beta-cell neogenesis during prolonged hyperglycemia in rats.
beta-cell neogenesis during prolonged hyperglycemia in rats.
复制标题
大鼠长期高血糖期间β细胞新生。
作者：
Mark Lipsett;D. Finegood
来自导管前体的β细胞新生，可能来自其他类型的胰腺细胞，有助于在啮齿类动物的发育过程中和受到非生理性侮辱后，促进β细胞团的扩张。使用基于数学模型的β细胞质量、复制和大小的分析，我们最近证明了在持续的高血糖期间，新生对于β细胞质量的扩大也是数量上的重要。在本研究中，我们观察了雄性SD大鼠注入生理盐水或50%葡萄糖(2ml/h)0、1、2、3、4、5或6天后新生灶区的形态、导管细胞复制和β细胞团的大小分布。以高密度小管状结构为特征的胰腺组织在输注葡萄糖2、3或4天后出现，以前被描述为新生灶区。以局灶性组织为特征的胰腺横截面积在注药后3天达到峰值，为2.9+/-0.8%。与胰岛部分切除的β细胞再生模型不同，在病灶形成之前或期间，导管细胞的复制没有增加。然而，病灶区域的管样结构中的细胞复制率是总胰管细胞的两倍，是小、中、大胰管细胞的15-40倍。与生理盐水输注的大鼠相比，小、中、大葡萄糖导管中的导管细胞复制显著减少(0.21+/-0.02比0.48+/-0.04%；P<；0.03)。葡萄糖和生理盐水组大鼠导管相关β细胞质量无明显差异(P=0.78)，而腺泡相关单个β细胞数量在葡萄糖输注3天和4天后增加了70%。除了小的管状结构外，病灶区域还有大量的T细胞浸润(151+/-30T细胞/mm(2))。与生理盐水注入的大鼠相比，葡萄糖腺泡组织中T细胞的浸润率也增加(0.43+/-0.11比0.03+/-0。01 T细胞/mm(2)；P<；0.0001)。综上所述，这些数据表明，这些葡萄糖注入的大鼠的新生病灶区域并不是由导管前体细胞的复制和分化产生的。相反，腺泡细胞转分化为β细胞，腺泡细胞去分化为新生的焦点区域，导致在长期高血糖期间形成新的β细胞。
beta-cell neogenesis from ductal precursors, and possibly from other pancreatic cell types, contributes to the expansion of beta-cell mass during development and after diabetogenic insults in rodents. Using a mathematical model-based analysis of beta-cell mass, replication, and size, we recently demonstrated that neogenesis is also quantitatively important to the expansion of beta-cell mass during prolonged hyperglycemia. In the present study, we examined the morphological appearance of neogenic focal areas, duct cell replication, and beta-cell cluster size distribution in male Sprague Dawley rats infused with either saline or 50% glucose (2 ml/h) for 0, 1, 2, 3, 4, 5, or 6 days. Pancreatic tissue characterized by a high density of small duct-like structures, previously described as neogenic focal areas, were present in glucose-infused rats after 2, 3, or 4 days of infusion. The cross-sectional area of the pancreas characterized as focal tissue peaked after 3 days of infusion at 2.9 +/- 0.8%. In contrast to the partial pancreatectomy model of beta-cell regeneration, duct cell replication was not increased before or during focal area formation. However, the replication rate of cells in the duct-like structures of the focal areas was twofold greater than in cells of the common pancreatic duct and 15- to 40-fold greater than in cells of small, medium, and large ducts. Duct-cell replication was significantly reduced in small, medium, and large ducts of glucose as compared to saline-infused rats (0.21 +/- 0.02 vs. 0.48 +/- 0.04%; P < 0.03). Duct-associated beta-cell mass was not different in glucose- and saline-infused rats (P = 0.78), whereas the number of acinar-associated single beta -cells increased by 70% after 3 and 4 days of glucose infusion. In addition to small duct-like structures, focal areas had considerable T-cell infiltration (151 +/- 30 T-cells/ mm(2)). There was also an increase in T-cell infiltration in acinar tissue of glucose as compared to saline-infused rats (0.43 +/- 0.11 vs. 0.03 +/- 0. 01 T-cells/mm(2); P < 0.0001). In conclusion, these data suggest that neogenic focal areas in these glucose-infused rats do not arise from replication and differentiation of ductal progenitor cells. Rather, acinar cell transdifferentiation into beta-cells and acinar cell dedifferentiation into neogenic focal areas lead to new beta-cell formation during prolonged hyperglycemia.