Selective Enhancement of Nutrient-Induced Insulin Secretion by ATP-Sensitive K+ Channel-Blocking Imidazolines

The contribution of ATP-sensitive K + channel (K ATP channel)-dependent and -independent signaling to the insulinotropic characteristics of imidazolines was explored using perifused mouse islets and β-cells. Up to a concentration of 100 μM efaroxan had no insulinotropic effect in the presence of a basal glucose concentration, but enhanced the effect of a stimulatory concentration of glucose or nonglucidic nutrients (ketoisocaproate plus glutamine). The secretion by a non-nutrient (40 mM KCl) was not enhanced. At 500 μM, efaroxan stimulated insulin secretion when glucose was basal. Likewise, at 0.1 to 10 μM RX871024 [2-(imidazolin-2-yl)-1-phenylindole] showed a purely enhancing effect, but at 100 μM it elicited a strong KCl-like secretory response in the presence of basal glucose. At 0.1 and 1 μM RX871024 did not significantly depolarize the β-cell membrane. However, at a purely enhancing drug concentration (10 μM RX871024 or 100 μM efaroxan) K ATP channel activity was strongly reduced, the membrane was depolarized, and the cytosolic Ca 2+ concentration was elevated in the presence of basal glucose. Insulin secretion by sulfonylurea receptor (SUR)1 knockout (KO) islets, which have no functional K ATP channels, was not increased by efaroxan (100 or 500 μM) or by 10 μM RX871024 but was increased by 100 μM RX871024. The imidazolines phentolamine and alinidine (100 μM) were also ineffective on SUR1 KO islets. It is concluded that a significant K ATP channel block is compatible with a purely enhancing effect of the imidazolines on nutrient-induced insulin secretion. Only RX871024 has an additional, nondepolarizing effect, which at a high drug concentration is able to elicit a K ATP channel-independent secretion.