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Diabetes 50:1562-1570, 2001
© 2001 by the American Diabetes Association, Inc.

Glucagon-Like Peptide-1 and Exendin-4 Stimulate ß-Cell Neogenesis in Streptozotocin-Treated Newborn Rats Resulting in Persistently Improved Glucose Homeostasis at Adult Age

Cécile Tourrel1,2, Danielle Bailbé1, Marie-Jo Meile1, Micheline Kergoat2, and Bernard Portha1

1 Laboratory of Physiopathology of Nutrition, Centre National de la Recherche Scientifique ESA 7059, Université Paris, Paris
2 MERCK-LIPHA, Chilly-Mazarin, France

In neonatal Wistar rats injected with streptozotocin (STZ) at birth (n0-STZ model), a recognized model of ß-cell regeneration, we investigated the capacity of early treatment with glucagon-like peptide 1 (GLP-1) or exendin-4 to promote ß-cell regeneration and thereby improve islet function in 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 their ß-cell mass and pancreatic functions were tested on day 7 and at 2 months. On day 7, both treatments increased body weight, decreased basal plasma glucose, decreased insulinemia, and increased pancreatic insulin content in n0-STZ rats. At the same age, the ß-cell mass, measured by immunocytochemistry 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%, respectively, of the ß-cell mass in Wistar rats, whereas n0-STZ ß-cell mass represented only 21% of the Wistar control value. Despite such early improved ß-cell mass, which is maintained at adult age, the basal and glucose-stimulated insulin secretion (in vivo after intravenous glucose load 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 untreated n0-STZ rats. However, both treated groups significantly exhibited a decreased basal plasma glucose level and an increased plasma glucose clearance rate compared with the 2-month-old untreated n0-STZ group at adult age. These 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- and long-term beneficial effects on ß-cell mass recovery and glucose homeostasis. However, the increase in ß-cell mass, which is still present in the adult n0-STZ rats previously treated, contrasts with the poor ß-cell responsiveness to glucose. Further studies are needed to understand the dissociation between ß-cell regeneration and the lack of improvement in ß-cell function.


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