Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age

In neonatal Wistar rats injected with streptozotocin (STZ) at birth (n0-STZ model), a recognized model of beta -cell regeneration, we investigated the capacity of early treatment with glucagon-like peptide 1 (GLP-1) or exendi n-4 to promote beta -cell regeneration and thereby improve islet function i n the long term, when animals become adults. To this end, n0-STZ rats were submitted to GLP-1 or exendin-4 from postnatal day 2 to day 6 only, and the ir beta -cell mass and pancreatic functions were tested on day 7 and at 2 m onths. On day 7, both treatments increased body weight, decreased basal pla sma glucose, decreased insulinemia, and increased pancreatic insulin conten t in n0-STZ rats. At the same age, the beta -cell mass, measured by immunoc ytochemistry and morphometry methods, was strongly increased in n0-STZ/GLP- 1 and n0-STZ/Ex rats compared with n0-STZ rats, representing 51 and 71%, re spectively, of the beta -cell mass in Wistar rats, whereas n0-STZ beta -cel l mass represented only 21% of the Wistar control value. Despite such early improved beta -cell mass, which is maintained at adult age, the basal and glucose-stimulated insulin secretion (in vivo after intravenous glucose loa d or in vitro using perfused pancreas) were not improved in the 2-month-old n0-STZ rats previously treated with GLP-1 or exendin-4 compared with untre ated n0-STZ rats. However, both treated groups significantly exhibited a de creased basal plasma glucose level and an increased plasma glucose clearanc e rate compared with the 2-month-old untreated n0-STZ group at adult age. T hese findings in the n0-STZ model indicate for the first time that GLP-1 or exendin-4 applied during the neonatal diabetic period exert both short- an d long-term beneficial effects on beta -cell mass recovery and glucose home ostasis. However, the increase in beta -cell mass, which is still present i n the adult n0-STZ rats previously treated, contrasts with the poor beta -c ell responsiveness to glucose. Further studies are needed to understand the dissociation between beta -cell regeneration and the lack of improvement i n beta -cell function.