title: Demonstration of two different processes of beta-cell regeneration in a new diabetic mouse model induced by selective perfusion of alloxan.
abstract: To clarify the regeneration process of pancreatic beta-cells, we established a new mouse model of diabetes induced by selective perfusion of alloxan after clamping the superior mesenteric artery. In this model, diabetes could be induced by the destruction of beta-cells in alloxan-perfused segments, while beta-cells in nonperfused segments were spared. Intraperitoneal glucose tolerance tests showed glucose intolerance, which gradually ameliorated and was completely normalized in 1 year with a concomitant increase of insulin content in the pancreas. Histological examination showed neo-islet formation in the alloxan-perfused segment and the proliferation of spared beta-cells in the nonperfused segment. In the alloxan-perfused segment, despite a marked reduction of islets in size and number at an early stage, both the number of islets, including islet-like cell clusters (ICCs), and the relative islet area significantly increased at a later stage. Increased single beta-cells and ICCs were located in close contact with duct cell lining, suggesting that they differentiated from duct cells and that such extra-islet precursor cells may be important for beta-cell regeneration in beta-cell-depleted segment. In addition to beta-cells, some nonhormone cells in ICCs were positive for nuclear insulin promoter factor 1, which indicated that most, if not all, nonhormone cells positive for this factor were beta-cell precursors. In the nonperfused segment, the islet area increased significantly, and the highest 5-bromo-2-deoxyuridine-labeling index in beta-cells was observed at day 5, while the number of islets did not increase significantly. This indicated that the regeneration of islet endocrine cells occurs mostly through the proliferation of preexisting intra-islet beta-cells in the nonperfused segment. In conclusion, the regeneration process of beta-cells varied by circumstance. Our mouse model is useful for studying the mechanism of regeneration, since differentiation and proliferation could be analyzed separately in one pancreas.
authors.affiliation: Second Department of Internal Medicine, Osaka University Medical School, Suita, Japan. waguri@imed2.med.osaka-u.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Waguri
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: J I
authors.initials: JI
authors.lastname: Miyagawa
authors.forename: Y
authors.initials: Y
authors.lastname: Tochino
authors.forename: K
authors.initials: K
authors.lastname: Yamamori
authors.forename: Y
authors.initials: Y
authors.lastname: Kajimoto
authors.forename: H
authors.initials: H
authors.lastname: Nakajima
authors.forename: H
authors.initials: H
authors.lastname: Watada
authors.forename: I
authors.initials: I
authors.lastname: Yoshiuchi
authors.forename: N
authors.initials: N
authors.lastname: Itoh
authors.forename: A
authors.initials: A
authors.lastname: Imagawa
authors.forename: M
authors.initials: M
authors.lastname: Namba
authors.forename: M
authors.initials: M
authors.lastname: Kuwajima
authors.forename: Y
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: T
authors.initials: T
authors.lastname: Hanafusa
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D000496:Alloxan; D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005934:Glucagon / Q000032:analysis / Q000276:immunology; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins; D007150:Immunohistochemistry; D007328:Insulin / Q000032:analysis / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology / Q000502:physiology* / Q000648:ultrastructure; D007633:Keratins / Q000032:analysis / Q000276:immunology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010191:Pancreatic Polypeptide / Q000032:analysis / Q000276:immunology; D010477:Perfusion; D012038:Regeneration / Q000502:physiology*; D013004:Somatostatin / Q000032:analysis / Q000276:immunology; D013997:Time Factors; D015534:Trans-Activators / Q000032:analysis / Q000276:immunology
chemical_list: D001786:Blood Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D013004:Somatostatin; D010191:Pancreatic Polypeptide; D007633:Keratins; D000496:Alloxan; D005934:Glucagon