title: Elevated serum levels of macrophage-derived cytokines precede and accompany the onset of IDDM.
abstract: To determine whether cytokines could have a role in the development of insulin-dependent diabetes mellitus (IDDM), we measured serum levels of cytokines derived from T helper 1 (interleukin-2 and interferon-gamma), T helper 2 (interleukin-4 and interleukin-10) lymphocytes and macrophages (tumour necrosis factor-alpha, interleukin-1 alpha and interleukin-1 beta) in patients before and after the onset of IDDM. Recently diagnosed IDDM patients had significantly higher levels of interleukin-2, interferon-gamma, tumour necrosis factor-alpha and interleukin-1 alpha than patients with either long-standing IDDM, non-insulin-dependent diabetes (NIDDM), Graves' disease, or control subjects (p < 0.05 for all). Compared with control subjects, patients with long-standing IDDM and those with NIDDM had higher interleukin-2 and tumour necrosis factor-alpha levels (p < 0.01 for all). Interleukin-4 and interleukin-10 were detectable in sera of patients with Graves' disease only, while interleukin-1 beta was not detectable in the serum of any control or test subject. To investigate whether high cytokine levels precede the onset of IDDM, we studied 28 non-diabetic identical co-twins of patients with IDDM, followed-up prospectively for up to 6 years after the diagnosis of the index. Levels of tumour necrosis factor-alpha and interleukin-1 alpha were elevated above the normal range more frequently in the eight twins who developed diabetes than in those 20 who did not (p < 0.005). Analysis of T helper 1 and T helper 2 profiles of the twin groups did not reveal a clear difference between prediabetic twins and twins remaining non-diabetic. These results support the notion that T helper 1 lymphocytes may play a role in the development of IDDM. This is associated with release of macrophage-derived cytokines, which is also a feature of the prediabetic period. The lack of evidence of a dominant T helper 1 profile of cytokine release before diabetes onset suggests that additional events, activating this arm of the cellular immune response, are required in the immediate prediabetic period.
authors.affiliation: Department of Immunology, King's College School of Medicine and Dentistry, London, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Hussain
authors.forename: M
authors.initials: M
authors.lastname: Peakman
authors.forename: H
authors.initials: H
authors.lastname: Gallati
authors.forename: S S
authors.initials: SS
authors.lastname: Lo
authors.forename: M
authors.initials: M
authors.lastname: Hawa
authors.forename: G C
authors.initials: GC
authors.lastname: Viberti
authors.forename: P J
authors.initials: PJ
authors.lastname: Watkins
authors.forename: R D
authors.initials: RD
authors.lastname: Leslie
authors.forename: D
authors.initials: D
authors.lastname: Vergani
mesh_terms: D001323:Autoantibodies / Q000097:blood; D015415:Biomarkers; D016207:Cytokines / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000276:immunology; D004200:Diseases in Twins; D005500:Follow-Up Studies; D005968:Glutamate Decarboxylase / Q000276:immunology; D006111:Graves Disease / Q000097:blood / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D007375:Interleukin-1 / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D008264:Macrophages / Q000276:immunology*; D011236:Prediabetic State / Q000097:blood* / Q000276:immunology*; D011446:Prospective Studies; D012016:Reference Values; D012044:Regression Analysis; D018709:Statistics, Nonparametric; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014430:Twins, Monozygotic
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D016207:Cytokines; D007375:Interleukin-1; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D005968:Glutamate Decarboxylase