β-Cell Neogenesis During Prolonged Hyperglycemia in Rats
- From the Diabetes Research Laboratory, School of Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada
β-cell neogenesis from ductal precursors, and possibly from other pancreatic cell types, contributes to the expansion of β-cell mass during development and after diabetogenic insults in rodents. Using a mathematical model−based analysis of β-cell mass, replication, and size, we recently demonstrated that neogenesis is also quantitatively important to the expansion of β-cell mass during prolonged hyperglycemia. In the present study, we examined the morphological appearance of neogenic focal areas, duct cell replication, and β-cell cluster size distribution in male Sprague Dawley rats infused with either saline or 50% glucose (2 ml/h) for 0, 1, 2, 3, 4, 5, or 6 days. Pancreatic tissue characterized by a high density of small duct-like structures, previously described as neogenic focal areas, were present in glucose-infused rats after 2, 3, or 4 days of infusion. The cross-sectional area of the pancreas characterized as focal tissue peaked after 3 days of infusion at 2.9 ± 0.8%. In contrast to the partial pancreatectomy model of β-cell regeneration, duct cell replication was not increased before or during focal area formation. However, the replication rate of cells in the duct-like structures of the focal areas was twofold greater than in cells of the common pancreatic duct and 15- to 40-fold greater than in cells of small, medium, and large ducts. Duct-cell replication was significantly reduced in small, medium, and large ducts of glucose as compared to saline-infused rats (0.21 ± 0.02 vs. 0.48 ± 0.04%; P < 0.03). Duct-associated β-cell mass was not different in glucose- and saline-infused rats (P = 0.78), whereas the number of acinar-associated single β -cells increased by 70% after 3 and 4 days of glucose infusion. In addition to small duct-like structures, focal areas had considerable T-cell infiltration (151 ± 30 T-cells/ mm2). There was also an increase in T-cell infiltration in acinar tissue of glucose as compared to saline-infused rats (0.43 ± 0.11 vs. 0.03 ± 0. 01 T-cells/mm2; P < 0.0001). In conclusion, these data suggest that neogenic focal areas in these glucose-infused rats do not arise from replication and differentiation of ductal progenitor cells. Rather, acinar cell transdifferentiation into β-cells and acinar cell dedifferentiation into neogenic focal areas lead to new β-cell formation during prolonged hyperglycemia.
Address correspondence and reprint requests to Diane T. Finegood, PhD, Diabetes Research Laboratory, School of Kinesiology, Simon Fraser University, 8888 University Dr., Burnaby, British Columbia, Canada V5A 1S6. E-mail:.
Received for publication 5 September 2000 and accepted in revised form 16 January 2002.
BrdU, 5-bromo-2′deoxyuridine; IFN-γ, γ-interferon; PDX-1, pancreatic duodenal homeobox 1.