Cyclical and alternating infusions of glucose and intralipid in rats inhibit insulin gene expression and Pdx-1 binding in islets
Cyclical and alternating infusions of glucose and intralipid in rats inhibit insulin gene expression and Pdx-1 binding in islets
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DOI：
10.2337/db07-1285
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发表时间：
2008-02-01
期刊：
影响因子：
7.7
通讯作者：
Poitout, Vincent
中科院分区：
文献类型：
--
作者：
Hagman, Derek K.;Latour, Martin G.;Poitout, Vincent
长期暴露于高水平的脂肪酸的分离胰岛，在高糖的存在下，通过涉及胰腺-十二指肠同源框-1（Pdx-1）的核排斥和MafA表达的丧失的转录机制损害胰岛素基因表达。这种现象是否也发生在体内是未知的。因此，我们的目标是确定是否慢性营养过剩抑制insulin基因的表达在vivo.RESEARCH设计和方法-Wistar大鼠接受交替4小时输注葡萄糖和Intralidid共72小时。对照组接受葡萄糖和生理盐水、生理盐水和Intraperoid或仅生理盐水的交替输注。在高血糖钳夹下测量胰岛素和C肽分泌。在分离的胰岛中评估胰岛素分泌和基因表达，并通过形态计量分析定量β细胞质量。胰岛素含量和胰岛素mRNA水平较低，从大鼠分离的胰岛输注葡萄糖加胰岛素。这与Pdx-1与内源性胰岛素启动子的结合减少以及Pdx-1定位于细胞质与细胞核的比例增加有关。与此相反，MafA mRNA和蛋白水平和β细胞质量和proliferation.CONCLUSIONS-Cyclical和交替输注的葡萄糖和Intraperoid在正常大鼠抑制胰岛素基因的表达，而不影响胰岛素分泌或β细胞质量。我们的结论是，脂肪酸抑制胰岛素基因的表达，在高糖的存在下，是一种早期功能缺陷，可能有助于β细胞衰竭的2型糖尿病。
OBJECTIVE-Prolonged exposure of isolated islets of Langerhans to elevated levels of fatty acids, in the presence of high glucose, impairs insulin gene expression via a transcriptional mechanism involving nuclear exclusion of pancreas-duodenum homeobox-1 (Pdx-1) and loss of MafA expression. Whether such a phenomenon also occurs in vivo is unknown. Our objective was therefore to ascertain whether chronic nutrient oversupply inhibits insulin gene expression in vivo.RESEARCH DESIGN AND METHODS-Wistar rats received alternating 4-h infusions of glucose and Intralipid for a total of 72 h. Control groups received alternating infusions of glucose and saline, saline and Intralipid, or saline only. Insulin and C-peptide secretion were measured under hyperglycemic clamps. Insulin secretion and gene expression were assessed in isolated islets, and beta-cell mass was quantified by morphometric analysis.RESULTS-Neither C-peptide secretion nor insulin sensitivity was different among infusion regimens. Insulin content and insulin mRNA levels were lower in islets isolated from rats infused with glucose plus Intralipid. This was associated with reduced Pdx-1 binding to the endogenous insulin promoter, and an increased proportion of Pdx-1 localized in the cytoplasm versus the nucleus. In contrast, MafA mRNA and protein levels and beta-cell mass and proliferation were unchanged.CONCLUSIONS-Cyclical and alternating infusions of glucose and Intralipid in normal rats inhibit insulin gene expression without affecting insulin secretion or beta-cell mass. We conclude that fatty acid inhibition of insulin gene expression, in the presence of high glucose, is an early functional defect that may contribute to beta-cell failure in type 2 diabetes.