Insulin And Gsk3

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In 1960 Joseph Larner reported that the activity of glycogen synthase was increased within minutes when rat diaphragms were incubated with insulin [11] and, a few years later, he showed that this resulted from decreased phos-phorylation of this enzyme [12]. Following the discovery that PKA can phos-phorylate and inhibit GSK-3 in vitro [13,14], it was thought that insulin must exert its effect on glycogen synthase by inhibiting PKA, but no decrease in the concentration of cyclic AMP could be detected in muscle under conditions where insulin stimulated glycogen synthase [12]. This led Joe Larner to suggest that insulin might trigger the formation of a "second messenger" or chemical mediator" distinct from cyclic AMP, which bound to PKA and prevented its activation by cyclic AMP but, despite much effort, no such molecule was ever purified and characterised. However, when other glycogen synthase kinases were identifieid, I suggested that insulin might instead activate glycogen synthase by inhibiting GSK-2 [5] and/or GSK-3, rather than PKA [6]. Strong support for this new idea came in 1983 when Peter Parker, a postdoc in my lab, demonstrated that the major residues on glycogen synthase that underwent dephosphorylation in response to insulin were those targeted by GSK-3, and not those targeted by PKA or other protein kinases [15].

In the early 1990's Jim Woodgett and Bill Benjamin [16], and another former graduate student Chris Proud [17], were able to establish that GSK-3 was indeed inhibited within minutes when cells were stimulated with insulin. My student Darren Cross then showed that the insulin-induced inhibition of GSK-3 was prevented by inhibition of phosphatidylinositol (PI) 3-kinase and reversed by treatment with a serine/threonine-specific phosphatase [18], which demonstrated that the inhibition of GSK-3 resulted from its phosphory-lation of a serine or threonine residue. The relevant residues were identified as Ser21 in GSK-3a and Ser9 in GSK-3P and the insulin stimulated protein kinase that inactivated GSK-3 was identified by Darren, as protein kinase B (PKB, also called Akt) in a collaboration with Brian Hemmings [19]. Dario Alessi, a postdoc, found that the activation of PKB was mediated by its phosphorylation [20] and he went on to identify and characterise a protein kinase that phosphorylated and activated PKB, but only in the presence of lipid vesicles containing PI(3,4,5)trisphosphate, the product of the PI 3-kinase reaction [21]. We therefore termed this enzyme 3-phosphoinositide-dependent protein kinase 1 (PDK1).

The discovery of PDK1 closed the chain of events by which insulin inhibits GSK-3 and made it possible to write a complete outline of this signalling pathway. The pathway was later validated genetically [22] and, in particular, Dario's group showed that insulin was unable to activate muscle glycogen synthase in mice that express knock-in mutants of GSK-3 that cannot be inactivated by PKB [23].

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