Author(s): Miralles F, Portha B
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Abstract 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.
This article was published in Diabetes
and referenced in Journal of Developing Drugs