Glucokinase-activating ureas

Glucose-Dependent Modulation of Insulin Secretion and Intracellular Calcium Ions by Gka50 - A Glucokinase Activator

“…MIN6 cell culture. MIN6 cells (passages [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] (34,35) were maintained in Dulbecco's modified Eagle's medium (DMEM; 25 mmol/l glucose; Invitrogen) supplemented with 15% FCS, penicillin/streptomycin (100 units/ml, 0.1 mg/ ml), 2 mmol/l/l L-glutamine, and 5 l/l 2-mercaptoethanol. Cells were incubated at 37°C in a 5% CO 2 humidified incubator.…”

“…Several groups have independently reported on a number of synthetic low-molecular weight molecules that act as activators of glucokinase (23)(24)(25)(26)(27)(28)(29)(30)(31). We have recently described a series of glucokinase activators (GKAs), GKA1, -2, -22, and -50, that can modulate hepatic glucokinase activity in vitro and potently reduce blood glucose levels in vivo (25,29,30,32).…”

Tweaking the Glucose Sensor: Adjusting Glucokinase Activity with Activator Compounds

“…GKAs, by reducing the S 0.5 , essentially make GK more sensitive to glucose concentrations that normally would not be as effective. Indeed, a reduction of fasting plasma glucose, and hypoglycemia, have been reported as a consequence of GKA treatment in some of the animal studies (9,12). The possible long-term complications of increased hepatic glycogen stores and lipid deposition in liver and muscle, perhaps as a consequence of prolonged hyperinsulinemia, represent concerns that may not become apparent until these agents have been used longterm in man.…”

“…This accumulated evidence suggests that adjusting GK activity could be used to regulate the plasma glucose concentration. Several companies have reported initial success in this endeavor (8,9,12), and LY2121260 can now be added to the list (13).…”

“…The increased plasma insulin should reduce hepatic glucose production and increase peripheral glucose utilization. These effects contribute to the reduction of fasting plasma glucose and improvement in glucose tolerance noted in normal animals and various animal models of diabetes, as described by Efanov et al (13) and others (8,9,12). In one study, rats were fasted for 18 h and were then subjected to a pancreatic clamp in which plasma insulin and glucose levels were kept constant (12).…”