title: Impaired immune responses in streptozotocin-induced type I diabetes in mice. Involvement of high glucose.
abstract: Diabetes is widely believed to predispose to serious infections. However, the mechanisms linking diabetes and immunosuppression are not well defined. One potential mediator of the altered defence mechanisms is hyperglycaemia. It has been identified as the main factor contributing to the development of diseases associated with diabetes mellitus. In this study we analyse the immune response in diabetes and the direct effect of hyperglycaemia on T and B lymphocyte reactivity. Diabetes induced an early decrease in IgG levels in the secondary response. However, both primary responses against a T-cell-dependent or independent antigen were affected after 6 months of diabetes induction. T- and B- cell proliferation was only decreased at this time. To gain insight into the potential mechanisms involved, we evaluated the influence of hyperglycaemia over the immune response. Pre-incubation of lymph node and spleen cells in a high glucose (HG) containing medium led to a significant time- and dose-dependent decrease in T- and B-cell proliferation. This effect was associated with the presence of HG-derived supernatants. Still viable cells after HG exposition were able to improve their proliferative response when cultured with the mitogen in a fresh standard medium. HG diminished cell viability, increased apoptosis and induced oxidative stress in lymphocytes. These results indicate that HG concentrations can directly affect lymphoid cell growth. An increase in oxidative stress would be implicated in this deleterious effect. The possibility that prolonged exposure to pathologically HG concentrations would result in the immunosuppressive state observed in diabetes is also discussed.
authors.affiliation: Laboratorio de Inmunofarmacología, Centro de Estudios Garmacológicos y Botánicos - Consejo Nacional de Investigaciones Científicas y Ténicas - Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina.
authors.forename: R
authors.initials: R
authors.lastname: Rubinstein
authors.forename: A M
authors.initials: AM
authors.lastname: Genaro
authors.forename: A
authors.initials: A
authors.lastname: Motta
authors.forename: G
authors.initials: G
authors.lastname: Cremaschi
authors.forename: M R
authors.initials: MR
authors.lastname: Wald
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D015227:Lipid Peroxidation / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens / Q000276:immunology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008934:Mitogens; D017382:Reactive Oxygen Species; D005947:Glucose
references.citation: Diabetes Care. 1980 Jan-Feb;3(1):187-97
references.pmid: 6996964
references.citation: Nature. 2001 Dec 13;414(6865):813-20
references.pmid: 11742414
references.citation: Diabet Med. 1994 Dec;11(10):935-41
references.pmid: 7895457
references.citation: Kidney Int. 2002 Feb;61(2):599-608
references.pmid: 11849402
references.citation: J Exp Med. 1993 Dec 1;178(6):2165-72
references.pmid: 8245789
references.citation: Intensive Care Med. 2004 Aug;30(8):1685-8
references.pmid: 15148570
references.citation: N Engl J Med. 1993 Sep 30;329(14):977-86
references.pmid: 8366922
references.citation: J Immunol Methods. 1991 Jun 3;139(2):271-9
references.pmid: 1710634
references.citation: Diabetes. 1995 Nov;44(11):1323-7
references.pmid: 7589831
references.citation: Am J Physiol. 1984 Jun;246(6 Pt 2):H776-83
references.pmid: 6331179
references.citation: Anesth Analg. 1999 May;88(5):1011-6
references.pmid: 10320160
references.citation: Diabetes. 1998 Jun;47(6):859-66
references.pmid: 9604860
references.citation: Diabetes Metab Res Rev. 2001 May-Jun;17(3):189-212
references.pmid: 11424232
references.citation: Methods Enzymol. 1978;52:302-10
references.pmid: 672633
references.citation: J Neuroimmunol. 2003 Nov;144(1-2):53-60
references.pmid: 14597098
references.citation: Cell Immunol. 1992 Oct 15;144(2):287-95
references.pmid: 1327541
references.citation: Diabetes Metab Res Rev. 2007 Jan;23(1):3-13
references.pmid: 16960917
references.citation: N Engl J Med. 2005 Dec 22;353(25):2643-53
references.pmid: 16371630
references.citation: Circ Res. 2000 Dec 8;87(12):1123-32
references.pmid: 11110769
references.citation: Am J Physiol. 1999 Dec;277(6):C1229-38
references.pmid: 10600775
references.citation: Diabetes. 1991 Apr;40(4):405-12
references.pmid: 2010041
references.citation: Diabetes Care. 1988 Nov-Dec;11 Suppl 1:73-9
references.pmid: 3069394
references.citation: Proc Natl Acad Sci U S A. 1982 Feb;79(4):1171-4
references.pmid: 6122209
references.citation: Circulation. 1999 Jun 8;99(22):2934-41
references.pmid: 10359739
references.citation: Diabetes. 2002 Apr;51(4):1076-82
references.pmid: 11916928
references.citation: J Immunol. 1983 Apr;130(4):1910-7
references.pmid: 6833755
references.citation: Lancet. 1998 Sep 12;352(9131):837-53
references.pmid: 9742976
references.citation: J Immunol. 1985 Oct;135(4):2740-7
references.pmid: 4031498
references.citation: Science. 1976 Jul 30;193(4251):415-7
references.pmid: 180605
references.citation: Immunol Today. 1992 Jun;13(6):211-4
references.pmid: 1378279
references.citation: Diabetes Res Clin Pract. 1995 May;28(2):137-46
references.pmid: 7587921
references.citation: Endocr Rev. 2004 Aug;25(4):612-28
references.pmid: 15294884
references.citation: Trends Cell Biol. 1991 Aug;1(2-3):39-42
references.pmid: 14731549
references.citation: Diabetologia. 2003 Apr;46(4):556-66
references.pmid: 12739028
references.citation: Diabetes Care. 1996 Mar;19(3):257-67
references.pmid: 8742574
references.citation: Pharmacotherapy. 2005 Jul;25(7):963-76
references.pmid: 16006275
references.citation: Diabetes Res. 1988 Sep;9(1):5-10
references.pmid: 2977107
references.citation: Blood. 1995 Jul 1;86(1):258-67
references.pmid: 7795231
references.citation: Diabetes. 2003 Jan;52(1):1-8
references.pmid: 12502486
references.citation: J Basic Clin Physiol Pharmacol. 1995;6(3-4):205-28
references.pmid: 8852268
references.citation: Ann Thorac Surg. 1999 Feb;67(2):352-60; discussion 360-2
references.pmid: 10197653
references.citation: Biochim Biophys Acta. 2006 Sep;1763(9):927-36
references.pmid: 16942810
references.citation: Nat Clin Pract Endocrinol Metab. 2008 May;4(5):285-93
references.pmid: 18332897
references.citation: Gen Physiol Biophys. 2003 Mar;22(1):15-27
references.pmid: 12870698
references.citation: Circulation. 2000 Jun 6;101(22):2618-24
references.pmid: 10840014
references.citation: Diabetologia. 1998 Mar;41(3):249-56
references.pmid: 9541163
references.citation: J Am Soc Nephrol. 2003 Aug;14(8 Suppl 3):S241-5
references.pmid: 12874439
references.citation: Clin Immunol. 2002 Jun;103(3 Pt 1):249-59
references.pmid: 12173299
references.citation: FEBS Lett. 1995 May 8;364(2):120-4
references.pmid: 7750555
references.citation: Free Radic Biol Med. 1995 Apr;18(4):775-94
references.pmid: 7750801
references.citation: Eur J Clin Invest. 1998 Apr;28(4):329-33
references.pmid: 9615913
references.citation: Immunity. 1999 Jun;10(6):735-44
references.pmid: 10403648
references.citation: Diabetes Res Clin Pract. 1999 Sep;45(2-3):147-51
references.pmid: 10588367
references.citation: Infect Dis Clin North Am. 1995 Mar;9(1):1-9
references.pmid: 7769211
references.citation: Diabet Med. 1995 Oct;12(10):916-20
references.pmid: 8846684
references.citation: Int Immunopharmacol. 2002 Mar;2(4):487-97
references.pmid: 11962728
references.citation: Cytometry. 1993 Nov;14(8):891-7
references.pmid: 8287732
references.citation: Arch Surg. 1993 Jan;128(1):29-34; discussion 34-5
references.pmid: 8418777
references.citation: Endothelium. 1997;5(4):241-50
references.pmid: 9588816
references.citation: Diabetes Care. 2001 Jun;24(6):1044-9
references.pmid: 11375368
references.citation: Free Radic Res. 1995 May;22(5):389-97
references.pmid: 7633568
references.citation: Infect Control Hosp Epidemiol. 2001 Oct;22(10):607-12
references.pmid: 11776345
references.citation: Lancet. 1992 Apr 11;339(8798):909-12
references.pmid: 1348307
references.citation: Infect Immun. 1978 Aug;21(2):425-9
references.pmid: 308493
references.citation: BMJ. 2000 Aug 12;321(7258):405-12
references.pmid: 10938048
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2003 Apr;27(2):283-90
references.pmid: 12657367
references.citation: N Engl J Med. 1999 Dec 16;341(25):1906-12
references.pmid: 10601511
references.citation: Diabete Metab. 1992 May-Jun;18(3):187-201
references.pmid: 1397473
references.citation: J Immunol. 2007 Dec 15;179(12):8051-8
references.pmid: 18056345
references.citation: Immunology. 2006 Jul;118(3):402-12
references.pmid: 16827901
references.citation: J Gerontol A Biol Sci Med Sci. 1999 Nov;54(11):M541-5
references.pmid: 10619315
references.citation: Diabetes. 1996 Apr;45(4):471-7
references.pmid: 8603769
references.citation: Eur J Immunol. 1994 Apr;24(4):999-1002
references.pmid: 8149968
references.citation: Blood. 1995 Aug 15;86(4):1383-91
references.pmid: 7632946
references.citation: Infect Immun. 1980 Apr;28(1):127-31
references.pmid: 6966615