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 exendin-4 to promote beta-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 beta-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 beta-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 beta-cell mass in Wistar rats, whereas n0-STZ beta-cell 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 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 beta-cell mass recovery and glucose homeostasis. However, the increase in beta-cell mass, which is still present in the adult n0-STZ rats previously treated, contrasts with the poor beta-cell responsiveness to glucose. Further studies are needed to understand the dissociation between beta-cell regeneration and the lack of improvement in beta-cell function.
Tourrel
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C
Laboratory of Physiopathology of Nutrition, Centre National de la Recherche Scientifique ESA 7059, Université Paris7/Denis Diderot, 2 place Jussieu, 75251 Paris Cedex 05, France. tourrel@paris7.jussieu.fr
Bailbé
D
D
Meile
M J
MJ
Kergoat
M
M
Portha
B
B
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism / Q000502:physiology*; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D000077270:Exenatide; D005260:Female; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D006706:Homeostasis / Q000187:drug effects*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014688:Venoms
D001786:Blood Glucose; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide