Hostname: page-component-669899f699-g7b4s Total loading time: 0 Render date: 2025-04-25T08:06:24.290Z Has data issue: false hasContentIssue false
  • English
  • Français

Insulin gene therapy from design to beta cell generation

Published online by Cambridge University Press:  15 October 2012

Ahter D. Sanlioglu ,
Hasan Ali Altunbas ,
Mustafa Kemal Balci ,
Thomas S. Griffith  and
Salih Sanlioglu
Ahter D. Sanlioglu
Affiliation:
Human Gene and Cell Therapy Center, Antalya, Turkey Department of Medical Biology and Genetics, Antalya, Turkey
Hasan Ali Altunbas
Affiliation:
Human Gene and Cell Therapy Center, Antalya, Turkey Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, Antalya, Turkey
Mustafa Kemal Balci
Affiliation:
Human Gene and Cell Therapy Center, Antalya, Turkey Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, Antalya, Turkey
Thomas S. Griffith
Affiliation:
Department of Urology, University of Minnesota, Minneapolis, MN, USA
Salih Sanlioglu*
Affiliation:
Human Gene and Cell Therapy Center, Antalya, Turkey Department of Medical Biology and Genetics, Antalya, Turkey
*
*Corresponding author: Salih Sanlioglu VMD, Human Gene and Cell Therapy Center, Akdeniz University Hospitals and Clinics, B Block, 1st Floor, Campus, Antalya, Turkey. Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Despite the fact that insulin injection can protect diabetic patients from developing diabetes-related complications, recent meta-analyses indicate that rapid and long-acting insulin analogues only provide a limited benefit compared with conventional insulin regarding glycemic control. As insulin deficiency is the main sequel of type-1 diabetes (T1D), transfer of the insulin gene-by-gene therapy is becoming an attractive treatment modality even though T1D is not caused by a single genetic defect. In contrast to human insulin and insulin analogues, insulin gene therapy targets to supplement patients not only with insulin but also with C-peptide. So far, insulin gene therapy has had limited success because of delayed and/or transient gene expression. Sustained insulin gene expression is now feasible using current gene-therapy vectors providing patients with basal insulin coverage, but management of postprandial hyperglycaemia is still difficult to accomplish because of the inability to properly control insulin secretion. Enteroendocrine cells of the gastrointestinal track (K cells and L cells) may be ideal targets for insulin gene therapy, but cell-targeting difficulties have limited practical implementation of insulin gene therapy for diabetes treatment. Therefore, recent gene transfer technologies developed to generate authentic beta cells through transdifferentiation are also highlighted in this review.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 14 , March 2012 , e18
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

References

1Teuscher, A. (1979) The biological effect of purely synthetic human insulin in patients with diabetes mellitus. Schweizerische Medizinische Wochenschrift 109, 743-747Google ScholarPubMed
2Moore, H.P. et al. (1983) Expressing a human proinsulin cDNA in a mouse ACTH-secreting cell. Intracellular storage, proteolytic processing, and secretion on stimulation. Cell 35, 531-538CrossRefGoogle Scholar
3Dong, H., Woo, S.L. (2001) Hepatic insulin production for type 1 diabetes. Trends in Endocrinology and Metabolism 12, 441-446CrossRefGoogle ScholarPubMed
4Wong, M.S., Hawthorne, W.J. and Manolios, N. (2010) Gene therapy in diabetes. Self and Nonself 1, 165-175CrossRefGoogle ScholarPubMed
5Hughes, A. et al. (2010) Gene therapy to improve pancreatic islet transplantation for Type 1 diabetes mellitus. Current Diabetes Review 6, 274-284CrossRefGoogle ScholarPubMed
6Bagley, J. et al. (2008) Gene therapy in type 1 diabetes. Critical Reviews in Immunology 28, 301-324CrossRefGoogle ScholarPubMed
7Nett, P.C., Sollinger, H.W. and Alam, T. (2003) Hepatic insulin gene therapy in insulin-dependent diabetes mellitus. American Journal of Transplantation 3, 1197-1203CrossRefGoogle ScholarPubMed
8Kobinger, G.P. et al. (2004) Transduction of human islets with pseudotyped lentiviral vectors. Human Gene Therapy 15, 211-219CrossRefGoogle ScholarPubMed
