Mechanism of glucose-induced biphasic insulin release: physiological role of adenosine triphosphate-sensitive K+ channel-independent glucose action.
The mechanism of glucose-induced biphasic insulin release by the B cell was investigated using isolated rat pancreatic islets. In perifusion experiments, 16.7 mM glucose in combination with 25 mM K+ transformed the high K(+)-induced monophasic insulin release into a biphasic one in the presence of diazoxide (Dz), an ATP-sensitive K+ channel opener. Inclusion of Dz during the initial 6 min of glucose stimulation abolished the first phase, but was without effect on the second phase. In batch incubation experiments, fuels, including 16.7 mM glucose, 6 mM D-glyceraldehyde, and 10 mM 2-ketoisocaproate, but not sulfonylurea, caused time-dependent potentiation of the B cell so that the response to 25 mM K+, applied later, was increased in the fuel-primed islets. Inclusion of Dz or lowering extracellular Ca2+ (to micromolar range) during the priming, which eliminates the initiation of insulin release, did not eradicate the potentiation. We conclude that high glucose closes ATP-sensitive K+ channels, leading to membrane depolarization, Ca2+ influx, and initiation of insulin release (first phase), and subsequently self-augments insulin release in an ATP-sensitive K+ channel-independent manner (second phase), acting at steps distal to cytosolic Ca2+ elevation. The biphasic insulin release is thus generated by an interaction of ATP-sensitive K+ channel-dependent and -independent glucose actions.
Taguchi
N
N
Department of Geriatrics, Endocrinology and Metabolism, Shinshu University School of Medicine, Nagano-ken, Japan.
Aizawa
T
T
Sato
Y
Y
Ishihara
F
F
Hashizume
K
K
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000032:analysis; D003600:Cytosol / Q000737:chemistry; D003981:Diazoxide / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D005960:Glucosides / Q000494:pharmacology; D005985:Glyceraldehyde / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007651:Keto Acids / Q000494:pharmacology; D008297:Male; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D005960:Glucosides; D007328:Insulin; D007651:Keto Acids; D015221:Potassium Channels; D005985:Glyceraldehyde; C019502:4-nitrophenyl alpha-glucoside; C013082:alpha-ketoisocaproic acid; D000255:Adenosine Triphosphate; D005947:Glucose; D003981:Diazoxide; D002118:Calcium