Diabetologie und Stoffwechsel 2007; 2 - V50
DOI: 10.1055/s-2007-982145

RX871024 but not Efaroxan stimulates insulin secretion by a KATP independent mechanism

M Willenborg 1, A Wienbergen 1, L Aguilar-Bryan 2, J Bryan 2, I Rustenbeck 1
  • 1Univerity of Braunschweig, Institute of Pharmacology, Braunschweig, Germany
  • 2Baylor College of Medicine, Houston/Texas, United States of America

Introduction: Within a certain concentration range the first generation imidazoline, RX871024, enhances insulin release only when the glucose concentration by itself is stimulatory (glucose-selectivity). This effect was ascribed to the activation of a KATP channel-independent pathway in addition to the direct closure of KATP-channels. Here we show that efaroxan, another glucose-selective, first generation imidazoline, produces an insulinotropic effect only via the KATP channel-dependent pathway and has no effect on insulin release from Sur1KO islets that lack KATP channels.

Methods: Three parameters were measured to evaluate the effect of these two imidazolines:

(1) insulin release was measured in perifusion experiments on freshly isolated islets from NMRI or Sur1KO mice,

(2) KATP channel activity was assessed by patch-clamp electrophysiology and

(3) [Ca2+]c was determined by microfluorometry.

Results: Mouse β-cell KATP channel activity was reduced by about 82% by 10µM RX871024 or 100µM efaroxan; complete closure was achieved with 100µM RX871024 and 500µM efaroxan, respectively. 10µM RX871024 and 100µM efaroxan stimulated insulin secretion in 10, but not 5 mM glucose. Under normoglycemic conditions (5 mM), although there was no stimulation of insulin secretion with 10µM RX871024 or 100µM efaroxan; there was an evident increase in [Ca2+]i. 100µM RX871024 elicited a strong increase in secretion when the islets were kept at 5 mM glucose. This effect lasted for a few minutes and was only transiently changed when glucose was increased to 10 mM. Likewise, 500µM efaroxan stimulated secretion in the presence of 5 mM glucose. In contrast to the stimulation with RX871024, this stimulatory effect of efaroxan was sustained and further augmented when the glucose concentration was increased to 10 mM. When the SUR1 KO mice islets were tested, 10µM RX871024 was virtually without effect, whereas 100µM had clear stimulatory effect in the presence of both glucose concentrations. Efaroxan on the other hand, at a glucose-selective (100µM) or non-selective concentration (500µM) concentrations was completely ineffective in stimulating insulin release in islets that lack KATP channels.

Conclusion: Within a certain concentration range, both imidazoline compounds exert a glucose-selective insulinotropic effect on wild-type mouse islets. However, only RX871024 has a KATP channel-independent effect on secretion. This effect does not appear to be responsible for the glucose selectivity of the first generation imidazolines.