Research Article: Amyloid formation reduces protein kinase B phosphorylation in primary islet β-cells which is improved by blocking IL-1β signaling

Date Published: February 23, 2018

Publisher: Public Library of Science

Author(s): Yun Zhang, Garth L. Warnock, Ziliang Ao, Yoo Jin Park, Nooshin Safikhan, Aziz Ghahary, Lucy Marzban, Massimo Pietropaolo.

http://doi.org/10.1371/journal.pone.0193184

Abstract

Amyloid formation in the pancreatic islets due to aggregation of human islet amyloid polypeptide (hIAPP) contributes to reduced β-cell mass and function in type 2 diabetes (T2D) and islet transplantation. Protein kinase B (PKB) signaling plays a key role in the regulation of β-cell survival, function and proliferation. In this study, we used human and hIAPP-expressing transgenic mouse islets in culture as two ex vivo models of human islet amyloid formation to: 1. Investigate the effects of amyloid formation on PKB phosphorylation in primary islet β-cells; 2. Test if inhibition of amyloid formation and/or interleukin-1β (IL-1β) signaling in islets can restore the changes in β-cell phospho-PKB levels mediated by amyloid formation. Human and hIAPP-expressing mouse islets were cultured in elevated glucose with an amyloid inhibitor (Congo red) or embedded within collagen matrix to prevent amyloid formation. To block the IL-1β signaling, human islets were treated with an IL-1 receptor antagonist (anakinra) or a glucagon-like peptide-1 agonist (exenatide). β-cell phospho-PKB levels, proliferation, apoptosis, islet IL-1β levels and amyloid formation were assessed. Amyloid formation in both cultured human and hIAPP-expressing mouse islets reduced β-cell phospho-PKB levels and increased islet IL-1β levels, both of which were restored by prevention of amyloid formation either by the amyloid inhibitor or embedding islets in collagen matrix, resulting in improved β-cell survival. Furthermore, inhibition of IL-1β signaling by treatment with anakinra or exenatide increased β-cell phospho-PKB levels, enhanced proliferation and reduced apoptosis in amyloid forming human islets during 7-day culture. These data suggest that amyloid formation leads to reduced PKB phosphorylation in β-cells which is associated with elevated islet IL-1β levels. Inhibitors of amyloid or amyloid-induced IL-1β production may provide a new approach to restore phospho-PKB levels thereby enhance β-cell survival and proliferation in conditions associated with islet amyloid formation such as T2D and clinical islet transplantation.

Partial Text

Islet amyloid polypeptide (IAPP; amylin) [1, 2] is a 37-amino acid peptide hormone that is normally produced and secreted along with insulin from islet β-cells [3]. In soluble form, IAPP reduces food intake and plays a physiological role in the regulation of postprandial glycaemia by suppression of glucagon release and inhibition of gastric emptying [4]. However, human IAPP (hIAPP) aggregates are toxic to β-cells [5–8] and contribute to progressive β-cell dysfunction and death in type 2 diabetes (T2D) [4, 9–11] as well as in cultured [6–8] and transplanted islets [12–15]. It is not clear why soluble hIAPP molecules form non-soluble toxic aggregates in T2D but it appears that increased hIAPP production, presence of an amyloidogenic sequence, and impaired prohIAPP processing, all contribute to hIAPP aggregation [4, 16].

While mechanisms of islet amyloid-induced β-cell apoptosis have intensively been investigated in the past decade, our current knowledge on the effects of amyloid formation on β-cell proliferation and the underlying signaling pathways are very limited. Less focus on the effects of hIAPP aggregates on β-cell proliferation is likely related to the notion that replication is a rare event in primary islet β-cells. Therefore, contribution of the changes in β-cell proliferation to reduced β-cell mass has been underestimated. However, growing evidence from recent studies have changed this notion by demonstrating proliferation of β-cells in human islets both in vitro and in vivo [36, 37]. The balance between β-cell proliferation and apoptosis is a key factor in the regulation of islet β-cell mass. Thus, chronic changes in β-cell proliferation in pathological conditions that are associated with increased β-cell apoptosis such as diabetes may play a significant role in the regulation of β-cell mass.

 

Source:

http://doi.org/10.1371/journal.pone.0193184

 

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