Dynamics of pancreatic cell growth and differentiation during diabetes reversion in STZ-treated newborn rats

Abstract

Cellular processes underlying ontogenesis and regression of streptozotocin (STZ)-induced diabetes in newborn rats were investigated at the most severe stage of diabetes at day 3 and after recovery of normoglycemia at day 8 by immunocytochemistry and quantitative analysis. A previously unknown endocrine cell type subpopulation (PEPS) was identified. It was characterized by granule polymorphism, coexpression of insulin and glucagon immunoreactivity, and a proliferative capacity transiently higher than in B cells. In STZ-treated rats at day 3, B cell mass decreased 14-fold, whereas PEPS cells were unaffected. The islet mass was restored to 55.7% by day 8, with a concomitant appearance of numerous small islets contiguous to small ducts. B cell mass increased by 6.9-fold compared with 1.8-fold in control rats, although proliferative capacities remained similar. Proliferation dropped considerably by day 8, preventing complete B cell mass recovery in STZ-treated rats. STZ-induced neonatal diabetes thus stimulates neogenesis of islets close to ducts and proliferation of PEPS cells. Those partially differentiated islet cells appear to be on the differentiation pathway of stem cells to fully differentiated B cells.

Recovery in the fetal pancreatic islet following fetal administration of streptozotocin in the rat in vivo and in vitro

“…It has been clarified that when a severe hyperglycemic condition is maintained after Px, B-cell differentiation is inhibited (Finegood et al, 1999;Jonas et al, 1999). Ferrand et al (1995) reported detailed regeneration of B-cells in newborn rats treated with STZ immediately after delivery using morphological techniques, but there was no evidence that these regenerated B-cells have the potency of insulin secretion. STZ treatment immediately after delivery decreases glucose tolerance in adults (Portha et al, 1989;Wang et al, 1994).…”

“…Conversely, in rats treated with STZ at birth (Portha et al, 1974), after 2 (BonnerWeir et al, 1981) or 3 days (Ferrand et al, 1995), a loss of B-cell mass triggered acute diabetes followed by a rapid regression and the reappearance of a large B-cell mass and normal insulin content. In a previous study, we demonstrated that fetal rats injected with STZ exhibit regenerative activity of the pancreatic B-cells using histological, immunochemical, and ultrastructural techniques (Yamamoto et al, 1997).…”

Clusterin expression during regeneration of pancreatic islet cells in streptozotocin-induced diabetic rats

“…Rats treated with streptozotocin at neonatal stage have been used as a model for Type II diabetes with insulin resistance and glucose intolerance [22,39,40]. It has been suggested that neonatal streptozotocin treatment stimulates neogenic proliferation of islet cells [31,32,34]. Indeed in streptozotocin-treated rat pups a remarkable regeneration of beta cells was recorded together with a noticeable reduction of blood glucose.…”

Is pancreas development abnormal in the non-obese diabetic mouse, a spontaneous model of type I diabetes?

“…Finally, the localization of the early immune cell infiltration (APC and lymphocytes) was intriguing: around ducts and especially islets, where the targets of the autoimmune reaction, i.e., the ß cells, form the core of the islet and are surrounded by non-ß cells. More particularly, we frequently found APC surrounding small islets connected to ducts (Figure 2), which correspond to islets undergoing neogenesis (14,15). However, some types of these APC were also similarly localized in early postnatal pancreata from normal mouse strains (10).…”

“…The pancreas arises from an endodermal budding of the embryonic foregut into the surrounding mesenchyme (15). During branching, differentiation, morphogenesis and growth of the pancreas, mesenchymalepithelial cell interactions are important (16).…”