Impaired gene and protein expression of exocytotic soluble N-ethylmaleimide attachment protein receptor complex proteins in pancreatic islets of type 2 diabetic patients
Impaired gene and protein expression of exocytotic soluble N-ethylmaleimide attachment protein receptor complex proteins in pancreatic islets of type 2 diabetic patients
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DOI：
10.2337/diabetes.55.02.06.db04-1575
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发表时间：
2006-02-01
期刊：
影响因子：
7.7
通讯作者：
Bartfai, T
中科院分区：
文献类型：
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作者：
Ostenson, CG;Gaisano, H;Bartfai, T
胰岛素的胞吐作用依赖于B细胞中的可溶性N-乙基马来酰亚胺附着蛋白受体（SNARE）复合物蛋白。我们评估了2型糖尿病患者（n = 4）和非糖尿病对照受试者（n = 4）的胰岛素释放以及SNARE复合蛋白的基因和蛋白表达。在糖尿病患者的胰岛中，与对照胰岛相比，对8.3和16.7 mmol/l葡萄糖的胰岛素反应显著降低（4.7 +/- 0.3和8.4 +/- 1.8对17.5 +/- 0.1和24.3 +/- 1.2 mu U）。胰岛（-1）。h（-1）; P < 0.001）。蛋白质印迹分析显示，糖尿病患者胰岛SNARE复合物和SNARE调节蛋白：syntaxin-1A的数量减少。(21对照水平的± 5%）、SNAP-25（12 ± 4%）、VAMP-2（7 ± 4%）、nSec 1（Munc 18; 34 ± 13%）、Munc 13-1（27 ± 4%）和突触素（64 ± 7%）。通过定量PCR证实的微阵列基因芯片分析显示，糖尿病胰岛中的基因表达降低：syntaxin-1A（对照水平的27 +/- 2%），SNAP-25（31 +/- 7%），VAMP-2（18 +/- 3%），nSec 1（27 +/- 5%），突触结合蛋白V（24 +/- 2%）和突触素（12 +/- 2%）。总之，这些数据支持这样的观点，即胰岛RNA和SNARE和SNARE调节蛋白的蛋白质表达减少在2型糖尿病患者胰岛素分泌受损中起作用。然而，目前尚不清楚这种缺陷在多大程度上是原发性的还是继发性的，例如，葡萄糖毒性
Exocytosis of insulin is dependent on the soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins in the B-cells. We assessed insulin release as well as gene and protein expression of SNARE complex protein in isolated pancreatic islets of type 2 diabetic patients (n = 4) and nondiabetic control subjects (n = 4). In islets from the diabetic patients, insulin responses to 8.3 and 16.7 mmol/l glucose were markedly reduced compared with control islets (4.7 +/- 0.3 and 8.4 +/- 1.8 vs. 17.5 +/- 0.1 and 24.3 +/- 1.2 mu U . islet(-1) . h(-1), respectively; P < 0.001). Western blot analysis revealed decreased amounts of islet SNARE complex and SNARE-modulating proteins in diabetes: syntaxin-1A. (21 +/- 5% of control levels), SNAP-25 (12 +/- 4%), VAMP-2 (7 +/- 4%), nSec1 (Munc 18; 34 +/- 13%), Munc 13-1 (27 +/- 4%), and synaptophysin (64 +/- 7%). Microarray gene chip analysis, confirmed by quantitative PCR, showed that gene expression was decreased in diabetes islets: syntaxin-1A (27 +/- 2% of control levels), SNAP-25 (31 +/- 7%), VAMP-2 (18 +/- 3%), nSec1 (27 +/- 5%), synaptotagmin V (24 +/- 2%), and synaptophysin (12 +/- 2%). In conclusion, these data support the view that decreased islet RNA and protein expression of SNARE and SNARE-modulating proteins plays a role in impaired insulin secretion in type 2 diabetic patients. It remains unclear, however, to which extent this defect is primary or secondary to, e.g., glucotoxicity.