Neutralizing Interleukin-1β (IL-1β) Induces β-Cell Survival by Maintaining PDX1 Protein Nuclear Localization

Abstract

The transcription factor PDX1 plays a critical role during ␤-cell development and in glucose-induced insulin gene transcription in adult ␤-cells. Acute glucose exposure leads to translocalization of PDX1 to the nucleoplasm, whereas under conditions of oxidative stress, PDX1 shuttles from the nucleus to the cytosol. Here we show that cytosolic PDX1 expression correlated with ␤-cell failure in diabetes. In isolated islets from patients with type 2 diabetes and from diabetic mice, we found opposite regulation of insulin and PDX1 mRNA; insulin was decreased in diabetes, but PDX1 was increased. This suggests that elevated PDX1 mRNA levels may be insufficient to regulate insulin. In diabetic islets, PDX1 protein was localized in the cytosol, whereas in non-diabetic controls, PDX1 was in the nucleus. In contrast, overexpression of either IL-1 receptor antagonist or shuttling-deficient PDX1 restored ␤-cell survival and function and PDX1 nuclear localization. Our results show that nuclear localization of PDX1 is essential for a functional ␤-cell and provides a novel mechanism of the protective effect of IL-1 receptor antagonist on ␤-cell survival and function.New therapies for diabetes that lead to protection of the insulin-producing ␤-cell are urgently needed. Only when the ␤-cell compensates for the higher insulin demand during insulin resistance can normoglycemia be maintained. Recent studies suggest that the low grade inflammation in type 2 diabetes mellitus (T2DM) 3 contributes to ␤-cell failure (1). Especially, interleukin-1␤ (IL-1␤), whose secretion has been postulated from intraislet macrophages (2) and from ␤-cells themselves when exposed to double-stranded RNA (3), to elevated glucose concentrations (4 -6), or to free fatty acids (7), initiates ␤-cell destruction.The receptor for IL-1␤, IL-1R1, is highly expressed in the ␤-cell, and more than 10-fold higher expression of IL-1R1 mRNA was observed in isolated islets than in total pancreas, which is attributed to the expression in ␤-cells (7). This may explain the high sensitivity of the ␤-cell to IL-1␤. A recent study shows that glucose-induced IL-1␤ secretion involves caspase 1 activation mediated by the NALP3 inflammasome. The inflammasome is activated by bacterial toxins or endogenous stress signals (e.g. ATP and ␤-amyloid (8 -10)) through the formation of reactive oxygen species (6, 11). Glucose-induced IL-1␤ secretion by the ␤-cell is prevented in NALP3 Ϫ/Ϫ mice, indicating that IL-1␤ is generated through glucose-induced reactive oxygen species production and oxidative stress (6). The thioredoxin-interacting protein, which has been linked to insulin resistance (12), functions as an activator of NALP3. In line with these data, another recent study shows that thioredoxin-interacting protein is highly increased by elevated glucose in ␤-cells and that thioredoxin-interacting protein-deficient islets are protected against glucose toxicity (13). Although glucose-induced IL-1␤ production in the ␤-cell was not observed in all studies (14), IL-1␤ expression in islets...

Pancreatic and duodenal homeobox-1 nuclear localization is regulated by glucose in dispersed rat islets but not in insulin-secreting cell lines

“…30 The interest in the regulation of PDX-1 nucleo-cytoplasmic shuttling stems from the observation that b¡cell dysfunction in islets from T2D patients correlates with the exclusion of PDX-1 from the nucleus. 31,32 Similar results were obtained in rodent models of metabolic stress, such as in db/db mice, 32 high fat diet in mice, 31,33 ZDF rats 34 nutrient infusion in rats, 35 and in vitro oxidative and glucolipotoxic stress. [35][36][37][38] Glucose 16,35 and other factors promoting insulin secretion and b-cell survival, including GLP-1, 31,39,40 TGF-b, 41 nitric oxide 42 and insulin 15,43 increase nuclear PDX-1.…”

“…PDX-1 is excluded from the nucleus of b cells in islets isolated from rats infused with glucose C Intralipid, 35 from db/db mice or mice fed a high fat -high sucrose diet 31 and in ZDF rats 51 and in vitro in islets exposed to glucose and palmitate. 37 Reactive oxygen species are thought to be the main trigger as oxidative stress leads to PDX-1 nuclear exclusion in HIT-T15 cells 37 and anti-oxidant treatment of ZDF rats restores PDX-1 nuclear localization.…”

Expression of Concern. Kathrin Maedler, Desiree M. Schumann, Fabienne Schulthess, José Oberholzer, Domenico Bosco, Thierry Berney, and Marc Y. Donath. Aging Correlates With Decreased β-Cell Proliferative Capacity and Enhanced Sensitivity to Apoptosis: A Potential Role for Fas and Pancreatic Duodenal Homeobox-1. Diabetes 2006;55:2455–2462. DOI: 10.2337/db05-1586. PMID: 16936193

“…The source image can be accessed by copying the underlying file of the left “Tubulin” panel of Fig. 1 E in the paper-in-press version of a 2011 Journal of Biological Chemistry ( JBC ) article by Ardestani et al (1), which was published on 10 March 2011 and is available at http://www.jbc.org/content/early/2011/03/10/jbc.M110.210526.full.pdf. It should be noted that the 2011 JBC paper was retracted in November 2015 (2).…”

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

“…The expression of concern was issued on 21 July 2016 to inform readers that images from the article by Maedler et al (1) were potentially republished in a 2009 PLoS One article (2) and a 2011 Journal of Biological Chemistry ( JBC ) paper (3). Kathrin Maedler is the first author on this article and is the senior/corresponding author on the PLoS One and JBC papers.…”

“…The source image can be accessed by copying the underlying file of the left “Tubulin” panel of Fig. 1 E in the paper-in-press version of the 2011 JBC paper by Ardestani et al (3), which was published on 10 March 2011 and is available at http://www.jbc.org/content/early/2011/03/10/jbc.M110.210526.full.pdf.…”