线粒体黄素腺嘌呤二核苷酸（FAD）连接的甘油-3-磷酸脱氢酶的过表达并不能纠正糖尿病GK大鼠胰岛中葡萄糖刺激的胰岛素分泌。

Overexpression of mitochondrial FAD-linked glycerol-3-phosphate dehydrogenase does not correct glucose-stimulated insulin secretion from diabetic GK rat pancreatic islets.

作者信息

Ueda K, Tanizawa Y, Ishihara H, Kizuki N, Ohta Y, Matsutani A, Oka Y

机构信息

Third Department of Internal Medicine, Yamaguchi University, School of Medicine, Ube, Japan.

出版信息

Diabetologia. 1998 Jun;41(6):649-53. doi: 10.1007/s001250050963.

DOI:10.1007/s001250050963

PMID:9662045

Abstract

Glucose-stimulated insulin secretion is impaired in GK (Goto-Kakizaki) rats, perhaps because of abnormalities in glucose metabolism in pancreatic islet beta cells. The glycerol phosphate shuttle plays a major role in glucose metabolism by reoxidizing cytosolic NADH generated by glycolysis. In the pancreatic islets of GK rats, the activity of mitochondrial FAD-linked glycerol-3-phosphate dehydrogenase (mGPDH), the key enzyme of the glycerol phosphate shuttle, is decreased and this abnormality may be responsible, at least in part, for impaired glucose-stimulated insulin secretion. To investigate this possibility, we overexpressed mGPDH in islets isolated from GK rats via recombinant adenovirus-mediated gene transduction, and examined glucose-stimulated insulin secretion. In islets isolated from diabetic GK rats at 8 to 10 weeks of age, glucose-stimulated insulin secretion was severely impaired, and mGPDH activity was decreased to 79 % of that in non-diabetic Wistar rats. When mGPDH was overexpressed in islets from GK rats, enzyme activity and protein content increased 2- and 6-fold, respectively. Basal (3 mmol/l glucose) and glucose-stimulated (20 mmol/l) insulin secretion from the Adex1CAlacZ-infected GK rat islets were, respectively, 4.4 +/- 0.7 and 8.1 +/- 0.7 ng. x islet(-1) x 30 min(-1), and those from mGPDH-overexpressed GK rat islets 4.7 +/- 0.3 and 9.1 +/- 0.8 ng x islet(-1) x 30 min(-1), in contrast to those from the AdexlCAlacZ-infected non-diabetic Wistar rat islets (4.7 +/- 1.6 and 47.6 +/- 11.9 ng x islet(-1) x 30 min(-1)). Thus, glucose-stimulated insulin secretion is severely impaired in GK rats even in the stage when mGPDH activity is modestly decreased, and at this stage, overexpression of mGPDH cannot restore glucose-stimulated insulin secretion. We conclude that decreased mGPDH activity in GK rat islets is not the defect primarily responsible for impaired glucose-stimulated insulin secretion.

摘要

在GK（Goto-Kakizaki）大鼠中，葡萄糖刺激的胰岛素分泌受损，这可能是由于胰岛β细胞中葡萄糖代谢异常所致。磷酸甘油穿梭在葡萄糖代谢中起着重要作用，它通过将糖酵解产生的胞质NADH重新氧化来实现这一过程。在GK大鼠的胰岛中，磷酸甘油穿梭的关键酶——线粒体FAD连接的3-磷酸甘油脱氢酶（mGPDH）的活性降低，这种异常可能至少部分地导致了葡萄糖刺激的胰岛素分泌受损。为了研究这种可能性，我们通过重组腺病毒介导的基因转导，在从GK大鼠分离的胰岛中过表达mGPDH，并检测葡萄糖刺激的胰岛素分泌。在8至10周龄的糖尿病GK大鼠分离的胰岛中，葡萄糖刺激的胰岛素分泌严重受损，mGPDH活性降至非糖尿病Wistar大鼠的79%。当mGPDH在GK大鼠的胰岛中过表达时，酶活性和蛋白质含量分别增加了2倍和6倍。感染Adex1CAlacZ的GK大鼠胰岛的基础（3 mmol/l葡萄糖）和葡萄糖刺激（20 mmol/l）胰岛素分泌分别为4.4±0.7和8.1±0.7 ng·胰岛⁻¹·30 min⁻¹，而mGPDH过表达的GK大鼠胰岛分别为4.7±0.3和9.1±0.8 ng·胰岛⁻¹·30 min⁻¹，与之形成对比的是感染AdexlCAlacZ的非糖尿病Wistar大鼠胰岛（4.7±1.6和47.6±11.9 ng·胰岛⁻¹·30 min⁻¹）。因此，即使在mGPDH活性适度降低的阶段，GK大鼠中葡萄糖刺激的胰岛素分泌也严重受损，并且在此阶段，mGPDH的过表达并不能恢复葡萄糖刺激的胰岛素分泌。我们得出结论，GK大鼠胰岛中mGPDH活性降低不是葡萄糖刺激的胰岛素分泌受损的主要缺陷原因。