title: Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats.
abstract: A constant remodeling of islet cell mass mediated by proliferative and apoptotic stimuli ensures a dynamic response to a changing demand for insulin. In this study, we investigated the effect of glucagon-like peptide-1 (GLP-1) in Zucker diabetic rats, an animal model in which the onset of diabetes occurs when the proliferative potential and the rate of beta-cell apoptosis no longer compensate for the increased demand for insulin. We subjected diabetic rats to a 2-d infusion of GLP-1 and tested their response to an ip glucose tolerance test. GLP-1 produced a significant increase of insulin secretion, which was paralleled by a decrease in plasma glucose levels (P < 0.001 and P < 0.01, respectively). Four days after the removal of the infusion pumps, rats were killed and the pancreas harvested to study the mechanism by which GLP-1 ameliorated glucose tolerance. Ex vivo immunostaining with the marker of cell proliferation, Ki-67, showed that the metabolic changes observed in rats treated with GLP-1 were associated with an increase in cell proliferation of the endocrine and exocrine component of the pancreas. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling staining, a marker of cellular apoptosis, indicated a reduction of apoptotic cells within the islet as well in the exocrine pancreas in GLP-1-treated rats. Double immunostaining for the apoptotic marker caspase-3 and for insulin showed a significant reduction of caspase-3 expression and an increase in insulin content in GLP-1-treated animals. Finally, staining of pancreatic sections with the nuclear dye 4,6-Diaminidino-2-phenyl-dihydrochloride demonstrated a marked reduction of fragmented nuclei in the islet cells of rats treated with GLP-1. Our findings provide evidence that the beneficial effects of GLP-1 in Zucker diabetic rats is mediated by an increase in islet cell proliferation and a decrease of cellular apoptosis.
authors.affiliation: Cedars-Sinai Medical Center, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Los Angeles, California 90048, USA.
authors.forename: Loredana
authors.initials: L
authors.lastname: Farilla
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Hui
authors.forename: Cristina
authors.initials: C
authors.lastname: Bertolotto
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kang
authors.forename: Angela
authors.initials: A
authors.lastname: Bulotta
authors.forename: Umberto
authors.initials: U
authors.lastname: Di Mario
authors.forename: Riccardo
authors.initials: R
authors.lastname: Perfetti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D002455:Cell Division / Q000187:drug effects*; D003920:Diabetes Mellitus / Q000473:pathology*; D005934:Glucagon / Q000097:blood / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000473:pathology*; D019394:Ki-67 Antigen / Q000032:analysis; D007700:Kinetics; D008297:Male; D010446:Peptide Fragments / Q000097:blood / Q000494:pharmacology*; D011498:Protein Precursors / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D007328:Insulin; D019394:Ki-67 Antigen; D010446:Peptide Fragments; D011498:Protein Precursors; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases