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Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, UK

(Correspondence should be addressed to P T W Cohen; Email: p.t.w.cohen{at}dundee.ac.uk)

A prediabetic phenotype of glucose intolerance, insulin resistance and obesity was observed at 12 months of age in mice homozygous for a null allele of the major skeletal muscle glycogen-targeting subunit G_M of protein phosphatase 1 (PP1) and derived from a 129/Ola donor strain. In this study, backcrossing of these mice (termed obese mice) onto two different genetic backgrounds gave rise to lean, glucose-tolerant, insulin-sensitive mice (termed lean mice), indicating that at least one variant gene in the 129/Ola background, not present in the C57BL/6 or 129s2/sV background, is required for the development of the prediabetic phenotype of obese mice. Slightly elevated AMP-activated protein kinase 2 activity in the skeletal muscle of lean C57BL/6 mice was also observed to a lesser extent in the obese mice. Normal or slightly raised in vivo glucose transport in lean C57BL/6 mice compared with decreased glucose transport in the obese mice supports the tenet that adequate transport of glucose may be a key factor in preventing the development of the prediabetic phenotype. The pH 6.8/pH 8.6 activity ratio of phosphorylase kinase was increased in lean C57BL/6 mice compared with controls indicating that phosphorylase kinase is an in vivo substrate of PP1-G_M.