Glucokinase (GK) is a key regulator of glucose homeostasis. It is a member of the Hexokinase family (Hexokinase IV) and is expressed in the endocrine cells of the Langerhans islets, in the liver, in the L- and K- cells of the intestine, and in the neurons of the central nervous system, primarily in the hypothalamus. GK acts as a glucose sensor by changing conformation, activity and/or intracellular location in parallel with changes in glucose concentrations. GK modulates blood glucose by inducing glucose-stimulated insulin release in the pancreas and by inducing glycogen formation and glucose breakdown in the liver. Furthermore, in pancreatic α-cells and in the intestinal endocrine cells, GK is assumed to be involved in the regulation of glucagon and of the incretin hormones, respectively.

In the liver, GK activity is acutely regulated by glucokinase regulatory protein (GKRP), which binds to and competitively inhibits GK activity. Binding of GKRP to GK leads to nuclear sequestration of the GKRP–GK protein complex. One of the important functions of GKRP is to maintain a reservoir of GK in the nucleus for rapid release into the cytoplasm as blood glucose concentration rises during a meal. Thus, it should be expected that the functional effect of a GKA will be greater in the presence of high glucose concentrations when most of the GK protein is free and active in the cytosol. Taking this into account, it is anticipated that a better therapeutic effect of a GKA will be seen in the postprandial state or in diabetic patients when blood glucose levels are elevated.

Validation of the critical role of GK in regulation of glucose homeostasis is provided by clinical characterization of patients with activating or inactivating mutations of the GK enzyme; Heterozygous inactivating mutations in GK have been associated with maturity-onset diabetes of the young type 2 (MODY 2). Homozygous inactivating GK mutations result in a more severe phenotype, presenting at birth as permanent neonatal diabetes mellitus. Moreover, heterozygous activating GK mutations causing hyperinsulinemic hypoglycemia have also been reported.

These observations support the vital role of GK enzyme in glucose homeostasis and suggest that a pharmacological induction of GK activity selective for the liver may be beneficial in patients with type 2 diabetes.

TTP399 has been identified using TTP Translational Technology®, as the lead novel, potent, selective and orally available GK activator. This molecule is in phase Ib/IIa trials assessing the effects of GKAs on glycemic control in patients with type 2 diabetes.