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Diabetes 52:596-604, 2003
© 2003 by the American Diabetes Association, Inc.
Disruption of the Striated Muscle Glycogen Targeting Subunit PPP1R3A of Protein Phosphatase 1 Leads to Increased Weight Gain, Fat Deposition, and Development of Insulin Resistance
1 Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom
2 GeneTargeting Laboratory, Centre for Genome Research, University of Edinburgh, Edinburgh, Scotland, United Kingdom
Disruption of the PPP1R3A gene encoding the glycogen targeting subunit (GM/RGL) of protein phosphatase 1 (PP1) causes substantial lowering of the glycogen synthase activity and a 10-fold decrease in the glycogen levels in skeletal muscle. Homozygous GM-/- mice show increased weight gain after 3 months of age and become obese, weighing 
20% more than their wild-type (WT) littermates after 12 months of age. Glucose tolerance is impaired in 11-month-old GM-/- mice, and their skeletal muscle is insulin-resistant at ≥12 months of age. The massive abdominal and other fat depositions observed at this age are likely to be a consequence of impaired blood glucose utilization in skeletal muscle. PP1-GM activity, assayed after specific immunoadsorption, was absent from GM-/- mice and stimulated in the hind limb muscles of WT mice by intravenous infusion of insulin. PP1-R5/PTG, another glycogen targeted form of PP1, was not significantly stimulated by insulin in the skeletal muscle of WT mice but showed compensatory stimulation by insulin in GM-/- mice. Our results suggest that dysfunction of PP1-GM may contribute to the pathophysiology of human type 2 diabetes.
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