Genetic regulation of metabolic pathways in beta-cells disrupted by hyperglycemia.
Genetic regulation of metabolic pathways in beta-cells disrupted by hyperglycemia.
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发表时间：
2002
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通讯作者：
D. R. Laybutt;Arun J Sharma;D. Sgroi;J. Gaudet;S. Bonner-Weir;G. Weir
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作者：
D. R. Laybutt;Arun J Sharma;D. Sgroi;J. Gaudet;S. Bonner-Weir;G. Weir
在 2 型糖尿病模型中，β 细胞基因的表达发生了改变，但这些变化并不能完全解释 β 细胞功能的损害。我们假设β细胞表型的变化以及碳水化合物和脂质途径的整体改变可能导致分泌异常。因此，在 85-95% 部分胰腺切除术 (Px) 4 周后，当 β 细胞葡萄糖诱导的胰岛素分泌和 ATP 合成受损时，对胰岛中涉及碳水化合物和脂质代谢的基因表达进行了分析。 1周后，Px大鼠出现轻度至重度高血糖，并在接下来的3周内保持稳定，而血浆甘油三酯、非酯化脂肪酸或胰岛甘油三酯水平均未改变。过氧化物酶体增殖物激活受体（PPAR）的表达与多个靶基因相互调节；即使在低水平高血糖下，PPARα 也显着降低，而 PPARγ 随着高血糖的增加而逐渐增加。解偶联蛋白 2 (UCP-2) 增加，其他基因在假胰岛中几乎不表达，包括乳酸脱氢酶-A (LDH-A)、乳酸（单羧酸）转运蛋白、葡萄糖-6-磷酸酶、果糖-1,6-二磷酸酶、12-脂氧合酶和环加氧酶 2。另一方面，β 细胞相关基因、胰岛素和GLUT2 减少。用根皮苷治疗 Px 大鼠可使高血糖正常化，而不影响血浆脂肪酸，并逆转基因表达的变化，表明高血糖本身在 β 细胞表型丧失中的重要性。此外，在通过激光捕获显微切割从胰岛中央核心解剖的富含 β 细胞的组织中观察到了平行的变化。总之，慢性高血糖导致 β 细胞分化严重丧失，涉及多种代谢途径的基因表达发生改变，从而转移到正常的 β 细胞葡萄糖代谢。在分泌需求增加时，这种基因表达的整体适应不良可能会导致糖尿病中发现的β细胞功能障碍。
In models of type 2 diabetes the expression of beta-cell genes is altered, but these changes have not fully explained the impairment in beta-cell function. We hypothesized that changes in beta-cell phenotype and global alterations in both carbohydrate and lipid pathways are likely to contribute to secretory abnormalities. Therefore, expression of genes involved in carbohydrate and lipid metabolism were analyzed in islets 4 weeks after 85-95% partial pancreatectomy (Px) when beta-cells have impaired glucose-induced insulin secretion and ATP synthesis. Px rats after 1 week developed mild to severe hyperglycemia that was stable for the next 3 weeks, whereas neither plasma triglyceride, non-esterified fatty acid, or islet triglyceride levels were altered. Expression of peroxisome proliferator-activated receptors (PPARs), with several target genes, were reciprocally regulated; PPARalpha was markedly reduced even at low level hyperglycemia, whereas PPARgamma was progressively increased with increasing hyperglycemia. Uncoupling protein 2 (UCP-2) was increased as were other genes barely expressed in sham islets including lactate dehydrogenase-A (LDH-A), lactate (monocarboxylate) transporters, glucose-6-phosphatase, fructose-1,6-bisphosphatase, 12-lipoxygenase, and cyclooxygenase 2. On the other hand, the expression of beta-cell-associated genes, insulin, and GLUT2 were decreased. Treating Px rats with phlorizin normalized hyperglycemia without effecting plasma fatty acids and reversed the changes in gene expression implicating the importance of hyperglycemia per se in the loss of beta-cell phenotype. In addition, parallel changes were observed in beta-cell-enriched tissue dissected by laser capture microdissection from the central core of islets. In conclusion, chronic hyperglycemia leads to a critical loss of beta-cell differentiation with altered expression of genes involved in multiple metabolic pathways diversionary to normal beta-cell glucose metabolism. This global maladaptation in gene expression at the time of increased secretory demand may contribute to the beta-cell dysfunction found in diabetes.