Wang X P, Yang J, Norman M A, Magnusson J, DeMayo F J, Brunicardi F C
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 402SA, One Baylor Plaza, Houston, TX 77030, USA.
FEBS Lett. 2005 Jun 6;579(14):3107-14. doi: 10.1016/j.febslet.2005.04.069.
Somatostatin (SST) peptide is a potent inhibitor of insulin secretion and its effect is mediated via somatostatin receptor 5 (SSTR5) in the endocrine pancreas. To investigate the consequences of gene ablation of SSTR5 in the mouse pancreas, we have generated a mouse model in which the SSTR5 gene was specifically knocked down in the pancreatic beta cells (betaSSTR5Kd) using the Cre-lox system. Immunohistochemistry analysis showed that SSTR5 gene expression was absent in beta cells at three months of age. At the time of gene ablation, betaSSTR5Kd mice demonstrated glucose intolerance with lack of insulin response and significantly reduced serum insulin levels. Insulin tolerance test demonstrated a significant increase of insulin clearance in vivo at the same age. In vitro studies demonstrated an absence of response to SST-28 stimulation in the betaSSTR5Kd mouse islet, which was associated with a significantly reduced SST expression level in betaSSTR5Kd mice pancreata. In addition, betaSSTR5Kd mice had significantly reduced serum glucose levels and increased serum insulin levels at 12 months of age. Glucose tolerance test at an older age also indicated a persistently higher insulin level in betaSSTR5Kd mice. Further studies of betaSSTR5Kd mice had revealed elevated serum C-peptide levels at both 3 and 12 months of age, suggesting that these mice are capable of producing and releasing insulin to the periphery. These results support the hypothesis that SSTR5 plays a pivotal role in the regulation of insulin secretion in the mouse pancreas.
生长抑素（SST）肽是胰岛素分泌的强效抑制剂，其作用通过内分泌胰腺中的生长抑素受体5（SSTR5）介导。为了研究小鼠胰腺中SSTR5基因缺失的后果，我们构建了一个小鼠模型，其中利用Cre-lox系统在胰腺β细胞中特异性敲低SSTR5基因（βSSTR5Kd）。免疫组织化学分析显示，3月龄时β细胞中不存在SSTR5基因表达。在基因敲除时，βSSTR5Kd小鼠表现出葡萄糖不耐受，缺乏胰岛素反应，血清胰岛素水平显著降低。胰岛素耐量试验表明，同一年龄的小鼠体内胰岛素清除率显著增加。体外研究表明，βSSTR5Kd小鼠胰岛对SST-28刺激无反应，这与βSSTR5Kd小鼠胰腺中SST表达水平显著降低有关。此外，βSSTR5Kd小鼠在12月龄时血清葡萄糖水平显著降低，血清胰岛素水平升高。老年时的葡萄糖耐量试验也表明，βSSTR5Kd小鼠的胰岛素水平持续较高。对βSSTR5Kd小鼠的进一步研究发现，在3月龄和12月龄时血清C肽水平均升高，表明这些小鼠能够产生胰岛素并将其释放到外周。这些结果支持了SSTR5在小鼠胰腺胰岛素分泌调节中起关键作用的假说。
