Molecular analysis of db gene-related pancreatic beta cell dysfunction; evidence for a compensatory mechanism inhibiting development of diabetes in the db gene heterozygote.

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.