesis (1). Previous studies using either transgenic models (2, 3) or adenoviral vectors targeting the liver (4) demonstrated improved glucose tolerance and/or a lowering of blood glucose in basal conditions. However, GK overexpression also increases flux through glycolysis, and in some circumstances this leads to hypertriglyceridemia (4). An alternative approach to modulating liver glycogen metabolism without stimulating glycolysis and triglyceride formation is through modifying the enzymes that are involved exclusively in glycogen synthesis and degradation or regulatory proteins that may affect the activity of the former, such as protein targeting to glycogen (PTG) (5). Overexpression of PTG in the liver by means of an adenoviral vector increases glucose tolerance without perturbing lipid homeostasis (6). However, a limitation of this experimental model is that it leads to the progressive accumulation of glycogen because PTG promotes the inactivation of glycogen phosphorylase (GP) also during fasting, and consequently there is ne...

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“…9,10 In recent years, the interaction of GP and glycogen targeting 60 subunit (G L ) of protein phosphatase 1 (PP1) has been identified as a novel molecular target for the treatment of T2DM. [11][12][13] It was demonstrated in an in vivo mouse model that disruption of G L -GP interaction resulted in an increased glycogen synthase activity and the mice had improved glucose tolerance. 14 X-ray crystallography showed that the G L -GP interaction took place by binding the C-terminal region of G L to the allosteric site of GP.…”

mentioning

confidence: 99%

Synthesis of tartaric acid analogues of FR258900 and their evaluation as glycogen phosphorylase inhibitors

Varga

Docsa

Gergely

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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The hepatic PP1 glycogen‐targeting subunit interaction with phosphorylase a can be blocked by C‐terminal tyrosine deletion or an indole drug

Cited by 27 publications

References 24 publications

Targeting glycogen synthase kinase-3 (GSK-3) in the treatment of Type 2 diabetes

Targeting glycogen synthase kinase-3 (GSK-3) in the treatment of Type 2 diabetes

Hepatic Overexpression of a Constitutively Active Form of Liver Glycogen Synthase Improves Glucose Homeostasis

Synthesis of tartaric acid analogues of FR258900 and their evaluation as glycogen phosphorylase inhibitors

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