Imidazoline compounds stimulate insulin release by inhibition of K(ATP) channels and interaction with the exocytotic machinery.
A novel imidazoline compound, RX871024, was used to investigate the mechanisms by which imidazoline derivatives promote insulin secretion in rat pancreatic beta-cells and HIT T15 cells. RX871024 stimulated insulin release from rat pancreatic beta-cells and HIT T15 cells in a glucose-dependent way. This effect was not related to alpha2-adrenergic, I1-, and I2-imidazoline receptors. RX871024 promoted insulin release by at least two modes of action. One included an increase in cytoplasmic free Ca2+ concentration ([Ca2+]i), subsequent to blocking of ATP-dependent K+ channels, membrane depolarization, and activation of voltage-dependent Ca2+ channels. The other, a more distal effect of imidazoline, affected the exocytotic machinery and was unrelated to changes in membrane potential and [Ca2+]i. The mechanism of RX871024-induced insulin release was dependent on protein kinases A and C. The sensitizing effect of a low dose of RX871024 on glucose-induced insulin secretion suggests that imidazoline compounds of this kind may constitute the basis for development of a new class of oral hypoglycemic agents.
Zaitsev
S V
SV
Department of Molecular Medicine, Rolf Luft Center for Diabetes Research, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
Efanov
A M
AM
Efanova
I B
IB
Larsson
O
O
Ostenson
C G
CG
Gold
G
G
Berggren
P O
PO
Efendić
S
S
D000818:Animals; D000068438:Brimonidine Tartrate; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D005089:Exocytosis; D005947:Glucose / Q000494:pharmacology; D019329:Idazoxan / Q000494:pharmacology; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007211:Indoles / Q000493:pharmacokinetics*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010646:Phentolamine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
C101943:2-(2-imidazolin-2-yl)-1-phenyl-1H-indole; D007093:Imidazoles; D007211:Indoles; D007328:Insulin; D015221:Potassium Channels; D011810:Quinoxalines; D000068438:Brimonidine Tartrate; D011189:Potassium Chloride; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D005947:Glucose; D003981:Diazoxide; D002118:Calcium; D019329:Idazoxan; D010646:Phentolamine