Metabolic Factors Early Development of -Cells Is Impaired in the GK Rat Model of Type 2 Diabetes

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 -cell mass of the GK rat is severely reduced compared with that of the Wistar rat. Therefore, -cell deficit could be the primary defect leading to type 2 diabetes in this model. To identify the abnormality at the origin of the -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 and -cells between the GK and Wistar pancreas. However, by E16, the average number of -cells in the GK pancreas represents only 50% that of the Wistar pancreas, and this difference persists until birth. The number of -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. Diabetes 50 (Suppl. 1): S84–S88, 2001 Some studies suggest that total -cell mass is decreased in type 2 diabetic patients compared with weight-matched control subjects (1–3). This supports the notion that a -cell mass inadequate to compensate for insulin resistance and/or -cell secretory defects results in insufficient insulin production and leads to overt diabetes. However, prospective data on the evolution of -cell mass during the course of type 2 diabetes are not available in humans, and hence it is unknown whether the -cell mass deficit results from -cell death and/or inadequate -cell expansion. This has been addressed in different animal models of type 2 diabetes, although with conflicting conclusions. Thus, in the ZDF rat, the failure of -cell mass expansion to compensate for insulin resistance is due to increased -cell apoptosis (4), whereas in the OLEFT rat, it seems to be due to impaired -cell proliferation (5). The Goto-Kakisaki (GK) rat is a genetic model of type 2 diabetes without obesity (6). The adult GK rat displays decreased -cell mass (7) together with mild hyperglycemia, glucose intolerance, impaired glucose-induced insulin secretion (8), hepatic glucose overproduction, and moderate peripheral insulin resistance in muscle and adipose tissue (9). Previous studies in our laboratory have shown that newborn GK rats have normal fasting glucose levels compared with Wistar rats and a drastically reduced -cell mass (7). Thus, the -cell mass deficit precedes other manifestations of the disease and could represent the primary defect leading to type 2 diabetes in the adult. This result prompted us to investigate the fetal development of the GK pancreas to clearly define at which stage the -cell mass deficit appears and try to identify the causes of such a deficit.