Tolbutamide and diazoxide modulate phospholipase C-linked Ca(2+) signaling and insulin secretion in beta-cells.
Arginine vasopressin (AVP), bombesin, and ACh increase cytosolic free Ca(2+) and potentiate glucose-induced insulin release by activating receptors linked to phospholipase C (PLC). We examined whether tolbutamide and diazoxide, which close or open ATP-sensitive K(+) channels (K(ATP) channels), respectively, interact with PLC-linked Ca(2+) signals in HIT-T15 and mouse beta-cells and with PLC-linked insulin secretion from HIT-T15 cells. In the presence of glucose, the PLC-linked Ca(2+) signals were enhanced by tolbutamide (3-300 microM) and inhibited by diazoxide (10-100 microM). The effects of tolbutamide and diazoxide on PLC-linked Ca(2+) signaling were mimicked by BAY K 8644 and nifedipine, an activator and inhibitor of L-type voltage-sensitive Ca(2+) channels, respectively. Neither tolbutamide nor diazoxide affected PLC-linked mobilization of internal Ca(2+) or store-operated Ca(2+) influx through non-L-type Ca(2+) channels. In the absence of glucose, PLC-linked Ca(2+) signals were diminished or abolished; this effect could be partly antagonized by tolbutamide. In the presence of glucose, tolbutamide potentiated and diazoxide inhibited AVP- or bombesin-induced insulin secretion from HIT-T15 cells. Nifedipine (10 microM) blocked both the potentiating and inhibitory actions of tolbutamide and diazoxide on AVP-induced insulin release, respectively. In glucose-free medium, AVP-induced insulin release was reduced but was again potentiated by tolbutamide, whereas diazoxide caused no further inhibition. Thus tolbutamide and diazoxide regulate both PLC-linked Ca(2+) signaling and insulin secretion from pancreatic beta-cells by modulating K(ATP) channels, thereby determining voltage-sensitive Ca(2+) influx.
Schöfl
C
C
Abteilung Klinische Endokrinologie, Medizinische Hochschule Hannover, 30623 Hannover, Germany. schefl.christof@mh-hannover.de
Börger
J
J
Mader
T
T
Waring
M
M
von zur Mühlen
A
A
Brabant
G
G
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D003981:Diazoxide / Q000494:pharmacology*; D004232:Diuretics; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018721:Muscarinic Agonists / Q000494:pharmacology; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology*; D014044:Tolbutamide / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000502:physiology*
D015220:Calcium Channels; D004232:Diuretics; D007004:Hypoglycemic Agents; D007328:Insulin; D018721:Muscarinic Agonists; D049993:Sodium Chloride Symporter Inhibitors; D002217:Carbachol; D014044:Tolbutamide; D010738:Type C Phospholipases; D003981:Diazoxide