Low concentration of interleukin-1beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets - PubMed (original) (raw)

. 2006 Oct;55(10):2713-22.

doi: 10.2337/db05-1430.

Affiliations

• PMID: 17003335
• DOI: 10.2337/db05-1430

Low concentration of interleukin-1beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets

Kathrin Maedler et al. Diabetes. 2006 Oct.

Retraction in

• Statement of Retraction. Kathrin Maedler, Desiree M. Schumann, Nadine Sauter, Helga Ellingsgaard, Domenico Bosco, Reto Baertschiger, Yoichiro Iwakura, José Oberholzer, Claes B. Wollheim, Benoit R. Gauthier, and Marc Y. Donath. Low Concentration of Interleukin-1β Induces FLICE-Inhibitory Protein-Mediated β-Cell Proliferation in Human Pancreatic Islets. Diabetes 2006;55:2713-2722. DOI: 10.2337/db05-1430. PMID: 17003335.
  American Diabetes Association. American Diabetes Association. Diabetes. 2020 Mar;69(3):493. doi: 10.2337/db20-rt03a. Epub 2020 Jan 13. Diabetes. 2020. PMID: 31932300 No abstract available.

Expression of concern in

• Expression of Concern. Low Concentration of Interleukin-1β Induces FLICE-Inhibitory Protein-Mediated β-Cell Proliferation in Human Pancreatic Islets. Diabetes 2006;55:2713-2722; DOI: 10.2337/db05-1430.
  Maedler K, Schumann DM, Sauter N, Ellingsgaard H, Bosco D, Baertschiger R, Iwakura Y, Oberholzer J, Wollheim CB, Gauthier BR, Donath MY. Maedler K, et al. Diabetes. 2016 Aug;65(8):2462. doi: 10.2337/db16-ec08a. Diabetes. 2016. PMID: 27456623 Updated. No abstract available.
• Update to Expression of Concern. Kathrin Maedler, Desiree M. Schumann, Nadine Sauter, Helga Ellingsgaard, Domenico Bosco, Reto Baertschiger, Yoichiro Iwakura, José Oberholzer, Claes B. Wollheim, Benoit R. Gauthier, and Marc Y. Donath. Low Concentration of Interleukin-1β Induces FLICE-Inhibitory Protein-Mediated β-Cell Proliferation in Human Pancreatic Islets. Diabetes 2006;55:2713-2722. DOI:10.2337/db05-1430. PMID: 17003335.
  American Diabetes Association. American Diabetes Association. Diabetes. 2018 Nov;67(11):2479-2480. doi: 10.2337/db18-ec2018b. Epub 2018 Sep 13. Diabetes. 2018. PMID: 30213822 Free PMC article. No abstract available.

Abstract

High glucose concentrations have a dual effect on beta-cell turnover, inducing proliferation in the short-term and apoptosis in the long-term. Hyperglycemia leads to beta-cell production of interleuking (IL)-1beta in human pancreatic islets. Fas, a death receptor regulated by IL-1beta, is involved in glucose-induced beta-cell apoptosis. Fas engagement can be switched from death signal to induction of proliferation when the caspase 8 inhibitor, FLICE-inhibitory protein (FLIP), is active. Here, we show that IL-1beta at low concentrations may participate in the mitogenic actions of glucose through the Fas-FLIP pathway. Thus, exposure of human islets to low IL-1beta concentrations (0.01-0.02 ng/ml) stimulated proliferation and decreased apoptosis, whereas increasing amounts of IL-1beta (2-5 ng/ml) had the reverse effects. A similarly bimodal induction of FLIP, pancreatic duodenal homeobox (PDX)-1, and Pax4 mRNA expression, as well as glucose-stimulated insulin secretion, was observed. In contrast, Fas induction by IL-1beta was monophasic. Low IL-1beta also induced the IL-1 receptor antagonist (IL-1Ra), suppression of which by RNA interference abrogated the beneficial effects of low IL-1beta. The Fas antagonistic antibody ZB4 and small interfering RNA to FLIP prevented low IL-1beta-stimulated beta-cell proliferation. Consistent with our in vitro results, IL-1beta knockout mice displayed glucose intolerance along with a decrease in islet Fas, FLIP, Pax4, and PDX-1 transcripts. These findings indicate that low IL-1beta levels positively influence beta-cell function and turnover through the Fas-FLIP pathway and that IL-1Ra production prevents harmful effects of high IL-1beta concentrations.

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