Glucose- and Metabolically Regulated Hepatic Insulin Gene Therapy for Diabetes

Hsu, Paul Yueh-Jen; Kotin, Robert M.; Yang, Yao-Hsu

doi:10.1007/s11095-008-9539-x

Cited by 19 publications

(15 citation statements)

References 35 publications

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“…However, their AAV production protocol utilizing helper adenovirus and observations that transgene expression was detected rapidly (within 24 h of viral injection) combine to suggest the presence of remnant helper adenovirus in their vector preparations [24]. Other studies have obtained hepatic transgenic insulin expression sufficient to partially ameliorate STZ-induced hyperglycemia in mice for up to 104 days by co-precipitating AAV with CaPO 4 or complexing with polyethylenimine before injecting directly into liver [25][26][27]. Yang et al [25] also used helper adenovirus to produce their AAV vectors, again suggesting additional effects to AAV2 transduction alone.…”

Section: Discussionmentioning

confidence: 99%

Long‐term glycemic control with hepatic insulin gene therapy in streptozotocin‐diabetic mice

Thulé

Campbell

Jia

et al. 2015

The Journal of Gene Medicine

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Section: Discussionmentioning

confidence: 99%

Long‐term glycemic control with hepatic insulin gene therapy in streptozotocin‐diabetic mice

Thulé

Campbell

Jia

et al. 2015

The Journal of Gene Medicine

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“…Previous attempts to mimic pancreatic function in regulating insulin have used nonislet cells, including hepatocytes, to express and secrete insulin (Lu et al 1998, Chen et al 2005, Wilson et al 2005, Hsu et al 2008. The general approach involved use of a glucose-responsive promoter or motif to control insulin gene transcription , Chen et al 2001, Alam & Sollinger 2002, Hsu et al 2008). An inherent feature of glucose-regulated insulin expression, as a control point, is that it gives rise to a lag phase during which the gene is transcribed and then translated.…”

Section: Discussionmentioning

confidence: 99%

“…This issue has been addressed using islet and non-islet cells (Efrat 1998, Yoon & Jun 2002, Olson & Thule 2008. In non-islet cell studies, proof of concept studies, in animals, using gene transfer to produce insulin involves a glucose-sensitive promoter that controls insulin gene transcription and thus in turn the synthesis of the hormone but not its secretion , Chen et al 2001, Alam & Sollinger 2002, Hsu et al 2008. In the absence of glucose-regulated insulin release, transcriptional control by itself might produce a lag phase in the secretory response of insulin to meals, which may lead to initial hyperglycemia followed later by hypoglycemia.…”

Section: Introductionmentioning

confidence: 99%

Glucose regulates secretion of exogenously expressed insulin from HepG2 cells in vitro and in a mouse model of diabetes mellitus in vivo

Liu¹,

Jia²,

Wanke³

et al. 2013

Journal of Molecular Endocrinology

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Glucose-controlled insulin secretion is a key component of its regulation. Here, we examined whether liver cell secretion of insulin derived from an engineered construct can be regulated by glucose. Adenovirus constructs were designed to express proinsulin or mature insulin containing the conditional binding domain (CBD). This motif binds GRP78 (HSPA5), an endoplasmic reticulum (ER) protein that enables the chimeric hormone to enter into and stay within the ER until glucose regulates its release from the organelle. Infected HepG2 cells expressed proinsulin mRNA and the protein containing the CBD. Immunocytochemistry studies suggested that GRP78 and proinsulin appeared together in the ER of the cell. The amount of hormone released from infected cells varied directly with the ambient concentration of glucose in the media. Glucose-regulated release of the hormone from infected cells was rapid and sustained. Removal of glucose from the cells decreased release of the hormone. In streptozotocin-induced diabetic mice, when infected with adenovirus expressing mature insulin, glucose levels declined. Our data show that glucose regulates release of exogenously expressed insulin from the ER of liver cells. This approach may be useful in devising new ways to treat diabetes mellitus.

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“…However, abnormal glucose tolerance was observed as a result of a lack of pancreatic transdifferentiation and expression of β-cell transcription factors. [105][106][107][108] Studies in our laboratory have also shown that these insulin-secreting liver cells are resistant to the detrimental effects of β-cell cytotoxins and proinflammatory cytokines that play a principle role in the pathogenesis of T1D. 109,110 In other experiments, no infiltrates of immune cells were observed in NOD mice engineered to express insulin in their livers.…”

Section: -101mentioning

confidence: 94%

Diabetes reversal via gene transfer: building on successes in animal models

Gerace¹,

Martiniello‐Wilks²,

Simpson³

2015

RRED

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Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulinproducing pancreatic β-cells. People with T1D manage their hyperglycemia using daily insulin injections; however, this does not prevent the development of long-term diabetic complications such as retinopathy, nephropathy, neuropathy, and various macrovascular disorders. Currently, the only "cure" for T1D is pancreas transplantation or islet-cell transplantation; however, this is hampered by the limited number of donors and the requirement for life-long immunosuppression. As a result, the need for alternative therapies is vital. One of the strategies employed to correct T1D is the use of gene transfer to generate the production of an "artificial" β-cell that is capable of secreting insulin in response to fluctuating glucose concentrations that normally occurs in people without T1D. The treatment of many diseases using cell and gene therapy is generating significant attention in the T1D research community; however, for a cell therapy to enter clinical trials, success and safety must first be shown in an appropriate animal model. Animal models have been used in diabetes research for over a century, have improved our understanding of the pathophysiology of diabetes, and have led to the discovery of useful drugs for the treatment of the disease. Currently, the nonobese diabetic mouse is the animal model of choice for the study of T1D as it most closely reflects disease development in humans. The aim of this review is to evaluate the success of cell and gene therapy to reverse T1D in animal models for future clinical application.

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Glucose- and Metabolically Regulated Hepatic Insulin Gene Therapy for Diabetes

Abstract: Glucose- and metabolically controlled hepatic insulin gene therapy was obtained both in vitro and in vivo.

Cited by 19 publications

References 35 publications

Long‐term glycemic control with hepatic insulin gene therapy in streptozotocin‐diabetic mice

Long‐term glycemic control with hepatic insulin gene therapy in streptozotocin‐diabetic mice

Glucose regulates secretion of exogenously expressed insulin from HepG2 cells in vitro and in a mouse model of diabetes mellitus in vivo

Diabetes reversal via gene transfer: building on successes in animal models

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