Glucose-dependent and Glucose-sensitizing Insulinotropic Effect of Nateglinide: Comparison to Sulfonylureas and Repaglinide

Nateglinide, a novel D-phenylalanine derivative, stimulates insulin release via closure of K_ATP channels in pancreatic β-cell, a primary mechanism of action it shares with sulfonylureas (SUs) and repaglinide. This study investigated (1) the influence of ambient glucose levels on the insulinotropic effects of nateglinide, glyburide and repaglinide, and (2) the influence of the antidiabetic agents on glucose-stimulated insulin secretion (GSIS) in vitro from isolated rat islets. The EC₅₀ of nateglinide to stimulate insulin secretion was 14 μM in the presence of 3mM glucose and was reduced by 6-fold in 8mM glucose and by 16-fold in 16mM glucose, indicating a glucose-dependent insulinotropic effect. The actions of glyburide and repaglinide failed to demonstrate such a glucose concentration-dependent sensitization. When tested at fixed and equipotent concentrations (~2x EC₅₀ in the presence of 8mM glucose) nateglinide and repaglinide shifted the EC₅₀s for GSIS to the left by 1.7mM suggesting an enhancement of islet glucose sensitivity, while glimepiride and glyburide caused, respectively, no change and a right shift of the EC₅₀. These data demonstrate that despite a common basic mechanism of action, the insulinotropic effects of different agents can be influenced differentially by ambient glucose and can differentially influence the islet responsiveness to glucose. Further, the present findings suggest that nateglinide may exert a more physiologic effect on insulin secretion than comparator agents and thereby have less propensity to elicit hypoglycemia in vivo.