Kei on GSK: a contribution by the 2007 recipient of the Young Scientist Award.

FROM TIME TO TIME, we like to highlight articles authored by winners of the awards offered by the American Physiological Society. The Endocrinology and Metabolism section of APS conferred the 2007 Young Scientist Award to Kei Sakamoto, PhD. Kei is a prolific young scientist who has contributed to the American Journal of Physiology-Endocrinology and Metabolism with numerous publications and by serving on its Editorial Board since January 2007. Kei began his doctoral training at Yokohama City University in his native Japan, but soon transferred to the Joslin Diabetes Center/Harvard Medical School to complete it under the supervision of Dr. Laurie Goodyear. In 2003 he joined the group led by Dr. Dario Alessi at the MRC Protein Phosphorylation Unit of the University of Dundee for further training as a postdoctoral fellow. Since January 2006 he has been a Principal Investigator in the same Unit, and this year he was appointed Head of Molecular Physiology. What is Kei focusing on now? These days it is glycogen metabolism. Muscle glycogen synthesis is stimulated by insulin, and this depends on increased glucose transport and phosphorylation to glucose 6-phosphate, an allosteric activator of glycogen synthase, along with the activation of glycogen synthase by insulin-promoted dephosphorylation of the enzyme on sites Ser and Ser. Insulin achieves the latter by inactivating glycogen synthase kinase-3 (GSK-3). Insulin-stimulated Akt phosphorylates and inactivates both the and -isoforms of GSK-3, thus allowing for a net decrease in glycogen synthase phosphorylation at Ser. Hence, it has been thought that insulin stimulates glycogen synthesis largely by dephosphorylating glycgen synthase through the PI3K-PKB-GSK-3 pathway. The study by Sakamoto and colleagues (1), highlighted below, provides genetic evidence that the insulin-stimulated muscle can synthesize glycogen normally in the absence of this system. The story began with a previous study in which Kei participated as a postodoctoral fellow in the group of Dr. Dario Alessi. McManus, Sakamoto, Alessi, and colleagues created a genetically modified homozygous mouse model in which the two endogenous GSK-3 genes had been eliminated and replaced, through gene knockin (KI), by corresponding genes encoding mutations at the NH2-terminal phosphorylation sites [from serine to alanine residues (2)]. The clear advantage of such a model is the complete replacement of the wild-type kinases with constitutively active forms whose expression is transcriptionally regulated by the wild-type GSK-3 gene promoters. Sakamoto and colleagues [Bouskila et al. (1)] now took advantage of that mouse model to show that, compared with wild-type littermates, muscles from these KI mice have similar glycogen content in the fasted and fed state or following a bolus injection of glucose, despite lack of insulin-stimulated glycogen synthase activity. The muscles from the KI mice also had similar rates of glycogen accumulation compared with controls 1 or 2 h after exposure to insulin in vitro. As well, insulin increased normally both glucose transport and glucose 6-phosphate levels in KI mice. Furthermore, KI mice did not have compensatory alterations in glycogen metabolism muscle phosphorylase activity and responded normally to epinephrine by inhibition of glycogen synthase and stimulation of glycogen phosphorylase. The authors suggest, by extrapolation of the results, that glucose 6-phosphate may be the major regulator of insulin-stimulated glycogen accumulation. This is an intriguing proposition that will likely elicit further direct analysis, a challenge that Kei Sakamoto contemplates, probably along with many of our reader experts in this area. We are pleased to highlight the work of this young scientist and hope that it will inspire young investigators in pursuit of the intricacies of endocrinology and metabolism.