Molecular Nutrition Unit and the Montreal Diabetes Research Center, the Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada H1W 4A4.
Endocrinology. 2010 Jul;151(7):3061-73. doi: 10.1210/en.2009-1238. Epub 2010 May 5.
Elevated glucose and saturated fatty acids synergize in inducing apoptosis in INS832/13 cells and in human islet cells. In order to gain insight into the molecular mechanism(s) of glucolipotoxicity (Gltox), gene profiling and metabolic analyses were performed in INS832/13 cells cultured at 5 or 20 mm glucose in the absence or presence of palmitate. Expression changes were observed for transcripts involved in mitochondrial, lipid, and glucose metabolism. At 24 h after Gltox, increased expression of lipid partitioning genes suggested a promotion of fatty acid esterification and reduced lipid oxidation/detoxification, whereas changes in the expression of energy metabolism genes suggested mitochondrial dysfunction. These changes were associated with decreased glucose-induced insulin secretion, total insulin content, ATP levels, AMP-kinase activity, mitochondrial membrane potential and fat oxidation, unchanged de novo fatty acid synthesis, and increased reactive oxygen species, cholesterol, ceramide, and triglyceride levels. However, the synergy between elevated glucose and palmitate to cause ss-cell toxicity in term of apoptosis and reduced glucose-induced insulin secretion only correlated with triglyceride and ceramide depositions. Overexpression of endoplasmic reticulum glycerol-3-phosphate acyl transferase to enhance lipid esterification amplified Gltox at intermediate glucose (11 mm), whereas reducing acetyl-coenzyme A carboxylase 1 expression by small interfering RNA to shift lipid partitioning to fat oxidation reduced Gltox. The results suggest that Gltox entails alterations in lipid partitioning, sterol and ceramide accumulation, mitochondrial dysfunction, and reactive oxygen species production, all contributing to altering ss-cell function. The data also suggest that the early promotion of lipid esterification processes is instrumental in the Gltox process.
高血糖和饱和脂肪酸协同诱导 INS832/13 细胞和人胰岛细胞凋亡。为了深入了解糖脂毒性（Gltox）的分子机制，我们在 5 或 20mm 葡萄糖条件下培养 INS832/13 细胞，并在存在或不存在棕榈酸的情况下进行基因谱分析和代谢分析。观察到参与线粒体、脂质和葡萄糖代谢的转录本表达变化。在 Gltox 后 24 小时，脂质分配基因的表达增加表明脂肪酸酯化的促进和脂质氧化/解毒的减少，而能量代谢基因表达的变化表明线粒体功能障碍。这些变化与葡萄糖诱导的胰岛素分泌、总胰岛素含量、ATP 水平、AMP 激酶活性、线粒体膜电位和脂肪氧化减少、新合成脂肪酸不变以及活性氧、胆固醇、神经酰胺和甘油三酯水平增加有关。然而，高血糖和棕榈酸协同作用导致β细胞毒性，表现为细胞凋亡和葡萄糖诱导的胰岛素分泌减少，仅与甘油三酯和神经酰胺沉积相关。内质网甘油-3-磷酸酰基转移酶的过表达增强了中间葡萄糖（11mm）条件下的 Gltox，而通过小干扰 RNA 降低乙酰辅酶 A 羧化酶 1 的表达将脂质分配转移到脂肪氧化会减轻 Gltox。结果表明，Gltox 涉及脂质分配、固醇和神经酰胺积累、线粒体功能障碍和活性氧产生的改变，所有这些都导致β细胞功能改变。数据还表明，早期促进脂质酯化过程是 Gltox 过程的关键。
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