9Zhang, B. et al. (2001) A highly efficient and consistent method for harvesting large volumes of high-titre lentiviral vectors. Gene Therapy 8, 1745-1751Google Scholar
10Doerschug, K. et al. (2002) First-generation adenovirus vectors shorten survival time in a murine model of sepsis. Journal of Immunol 169, 6539-6545Google Scholar
11Barbu, A.R., Akusjarvi, G. and Welsh, N. (2005) Adenoviral-mediated transduction of human pancreatic islets: importance of adenoviral genome for cell viability and association with a deficient antiviral response. Endocrinology 146, 2406-2414CrossRefGoogle ScholarPubMed
12Zhang, J.A. et al. (2009) Hepatic insulin gene therapy diminishes liver glycogen despite insulin responsive transcriptional effects in diabetic CD-1 mice. Journal of Gene Medicine 11, 588-597CrossRefGoogle ScholarPubMed
13Sanlioglu, S. et al. (2001) Rate limiting steps of AAV transduction and implications for human gene therapy. Current Gene Therapy 1, 137-147CrossRefGoogle ScholarPubMed
14Sanlioglu, S. and Engelhardt, J.F. (1999) Cellular redox state alters recombinant adeno-associated virus transduction through tyrosine phosphatase pathways. Gene Therapy 6, 1427-1437CrossRefGoogle ScholarPubMed
15Sanlioglu, S. et al. (2000) Endocytosis and nuclear trafficking of adeno-associated virus type 2 are controlled by rac1 and phosphatidylinositol-3 kinase activation. Journal of Virology 74, 9184-9196CrossRefGoogle ScholarPubMed
16Sanlioglu, S., Benson, P. and Engelhardt, J.F. (2000) Loss of ATM function enhances recombinant adeno-associated virus transduction and integration through pathways similar to UV irradiation. Virology 268, 68-78CrossRefGoogle ScholarPubMed
17Alba, R., Bosch, A. and Chillon, M. (2005) Gutless adenovirus: last-generation adenovirus for gene therapy. Gene Therapy 12(Suppl 1), S18-S27CrossRefGoogle ScholarPubMed
18Palmer, D.J. and Ng, P. (2005) Helper-dependent adenoviral vectors for gene therapy. Human Gene Therapy 16, 1-16CrossRefGoogle ScholarPubMed
19Kolodka, T.M. et al. (1995) Gene therapy for diabetes mellitus in rats by hepatic expression of insulin. Proceedings of the National Academy of Sciences of the United States of America 92, 3293-3297CrossRefGoogle ScholarPubMed
20Falqui, L. et al. (1999) Reversal of diabetes in mice by implantation of human fibroblasts genetically engineered to release mature human insulin. Human Gene Therapy 10, 1753-1762Google Scholar
21Auricchio, A. et al. (2002) Constitutive and regulated expression of processed insulin following in vivo hepatic gene transfer. Gene Therapy 9, 963-971Google Scholar
22Vollenweider, F. et al. (1995) Processing of proinsulin by furin, PC2, and PC3 in (co) transfected COS (monkey kidney) cells. Diabetes 44, 1075-1080CrossRefGoogle ScholarPubMed
23Groskreutz, D.J., Sliwkowski, M.X. and Gorman, C.M. (1994) Genetically engineered proinsulin constitutively processed and secreted as mature, active insulin. Journal of Biological Chemistry 269, 6241-6245CrossRefGoogle ScholarPubMed
24Simonson, G.D. et al. (1996) Synthesis and processing of genetically modified human proinsulin by rat myoblast primary cultures. Human Gene Therapy 7, 71-78Google Scholar
25Irminger, J.C., Meyer, K. and Halban, P. (1996) Proinsulin processing in the rat insulinoma cell line INS after overexpression of the endoproteases PC2 or PC3 by recombinant adenovirus. Biochemical Journal 320, 11-15Google Scholar
26Short, D.K. et al. (1998) Adenovirus-mediated transfer of a modified human proinsulin gene reverses hyperglycemia in diabetic mice. American Journal of Physiology 275, E748-E756Google ScholarPubMed
27Dong, H. et al. (2001) Hepatic insulin expression improves glycemic control in type 1 diabetic rats. Diabetes Research and Clinical Practice 52, 153-163CrossRefGoogle ScholarPubMed
28Tanaka, S.I. et al. (2004) Daily nasal inoculation with the insulin gene ameliorates diabetes in mice. Diabetes Research and Clinical Practice 63, 1-9CrossRefGoogle ScholarPubMed
29Park, Y.M. et al. (2005) Safety and efficacy of adeno-associated viral vector-mediated insulin gene transfer via portal vein to the livers of streptozotocin-induced diabetic Sprague-Dawley rats. Journal of Gene Medicine 7, 621-629CrossRefGoogle Scholar
30Elsner, M. et al. (2012) Reversal of diabetes through gene therapy of diabetic rats by hepatic insulin expression via lentiviral transduction. Molecular Therapy 20, 918-926CrossRefGoogle ScholarPubMed
31Lu, D. et al. (1998) Regulatable production of insulin from primary-cultured hepatocytes: insulin production is up-regulated by glucagon and cAMP and down-regulated by insulin. Gene Therapy 5, 888-895CrossRefGoogle ScholarPubMed
32Han, J. et al. (2011) Remission of diabetes by insulin gene therapy using a hepatocyte-specific and glucose-responsive synthetic promoter. Molecular Therpy 19, 470-478CrossRefGoogle ScholarPubMed
33Shih, H. and Towle, H.C. (1994) Definition of the carbohydrate response element of the rat S14 gene. Context of the CACGTG motif determines the specificity of carbohydrate regulation. Journal of Biological Chemistry 269, 9380-9387CrossRefGoogle ScholarPubMed
34Alam, T. and Sollinger, H.W. (2002) Glucose-regulated insulin production in hepatocytes. Transplantation 74, 1781-1787CrossRefGoogle ScholarPubMed
35Thule, P.M., Liu, J. and Phillips, L.S. (2000) Glucose regulated production of human insulin in rat hepatocytes. Gene Therapy 7, 205-214CrossRefGoogle ScholarPubMed
36Thule, P.M. et al. (2006) Hepatic insulin gene therapy prevents deterioration of vascular function and improves adipocytokine profile in STZ-diabetic rats. American Journal of Physiology, Endocrinology and Metabolism 290, E114-E122CrossRefGoogle ScholarPubMed
37Argaud, D. et al. (1996) Regulation of rat liver glucose-6-phosphatase gene expression in different nutritional and hormonal states: gene structure and 5′-flanking sequence. Diabetes 45, 1563-1571CrossRefGoogle Scholar
38Chen, R. et al. (2000) Glucose-stimulated and self-limiting insulin production by glucose 6-phosphatase promoter driven insulin expression in hepatoma cells. Gene Therapy 7, 1802-1809Google Scholar
39Chen, R., Meseck, M.L. and Woo, S.L. (2001) Auto-regulated hepatic insulin gene expression in type 1 diabetic rats. Molecular Therapy 3, 584-590CrossRefGoogle ScholarPubMed
40Burkhardt, B.R. et al. (2003) Glucose-responsive expression of the human insulin promoter in HepG2 human hepatoma cells. Annals of the New York Academy of Sciences 1005, 237-241CrossRefGoogle ScholarPubMed
41Duan, D. et al. (1999) Formation of adeno-associated virus circular genomes is differentially regulated by adenovirus E4 ORF6 and E2a gene expression. Journal of Virology 73, 161-169CrossRefGoogle ScholarPubMed
42Sanlioglu, S., Duan, D. and Engelhardt, J.F. (1999) Two independent molecular pathways for recombinant adeno-associated virus genome conversion occur after UV-C and E4orf6 augmentation of transduction. Human Gene Therapy 10, 591-602CrossRefGoogle ScholarPubMed
43Yasutomi, K. et al. (2003) Intravascular insulin gene delivery as potential therapeutic intervention in diabetes mellitus. Biochemical and Biophysical Research Communication 310, 897-903Google Scholar
44Yang, Y.W. and Chao, C.K. (2003) Incorporation of calcium phosphate enhances recombinant adeno-associated virus-mediated gene therapy in diabetic mice. Journal of Gene Medicine 5, 417-424CrossRefGoogle ScholarPubMed
45Hsu, P.Y. and Yang, Y.W. (2005) Effect of polyethylenimine on recombinant adeno-associated virus mediated insulin gene therapy. Journal of Gene Medicine 7, 1311-1321CrossRefGoogle ScholarPubMed
46Hsu, P.Y., Kotin, R.M. and Yang, Y.W. (2008) Glucose- and metabolically regulated hepatic insulin gene therapy for diabetes. Pharmaceutical Research 25, 1460-1468CrossRefGoogle ScholarPubMed
47Brockstedt, D.G. et al. (1999) Induction of immunity to antigens expressed by recombinant adeno-associated virus depends on the route of administration. Clinical Immunology 92, 67-75CrossRefGoogle ScholarPubMed
48Flotte, T.R. (2004) Immune responses to recombinant adeno-associated virus vectors: putting preclinical findings into perspective. Human Gene Therapy 15, 716-717CrossRefGoogle ScholarPubMed
49Sun, J.Y. et al. (2003) Immune responses to adeno-associated virus and its recombinant vectors. Gene Therapy 10, 964-976Google Scholar
50Rivera, V.M. et al. (2000) Regulation of protein secretion through controlled aggregation in the endoplasmic reticulum. Science 287, 826-830Google Scholar
51Cheung, A.T. et al. (2000) Glucose-dependent insulin release from genetically engineered K cells. Science 290, 1959-1962CrossRefGoogle ScholarPubMed
