Type 2 diabetes mellitus is a severe disease with large economic consequences, which is significantly under-diagnosed and incompletely treated in the general population. Control of
blood glucose levels is a key objective in treating diabetic patients, who are most often prescribed one or more oral hypoglycaemic agents in addition to diet and exercise modification as well as
insulin. In spite of the availability of different classes of hypoglycaemic drugs, treatment regimens are often unable to achieve an intensive degree of
glucose control known to most effectively reduce the incidence and severity of
diabetic complications. Hepatic
glucose output is elevated in type 2 diabetic patients and current evidence indicates that glycogenolysis (release of monomeric
glucose from the
glycogen polymer storage form) is an important contributor to the abnormally high production of
glucose by the liver.
Glycogen phosphorylase is the
enzyme that catalyses this release and recent advances in new inhibitors of this structurally and kinetically well studied
enzyme have enabled work which further delineate the pharmacological and physiological consequences of inhibiting
glucose production by this pathway. Most notably, these agents lower
glucose in diabetic animal models, both acutely and chronically, appear to affect both gluconeogenic and glycogenolytic pathways and demonstrate potential for a beneficial effect on cardiovascular risk factors. Cumulatively, this information has bolstered interest and promise in
glycogen phosphorylase inhibitors (GPIs) as potential new hypoglycaemic agents for treatment of
type 2 diabetes mellitus.