Glucagon-Like Peptide-1 and Exendin-4 Stimulate β-Cell Neogenesis in Streptozotocin-Treated Newborn Rats Resulting in Persistently Improved Glucose Homeostasis at Adult Age
- 1Laboratory of Physiopathology of Nutrition, Centre National de la Recherche Scientifique ESA 7059, Université Paris, Paris
- 2MERCK-LIPHA, Chilly-Mazarin, France
In neonatal Wistar rats injected with streptozotocin (STZ) at birth (n0-STZ model), a recognized model of β-cell regeneration, we investigated the capacity of early treatment with glucagon-like peptide 1 (GLP-1) or exendin-4 to promote β-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 β-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 β-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 β-cell mass in Wistar rats, whereas n0-STZ β-cell mass represented only 21% of the Wistar control value. Despite such early improved β-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 β-cell mass recovery and glucose homeostasis. However, the increase in β-cell mass, which is still present in the adult n0-STZ rats previously treated, contrasts with the poor β-cell responsiveness to glucose. Further studies are needed to understand the dissociation between β-cell regeneration and the lack of improvement in β-cell function.
Address correspondence and reprint requests to C. Tourrel, Lab. Physiopathology of Nutrition, CNRS ESA 7059, Université Paris7/Denis Diderot, 2 place Jussieu, 75251 Paris Cedex 05, France. E-mail:.
Received for publication 14 September 2000 and accepted in revised form 21 March 2001.
BrdU, 5′-bromo-2′-deoxyuridine; DAB, 3,3′-diaminobenzidine-tetra-hydrochloride; ΔG, integrated change in plasma glucose; ΔI, incremental change in plasma insulin; GLP-1, glucagon-like peptide 1; STZ, streptozotocin.