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.
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.
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 . 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 . 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.