Defective morphogenesis and functional maturation in fetal islet-like cell clusters from OLETF rat, a model of NIDDM.
A failure in the compensate proliferation of pancreatic beta-cells, as the primary pathogenic event, has been reported in OLETF rat, a model of NIDDM. The aim of the present study is to define whether the beta-cell defect is attributed to the fetal stage islet development, if so, whether the defect involves down regulation of PDX-1 protein expression. Morphological changes, beta-cell function, and the expression of PDX-1 protein were examined in the cultured fetal islet-like cell clusters (ICCs) from OLETF rats along with their diabetes-resistant control counterpart LETO rats in the presence of 5.5 or 11.1mM glucose for 48, 72, 96, and 120-hr, respectively. We have observed four abnormalities in the ICCs of OLETF rats. First, a defective morphogenesis was noted during the 72 to 120-hr ICC culture, a period characterized by a dramatic increase in both beta-cell and non-beta-cell (alpha, delta, and PP) populations in control rats. This defective morphogenesis was demonstrated by a growth retardation of epithelial stratification and poor development of both beta-cell and non-beta-cell masses along with a parallel decline in relevant islet hormone contents. Second, a functional defect was characterized by failure to response to glucose during the 96 to 120-hr-cultured ICCs. Third, the ultrastructural analysis revealed a significant reduction in the number of secretory granules. Four, Western blot analysis showed a significant decrease of PDX-1 protein expression in the OLETF ICCs cultured in 11.1mM glucose for 48 to 72-hr and in 5.5mM glucose for 120-hr. Therefore, we concluded that during the fetal stage of islet development, OLETF rats exhibit both morphological and functional defects.
Zhu
M
M
Research Institute for Children, Children's Hospital, Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans 70112, USA.
Mizuno
A
A
Noma
Y
Y
Murakami
T
T
Kuwajima
M
M
Shima
K
K
Lan
M S
MS
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000196:embryology*; D005260:Female; D005934:Glucagon / Q000032:analysis; D018398:Homeodomain Proteins; D007328:Insulin / Q000032:analysis / Q000097:blood; D007515:Islets of Langerhans / Q000002:abnormalities / Q000737:chemistry / Q000196:embryology*; D009024:Morphogenesis; D011247:Pregnancy; D051381:Rats; D020334:Rats, Inbred OLETF; D013997:Time Factors; D015534:Trans-Activators / Q000032:analysis
D001786:Blood Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005934:Glucagon