Chronic exposure of pancreatic islets to sulfonylureas
(SUs) is known to impair the ability of islets
to respond to subsequent acute stimulation by
SUs or glucose. Nateglinide (NAT) is a novel
insulinotropic agent with a primarily site of action
at β-cell KATP channels, which is common to the
structurally diverse drugs like repaglinide (REP)
and the SUs. Earlier studies on the kinetics, glucosedependence
and sensitivity to metabolic inhibitors
of the interaction between NAT and KATP channels
suggested a distinct signaling pathways with NAT
compared to REP, glyburide (GLY) or glimepiride
(GLI). To obtain further evidence for this concept,
the present study compared the insulin secretion in
vitro from rat islets stimulated acutely by NAT, GLY,
GLI or REP at equipotent concentrations during 1-hr
static incubation following overnight treatment
with GLY or tolbutamide (TOL). The islets fully
retained the responsiveness to NAT stimulation
after prolonged pretreatment with both SUs, while
their acute response to REP, GLY, and GLI was
markedly attenuated, confirming the desensitization
of islets. The insulinotropic efficacy of NAT in islets
desensitized to SUs may result from a distinct
receptor/effector mechanism, which contributes to
the unique pharmacological profile of NAT.
