Long-term exposure of β-INS cells to high glucose concentrations increases anaplerosis, lipogenesis, and lipogenic gene expression
Long-term exposure of β-INS cells to high glucose concentrations increases anaplerosis, lipogenesis, and lipogenic gene expression
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DOI：
10.2337/diabetes.47.7.1086
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发表时间：
1998-07-01
期刊：
影响因子：
7.7
通讯作者：
Prentki, M
中科院分区：
文献类型：
--
作者：
Roche, E;Farfari, S;Prentki, M
胰腺β细胞长期暴露于高糖对β细胞功能具有多效性作用。特别是，它诱导关键的糖酵解基因，促进糖原沉积，并导致β细胞增殖和改变胰岛素分泌，其特征在于对低葡萄糖敏感。糖酵解后事件，特别是回补和脂质信号传导，被认为与葡萄糖激活β细胞有关。为了了解β细胞对高血糖适应过程的生物化学性质，我们研究了β细胞系INS-1中葡萄糖对脂肪生成基因的调节。细胞暴露于升高的葡萄糖（5-25 mmol/l）3天，脂肪酸合成酶的酶活性增加3倍，乙酰辅酶A羧化酶增加30倍，苹果酸酶增加1.3倍。丙酮酸羧化酶和柠檬酸裂解酶的表达保持不变。除了苹果酸酶mRNA没有变化之外，在蛋白质和mRNA水平上也进行了类似的观察。代谢基因表达的变化仅仅与柠檬酸盐、苹果酸盐、丙二酰辅酶A水平的长期升高以及葡萄糖碳转化为脂质相关，即使在随后仅仅暴露于低葡萄糖的细胞中也是如此。同样，脂肪酸氧化被抑制，磷脂和甘油三酯的合成增强独立的外部葡萄糖浓度在细胞预先暴露于高葡萄糖。结果表明，协调诱导糖酵解和脂肪生成基因与糖原和甘油三酯沉积，以及回补增加和改变脂质分配，有助于适应过程中的高血糖症和葡萄糖敏感的β细胞。
Chronic exposure of pancreatic beta-cells to high glucose has pleiotropic action on beta-cell function. In particular, it induces key glycolytic genes, promotes glycogen deposition, and causes beta-cell proliferation and altered insulin secretion characterized by sensitization to low glucose. Postglycolytic events, in particular, anaplerosis and lipid signaling, are thought to be implicated in beta-cell activation by glucose. To understand the biochemical nature of the beta-cell adaptive process to hyperglycemia, we studied the regulation by glucose of lipogenic genes in the beta-cell line INS-1. A 3-day exposure of cells to elevated glucose (5-25 mmol/l) increased the enzymatic activities of fatty acid synthase 3-fold, acetyl-CoA carboxylase 30-fold, and malic enzyme 1.3-fold. Pyruvate carboxylase and citrate lyase expression remained constant. Similar observations mere made at the protein and mRNA levels except for malic enzyme mRNA, which did not vary. Metabolic gene expression changes mere associated with chronically elevated levels of citrate, malate, malonyl-CoA, and conversion of glucose carbon into lipids, even in cells that mere subsequently exposed to low glucose. Similarly, fatty acid oxidation was suppressed and phospholipid and triglyceride synthesis was enhanced independently of the external glucose concentration in cells preexposed to high glucose. The results suggest that a coordinated induction of glycolytic and lipogenic genes in conjunction with glycogen and triglyceride deposition, as well as increased anaplerosis and altered lipid partitioning, contribute to the adaptive process to hyperglycemia and glucose sensitization of the beta-cell.