Biopolym. Cell. 2003; 19(1):11-18.
The insulin-dependent diabetes mellitus, potential of gene therapy
1Titok T. G.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680


The gene engineering approaches to the Insulin-dependent diabetes mellitus (IDDM) treatment are presented in the review. On the one hand, some studies are directed to provide the insulin de novo synthesis in non-specific cells by transferring the insulin gene into them to compensate the function of destroyed pancreatic β-cells. The search for the target cells and providing them with essential qualities such as sensitivity to glucose and production of functionally matured protein in vivo are also discussed. On the other hand, it was shown a possibility of IDDM treatment by transferring some cytokine genes to Th-cells, that caused changes in the subpopulation ratio of T-cells composition. In such a way it is possible to interrupt or balance the specific immune process in the island cells, which contributes substantially to the I type diabetes pathogenesis.


[1] Newgard CB. Cellular engineering and gene therapy strategies for insulin replacement in diabetes. Diabetes. 1994;43(3):341-50.
[2] Newgard CB, Clark S, BeltrandelRio H, Hohmeier HE, Quaade C, Normington K. Engineered cell lines for insulin replacement in diabetes: current status and future prospects. Diabetologia. 1997;40 Suppl 2:S42-7.
[3] Kolodka TM, Finegold M, Moss L, Woo SL. Gene therapy for diabetes mellitus in rats by hepatic expression of insulin. Proc Natl Acad Sci U S A. 1995;92(8):3293-7. PubMed PMID: 1582242.
[4] Miller AD. Retroviral vectors. Curr Top Microbiol Immunol. 1992;158:1-24.
[5] Vile RG, Russell SJ. Retroviruses as vectors. Br Med Bull. 1995;51(1):12-30.
[6] Zelenin AV, Ka?gorodov VA, Prasolov VS. [Gene therapy today and tomorrow]. Mol Biol (Mosk). 1998;32(2):219-28.
[7] Kay MA, Liu D, Hoogerbrugge PM. Gene therapy. Proc Natl Acad Sci U S A. 1997;94(24):12744-6.
[8] Moore HP, Walker MD, Lee F, Kelly RB. Expressing a human proinsulin cDNA in a mouse ACTH-secreting cell. Intracellular storage, proteolytic processing, and secretion on stimulation. Cell. 1983;35(2 Pt 1):531-8.
[9] Stewart C, Taylor NA, Green IC, Docherty K, Bailey CJ. Insulin-releasing pituitary cells as a model for somatic cell gene therapy in diabetes mellitus. J Endocrinol. 1994;142(2):339-43.
[10] Knaack D, Fiore DM, Surana M, Leiser M, Laurance M, Fusco-DeMane D, Hegre OD, Fleischer N, Efrat S. Clonal insulinoma cell line that stably maintains correct glucose responsiveness. Diabetes. 1994;43(12):1413-7.
[11] Clark SA, Quaade C, Constandy H, Hansen P, Halban P, Ferber S, Newgard CB, Normington K. Novel insulinoma cell lines produced by iterative engineering of GLUT2, glucokinase, and human insulin expression. Diabetes. 1997;46(6):958-67.
[12] Palmer TD, Rosman GJ, Osborne WR, Miller AD. Genetically modified skin fibroblasts persist long after transplantation but gradually inactivate introduced genes. Proc Natl Acad Sci U S A. 1991;88(4):1330-4.
[13] Simpson AM, Tuch BE, Swan MA, Tu J, Marshall GM. Functional expression of the human insulin gene in a human hepatoma cell line (HEP G2). Gene Ther. 1995;2(3):223-31.
[14] Simpson AM, Marshall GM, Tuch BE, Maxwell L, Szymanska B, Tu J, Beynon S, Swan MA, Camacho M. Gene therapy of diabetes: glucose-stimulated insulin secretion in a human hepatoma cell line (HEP G2ins/g). Gene Ther. 1997;4(11):1202-15.
[15] Bailey CJ, Davies EL, Docherty K. Prospects for insulin delivery by ex-vivo somatic cell gene therapy. J Mol Med (Berl). 1999;77(1):244-9.
[16] Docherty K. Gene therapy for diabetes mellitus. Clin Sci (Lond). 1997;92(4):321-30.
[17] Yanagita M, Hoshino H, Nakayama K, Takeuchi T. Processing of mutated proinsulin with tetrabasic cleavage sites to mature insulin reflects the expression of furin in nonendocrine cell lines. Endocrinology. 1993;133(2):639-44.
[18] Cheung AT, Dayanandan B, Lewis JT, Korbutt GS, Rajotte RV, Bryer-Ash M, Boylan MO, Wolfe MM, Kieffer TJ. Glucose-dependent insulin release from genetically engineered K cells. Science. 2000;290(5498):1959-62.
[19] Sugiyama A, Hattori S, Tanaka S, Isoda F, Kleopoulos S, Rosenfeld M, Kaplitt M, Sekihara H, Mobbs C. Defective adenoassociated viral-mediated transfection of insulin gene by direct injection into liver parenchyma decreases blood glucose of diabetic mice. Horm Metab Res. 1997;29(12):599-603.
