Miralles F, Portha B
Laboratoire de Physiopathologie de la Nutrition, CNRS-ESA7059, Université Paris, France.
Diabetes. 2001 Feb;50 Suppl 1:S84-8. doi: 10.2337/diabetes.50.2007.s84.
The Goto-Kakisaki (GK) rat is a genetic model of type 2 diabetes obtained by selective inbreeding of mildly glucose-intolerant Wistar rats. Previous studies have shown that at birth, the beta-cell mass of the GK rat is severely reduced compared with that of the Wistar rat. Therefore, beta-cell deficit could be the primary defect leading to type 2 diabetes in this model. To identify the abnormality at the origin of the beta-cell mass deficit, we compared the fetal development of GK and Wistar rats. Our study reveals that during early development (embryonic day 12-14 [E12-14]), GK fetuses present a delayed global growth that progressively recovers: at birth, no size or weight difference persists. However, from E18 onward, the weight and DNA content of the pancreas and liver are reduced by 30% in the GK fetuses. Cell proliferation is reduced in the GK pancreas from E16 to E20. Whereas apoptotic cells are scarce in the Wistar fetal pancreas, a wave of apoptosis from E16 to E18 was detected in the GK pancreas. Analysis of pancreas differentiation revealed that from E12 to E14, there are no significant differences in the number of alpha- and beta-cells between the GK and Wistar pancreas. However, by E16, the average number of beta-cells in the GK pancreas represents only 50% that of the Wistar pancreas, and this difference persists until birth. The number of alpha-cells was reduced by 25% from E18 to E21. To determine whether the defect in GK pancreas development depends on intrinsic pancreatic factors or on endocrine extrapancreatic factors, we performed in vitro cultures of E12 pancreatic rudiments. The cultures show that in vitro, the growth and endocrine differentiation of the GK and Wistar pancreatic rudiments are identical. Thus, impaired development of the GK pancreas probably results from insufficiency of extrapancreatic factor(s) necessary for the growth and survival of fetal pancreatic cells.
Goto-Kakisaki（GK）大鼠是通过对轻度葡萄糖不耐受的Wistar大鼠进行选择性近亲繁殖获得的2型糖尿病遗传模型。先前的研究表明，出生时，GK大鼠的β细胞量与Wistar大鼠相比严重减少。因此，β细胞缺陷可能是该模型中导致2型糖尿病的主要缺陷。为了确定β细胞量缺陷起源处的异常，我们比较了GK和Wistar大鼠的胎儿发育情况。我们的研究表明，在早期发育阶段（胚胎第12 - 14天[E12 - 14]），GK胎儿出现整体生长延迟，这种延迟会逐渐恢复：出生时，大小或体重差异不再存在。然而，从E18起，GK胎儿的胰腺和肝脏重量及DNA含量减少了30%。从E16到E20，GK胰腺中的细胞增殖减少。在Wistar胎儿胰腺中凋亡细胞很少，而在GK胰腺中检测到从E16到E18有一波凋亡。胰腺分化分析表明，从E12到E14，GK和Wistar胰腺中α细胞和β细胞的数量没有显著差异。然而，到E16时，GK胰腺中β细胞的平均数量仅为Wistar胰腺的50%，且这种差异一直持续到出生。从E18到E21，α细胞数量减少了25%。为了确定GK胰腺发育缺陷是取决于胰腺内在因素还是胰腺外内分泌因素，我们对E12胰腺原基进行了体外培养。培养结果表明，在体外，GK和Wistar胰腺原基的生长和内分泌分化是相同的。因此，GK胰腺发育受损可能是由于胎儿胰腺细胞生长和存活所需的胰腺外因子不足所致。
