TMG-123 (TMG123) is a potent small molecule activator of glucokinase (GK) with EC50 of 0.35 and 0.32 uM for human liver and pancreas GK, respectively.
TMG-123 activates rat liver and pancreas GK with IC50 of 0.32 and 0.36 uM, respectively, in the presence of 5 mM glucose and IC50 of 0.38 and 0.32 μM for mouse liver and pancreas GK.
TMG-123 selectively activates GK over other HK family members, not alter the activities of HKI, II, and III at 1-100 uM.
TMG-123 induces selective activation of GK enzyme activity without increasing Vmax.
At 4 mM glucose, TMG-123 (30 nM-300 μM) increased glucose uptake in a concentration-dependent manner in rat primary hepatocytes, with 300 μM TMG-123 increasing uptake 2.6 times more than control.
Administration of TMG-123 (1-10 mg/kg) improves glucose tolerance without stimulating insulin secretion in animal models of insulin-deficient and -resistant diabetes.
Administration of TMG-123 improves glucose tolerance more than metformin and glibenclamide, and exerts additional efficacy in combination with metformin.
TMG-123 produces a sustained reduction in HbA1c levels in animal models of insulin-deficient and -resistant diabetes.