Impaired development of pancreatic beta-cell mass is a primary event during the progression to diabetes in the GK rat
Impaired development of pancreatic beta-cell mass is a primary event during the progression to diabetes in the GK rat
复制标题
DOI：
10.1007/s001250050768
复制
发表时间：
1997-08-01
期刊：
影响因子：
8.2
通讯作者：
Portha, B
中科院分区：
文献类型：
--
作者：
Movassat, J;Saulnier, C;Portha, B
在非胰岛素依赖型糖尿病（NIDDM）遗传模型GK大鼠的内分泌胰腺中，目前尚不清楚迄今为止报道的组织病理学变化是否与高血糖的发病机制有关，或者是否继发于代谢改变。我们的研究使用来自巴黎殖民地的 GK 大鼠，首次记录了 GK 胰腺从胎儿晚期（第 21.5 天）到成年（18 周）期间发生的病理生理变化：与 Wistar 对照相比，GK 胎儿表现出较高的血浆葡萄糖水平、较低的血浆胰岛素水平和正常的血浆胰高血糖素水平。他们的胰腺胰岛素含量以及β细胞的相对体积和总质量急剧下降，分别仅为对照值的23%、38%和23%。出生后4天至14天期间，GK新生儿尽管血浆胰岛素水平下降，但基础血浆葡萄糖和胰高血糖素水平正常。它们的胰腺胰岛素含量仅代表与年龄相关的对照胰腺中发现的值的31-40%，并且它们的总β细胞质量在第4天仅为35%，在第7天为30%，在第14天为37%。成年糖尿病GK大鼠表现出较高的基础血浆葡萄糖和胰岛素水平，而其基础血浆胰高血糖素水平保持正常。他们的胰腺胰岛素含量和总 β 细胞质量仍然下降，分别仅为对照值的 32% 和 47%。此外，成年 GK 胰腺的大胰岛亚群结构表现出明显的改变，其表现出相当大的纤维化，β细胞簇被结缔组织链彼此广泛分开。关于 GK 大鼠α细胞的发育，发现它们的相对体积在胎儿期和新生儿早期是正常的。发现 14 日龄新生儿和成年 GK 大鼠中度适度下降（相当于相应对照值的 64-67%）。我们的研究结果表明，在 GK 大鼠中，在成年动物中观察到的总 β 细胞质量的缺陷与 β 细胞发育受损有关。在该 NIDDM 模型中，β 细胞量的限制必须被视为导致明显糖尿病的序列中的主要和关键事件。
In the endocrine pancreas of the GK rat, a genetic model of non-insulin-dependent diabetes mellitus (NIDDM), it is not clear whether the histopathological changes reported up to now are related to the pathogenesis of hyperglycaemia or whether they occur secondarily to metabolic alterations. Using GK rats from the Paris colony, our study chronicles for the first time the pathophysiologic changes that occur in the GK pancreas from the late fetal period (day 21.5) until adult age (18 weeks): As compared to Wistar controls, GK fetuses exhibited higher plasma glucose level, lower plasma insulin level and normal plasma glucagon level. Their pancreatic insulin content and the relative volume and the total mass of their beta cells were sharply decreased, representing only 23, 38 and 23% of control values, respectively. During the period from 4 days to 14 days after birth, GK neonates exhibited normal basal plasma glucose and glucagon levels despite decreased plasma insulin level. Their pancreatic insulin content represented only 31-40% of values found in the age-related control pancreases and their total beta-cell mass was only 35% on day 4, 30% on day 7 and 37% on day 14. The adult diabetic GK rats exhibited higher basal plasma glucose and insulin levels while their basal plasma glucagon level remained normal. Their pancreatic insulin content and the total beta-cell mass remained decreased, representing only 32% and 47% of control values, respectively. Moreover, the adult GK pancreases exhibited noticeable alteration in the architecture of the large islet subpopulation which displayed considerable fibrosis with clusters of beta cells widely separated from each other by strands of connective tissue. Concerning the development of alpha cells in the GK rats, their relative volume was found to be normal during fetal and early neonatal periods. It was found to be moderately decreased (representing 64-67% of corresponding control values) in 14-day-old neonates and adult GK rats. Our findings demonstrate that in the GK rat, the deficit of total beta-cell mass as observed in the adult animal is related to impaired beta-cell development. The restriction of the beta-cell mass must be considered as a primary and crucial event in the sequence leading to overt diabetes in this NIDDM model.