title: Molecular analysis of db gene-related pancreatic beta cell dysfunction; evidence for a compensatory mechanism inhibiting development of diabetes in the db gene heterozygote.
abstract: The db gene homozygous, but not heterozygous, mice develop diabetes with severe beta-cell damage. We investigated the molecular mechanism underlying db gene-associated pancreatic beta-cell dysfunction. Islet morphology, beta-cell function, and gene expression profiles specific for pancreatic islet cells were compared among db gene homozygous(db/db), heterozygous (db/m) and unrelated m/m mice. The beta-cell ratio decreased in db/db mice with age, but not in non-diabetic db/m and m/m mice. The islet insulin content was lower, but the triglyceride content was higher in db/db than other mice. The islet cell specific gene expression profiles analyzed by laser capture microdissection method and morphological findings suggested an augmentation of beta-cell apoptosis, oxidative stress and ER stress in db/db mice. Interestingly, insulin I and II, anti-apoptotic bcl-2, and proliferation promoting ERK-1 gene expressions were significantly upregulated in db/m mice. An impaired glucose tolerance was shown in m/m mice fed a high fat diet, but not in db/m mice, in which a higher insulin response and increased beta-cell mass were observed. Expressions of insulin I and II, bcl-2, and ERK-1 gene were increased in db/m mice, but not in m/m fed a high fat diet. The present results strongly suggest that the db gene heterozygote, but not homozygote, acquires a compensatory mechanism suppressing beta-cell apoptosis and augmenting the capacity of beta-cell function.
authors.affiliation: Diabetes and Endocrine Division, Department of Internal Medicine, Kawasaki Medical School, Kurashiki 701-0192, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kanda
authors.forename: Masashi
authors.initials: M
authors.lastname: Shimoda
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tawaramoto
authors.forename: Sumiko
authors.initials: S
authors.lastname: Hamamoto
authors.forename: Fuminori
authors.initials: F
authors.lastname: Tatsumi
authors.forename: Fumiko
authors.initials: F
authors.lastname: Kawasaki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashiramoto
authors.forename: Koji
authors.initials: K
authors.lastname: Nakashima
authors.forename: Michihiro
authors.initials: M
authors.lastname: Matsuki
authors.forename: Kohei
authors.initials: K
authors.lastname: Kaku
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000494:pharmacology; D006579:Heterozygote; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D007328:Insulin; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D005947:Glucose