Double-gene ablation of SSTR1 and SSTR5 results in hyperinsulinemia and improved glucose tolerance in mice.
Double-gene ablation of SSTR1 and SSTR5 results in hyperinsulinemia and improved glucose tolerance in mice.
复制标题
SSTR1 和 SSTR5 双基因消除导致小鼠高胰岛素血症并改善葡萄糖耐量。
DOI：
10.1016/j.surg.2004.05.042
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Brunicardi,FC
中科院分区：
文献类型：
--
作者：
Wang,XP;Norman,MA;Yang,J;Cheung,A;Moldovan,S;Demayo,FJ;Brunicardi,FC
我们实验室之前的研究表明，单基因消蚀生长抑素受体（SSTR）1或5会导致小鼠糖尿病。本研究旨在确定双基因消融SSTR1和SSTR5对小鼠胰岛素分泌和葡萄糖稳态的影响。方法制备ssstr1 /5-/-小鼠和野生型（WT）对照小鼠，通过聚合酶链反应验证其基因型。采用腹腔葡萄糖耐量试验（1.2-2.0 g/kg体重）检测小鼠的胰岛素分泌和葡萄糖水平。采用离体灌注小鼠胰腺模型和胰岛培养技术，研究了体外葡萄糖刺激胰岛素分泌。测定胰腺形态学改变，并进行免疫组织化学分析。结果用生长抑素肽体外培养WT小鼠离体胰岛，胰岛素分泌显著减少，而SSTR1/5-/-小鼠胰岛对生长抑素肽无反应，证实SSTR1/5基因消融。体外实验中，SSTR1/5-/-小鼠的基础胰岛素和葡萄糖刺激胰岛素水平均显著升高。在腹腔内糖耐量试验中，SSTR1/5-/-小鼠体内糖耐量显著改善，后期胰岛素分泌持续增加。组织学分析显示SSTR 1/5-/-小鼠胰腺中存在显著的胰岛增生。免疫染色显示SSTR1/5-/-小鼠胰岛中胰高血糖素和胰腺多肽产生细胞的整体增加。结论小鼠双基因消融SSTR1和SSTR5可导致胰岛细胞增生、高胰岛素血症和糖耐量改善。这种形式的糖尿病不同于仅切除SSTR1或SSTR5基因的小鼠。这些结果表明SSTR1和SSTR5是胰岛素分泌和葡萄糖调节的重要调节因子，提示SSTR1和SSTR5是协调调节的。
BACKGROUNDPrevious studies conducted in our laboratory showed that single-gene ablation of somatostatin receptor (SSTR)1 or 5 results in diabetes in mice. The objective of this study was to determine the effect of double-gene ablation of SSTR1 and SSTR5 on insulin secretion and glucose homeostasis in mice.METHODSSSTR1/5-/-mice and wild-type (WT) control mice were generated and their genotype verified via polymerase chain reaction. Insulin secretion and glucose levels in these mice were examined with the use of an intraperitoneal glucose tolerance test (1.2-2.0 g/kg body weight). In vitro glucose-stimulated insulin secretion was studied with the use of the isolated perfused mouse pancreas model and islet culture techniques. Pancreata morphologic alterations were determined, and an immunohistochemistry analysis was performed.RESULTSIn vitro incubation of isolated islets from WT mice with somatostatin peptides resulted in significant reduction in insulin secretion, whereas SSTR1/5-/-mouse islets had no response to somatostatin peptides confirming SSTR1/5 gene ablation. SSTR1/5-/-mice also had significant increase of both basal and glucose-stimulated insulin levels in vitro. During the intraperitoneal glucose tolerance test, SSTR1/5-/-mice had significantly improved glucose tolerance and sustained an increase in late-phase insulin secretion in vivo. Histological analysis demonstrated significant islet hyperplasia in the SSTR 1/5-/-mouse pancreas. Immunostaining revealed an overall increase of glucagon and pancreatic polypeptide–producing cells in the islets of SSTR1/5-/-mice.CONCLUSIONSDouble-gene ablation of SSTR1 and SSTR5 in mice resulted in a distinct phenotype with islet cell hyperplasia, hyperinsulinemia, and improved glucose tolerance. This form of diabetes differs from that seen in mice in which only the SSTR1 or SSTR5 gene was ablated. These results demonstrate that SSTR1 and SSTR5 are important regulators of insulin secretion and glucose regulation, and suggest that SSTR1 and SSTR5 are coordinately regulated.