[20] Vaulont S, Kahn A. Transcriptional control of metabolic regulation genes by carbohydrates. FASEB J. 1994;8(1):28-35.
[21] Valera A, Fillat C, Costa C, Sabater J, Visa J, Pujol A, Bosch F. Regulated expression of human insulin in the liver of transgenic mice corrects diabetic alterations. FASEB J. 1994;8(6):440-7.
[22] Galloway JA, Hooper SA, Spradlin CT, Howey DC, Frank BH, Bowsher RR, Anderson JH. Biosynthetic human proinsulin. Review of chemistry, in vitro and in vivo receptor binding, animal and human pharmacology studies, and clinical trial experience. Diabetes Care. 1992;15(5):666-92.
[23] Mitanchez D, Chen R, Massias JF, Porteu A, Mignon A, Bertagna X, Kahn A. Regulated expression of mature human insulin in the liver of transgenic mice. FEBS Lett. 1998;421(3):285-9.
[24] Thul? PM, Liu JM. Regulated hepatic insulin gene therapy of STZ-diabetic rats. Gene Ther. 2000;7(20):1744-52.
[25] Straus DS. Nutritional regulation of hormones and growth factors that control mammalian growth. FASEB J. 1994;8(1):6-12.
[26] Martin JL. IGFBPs down under. Trends Endocrinol Metab. 2001;12(4):142-4.
[27] Grebenschikov YuB, Moshkovskiy YuSh. Physico-chemical properties, structure and functional activity of insulin. M.: VINITI, (Itogi Nauki i Tekhniki. Ser. Biorg. Khim; Vol. 7) 1986;186.
[28] Balabolkin MI. Diabetology. M.: Meditsina, 2000; 672 p.
[29] Corbett JA. K cells: a novel target for insulin gene therapy for the prevention of diabetes. Trends Endocrinol Metab. 2001;12(4):140-2.
[30] Herrmann C, G?ke R, Richter G, Fehmann HC, Arnold R, G?ke B. Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion. 1995;56(2):117-26.
[31] Hoist JJ, Wojdemann M, Andre W, Lars R. Potent enterogastrone action of the insulinotropic hormone, glucagonlike peptide-1 (GLP-1). Mechanisms of action. Diabetes. 1999; 48(Suppl N 92): 21.
[32] Delaney CA, Pavlovic D, Hoorens A, Pipeleers DG, Eizirik DL. Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells. Endocrinology. 1997;138(6):2610-4.
[33] Rabinovitch A, Suarez-Pinzon WL. Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus. Biochem Pharmacol. 1998;55(8):1139-49.
[34] Ziegler AG, Hillebrand B, Rabl W, Mayrhofer M, Hummel M, Mollenhauer U, Vordemann J, Lenz A, Standl E. On the appearance of islet associated autoimmunity in offspring of diabetic mothers: a prospective study from birth. Diabetologia. 1993;36(5):402-8.
[35] Bennett ST, Lucassen AM, Gough SC, Powell EE, Undlien DE, Pritchard LE, Merriman ME, Kawaguchi Y, Dronsfield MJ, Pociot F, et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet. 1995;9(3):284-92.
[36] Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, Wickramasinghe S, Colle E, Polychronakos C. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet. 1997;15(3):289-92.
[37] Pugliese A, Zeller M, Fernandez A Jr, Zalcberg LJ, Bartlett RJ, Ricordi C, Pietropaolo M, Eisenbarth GS, Bennett ST, Patel DD. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet. 1997;15(3):293-7.
[38] Jolicoeur C, Hanahan D, Smith KM. T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in thymus. Proc Natl Acad Sci U S A. 1994;91(14):6707-11.
[39] Sebzda E, Wallace VA, Mayer J, Yeung RS, Mak TW, Ohashi PS. Positive and negative thymocyte selection induced by different concentrations of a single peptide. Science. 1994;263(5153):1615-8.
[40] French MB, Allison J, Cram DS, Thomas HE, Dempsey-Collier M, Silva A, Georgiou HM, Kay TW, Harrison LC, Lew AM. Transgenic expression of mouse proinsulin II prevents diabetes in nonobese diabetic mice. Diabetes. 1997;46(1):34-9.
[41] Geluk A, van Meijgaarden KE, Schloot NC, Drijfhout JW, Ottenhoff TH, Roep BO. HLA-DR binding analysis of peptides from islet antigens in IDDM. Diabetes. 1998;47(10):1594-601.
[42] Roitt I, Brostoff J, Male D. Immunology, Mosby-Year Book; 5th edition. 1998; 416 p.
[43] Moritani M, Yoshimoto K, Ii S, Kondo M, Iwahana H, Yamaoka T, Sano T, Nakano N, Kikutani H, Itakura M. Prevention of adoptively transferred diabetes in nonobese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes. A gene therapy model for autoimmune diabetes. J Clin Invest. 1996;98(8):1851-9.