Nateglinide, a novel D-phenylalanine derivative,
stimulates insulin release via closure of KATP 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.
