Glucose-regulated pulsatile insulin release from mouse islets via the K(ATP) channel-independent pathway.
OBJECTIVE
Regulation of insulin release by glucose involves dual pathways, including or not inhibition of ATP-sensitive K(+) channels (K(ATP) channels). Whereas the K(ATP) channel-dependent pathway produces pulsatile release of insulin it is not clear whether the independent pathway also generates such kinetics.


METHODS
To clarify this matter, insulin secretion and cytoplasmic Ca(2+) ([Ca(2+)](i)) were studied in perifused pancreatic islets from ob/ob mice. Insulin release was measured by ELISA technique and [Ca(2+)](i) by dual-wavelength fluorometry.


RESULTS
Insulin secretion was pulsatile (0.2--0.3/min) at 3 mmol/l glucose when [Ca(2+)](i) was low and stable. Stimulation with 11 mmol/l of the sugar increased the amplitude of the insulin pulses with maintained frequency and induced oscillations in [Ca(2+)](i). Permanent opening of the K(ATP) channels with diazoxide inhibited glucose-stimulated insulin secretion back to basal levels with maintained pulsatility despite stable and basal [Ca(2+)](i) levels. Increase of the K(+) concentration to 30.9 mmol/l in the continued presence of diazoxide and 11 mmol/l glucose restored the secretory rate with maintained pulsatility and caused stable elevation in [Ca(2+)](i). Simultaneous introduction of diazoxide and elevation of K(+) augmented average insulin release almost 30-fold in 3 mmol/l glucose with maintained pulse frequency. Subsequent elevation of the glucose concentration to 11 and 20 mmol/l increased the release levels. After prolonged exposure to diazoxide, elevated K(+) and 20 mmol/l glucose, the pulse frequency decreased significantly.


CONCLUSIONS
Not only glucose signaling via the K(ATP) channel-dependent but also that via the independent pathway generates amplitude-modulated pulsatile release of insulin from isolated islets.
Westerlund
J
J
Department of Medical Cell Biology, Biomedical Center, Uppsala University, Box 571, SE-751 23 Uppsala, Sweden.
Ortsäter
H
H
Palm
F
F
Sundsten
T
T
Bergsten
P
P
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003981:Diazoxide / Q000494:pharmacology; D004232:Diuretics; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D054086:KATP Channels; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008820:Mice, Obese; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D004232:Diuretics; D007328:Insulin; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D049993:Sodium Chloride Symporter Inhibitors; C092520:uK-ATP-1 potassium channel; D005947:Glucose; D003981:Diazoxide; D002118:Calcium