α-Cell Neogenesis in an Animal Model of IDDM

Abstract

Currently there is debate regarding the capacity of pancreatic islets to regenerate in adult animals. Because pancreatic endocrine cells are thought to arise from duct cells, we examined the pancreatic ductal epithelium of the diabetic NOD mouse for evidence of islet neogenesis. We have evidence of duct proliferation as well as ductal cell differentiation, as suggested by bromodeoxyuridine-labeling and the presence of glucagon-containing cells within these ducts. In addition, the ductal epithelia in diabetic NOD mice expressed the neuroendocrine markers neuropeptide Y and tyrosine hydroxylase. These ducts also expressed the homeobox gene product, insulin promoter factor 1. Ductal cell proliferation and expression of these markers was not observed in transgenic NOD mice (NOD-E), which do not develop clinical or histopathological symptoms of IDDM. This suggests that the observed ductal cell proliferation and differentiation was a direct result of beta-cell destruction and insulin insufficiency in these adult diabetic mice, which further suggests that these events are recapitulating islet ontogeny observed during embryogenesis. It is possible that comparable processes occur in the human diabetic pancreas.

Patients With Chronic Pancreatitis Have Islet Progenitor Cells in Their Ducts, but Reversal of Overt Diabetes in NOD Mice by Anti-CD3 Shows No Evidence for Islet Regeneration

“…In contrast, our studies in spontaneously diabetic NOD mice, while showing increased development of glucagon-containing cells in the pancreatic ducts, did not show an increase in cells containing insulin. Indeed, there was a significant reduction in the presence of such cells in the adult diabetic mouse pancreas (22). This was consistent with an autoimmune destruction targeting presumptive new ␤-cells.…”

“…We used Ki67 to identify proliferating cells and antibodies to glucagon, insulin, and amylase to identify the cells that were undergoing differentiation. The homeodomain protein PDX-1 has been shown to be expressed in the pancreatic ducts following partial pancreatectomy in rats (27), as well as in the ducts of diabetic NOD mice (22). Its presence in pancreatic ducts has been shown to follow proliferation, leading to the suggestion that its expression in the ducts may reflect a pluripotent state enabling further differentiation (27).…”

“…We felt that this would be an appropriate model, as the early data preceding the translation to the clinic of anti-CD3 treatment had been carried out in NOD mice (18). Furthermore, there is evidence for the presence of ductal progenitors in the pancreas of diabetic NOD mice (22). These cells were identified by expression of the homeodomain protein pancreatic duodenal homeobox (PDX)-1, a factor shown to be essential for the development of both the exocrine and endocrine pancreas and expressed in pancreatic progenitors (23).…”

Expression of Reg and cytokeratin 20 during ductal cell differentiation and proliferation in a mouse model of autoimmune diabetes

“…In animal models of autoimmune diabetes, such as NOD mice, alfa cell neogenesis has been reported as a result of ductal epithelial proliferation and differentiation (16).…”

Serum reg protein level is not related to the beta cell destruction/regeneration process during early phases of diabetogenesis in type I diabetes

“…Transient glucose intolerances associated with autoimmune markers have been noted in twin studies, confirming that, on rare occasions, beta cells could overcome autoimmune aggression (4). Regeneration of endocrine cells from the duct, mainly with the glucagon cell phenotype, has been also noted by O'Reilly (17) in the non-obese diabetic (NOD) mouse. As exocrine pancreatic proteins can be measured in blood, we made the assumption that serum reg protein levels might reflect pancreatic expression during the early phases of the disease in diabetic patients, and then these could be a marker of the destruction/regeneration balance.…”