Tj. Kieffer et al., LEPTIN SUPPRESSION OF INSULIN-SECRETION BY THE ACTIVATION OF ATP-SENSITIVE K-CELLS( CHANNELS IN PANCREATIC BETA), Diabetes, 46(6), 1997, pp. 1087-1093
In the genetic mutant mouse models ob/ob or db/db, leptin deficiency o
r resistance, respectively, results in severe obesity and the developm
ent of a syndrome resembling NIDDM, One of the earliest manifestations
in these mutant mice is hyperinsulinemia, suggesting that leptin may
normally directly suppress the secretion of insulin. Here, we show tha
t pancreatic islets express a long (signal-transducing) form of leptin
-receptor mRNA and that beta-cells bind a fluorescent derivative of le
ptin (Cy3-leptin). The expression of leptin receptors on insulin-secre
ting beta-cells was also visualized utilizing antisera generated again
st an extracellular epitope of the receptor, A functional role for the
beta-cell leptin receptor is indicated by our observation that leptin
(100 ng/ml) suppressed the secretion of insulin from islets isolated
from ob/ob mice, Furthermore, leptin produced a marked lowering of [Ca
2+](i) in ob/ob beta-cells, which was accompanied by cellular hyperpol
arization and increased membrane conductance. Cell-attached patch meas
urements of ob/ob beta-cells demonstrated that leptin activated ATP-se
nsitive potassium channels (K-ATP) by increasing the open channel prob
ability, while exerting no effect on mean open time, These effects wer
e reversed by the sulfonylurea tolbutamide, a specific inhibitor of K-
ATP. Taken together, these observations indicate an important physiolo
gical role for leptin as an inhibitor of insulin secretion and lead us
to propose that the failure of leptin to inhibit insulin secretion fr
om the beta-cells of ob/ob and db/db mice may explain, in part, the de
velopment of hyperinsulinemia, insulin resistance, and the progression
to NIDDM.