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Irreversible Inhibition of Metabolic Function and Islet Destruction after a 36-Hour Exposure to Interleukin-1ß¹

The Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri 63104

Address all correspondence and requests for reprints to: Dr. John A. Corbett, Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1402 South Grand Boulevard, Saint Louis, Missouri 63104. E-mail: corbettj{at}wpogate.slu.edu

The purpose of this study was to identify the duration of exposure of islets to interleukin 1ß (IL-1ß) that results in irreversible damage. Treatment of rat islets for 18 h with IL-1ß results in an inhibition of glucose-stimulated insulin secretion, mitochondrial aconitase activity, and total protein synthesis. The addition of N^G-monomethyl-L-arginine (NMMA) or aminoguanidine to islets preincubated for 18 h with IL-1ß, followed by continued culture for 8 h (with both NMMA and IL-1ß), results in the recovery of islet secretory function, aconitase activity, and protein synthesis. However, islet metabolic function is irreversibly inhibited after a 36-h incubation with IL-1ß, as an additional 8-h incubation with NMMA or aminoguanidine does not stimulate the recovery of insulin secretion, aconitase activity, or protein synthesis. The irreversible inhibition of metabolic function correlates with the commitment of islets to destruction. Treatment of islets for 96 h with IL-1ß results in islet degeneration. NMMA, added to islets 24 h after the addition of IL-1ß, followed by continued culture for 72 h (with NMMA and IL-1ß), prevents islet degeneration. However, NMMA added to islets 36 h or 48 h after the addition of IL-1ß, followed by continued culture for a total of 96 h, does not prevent islet degeneration. New messenger RNA expression appears to be required for islet recovery from IL-1ß-induced damage as actinomycin D prevents the recovery of islet aconitase activity. Lastly, treatment of human islets with a combination of IL-1ß and interferon- (IFN) results in a potent inhibition of mitochondrial aconitase activity. NMMA, when cocultured with IL-1ß + IFN, completely prevents cytokine-induced inhibition of human islet aconitase activity. NMMA, when added to human islets pretreated for 18 h with IL-1ß + IFN, stimulates the recovery of mitochondrial aconitase activity after an additional 8 h incubation. These findings indicate that nitric oxide-induced islet damage is reversible; however, prolonged production of nitric oxide (after a 36-h exposure to IL-1ß) results in the irreversible inhibition of islet metabolic and secretory function.

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