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

Abstract

The purpose of this study was to identify the duration of exposure of islets to interleukin 1␤ (IL-1␤) that results in irreversible damage. Treatment of rat islets for 18 h with IL-1␤ results in an inhibition of glucose-stimulated insulin secretion, mitochondrial aconitase activity, and total protein synthesis. The addition of N G -monomethyl-Larginine (NMMA) or aminoguanidine to islets preincubated for 18 h with IL-1␤, followed by continued culture for 8 h (with both NMMA and IL-1␤), 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-1␤, 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-1␤ results in islet degeneration. NMMA, added to islets 24 h after the addition of IL-1␤, followed by continued culture for 72 h (with NMMA and IL-1␤), prevents islet degeneration. However, NMMA added to islets 36 h or 48 h after the addition of IL-1␤, 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-1␤-induced damage as actinomycin D prevents the recovery of islet aconitase activity. Lastly, treatment of human islets with a combination of IL-1␤ and interferon-␥ (IFN␥) results in a potent inhibition of mitochondrial aconitase activity. NMMA, when cocultured with IL-1␤ ϩ IFN␥, completely prevents cytokine-induced inhibition of human islet aconitase activity. NMMA, when added to human islets pretreated for 18 h with IL-1␤ ϩ IFN␥, stimulates the recovery of mitochondrial aconitase activity after an additional 8 h incubation. These findings indicate that nitric oxideinduced islet damage is reversible; however, prolonged production of nitric oxide (after a 36-h exposure to IL-1␤) results in the irreversible inhibition of islet metabolic and secretory function. (Endocrinology 138: [5301][5302][5303][5304][5305][5306][5307] 1997)

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

“…Metabolic alterations were also reported early in the pathogenesis of Type 1 Diabetes (T1D) [ 131 ]. Following exposure to proinflammatory cytokines, disruptions to mitochondrial metabolism, such as decreased oxygen consumption, generation of free radicals, and oxidative stress, are associated with substantial fragmentation of mitochondrial networks [ 132 , 133 , 134 ]. Evidence of secretory dysfunction in T1D etiology in the form of neoantigens, identified as hybrid peptides containing fragments of insulin, C-peptide, IAPP, and/or CgA, suggest that alterations to prohormone trafficking and processing contribute to the development of CD4 + autoimmunity early in disease progression [ 135 , 136 , 137 ].…”

Reduced sensitivity of inducible nitric oxide synthase-deficient mice to multiple low-dose streptozotocin-induced diabetes.

“…While some studies suggest that NOS inhibitors protect human islets against cytokine-induced functional inhibition (50)(51)(52), other studies using the same inhibitors have failed to prevent human -cell dysfunction (53,54) and death (22) ensuing from cytokine exposure i n vitro. On the other hand, there are data to suggest that human islets are susceptible to the DNA-damaging effects of the high concentrations of NO (55) and peroxynitrite (56) liberated by chemical donors.…”

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“…However, their exact role in the beta-cell destruction mechanism is still under research 32. Beta cells have a temporally limited capacity to recover from cytokine action, by repairing the DNA damage, and by improving insulin secretion if the cytokine action is shorter than 24 hrs 33. After this, irreversible cell destruction will result 33.…”

“…Beta cells have a temporally limited capacity to recover from cytokine action, by repairing the DNA damage, and by improving insulin secretion if the cytokine action is shorter than 24 hrs 33. After this, irreversible cell destruction will result 33. The pro-inflammatory cytokines stimulate an early necrotic process of islet cells, that can be turned to late apoptosis if the cytokine action is longer than 36 hrs 34.…”