OP-4：Exendin-4 upregulates the expression of PDX-1 and Ngn3 during pancreatic b-cell regeneration in streptozotocin-treated mice.

Tetsushi Toyonaga¹, Shoko Kodama¹, Tatsuya Kondo¹, Kazuhiko Kume², Shoen Kume², and Eiichi Araki¹

1 Department of Metabolic Medicine, GraduateSchoolof Medical Sciences

2 Division of Stem Cell Biology, Department of Regeneration Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan

Aim:  Pancreatic and duodenal homeobox gene-1 (PDX-1) and Neurogenin3 (Ngn3) are transcription factors which are necessary for the pancreatic b-cell development.  The aim of this study is to analyze the expression of these transcription factors and effects of the exendin-4 during the pancreatic bcell regeneration after streptozotocin (STZ)-induced damage.

Methods:  Transgenic mice in which PDX-1 expression can be traced by GFP were established.  These mice were treated with STZ or STZ + exendin-4 for 7 days.  The expression of PDX-1, Ngn3 and IRS-2, and the expression and cellular distribution of forkhead box transcription factor O1 (Foxo1) were investigated by real time RT-PCR and immunohistochemistry.

Results:  Beta cell regeneration after STZ treatment was associated with biphasic upregulation of PDX-1 mRNA expression and induction of Ngn3 mRNA expression shortly after the first increase of PDX-1.  PDX-1-positive cells appeared both in pancreatic ducts and in residual islets, and all islet-like cell clusters contained somatostatin-positive delta cells.  Exendin-4 treatment significantly stimulated bcell regeneration by upregulation of PDX-1 expression, which paralleled increased IRS-2 expression and translocation of Foxo1 from nucleus to cytoplasm.

Conclusion:  These observations suggest that both transcription factors and insulin signaling molecules are involved in bcell regeneration and these molecules could be therapeutic targets to increase bcell mass in diabetic patients.

(270 words)

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