Kieffer T J, Heller R S, Leech C A, Holz G G, Habener J F
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Diabetes. 1997 Jun;46(6):1087-93. doi: 10.2337/diab.46.6.1087.
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.
在基因变异小鼠模型ob/ob或db/db中，分别由于瘦素缺乏或抵抗导致严重肥胖，并出现类似非胰岛素依赖型糖尿病（NIDDM）的综合征。这些变异小鼠最早出现的症状之一是高胰岛素血症，这表明瘦素通常可能直接抑制胰岛素分泌。在此，我们发现胰岛表达一种长型（信号转导型）瘦素受体mRNA，并且β细胞能结合瘦素的荧光衍生物（Cy3-瘦素）。利用针对受体细胞外表位产生的抗血清，也可观察到胰岛素分泌β细胞上瘦素受体的表达。我们观察到瘦素（100 ng/ml）抑制从ob/ob小鼠分离的胰岛分泌胰岛素，这表明β细胞瘦素受体具有功能作用。此外，瘦素使ob/obβ细胞内的[Ca2+]i显著降低，同时伴有细胞超极化和膜电导增加。对ob/obβ细胞进行细胞贴附式膜片钳测量表明，瘦素通过增加开放通道概率激活ATP敏感性钾通道（K(ATP)），而对平均开放时间无影响。这些效应可被磺脲类药物甲苯磺丁脲（K(ATP)的特异性抑制剂）逆转。综上所述，这些观察结果表明瘦素作为胰岛素分泌抑制剂具有重要的生理作用，并使我们提出，ob/ob和db/db小鼠β细胞中瘦素无法抑制胰岛素分泌可能部分解释了高胰岛素血症、胰岛素抵抗的发生以及向NIDDM的进展。
