Aspects of the involvement of interleukin-1 and nitric oxide in the pathogenesis of insulin-dependent diabetes mellitus.
The possible involvement of the cytokine interleukin-1 (IL-1) and nitric oxide (NO) in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) is reviewed and current and potential therapies are discussed. IDDM is a common disorder in the Western world and it is rising in incidence. In IDDM, islet-infiltrating macrophages produce IL-1 which is cytotoxic specifically to beta-cells in vitro. IL-1 increases beta-cell formation of NO, ceramide, prostaglandins, heat-shock proteins, and activates a protease. Additionally, IL-1 depresses beta-cell energy production, insulin gene expression and cyclic AMP synthesis, and impacts negatively on different parts of the insulin stimulus-secretion coupling, actions mimicked by NO. Conversely, blocking NO formation prevented many of these effects in most reports published. Also, changes in cyclic AMP and prostaglandins seem unlikely events in mediating the cytotoxicity of IL-1, while the role of ceramide remains less clear. Peptides capable of blocking beta-cell IL-1 receptors, and agents blocking NO synthesis may prove valuable in preserving beta-cell function in IDDM. Although IDDM causes immense morbidity and expense, uniformly effective preventive or beta-cell protective therapy is not currently available. If IL-1 is causing beta-cell dysfunction in human IDDM through NO production, several processes in the IL-1-NO connection are appropriate targets for agents protecting beta-cells from destruction and functional inhibition in IDDM.
Sjöholm
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Department of Molecular Medicine, The Endocrine and Diabetes Unit, The Rolf Luft Center for Diabetes Research, Karolinska Institute, Karolinska Hospital (L6:01B), S-171 76, Stockholm, Sweden. ake@enk.ks.se
D017209:Apoptosis / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000628:therapy; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D007328:Insulin; D007375:Interleukin-1; D011453:Prostaglandins; D017382:Reactive Oxygen Species; D009569:Nitric Oxide