52Corbett, J.A. (2001) K cells: a novel target for insulin gene therapy for the prevention of diabetes. Trends in Endocrinology and Metabolism 12, 140-142CrossRefGoogle Scholar
53Tang, S.C. and Sambanis, A. (2004) Differential rAAV2 transduction efficiencies and insulin secretion profiles in pure and co-culture models of human enteroendocrine L-cells and enterocytes. Journal of Gene Medicine 6, 1003-1013CrossRefGoogle ScholarPubMed
54Niu, L. et al. (2008) Gene therapy for type 1 diabetes mellitus in rats by gastrointestinal administration of chitosan nanoparticles containing human insulin gene. World Journal of Gastroenterology 14, 4209-4215CrossRefGoogle ScholarPubMed
55Halban, P.A. et al. (2001) Gene and cell-replacement therapy in the treatment of type 1 diabetes: how high must the standards be set? Diabetes 50, 2181-2191CrossRefGoogle ScholarPubMed
56Wahren, J., Kallas, A. and Sima, A.A. (2012) The clinical potential of C-peptide replacement in type 1 diabetes. Diabetes 61, 761-772CrossRefGoogle ScholarPubMed
57Kahraman, S. et al. (2011) Tracing of islet graft survival by way of in vivo fluorescence imaging. Diabetes Metabolism Research and Reviews 27, 575-583CrossRefGoogle ScholarPubMed
58Shapiro, A.M. et al. (2005) Strategic opportunities in clinical islet transplantation. Transplantation 79, 1304-1307CrossRefGoogle ScholarPubMed
59Collombat, P. et al. (2010) Pancreatic beta-cells: from generation to regeneration. Seminars in Cell and Developmental Biology 21, 838-844CrossRefGoogle ScholarPubMed
60Yi, F., Liu, G.H. and Izpisua Belmonte, J.C. (2012) Rejuvenating liver and pancreas through cell transdifferentiation. Cell Research 22, 616-619CrossRefGoogle ScholarPubMed
61Ferber, S. et al. (2000) Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nature Medicine 6, 568-572CrossRefGoogle ScholarPubMed
62Ferber, S. (2000) Can we create new organs from our own tissues? Israel Medical Association Journal 2(Suppl), 32-36Google ScholarPubMed
63Ber, I. et al. (2003) Functional, persistent, and extended liver to pancreas transdifferentiation. Journal of Biological Chemistry 278, 31950-31957CrossRefGoogle ScholarPubMed
64Shternhall-Ron, K. et al. (2007) Ectopic PDX-1 expression in liver ameliorates type 1 diabetes. Journal of Autoimmunity 28, 134-142CrossRefGoogle ScholarPubMed
65Kaneto, H. et al. (2007) Role of PDX-1 and MafA as a potential therapeutic target for diabetes. Diabetes Research and Clinical Practice 77(Suppl 1), S127-S137Google Scholar
66Tang, D.Q. et al. (2006) Role of Pax4 in Pdx1-VP16-mediated liver-to-endocrine pancreas transdifferentiation. Laboratory Investigation 86, 829-841CrossRefGoogle ScholarPubMed
67Wang, A.Y. et al. (2007) Adenovirus transduction is required for the correction of diabetes using Pdx-1 or Neurogenin-3 in the liver. Molecular Therapy 15, 255-263CrossRefGoogle ScholarPubMed
68Sapir, T. et al. (2005) Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells. Proceedings of the National Academy of Sciences of the United States of America 102, 7964-7969CrossRefGoogle ScholarPubMed
69Baeyens, L. and Bouwens, L. (2008) Can beta-cells be derived from exocrine pancreas? Diabetes, Obesity and Metabolism 10(Suppl 4), 170-178CrossRefGoogle ScholarPubMed
70Zhou, Q. et al. (2008) In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455, 627-632CrossRefGoogle ScholarPubMed
71Mauda-Havakuk, M. et al. (2011) Ectopic PDX-1 expression directly reprograms human keratinocytes along pancreatic insulin-producing cells fate. PLoS One 6, e26298Google Scholar
72Swales, N. et al. (2012) Plasticity of adult human pancreatic duct cells by neurogenin3-mediated reprogramming. PLoS One 7, e37055CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

Roth, J et al. (2012) Insulin's discovery: new insights on its ninetieth birthday. Diabetes Metabolism Research and Reviews 28, 293-304CrossRefGoogle ScholarPubMed
US National Diabetes Fact Sheet 2011 can be found at http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf website. The data is generated from Centers for Disease Control and Prevention (CDC), the Indian Health Service's (IHS) National Patient Information Reporting System (NPIRS), the US. Renal Data System of the National Institutes of Health (NIH), the US. Census Bureau, and published studies.Google Scholar