Faculty Collaboration Database

Irreversible inhibition of metabolic function and islet destruction after a 36-hour exposure to interleukin-1beta. Endocrinology 1997 Dec;138(12):5301-7

Date

12/06/1997

Pubmed ID

9389514

DOI

10.1210/endo.138.12.5583

Scopus ID

2-s2.0-0030684124 (requires institutional sign-in at Scopus site)   66 Citations

Abstract

The purpose of this study was to identify the duration of exposure of islets to interleukin 1beta (IL-1beta) that results in irreversible damage. Treatment of rat islets for 18 h with IL-1beta 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-1beta, followed by continued culture for 8 h (with both NMMA and IL-1beta), 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-1beta, 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-1beta results in islet degeneration. NMMA, added to islets 24 h after the addition of IL-1beta, followed by continued culture for 72 h (with NMMA and IL-1beta), prevents islet degeneration. However, NMMA added to islets 36 h or 48 h after the addition of IL-1beta, 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-1beta-induced damage as actinomycin D prevents the recovery of islet aconitase activity. Lastly, treatment of human islets with a combination of IL-1beta and interferon-gamma (IFNgamma) results in a potent inhibition of mitochondrial aconitase activity. NMMA, when cocultured with IL-1beta + IFNgamma, completely prevents cytokine-induced inhibition of human islet aconitase activity. NMMA, when added to human islets pretreated for 18 h with IL-1beta + IFNgamma, 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-1beta) results in the irreversible inhibition of islet metabolic and secretory function.

Author List

Scarim AL, Heitmeier MR, Corbett JA

Author

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aconitate Hydratase
Animals
Dactinomycin
Enzyme Induction
Enzyme Inhibitors
Hormone Antagonists
Humans
Insulin
Insulin Antagonists
Interleukin-1
Islets of Langerhans
Male
Nitric Oxide Synthase
Protein Biosynthesis
Rats
Rats, Sprague-Dawley
Time Factors
omega-N-Methylarginine