Extrapancreatic insulin-producing cells in multiple organs in diabetes
Extrapancreatic insulin-producing cells in multiple organs in diabetes
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DOI：
10.1073/pnas.0308690100
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发表时间：
2004-02-24
影响因子：
11.1
通讯作者：
Chan, L
中科院分区：
文献类型：
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作者：
Kojima, H;Fujimiya, M;Chan, L
产生胰岛素的细胞通常只存在于胰腺和胸腺。令人惊讶的是，我们在不同的糖尿病小鼠和大鼠模型中发现了广泛的胰岛素mRNA和蛋白表达，包括链脲佐菌素治疗的小鼠和大鼠，ob/ob小鼠和喂食高脂肪饮食的小鼠。我们在糖尿病小鼠的肝脏、脂肪组织、脾脏、骨髓和胸腺中检测到胰岛素原细胞和胰岛素阳性细胞；许多细胞还产生胰高血糖素、生长抑素和胰多肽。通过原位核酸杂交，糖尿病小鼠肝脏显示胰岛素转录阳性细胞，而不是非糖尿病小鼠肝脏，表明胰岛素是由这些细胞合成的。在由小鼠胰岛素启动子驱动表达GFP的转基因小鼠中，链脲佐菌素诱导的糖尿病导致肝脏、脂肪组织和骨髓中出现GFP阳性细胞；荧光信号与免疫反应性胰岛素原的存在完全一致。在非糖尿病小鼠中，葡萄糖注射产生的高血糖导致胰岛素原细胞和胰岛素阳性细胞在3天内出现。骨髓移植实验表明，胰腺外产生胰岛素原细胞大部分来源于骨髓。在糖尿病大鼠的肝脏、脂肪组织和骨髓中也检测到免疫反应性胰岛素原细胞和胰岛素阳性细胞，这表明胰腺外、胸腺外胰岛素的产生发生在不止一种物种中。这些观察结果对胰岛素基因表达的调控、胰岛素基因表达对自身耐受性的调节以及胰岛素生成细胞治疗糖尿病的策略具有重要意义。
Insulin-producing cells normally occur only in the pancreas and thymus. Surprisingly, we found widespread insulin mRNA and protein expression in different diabetic mouse and rat models, including streptozotocin-treated mice and rats, ob/ob mice, and mice fed high-fat diets. We detected in diabetic mice proinsulin-and insulin-positive cells in the liver, adipose tissue, spleen, bone marrow, and thymus; many cells also produced glucagon, somatostatin, and pancreatic polypeptide. By in situ nucleic acid hybridization, diabetic, but not nondiabetic, mouse liver exhibited insulin transcript-positive cells, indicating that insulin was synthesized by these cells. In transgenic mice that express GFP driven by the mouse insulin promoter, streptozotocin-induced diabetes led to the appearance of GFP-positive cells in liver, adipose tissue, and bone marrow; the fluorescent signals showed complete concordance with the presence of immunoreactive proinsulin. Hyperglycemia produced by glucose injections in nondiabetic mice led to the appearance of proinsulin- and insulin-positive cells within 3 days. Bone marrow transplantation experiments showed that most of the extrapancreatic proinsulin-producing cells originated from the bone marrow. Immunoreactive proinsulin- and insulin-positive cells were also detected in the liver, adipose tissue, and bone marrow of diabetic rats, indicating that extrapancreatic, extrathymic insulin production occurs in more than one species. These observations have implications for the regulation of insulin gene expression, modulation of self-tolerance by insulin gene expression, and strategies for the generation of insulin-producing cells for the treatment of diabetes.