Inhibition of insulin secretion by leptin in normal rodent islets of Langerhans.
The recently discovered adipose cell-specific hormone called leptin decreases food intake and increases energy expenditure in rodents through a pathway involving hypothalamic leptin receptors, OB-R. In addition, leptin decreases insulin circulating levels independent of the reduction in food intake. Whether or not the hormone has a direct effect on pancreatic beta-cells is not clear, because previous in vitro studies have led to controversial results depending on the animal model used. The present study was designed to investigate the effects of leptin in islets of Langerhans isolated from normal rodents. Three isoforms of the leptin receptor, OB-Ra, b, and f, were detected by RT-PCR analysis of total RNA from rat islets. In static incubations, leptin (10 ng/ml) did not alter basal insulin secretion nor insulin secretion stimulated by glucose alone, potassium chloride, or ketoisocaproic acid. In contrast, insulin secretion stimulated by glucose + 3-isobutyl 1-methylxanthine (IBMX) was inhibited by 34 +/- 15% (n = 4, P < 0.05). This was further substantiated in perifusion experiments, in which leptin decreased by 31 +/- 3% (n = 5, P < 0.01) glucose + IBMX-stimulated insulin release. Similarly, in mouse islets a significant inhibitory effect of leptin (-31 +/- 4%, n = 6, P < 0.05) was observed only on glucose + IBMX-stimulated insulin secretion, with no effect of the hormone on basal nor glucose-stimulated secretion. Finally, leptin was totally inefficient in islets isolated from obese fa/fa rats, which bear a mutation in OB-R. These results suggest that, in normal rodent islets, leptin specifically inhibits IBMX-potentiated glucose-induced insulin secretion, through a direct effect involving at least one of the three isoforms of OB-R expressed in islets.
Poitout
V
V
INSERM U341, Service de Diabétologie, Paris, France. poitout@infobiogen.fr
Rouault
C
C
Guerre-Millo
M
M
Briaud
I
I
Reach
G
G
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D020738:Leptin; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D011506:Proteins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin
D002352:Carrier Proteins; D007328:Insulin; D020738:Leptin; D011506:Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D015056:1-Methyl-3-isobutylxanthine