The novel imidazoline compound BL11282 potentiates glucose-induced insulin secretion in pancreatic beta-cells in the absence of modulation of K(ATP) channel activity.
The insulinotropic activity of the novel imidazoline compound BL11282 was investigated. Intravenous administration of BL11282 (0.3 mg x kg(-1) x min(-1)) to anesthetized rats did not change blood glucose and insulin levels under basal conditions, but produced a higher increase in blood insulin levels and a faster glucose removal from the blood after glucose infusion. Similarly, in isolated Wistar rat pancreatic islets, 0.1-100 micromol/l BL11282 potently stimulated glucose-induced insulin secretion but did not modulate basal insulin secretion. Unlike previously described imidazolines, BL11282 did not block ATP-dependent K+ channels. Furthermore, the compound stimulated insulin secretion in islets depolarized with high concentrations of KCl or permeabilized with electric shock. Insulinotropic activity of BL11282 was dependent on activity of protein kinases A and C. In pancreatic islets from spontaneously diabetic GK rats, the imidazoline compound restored the impaired insulin response to glucose. In conclusion, the imidazoline BL11282 constitutes a new class of insulinotropic compounds that exerts an exclusive glucose-dependent insulinotropic activity in pancreatic islets by stimulating insulin exocytosis.
Efanov
A M
AM
Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Zaitsev
S V
SV
Mest
H J
HJ
Raap
A
A
Appelskog
I B
IB
Larsson
O
O
Berggren
P O
PO
Efendic
S
S
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D004357:Drug Synergism; D004558:Electric Stimulation; D005947:Glucose / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D015221:Potassium Channels / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
C423844:BL 11282; D007093:Imidazoles; D007328:Insulin; D015221:Potassium Channels; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D005947:Glucose