Glucokinase Activators

Diabetes

Glucokinase (GK), also called Hexokinase IV or D, plays an essential role in blood glucose homeostasis. It catalyses glucose phosphorylation, and is the rate-limiting reaction for glycolysis in hepatocytes and pancreatic β-cells. In liver GK determines the rates of both glucose uptake and glycogen synthesis, and it is also thought to be essential for the regulation of various glucose-responsive genes. In the β-cells, GK determines glucose utilization and thus is necessary for glucose-stimulated insulin secretion. GK is also expressed in discrete populations of neurons in the hypothalamus and brain stem involved in energy homeostasis, and in the gut cells secreting enteroincretins (e.g. GIP, GLP-1) however, the functional importance of GK in these tissues has not been defined.

GK has two main distinctive characteristics: its expression, which is limited to tissues that require glucose-sensing (mainly liver and pancreatic β-cells), and its kinetics, characterized by a sigmoidal saturation curve, a very low affinity for glucose compared to the other members of the hexokinase family, and the lack of inhibition by the product of the reaction, glucose-6-phosphate. Due to these kinetic characteristics, changes in serum glucose levels are paralleled by (i) changes in glucose metabolism in liver which in turn regulate the balance between hepatic glucose production (HGP) and glucose consumption, and (ii) changes in insulin secretion by the β-cells.

Our lead molecule, TTP355 is in clinical development and TTP399, representing a different chemical series, is in preclinical development.