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Reversal of Streptozotocin-Induced Diabetes in Mice by Cellular Transduction With Recombinant Pancreatic Transcription Factor Pancreatic Duodenal Homeobox-1

A Novel Protein Transduction Domain–Based Therapy

¹ Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida
² Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida

Address correspondence and reprint requests to Li-Jun Yang, MD, Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, 1600 SW Archer Rd., P.O. Box 100275, Gainesville, FL 32610-0275. E-mail: yanglj{at}pathology.ufl.edu

Key Words: C_T, threshold cycle • IPC, insulin-producing cell • IPGTT, intraperitoneal glucose tolerance test • LV, lentiviral vectors • Pdx1, pancreatic duodenal homeobox-1 • PTD, protein transduction domain • PTD-GFP, PTD–green fluorescent protein • rPdx1, recombinant Pdx1

OBJECTIVE—The key pancreatic transcription factor pancreatic duodenal homeobox-1 (Pdx1), known to control development and maintenance of pancreatic β-cells, possesses a protein transduction domain (PTD) that facilitates its entry into cells. We therefore sought to evaluate the capacity of in vivo–administered recombinant Pdx1 (rPdx1) to ameliorate hyperglycemia in mice with streptozotocin-induced diabetes.

RESEARCH DESIGN AND METHODS—Cell entry and transcriptional regulatory properties of rPdx1 protein and its PTD-deletion mutant rPdx1 protein, as well as a PTD–green fluorescent protein, were evaluated in vitro. After intraperitoneal rPdx1 injection into mice with streptozotocin-induced diabetes, we assessed its action on blood glucose levels, insulin content, intraperitoneal glucose tolerance test (IPGTT), Pdx1 distribution, pancreatic gene expression, islet cell proliferation, and organ histology.

RESULTS—Restoration of euglycemia in Pdx1-treated diabetic mice was evident by improved IPGTT and glucose-stimulated insulin release. Insulin, glucagon, and Ki67 immunostaining revealed increased islet cell number and proliferation in pancreata of rPdx1-treated mice. Real-time PCR of pancreas and liver demonstrated upregulation of INS and PDX1 genes and other genes relevant to pancreas regeneration. While the time course of β-cell gene expression and serum/tissue insulin levels indicated that both liver- and pancreas-derived insulin contributed to restoration of normoglycemia, near-total pancreatectomy resulted in hyperglycemia, suggesting that β-cell regeneration played the primary role in rPdx1-induced glucose homeostasis.

CONCLUSIONS—rPdx1 treatment of mice with streptozotocin-induced diabetes promotes β-cell regeneration and liver cell reprogramming, leading to restoration of normoglycemia. This novel PTD-based protein therapy offers a promising way to treat patients with diabetes while avoiding potential side effects associated with the use of viral vectors.

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