Effects of galnon, a non-peptide galanin-receptor agonist, on insulin release from rat pancreatic islets.
Galanin is a neurotransmitter peptide that suppresses insulin secretion. The present study aimed at investigating how a non-peptide galanin receptor agonist, galnon, affects insulin secretion from isolated pancreatic islets of healthy Wistar and diabetic Goto-Kakizaki (GK) rats. Galnon stimulated insulin release potently in isolated Wistar rat islets; 100 microM of the compound increased the release 8.5 times (p<0.001) at 3.3 mM and 3.7 times (p<0.001) at 16.7 mM glucose. Also in islet perifusions, galnon augmented several-fold both acute and late phases of insulin response to glucose. Furthermore, galnon stimulated insulin release in GK rat islets. These effects were not inhibited by the presence of galanin or the galanin receptor antagonist M35. The stimulatory effects of galnon were partly inhibited by the PKA and PKC inhibitors, H-89 and calphostin C, respectively, at 16.7 but not 3.3 mM glucose. In both Wistar and GK rat islets, insulin release was stimulated by depolarization of 30 mM KCl, and 100 microM galnon further enhanced insulin release 1.5-2 times (p<0.05). Cytosolic calcium levels, determined by fura-2, were increased in parallel with insulin release, and the L-type Ca2+-channel blocker nimodipine suppressed insulin response to glucose and galnon. In conclusion, galnon stimulates insulin release in islets of healthy rats and diabetic GK rats. The mechanism of this stimulatory effect does not involve galanin receptors. Galnon-induced insulin release is not glucose-dependent and appears to involve opening of L-type Ca2+-channels, but the main effect of galnon seems to be exerted at a step distal to these channels, i.e., at B-cell exocytosis.
Quynh
Nguyen Thi Thu
NT
Department of Molecular Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden.
Islam
Md Shahidul
MS
Islam
Shahidul Md
SM
Florén
Anders
A
Bartfai
Tamas
T
Langel
Ulo
U
Ostenson
Claes-Göran
CG
D000818:Animals; D002478:Cells, Cultured; D003374:Coumarins / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044088:Receptors, Galanin / Q000819:agonists*
C456547:7-((9-fluorenylmethoxycarbonyl)cyclohexylalanyllysyl)amino-4-methylcoumarin; D003374:Coumarins; D007328:Insulin; D010455:Peptides; D044088:Receptors, Galanin