Ectopic PDX-1 expression in liver ameliorates type 1 diabetes

Shternhall-Ron, Keren; Quintana, Francisco J.; Perl, Shira; Meivar‐Levy, Irit; Barshack, Iris; Cohen, Irun R.; Ferber, Sarah

doi:10.1016/j.jaut.2007.02.010

Cited by 68 publications

(51 citation statements)

References 46 publications

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“…Pdx1 is widely regarded as a master transcriptional regulator of the pancreas and is critical for development (11)(12)(13), regeneration (10,14), and maintenance of ␤-cell function (14,15). Liver stem cells (16) and adult hepatocytes (17,18) reportedly have been reprogrammed by ectopic overexpression of PDX1 into IPCs that are also capable of restoring euglycemia in diabetic mice. However, the strategies involving the use of viruses as a means for gene delivery in these studies raise safety concerns.…”

mentioning

confidence: 99%

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

Koya

Sun

et al. 2008

Diabetes

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OBJECTIVE-The key pancreatic transcription factor pancreatic duodenal homeobox-1 (Pdx1), known to control development and maintenance of pancreatic ␤-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 PTDdeletion 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 ␤-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 ␤-cell regeneration played the primary role in rPdx1-induced glucose homeostasis.CONCLUSIONS-rPdx1 treatment of mice with streptozotocininduced diabetes promotes ␤-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. Diabetes 57:757-769, 2008

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mentioning

confidence: 99%

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

Koya

Sun

et al. 2008

Diabetes

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“…since it is a transcription factor [19,20], Pdx1 was mainly expressed in the nuclei of he- in addition to the hypoglycemic effects that Hda delivery of Pdx1-expressing vectors induces in the transfected murine liver, this process was reported to induce autoimmune hepatitis in sTZ-induced diabetic mice [7]. in the latter case, the amelioration of hyperglycemia was transient and was no longer noted after 1 wk.…”

Section: Discussionmentioning

confidence: 99%

Hydrodynamics-based Transfection of Pancreatic Duodenal Homeobox 1 DNA Improves Hyperglycemia and is Associated with Limited Complications in Diabetic Mice

Chen

Yeh

et al. 2009

Endocr J

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Abstract. The biohazards caused by the viral delivery of pancreatic duodenal homeobox gene 1 (Pdx1) to the murine liver limits its application. We aimed to evaluate the feasibility of hydrodynamics-based transfection (HBT) with Pdx1 in improving hyperglycemia. Murine hepatocellular carcinoma (Hepa1-6) cells were transfected with the Pdx1-expressing plasmid, pcdna3.1/V5-His a (pcdna)-Pdx1. Hepatic delivery of pcdna-Pdx1 or pcdna in streptozocin-induced diabetic mice was achieved by HBT. The sequential serum glucose and alanine aminotransferase (aLT) levels were assessed. On the 3 rd day after transfection, the transfection efficiency in the Hepa1-6 cells and the mice livers was 5% and 0.35 %, respectively. At 1 wk after HBT, asides from hepatic expression of insulin, the diabetic mice transfected with pcDNA-Pdx1 had a significantly lower sugar (211 ± 61.6 vs. 413 ± 62 mg/dL; p = 0.002) level than those transfected with pcDNA; however, the difference diminished afterward. No significant difference in the ALT levels was observed between the 2 groups. no mortality was noted in the mice transfected with pcdna-Pdx1. The hypoglycemic effect of Pdx1 delivered by HBT was transient and associated with negligible complications. in studies on the short-term biological effects of Pdx1 in vivo, HBT is a potential alternative to viral delivery of Pdx1 to the murine liver.

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“…Ectopic expression of PDX1 has proven quite successful at converting non-β cells into β cells capable of synthesizing, processing, and secreting insulin. [18][19][20] In conjunction with PDX1, other transcription factors like NKX6.1, 21 Neurogenin 3,13,22 and NeuroD 22 have been shown to enhance reprogramming efficiency. Importantly, many studies have found that surrogate β cells produced from reprogramming are able to ameliorate streptozotocin-induced hyperglycemia in mice.…”

Section: Reprogramming Non-β Cells Into β Cellsmentioning

confidence: 99%

“…18 Despite these successes, the overall efficacy of reprogramming strategies relies on the long-term absence of recurring autoimmunity against newly formed β cells, which inevitably express a variety of autoantigens that ultimately led to the destruction of native β cells to begin with. 23 While studies in nonobese diabetic mice, a model of autoimmune diabetes, provide hope that autoimmunity could be averted through reprogramming strategies, 20 these studies must be performed for longer time periods to assess true efficacy. Ultimately, these strategies will require either lifelong immunosuppression or selective immunomodulation to prolong the survival of the newly generated β cells.…”

Section: Reprogramming Non-β Cells Into β Cellsmentioning

confidence: 99%

Untitled

2015

Exp Clin Transplant

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Type 1 diabetes mellitus is an autoimmune disease resulting from the destruction of pancreatic β cells. Current treatments for patients with type 1 diabetes mellitus include daily insulin injections or wholepancreas transplant, each of which are associated with profound drawbacks. Insulin gene therapy, which has shown great efficacy in correcting hyperglycemia in animal models, holds great promise as an alternative strategy to treat type 1 diabetes mellitus in humans. Insulin gene therapy refers to the targeted expression of insulin in non-β cells, with hepatocytes emerging as the primary therapeutic target. In this review, we present an overview of the current state of insulin gene therapy to treat type 1 diabetes mellitus, including the need for an alternative therapy, important features dictating the success of the therapy, and current obstacles preventing the translation of this treatment option to a clinical setting. In so doing, we hope to shed light on insulin gene therapy as a viable option to treat type 1 diabetes mellitus.

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Ectopic PDX-1 expression in liver ameliorates type 1 diabetes

Cited by 68 publications

References 46 publications

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

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

Hydrodynamics-based Transfection of Pancreatic Duodenal Homeobox 1 DNA Improves Hyperglycemia and is Associated with Limited Complications in Diabetic Mice

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