| Summary: | 碩士 === 高雄醫學大學 === 藥理學研究所 === 99 === Pancreatic β-cells release insulin depending on glucose metabolism
and membrane depolarization. Insulin secretion is triggered by the closure
of ATP-sensitive K+ (KATP) channels, causing a membrane depolarization
and Ca2+ influx. Insulin release process is terminated by membrane
repolarization via opening of voltage-dependent K+ (Kv) channels.
KMUP-1, a chemically synthetic xanthine-based derivative, has been
demonstrated not only effective on K+ channels, but also a
phosphodiesterases inhibitor. However, it has newer been addressed in the
inhibition of Kv channels in pancreatic β-cells.
In this study, we examined the action mechanisms by which
KMUP-1 could inhibit high glucose (25 mM)-induced Kv current
activation in pancreatic β-cells. Pancreatic islets were isolated from
Wistar rats. For electrophysiological study, islets were dispersed into
single β-cells by 0.05% trypsin-EDTA solution and plated onto 35-mm
culture dishes for 2-4 days. Perforated patch-clamp (nystatin 200 μg/mL
in pipette solution) technique was used to investigate Kv currents.
Pancreatic β-cells were identified by the size, capacitance and membrane
potential. The peak Kv current in 25 mM glucose-treated β-cells was
~1.4-fold greater than in 5.6 mM glucose (normal)-treated, measured at
+50 mV. KMUP-1 (1, 10, 30 μM) prevented 25 mM glucose-stimulated
Kv currents in a concentration-dependent manner. Insulin secretion was
decreased after high glucose incubation, and increased by treating
KMUP-1. Reduction of high glucose-mediated Kv current was found in
incubating protein kinase A (PKA) activator 8-Br-cAMP (100 μM).
Additionally, KMUP-1 (30 μM)-inhibited this current was partially
reversed by the PKA inhibitor H-89 (1 μM). Otherwise, pretreatment with
PKC activator or inhibitor had no effect on Kv currents in normal or high
glucose condition.
In conclusion, glucose-stimulated insulin secretion was reduced by
the Kv channels opening. KMUP-1 could decrease high
glucose-stimulated Kv currents via the PKA but not PKC signaling
pathway. According to these results, we provide an evidence that
KMUP-1 might be useful in the control of type II diabetes.
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