In the Goto-Kakizaki (GK) rat, a genetic model of type 2 diabetes, the neonatal ␤-cell mass deficit is considered to be the primary defect leading to basal hyperglycemia, which is detectable for the first time 3 weeks after birth. We investigated in GK females the short-and the longterm effects of a treatment with glucagon-like peptide-1 (GLP-1) or its long-acting analog exendin-4 (Ex-4) during the first postnatal week (during the prediabetic period). GK rats were treated with daily injections of glucagon-like peptide-1 (400 g ⅐ kg ؊1 ⅐ day ؊1 ) or Ex-4 (3 g ⅐ kg ؊1 ⅐ day ؊1 ) from day 2 to day 6 after birth and were evaluated against Wistar and untreated GK rats. Under these conditions, on day 7 both treatments enhanced pancreatic insulin content and total ␤-cell mass by stimulating ␤-cell neogenesis and regeneration. Follow-up of biological characteristics from day 7 to adult age (2 months) showed that such a GLP-1 or Ex-4 treatment exerted long-term favorable influences on ␤-cell mass and glycemic control at adult age. As compared to untreated GK rats, 2-month-old treated rats exhibited significantly decreased basal plasma glucose. Their glucose-stimulated insulin secretion, in vivo after intravenous glucose load or in vitro using isolated perfused pancreas, was slightly improved. This contributed at least partly to improve the in vivo plasma glucose disappearance rate, which was found to be increased in both treated GK groups compared to the untreated GK group. These findings in the GK model indicated, for the first time, that GLP-1 or Ex-4 treatment limited to the prediabetic period delays the installation and limits the severity of type 2 diabetes. Under these conditions, GLP-1 represents a unique tool because of its ␤-cell replenishing effect in spontaneously diabetic rodents. It may prove to be an invaluable agent for the prevention of human type 2 diabetes. Diabetes

At late fetal age (21.5 days postcoitum [dpc]), GK rats present a severely reduced ␤-cell mass compared with Wistar rats. This anomaly largely antedates the onset of hyperglycemia in GK rats. Thus, the ␤-cell mass deficit could represent the primary defect leading to type 2 diabetes in the adult. The aim of this work was to investigate, in GK fetuses at the end of fetal age (21.5 dpc), whether impaired availability of growth factors such as insulin, growth hormone, and IGFs and their IGF binding proteins (IGFBPs) could be instrumental in this anomaly. Although it confirms that GK fetuses are hypoinsulinemic despite enhanced plasma glucose level due to maternal hyperglycemia, the present study shows for the first time that IGF-2 expression in the liver and pancreas and IGF-2 serum levels are decreased in GK fetuses. Serum level as well as liver and pancreatic mRNA expression of IGFBP-2 were found to be normal in GK fetuses, whereas serum level and liver mRNA expression of IGFBP-1 were increased. Finally, we found that the maximal ␤-cell mitogenic response to IGFs in vitro is kept intact, therefore suggesting that the direct biological action of IGFs on fetal GK ␤-cells is not grossly impaired. In conclusion, in GK fetuses at 21.5 dpc, the defective IGF-2 production appears to be an early landmark in the pathological sequence leading to retardation of ␤-cell growth in the fetal GK rat.

We have previously shown that fetuses from protein-caloric undernourished pregnant rats (35% of control diet during the last week of pregnancy) at 21.5 d post coitum exhibit increased beta-cell mass. This alteration is correlated with increased insulinemia and total pancreatic insulin content, a pattern similar to that reported in infants of mild diabetic mothers. In this work, we investigated in undernourished fetuses: 1) whether availability of growth factors such as insulin, GH, and IGFs and their binding proteins (IGFBPs) could be implicated in this alteration, and 2) the beta-cell mitogenic response to IGFs in vitro. The results show that maternal undernutrition increases pancreatic IGF-I expression and islet IGF-I receptor content in undernourished fetuses, whereas hepatic IGF-I expression and serum IGF-I levels were decreased. No changes were observed in serum IGF-II, and its expression was diminished in undernourished pancreases and unchanged in the liver, compared with control fetuses. Serum levels and liver and pancreatic mRNA expression of IGFBP-1 were found to be normal in undernourished fetuses, whereas the serum concentration and abundance of IGFBP-2 mRNA in pancreas were increased. Finally, the beta-cell mitogenic response to IGFs in vitro was significantly increased in undernourished fetal islets, compared with controls. In conclusion, in undernourished fetuses the increased beta-cell mass can be related to the stimulation of replicative beta-cell response due to locally increased pancreatic IGF-I mRNA; this effect is perhaps potentiated or favored by the enhanced islet IGF-I receptor content and pancreatic IGFBP-2 gene expression.