title: Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells.
abstract: In the genetic mutant mouse models ob/ob or db/db, leptin deficiency or resistance, respectively, results in severe obesity and the development 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 that pancreatic islets express a long (signal-transducing) form of leptin-receptor mRNA and that beta-cells bind a fluorescent derivative of leptin (Cy3-leptin). The expression of leptin receptors on insulin-secreting beta-cells was also visualized utilizing antisera generated against 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 [Ca2+]i in ob/ob beta-cells, which was accompanied by cellular hyperpolarization and increased membrane conductance. Cell-attached patch measurements of ob/ob beta-cells demonstrated that leptin activated ATP-sensitive potassium channels (K(ATP)) by increasing the open channel probability, while exerting no effect on mean open time. These effects were reversed by the sulfonylurea tolbutamide, a specific inhibitor of K(ATP). Taken together, these observations indicate an important physiological role for leptin as an inhibitor of insulin secretion and lead us to propose that the failure of leptin to inhibit insulin secretion from the beta-cells of ob/ob and db/db mice may explain, in part, the development of hyperinsulinemia, insulin resistance, and the progression to NIDDM.
authors.affiliation: Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Kieffer
authors.forename: R S
authors.initials: RS
authors.lastname: Heller
authors.forename: C A
authors.initials: CA
authors.lastname: Leech
authors.forename: G G
authors.initials: GG
authors.lastname: Holz
authors.forename: J F
authors.initials: JF
authors.lastname: Habener
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D046508:Culture Techniques; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000737:chemistry / Q000502:physiology* / Q000648:ultrastructure; D020738:Leptin; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008820:Mice, Obese; D016133:Polymerase Chain Reaction; D015221:Potassium Channels / Q000378:metabolism*; D011506:Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D015398:Signal Transduction; D013004:Somatostatin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D007328:Insulin; D020738:Leptin; D015221:Potassium Channels; D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D013004:Somatostatin; D000255:Adenosine Triphosphate