Abnormal expression of pancreatic islet exocytotic soluble N-ethylmaleimide-sensitive factor attachment protein receptors in Goto-Kakizaki rats is partially restored by phlorizin treatment and accentuated by high glucose treatment
Abnormal expression of pancreatic islet exocytotic soluble N-ethylmaleimide-sensitive factor attachment protein receptors in Goto-Kakizaki rats is partially restored by phlorizin treatment and accentuated by high glucose treatment
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DOI：
10.1210/en.2002-220237
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发表时间：
2002-11-01
期刊：
影响因子：
4.8
通讯作者：
Efendic, S
中科院分区：
文献类型：
--
作者：
Gaisano, HY;Ostenson, CG;Efendic, S
在高血糖Goto-Kakizaki（GK）大鼠中，探讨了糖毒性在胰岛胞吐可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）复合物蛋白和胰岛素反应失调中的作用。驱动胰岛素颗粒胞吐融合的Syntaxin-1A和囊泡相关膜蛋白亚型2以及调节SNARE复合物组装的相关nSec 1在GK胰岛中减少至对照Wistar大鼠胰岛中水平的约40%。根皮苷治疗（12天）诱导GK大鼠血糖控制正常，导致胰岛素对葡萄糖的反应部分恢复。此外，胰岛SNARE复合物和nSec 1蛋白增加约40%。根皮苷处理不影响对照组中胰岛SNARE蛋白的水平或GK大鼠脑中相同SNARE复合物蛋白的水平。为了检查高血糖本身的作用，GK和对照大鼠胰岛在培养物中暴露于5.5和16.7 mM葡萄糖5天。高糖治疗大大增加了突触体相关的膜蛋白25 kDa的水平，不太明显，突触融合蛋白-1A和nSec 1的水平在对照组胰岛比在GK大鼠胰岛，而水平均降低。这伴随着GK胰岛中胰岛素对葡萄糖的反应的持续损害和对照胰岛中的正常反应。因此，GK胰岛表现出SNARE蛋白表达的失调，并且它们由高葡萄糖暴露引起的代偿性增加被废除。相反，血糖正常控制导致胰岛素胞吐机制的这些关键组分的部分补充和胰岛素应答的改善。我们认为SNARE蛋白的失调是葡萄糖毒性介导的胰岛素对葡萄糖反应受损的重要机制。
The role of glucotoxicity in dysregulation of islet exocytotic soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex proteins and insulin response was explored in the hyperglycemic Goto-Kakizaki (GK) rat. Syntaxin-1A and vesicle-associated membrane protein isoform 2, which drive insulin granule exocytotic fusion, and the associated nSec1, which modulates the SNARE complex assembly, were diminished in GK pancreatic islets to approximately 40% of the levels in control Wistar rat islets. Phlorizin treatment (12 d) induced normoglycemic control in GK rats, resulting in partial restoration of the insulin response to glucose. Furthermore, islet SNARE complex and nSec1 proteins increased by about 40%. Phlorizin treatment did not affect levels of islet SNARE proteins in controls or on the same SNARE complex proteins in GK rat brain. To examine the role of hyperglycemia per se, GK and control rat islets were exposed for 5 d in culture to 5.5 and 16.7 mm glucose. High glucose treatment greatly increased the levels of synaptosomal-associated membrane protein of 25 kDa and, less markedly, the levels of syntaxin-1A and nSec1 in control islets more than in GK rat islets, whereas levels were reduced in both. This was accompanied by sustained impairment of the insulin response to glucose in GK islets and a normal response in control islets. Thus, GK islets demonstrate dysregulation of SNARE protein expression, and their compensatory increase by high glucose exposure is abrogated. Conversely, normoglycemic control results in partial replenishment of these critical components of the insulin exocytotic machinery and improvement in the insulin response. We propose that dysregulation of SNARE proteins is an important mechanism behind glucotoxicity-mediated impairment of the insulin response to glucose.