Streptozotocin-induced diabetes can be reversed by hepatic oval cell activation through hepatic transdifferentiation and pancreatic islet regeneration.

• Abstract: Hepatic oval cells have shown the potential to transdifferentiate into insulin-producing cells when cultured with high glucose concentrations. However, it remains unknown whether the oval cells can contribute to insulin production in diabetic mice. In this study, our aim was to investigate the response of activated hepatic oval cells to hyperglycemic conditions. C57BL/6 mice were fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 4 weeks to activate the hepatic oval cell population before inducing hyperglycemia with streptozotocin (STZ). Despite the initial hyperglycemia (341+/-15 mg/dl), the blood glucose levels of DDC-STZ-treated mice were significantly improved within 6 weeks (185+/-12 mg/dl). During the initial hyperglycemic stage, DDC-STZ-treated livers expressed pancreatic developmental, endocrine and exocrine genes. Hepatic insulin production was confirmed by immunohistochemistry and ELISA. These results suggested that transdifferentiated hepatic oval cell population contributed to the amelioration of hyperglycemia. We additionally determined that DDC-STZ-treated pancreata played a critical role in complete reversal of hyperglycemia as evidenced by extensive beta-cell regeneration and increase of pancreatic insulin content after STZ treatment, which is rarely observed in other adult STZ models. Reversal of hyperglycemia in this model seems to be accomplished by biphasic insulin augmentation, first by hepatic transdifferentiation, and followed by endogenous beta-cell regeneration in the pancreas. The DDC-STZ treatment provides a novel injury model for better understanding of the functional behavior of hepatic and pancreatic stem/progenitor cell population under hyperglycemic condition, which may yield critical information for developing beta-cell-based therapies to treat diabetes.
• Authors: Seungbum Kim, Jun-Seop Shin, Hyun-Jung Kim, Robert C Fisher, Mi-Ji Lee, Chan-Wha Kim (Affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.)
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 87 Issue 7 Pg. 702-12 (Jul 2007) ISSN: 0023-6837 [Print] United States
• PMID: 17483848 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Insulin
• Streptozocin
• Dicarbethoxydihydrocollidine

Topics

• Animals
• Blood Glucose (metabolism)
• Cell Differentiation
• Diabetes Mellitus, Experimental (chemically induced, pathology, physiopathology)
• Dicarbethoxydihydrocollidine
• Disease Models, Animal
• Gene Expression Regulation, Developmental
• Hepatocytes (classification, pathology)
• Hyperglycemia (metabolism)
• Insulin (secretion)
• Insulin-Secreting Cells (pathology, secretion)
• Liver (pathology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Organ Specificity
• Regeneration
• Streptozocin