Chronic hyperglycemia triggers loss of pancreatic β cell differentiation in an animal model of diabetes
Chronic hyperglycemia triggers loss of pancreatic β cell differentiation in an animal model of diabetes
复制标题
慢性高血糖引发糖尿病动物模型胰腺β细胞分化丧失
DOI：
10.1074/jbc.274.20.14112
复制
发表时间：
1999-05-14
影响因子：
4.8
通讯作者：
Weir, GC
中科院分区：
文献类型：
--
作者：
Jonas, JC;Sharma, A;Weir, GC
分化的胰腺β细胞具有独特的能力，能够响应血浆葡萄糖的升高而分泌胰岛素。我们提出，由于慢性高血糖的有害影响，它们表达的独特基因群可能会在糖尿病中丢失。为了检验这一假设，对 Sprague-Dawley 大鼠进行了 85-95% 的胰腺切除术或假胰腺切除术。一周后，动物出现轻度至重度慢性高血糖，并在接下来的三周内保持稳定，血浆非酯化脂肪酸水平没有显着变化。随着高血糖的增加，许多对葡萄糖诱导的胰岛素释放重要的基因的表达逐渐减少，同时与β细胞发育和分化有关的几种胰岛转录因子也减少。相比之下，假胰岛中几乎不表达的基因（乳酸脱氢酶 A 和己糖激酶 I）显着增加，同时转录因子 c-Myc（细胞生长的有效刺激剂）也增加。这些异常伴随着β细胞肥大。胰腺切除术后两周，基因表达的变化完全显现。在接下来的两周内，通过根皮苷校正血糖，使胰岛基因表达和β细胞体积正常化，而不影响血浆非酯化脂肪酸水平，强烈表明Chat高血糖会引发这些异常。总之，慢性高血糖会导致 β 细胞肥大和 β 细胞分化丧失，这与 c-Myc 和其他关键转录因子的变化相关。 β细胞分化的类似变化可能导致人类糖尿病中胰岛素分泌的严重紊乱。
Differentiated pancreatic beta cells are unique in their ability to secrete insulin in response to a rise in plasma glucose. We have proposed that the unique constellation of genes they express may be lost in diabetes due to the deleterious effect of chronic hyperglycemia. To test this hypothesis, Sprague-Dawley rats were submitted to a 85-95% pancreatectomy or sham pancreatectomy. One week later, the animals developed mild to severe chronic hyperglycemia that was stable for the next 3 weeks, without significant alteration of plasma nonesterified fatty acid levels. Expression of many genes important for glucose-induced insulin release decreased progressively with increasing hyperglycemia, in parallel with a reduction of several islet transcription factors involved in beta cell development and differentiation. In contrast, genes barely expressed in sham islets (lactate dehydrogenase A and hexokinase I) were markedly increased, in parallel with an increase in the transcription factor c-Myc, a potent stimulator of cell growth. These abnormalities were accompanied by beta cell hypertrophy. Changes in gene expression were fully developed 2 weeks after pancreatectomy. Correction of blood glucose by phlorizin for the next 2 weeks normalized islet gene expression and beta cell volume without affecting plasma nonesterified fatty acid levels, strongly suggesting Chat hyperglycemia triggers these abnormalities. In conclusion, chronic hyperglycemia leads to beta cell hypertrophy and loss of beta cell differentiation that is correlated with changes in c-Myc and other key transcription factors. A similar change in beta cell differentiation could contribute to the profound derangement of insulin secretion in human diabetes.