Disruption of the allosteric phosphorylase a regulation of the hepatic glycogen-targeted protein phosphatase 1 improves glucose tolerance in vivo |
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| Authors: | Ian R Kelsall Doron Rosenzweig Patricia TW Cohen |
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| Institution: | 3. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202;4. Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602;1. Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 2, CH-8093 Zurich, Switzerland;2. Philochem AG, Libernstrasse 3, CH-8112 Otelfingen, Switzerland;1. Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, Hubei 430030, China;2. Joint International Research Laboratory of Agriculture and Agri-Product Safety, College of Agriculture, Yangzhou University, Yangzhou 225009, Jiangsu Province, China;3. Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China;4. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072, Australia;5. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China;6. The University of Queensland, Centre for Nutrition and Food Science, Queensland Alliance for Agriculture and Food Innovation, Brisbane, QLD 4072, Australia;7. Glycation and Diabetes, Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia;8. Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China;3. Key Laboratory of MOE for Modern Teaching Technology, Shaanxi Normal University, Xi''an 710062, China,;4. Model Animal Research Center and MOE Key Laboratory of Animal Models of Disease, Nanjing University, Nanjing 210061, China,;5. Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, China,;6. State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing 100071, China, and |
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| Abstract: | Type 2 diabetes is characterised by elevated blood glucose concentrations, which potentially could be normalised by stimulation of hepatic glycogen synthesis. Under glycogenolytic conditions, the interaction of hepatic glycogen-associated protein phosphatase-1 (PP1–GL) with glycogen phosphorylase a is believed to inhibit the dephosphorylation and activation of glycogen synthase (GS) by the PP1–GL complex, suppressing glycogen synthesis. Consequently, the interaction of GL with phosphorylase a has emerged as an attractive anti-diabetic target, pharmacological disruption of which could provide a novel mechanism to lower blood glucose levels by increasing hepatic glycogen synthesis. Here we report for the first time the in vivo consequences of disrupting the GL–phosphorylase a interaction, using a mouse model containing a Tyr284Phe substitution in the phosphorylase a-binding region of the GL protein. The resulting GLY284F/Y284F mice display hepatic PP1–GL activity that is no longer sensitive to allosteric inhibition by phosphorylase a, resulting in increased GS activity under glycogenolytic conditions, demonstrating that regulation of GL by phosphorylase a operates in vivo. GLY284F/Y284F and GLY284F/+ mice display improved glucose tolerance compared with GL+/+ littermates, without significant accumulation of hepatic glycogen. The data provide the first in vivo evidence in support of targeting the GL–phosphorylase a interaction for treatment of hyperglycaemia. During prolonged fasting the GLY284F/Y284F mice lose more body weight and display decreased blood glucose levels in comparison with their GL+/+ littermates. These results suggest that, during periods of food deprivation, the phosphorylase a regulation of GL may prevent futile glucose–glycogen cycling, preserving energy and thus providing a selective biological advantage that may explain the observed conservation of the allosteric regulation of PP1–GL by phosphorylase a in mammals. |
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