Physiological control of liver glycogen metabolism: lessons from novel glycogen phosphorylase inhibitors

Liver glycogen is synthesized in the postprandial state in response to elevated concentrations of glucose and insulin or by activation of neuroendocrine signals and it is degraded in the postabsorptive state in response to changes in the concentrations of insulin and counter-regulatory hormones. Dysregulation of either glycogen degradation or synthesis through changes in allosteric control or covalent modification of glycogen phosphorylase and glycogen synthase leads to disturbance of blood glucose homeostasis. Liver glycogen phosphorylase has a dual role in the control of glycogen metabolism by regulation of both glycogen degradation and synthesis. The phosphorylated form (GPa) is the active form and determines the rate of degradation of glycogen and it is also a potent allosteric inhibitor of the protein complex, involving the glycogen targeting protein G(L) and protein phosphatase-1, which catalyses dephosphorylation (activation) of glycogen synthase. Drug discovery programmes exploring the validity of glycogen phosphorylase as a therapeutic target for type 2 diabetes have generated a wide array of selective phosphorylase ligands that modulate the catalytic activity and / or the phosphorylation state (interconversion of GPa and GPb) as well as the binding of GPa to the allosteric site of G(L). Glycogen phosphorylase inhibitors that act in hepatocytes either exclusively by dephosphorylating GPa (e.g. indole carboxamides) or by allosteric inhibition of GPa (1,4-dideoxy-1,4-D-arabinitol) are very powerful experimental tools to determine the relative roles of covalent modification of glycogen phosphorylase and/or cycling between glycogen synthesis and degradation in the mechanism(s) by which insulin and neurotransmitters regulate hepatic glycogen metabolism.