Department of Medical Cell Biology, Uppsala University, Box 571, SE-75123, Uppsala, Sweden.
Lipids Health Dis. 2011 Jul 11;10:115. doi: 10.1186/1476-511X-10-115.
Prolonged elevated levels of lipids have negative effects on beta-cell function and mass (lipotoxicity). To what extent exposure to high glucose concentration is important in the harmful effects of lipids (glucolipotoxicity) has been debated.
We addressed beta-cell lipotoxicity by measuring apoptosis in isolated intact control human islets and insulin-secreting cell lines MIN6 and INS-1E cultured in the presence of palmitate and low (5.5 mM) or high (25 mM) glucose for 48 hours.
In both cell lines and human islets palmitate induced apoptosis after culture at low glucose. Palmitate-induced apoptosis was not increased after culture at high compared to low glucose in human islets and MIN6 cells but glucose-induced rise in apoptosis was observed in INS-1E cells. The rise in apoptosis in INS-1E cells was partially reversed by inclusion of AMPK-agonist AICAR. When CPT1-inhibitor etomoxir was included during culture at low glucose palmitate-triggered apoptosis was accentuated both in the islets and the cell lines. Palmitate oxidation in human islets and the cell lines was comparable after culture at low glucose. At high glucose, palmitate oxidation was reduced by 30% in human islets and MIN6 cells but by 80% in INS-1E cells. In INS-1E cells, AICAR increased oxidation of palmitate. Presence of etomoxir at low glucose decreased palmitate oxidation both in the islets and the cell lines.
In summary, lipotoxicity is evident not only in the presence of high but also low glucose concentrations. Additional effects of glucose are prominent in INS-1E but not in MIN6 cells and intact control human islets, which are able to efficiently oxidize fatty acids at high glucose and in this way avoid glucolipotoxicity.
脂质水平持续升高对β细胞功能和质量（脂毒性）有负面影响。在脂质（糖脂毒性）的有害影响中，高葡萄糖浓度的暴露程度有多重要一直存在争议。
我们通过测量分离的完整对照人胰岛以及在棕榈酸和低（5.5mM）或高（25mM）葡萄糖存在下培养 48 小时的胰岛素分泌细胞系 MIN6 和 INS-1E 中细胞凋亡来研究β细胞的脂毒性。
在两种细胞系和人胰岛中，低葡萄糖培养后棕榈酸诱导细胞凋亡。与低葡萄糖相比，高葡萄糖培养时棕榈酸诱导的凋亡在人胰岛和 MIN6 细胞中没有增加，但在 INS-1E 细胞中观察到葡萄糖诱导的凋亡增加。在 INS-1E 细胞中，加入 AMPK 激动剂 AICAR 部分逆转了凋亡的增加。当在低葡萄糖培养时加入 CPT1 抑制剂 etomoxir 时，人胰岛和细胞系中棕榈酸触发的凋亡都加剧了。低葡萄糖培养后，人胰岛和细胞系中的棕榈酸氧化相似。在高葡萄糖下，人胰岛和 MIN6 细胞中的棕榈酸氧化减少了 30%，但 INS-1E 细胞中的棕榈酸氧化减少了 80%。在 INS-1E 细胞中，AICAR 增加了棕榈酸的氧化。在低葡萄糖存在下加入 etomoxir 会降低人胰岛和细胞系中棕榈酸的氧化。
总之，不仅在高葡萄糖浓度存在下，而且在低葡萄糖浓度存在下也存在脂毒性。葡萄糖的额外作用在 INS-1E 中很明显，但在 MIN6 细胞和完整对照人胰岛中不明显，这些细胞能够在高葡萄糖下有效地氧化脂肪酸，从而避免糖脂毒性。
