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J Clin Invest. Sep 15, 1997; 100(6): 1344–1348.
PMCID: PMC508312

Metabolically inactive insulin analog prevents type I diabetes in prediabetic NOD mice.

Abstract

The purpose of this study was to determine the relative importance of the metabolic effects of insulin for diabetes prevention by administering insulin or an inactive insulin analog by daily subcutaneous injections to prediabetic mice. A recombinant monomeric human insulin analog, which does not bind to the insulin receptor as a consequence of an alteration of a single amino acid at position 25 of the B chain, was shown to be equally effective at diabetes prevention as was intact insulin. In contrast to native insulin, the insulin analog did not cause hypoglycemia after subcutaneous injection. The insulin analog, however, protected young adult mice from diabetes, even when it was initiated after the onset of extensive lymphocytic infiltration of the islets. Thus, preventative therapy by daily subcutaneous injections of insulin does not require the hypoglycemic response, or binding to the insulin receptor to prevent the onset of type I diabetes.

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Selected References

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  • Serreze DV, Leiter EH. Genetic and pathogenic basis of autoimmune diabetes in NOD mice. Curr Opin Immunol. 1994 Dec;6(6):900–906. [PubMed]
  • Karounos DG, Thomas JW. Recognition of common islet antigen by autoantibodies from NOD mice and humans with IDDM. Diabetes. 1990 Sep;39(9):1085–1090. [PubMed]
  • Atkinson MA, Maclaren NK. Autoantibodies in nonobese diabetic mice immunoprecipitate 64,000-Mr islet antigen. Diabetes. 1988 Nov;37(11):1587–1590. [PubMed]
  • Serreze DV, Leiter EH, Kuff EL, Jardieu P, Ishizaka K. Molecular mimicry between insulin and retroviral antigen p73. Development of cross-reactive autoantibodies in sera of NOD and C57BL/KsJ db/db mice. Diabetes. 1988 Mar;37(3):351–358. [PubMed]
  • Atkinson MA, Maclaren NK, Luchetta R. Insulitis and diabetes in NOD mice reduced by prophylactic insulin therapy. Diabetes. 1990 Aug;39(8):933–937. [PubMed]
  • Daniel D, Wegmann DR. Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9-23). Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):956–960. [PMC free article] [PubMed]
  • Hancock WW, Polanski M, Zhang J, Blogg N, Weiner HL. Suppression of insulitis in non-obese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta, and prostaglandin-E. Am J Pathol. 1995 Nov;147(5):1193–1199. [PMC free article] [PubMed]
  • Hutchings PR, Cooke A. Comparative study of the protective effect afforded by intravenous administration of bovine or ovine insulin to young NOD mice. Diabetes. 1995 Aug;44(8):906–910. [PubMed]
  • Aaen K, Rygaard J, Josefsen K, Petersen H, Brogren CH, Horn T, Buschard K. Dependence of antigen expression on functional state of beta-cells. Diabetes. 1990 Jun;39(6):697–701. [PubMed]
  • Kämpe O, Andersson A, Björk E, Hallberg A, Karlsson FA. High-glucose stimulation of 64,000-Mr islet cell autoantigen expression. Diabetes. 1989 Oct;38(10):1326–1328. [PubMed]
  • Gladstone P, Nepom GT. The prevention of IDDM. Injecting insulin into the cytokine network. Diabetes. 1995 Jul;44(7):859–862. [PubMed]
  • Peakman M, Hussain MJ, Millward BA, Leslie RD, Vergani D. Effect of initiation of insulin therapy on T-lymphocyte activation in type 1 diabetes. Diabet Med. 1990 May;7(4):327–330. [PubMed]
  • Helderman JH, Pietri AO, Raskin P. In vitro control of T-lymphocyte insulin receptors by in vivo modulation of insulin. Diabetes. 1983 Aug;32(8):712–717. [PubMed]
  • Vølund A, Brange J, Drejer K, Jensen I, Markussen J, Ribel U, Sørensen AR, Schlichtkrull J. In vitro and in vivo potency of insulin analogues designed for clinical use. Diabet Med. 1991 Nov;8(9):839–847. [PubMed]
  • Drejer K, Kruse V, Larsen UD, Hougaard P, Bjørn S, Gammeltoft S. Receptor binding and tyrosine kinase activation by insulin analogues with extreme affinities studied in human hepatoma HepG2 cells. Diabetes. 1991 Nov;40(11):1488–1495. [PubMed]
  • Serreze DV, Leiter EH, Christianson GJ, Greiner D, Roopenian DC. Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant. Diabetes. 1994 Mar;43(3):505–509. [PubMed]
  • Brange J, Owens DR, Kang S, Vølund A. Monomeric insulins and their experimental and clinical implications. Diabetes Care. 1990 Sep;13(9):923–954. [PubMed]
  • Zhang ZJ, Davidson L, Eisenbarth G, Weiner HL. Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10252–10256. [PMC free article] [PubMed]
  • Muir A, Peck A, Clare-Salzler M, Song YH, Cornelius J, Luchetta R, Krischer J, Maclaren N. Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription. J Clin Invest. 1995 Feb;95(2):628–634. [PMC free article] [PubMed]
  • Miller GG, Pollack MS, Nell LJ, Thomas JW. Insulin-specific human T cells. Epitope specificity, major histocompatibility complex restriction, and alloreactivity to a diabetes-associated haplotype. J Immunol. 1987 Dec 1;139(11):3622–3629. [PubMed]
  • Nell LJ, Thomas JW. The human immune response to insulin. I. Kinetic and cellular aspects of lymphocyte proliferative responses in diabetics. J Immunol. 1983 Aug;131(2):701–705. [PubMed]
  • Wegmann DR, Gill RG, Norbury-Glaser M, Schloot N, Daniel D. Analysis of the spontaneous T cell response to insulin in NOD mice. J Autoimmun. 1994 Dec;7(6):833–843. [PubMed]
  • Daniel D, Gill RG, Schloot N, Wegmann D. Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice. Eur J Immunol. 1995 Apr;25(4):1056–1062. [PubMed]

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