Morioka Tomoaki, Dishinger John F, Reid Kendra R, Liew Chong Wee, Zhang Ting, Inaba Masaaki, Kennedy Robert T, Kulkarni Rohit N
Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Mol Endocrinol. 2012 Jun;26(6):967-76. doi: 10.1210/me.2011-1306. Epub 2012 Apr 3.
We have previously reported that the absence of leptin signaling in β-cells enhances glucose-stimulated insulin secretion and improves glucose tolerance in vivo. To investigate the relevance of β-cell leptin signaling in the context of postprandial or therapeutic insulin secretion, we examined the cross talk between leptin and glucagon-like peptide (GLP)-1 and sulfonylurea actions. Single and size-matched islets isolated from control or pancreas-specific leptin receptor knockout (pancreas-ObR-KO) mice were treated either with GLP-1 or with glibenclamide. Leptin suppressed GLP-1-stimulated intracellular Ca(2+) concentrations (Ca(2+)) increase that paralleled the decrease in insulin secretion in controls. In contrast, and as expected, the ObR-KO islets were nonresponsive to leptin, and instead, showed a 2.8-fold greater GLP-1-stimulated Ca(2+) increase and a 1.7-fold greater insulin secretion. Phosphorylation of cAMP-responsive element binding protein was enhanced, and phosphodiesterase enzymatic activity was suppressed in MIN6 β-cells with ObR knockdown compared with controls. The ObR-KO islets also showed significantly higher glibenclamide-induced insulin secretion compared with control islets, whereas Ca(2+) was similar to the controls. These data support enhanced insulinotropic effects of glucose, GLP-1, and sulfonylureas in the islets lacking leptin signaling with potential therapeutic implications.
我们之前曾报道，β细胞中缺乏瘦素信号会增强葡萄糖刺激的胰岛素分泌，并改善体内的葡萄糖耐量。为了研究餐后或治疗性胰岛素分泌情况下β细胞瘦素信号的相关性，我们检测了瘦素与胰高血糖素样肽（GLP）-1以及磺脲类药物作用之间的相互作用。从对照或胰腺特异性瘦素受体敲除（胰腺-ObR-KO）小鼠分离出的单个且大小匹配的胰岛，分别用GLP-1或格列本脲处理。瘦素抑制了GLP-1刺激的细胞内Ca（2+）浓度（[Ca（2+）]i）升高，这与对照中胰岛素分泌的减少平行。相比之下，正如预期的那样，ObR-KO胰岛对瘦素无反应，反而显示出GLP-1刺激的[Ca（2+）]i升高幅度大2.8倍，胰岛素分泌增加1.7倍。与对照相比，ObR敲低的MIN6β细胞中cAMP反应元件结合蛋白的磷酸化增强，磷酸二酯酶活性受到抑制。与对照胰岛相比，ObR-KO胰岛还显示出格列本脲诱导的胰岛素分泌明显更高，而[Ca（2+）]i与对照相似。这些数据支持在缺乏瘦素信号的胰岛中，葡萄糖、GLP-1和磺脲类药物的促胰岛素作用增强，具有潜在的治疗意义。
