Hatlapatka K, Wienbergen A, Kuehne C, Joerns A, Willenborg M, Rustenbeck I
Selective enhancement of nutrient-induced insulin secretion by KATP channel-blocking imidazolines. [JOURNAL ARTICLE]
J Pharmacol Exp Ther 2009 Sep 10.
The contribution of KATP channel-dependent and -independent signalling to the insulinotropic characteristics of imidazolines was explored using perifused mouse islets and beta-cells. Up to a concentration of 100 microM efaroxan had no insulinotropic effect in the presence of a basal glucose concentration, but enhanced the effect of a stimulatory concentration of glucose or non-glucidic nutrients (ketoisocaproate plus glutamine). The secretion by a non-nutrient (40 mM KCl) was not enhanced. At 500 microM efaroxan stimulated insulin secretion when glucose was basal. Similarly, at 0.1 to 10 microM RX871024 showed a purely enhancing effect, but at 100 microM it elicited a strong KCl-like secretory response in the presence of basal glucose. At 0.1 and 1 microM RX871024 did not significantly depolarize the beta-cell membrane. However, at a purely enhancing drug concentration (10 microM RX871024 or 100 microM efaroxan) KATP channel activity was strongly reduced, the membrane was depolarized, and the cytosolic Ca(2+) concentration was elevated in the presence of basal glucose. The insulin secretion by SUR1 KO islets, which have no functional KATP channels, was neither increased by efaroxan (100 or 500 microM) nor by 10 microM RX871024, but by 100 microM RX871024. The imidazolines phentolamine and alinidine (100 microM) were also ineffective on SUR1 KO islets. It is concluded that a significant KATP channel block is compatible with a purely enhancing effect of the imidazolines on nutrient-induced insulin secretion. Only RX871024 has an additional, non-depolarizing effect, which at a high drug concentration is able to elicit a KATP channel-independent secretion.
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