title: Poor capacity for proliferation of pancreatic beta-cells in Otsuka-Long-Evans-Tokushima Fatty rat: a model of spontaneous NIDDM.
abstract: Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat, a genetic model of spontaneous development of NIDDM, exhibits hyperglycemic obesity with hyperinsulinemia and insulin resistance similar to that in humans. It is still unclear whether a defect in the beta-cell proliferation per se is the primary pathogenetic event in OLETF rat. To determine whether it is, we used partially pancreatectomized rats as a model, with administration of phlorizin to control blood glucose level, to examine whether the capacity for proliferation of beta-cells during hyperglycemia or normoglycemia differs between OLETF and their diabetes-resistant counterparts, Long-Evans-Tokushima-Otsuka (LETO) rats. We also examined whether such a defect, if present, could be improved by nicotinamide. Male rats, 6 weeks of age, were allocated at random to two groups: 70% pancreatectomy (Px) and sham-pancreatectomy (sham). Each group was divided into four subgroups by date of killing after surgery: 3-day, 7-day, 28-day (treated with phlorizin, nicotinamide, or saline), and 91-day. A sustained hyperglycemia was evident in the Px OLETF rats after surgery, which was associated with insufficient proliferation of beta-cells, characterized by decrease in beta-cell labeling index in proportion to decrease in beta-cell mass and reduction in insulin content in the remnant pancreas. This defect was unaffected by restoration of normoglycemia induced by phlorizin injection. Administration of nicotinamide, however, ameliorated the sustained hyperglycemia by increasing beta-cell proliferation. These findings suggest that OLETF rats have poor capacity for proliferation of pancreatic beta-cells and that this change may be the critical pathogenetic event before the onset of overt diabetes.
authors.affiliation: Department of Laboratory Medicine, School of Medicine, University of Tokushima, Tokushima City, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Zhu
authors.forename: Y
authors.initials: Y
authors.lastname: Noma
authors.forename: A
authors.initials: A
authors.lastname: Mizuno
authors.forename: T
authors.initials: T
authors.lastname: Sano
authors.forename: K
authors.initials: K
authors.lastname: Shima
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight; D002455:Cell Division / Q000187:drug effects; D003920:Diabetes Mellitus / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D009536:Niacinamide / Q000494:pharmacology; D009765:Obesity; D010180:Pancreatectomy; D010695:Phlorhizin / Q000494:pharmacology; D051381:Rats; D011922:Rats, Mutant Strains
chemical_list: D001786:Blood Glucose; D009536:Niacinamide; D010695:Phlorhizin