Myricetin protects pancreatic β-cells from human islet amyloid polypeptide (hIAPP) induced cytotoxicity and restores islet function

Abstract

The aberrant misfolding and self-assembly of human islet amyloid polypeptide (hIAPP)–a hormone that is co-secreted with insulin from pancreatic β-cells–into toxic oligomers, protofibrils and fibrils has been observed in type 2 diabetes mellitus (T2DM). The formation of these insoluble aggregates has been linked with the death and dysfunction of β-cells. Therefore, hIAPP aggregation has been identified as a therapeutic target for T2DM management. Several natural products are now being investigated for their potential to inhibit hIAPP aggregation and/or disaggregate preformed aggregates. In this study, we attempt to identify the anti-amyloidogenic potential of Myricetin (MYR)- a polyphenolic flavanoid, commonly found in fruits (like Syzygium cumini). Our results from biophysical studies indicated that MYR supplementation inhibits hIAPP aggregation and disaggregates preformed fibrils into non-toxic species. This protection was accompanied by inhibition of oxidative stress, reduction in lipid peroxidation and the associated membrane damage and restoration of mitochondrial membrane potential in INS-1E cells. MYR supplementation also reversed the loss of functionality in hIAPP exposed pancreatic islets via restoration of glucose-stimulated insulin secretion. Molecular dynamics simulation studies suggested that MYR molecules interact with the hIAPP pentameric fibril model at the amyloidogenic core region and thus prevents aggregation and distort the fibrils.

Linking Alzheimer’s Disease and Type 2 Diabetes: Characterization and Inhibition of Cytotoxic Aβ and IAPP Hetero-Aggregates

“…Despite these challenges, naturally-derived small molecules, specifically polyphenols, are commonly investigated for preventing Aβ40/IAPP self-aggregation ( Porat et al, 2006 ; Dhouafli et al, 2018 ). In this research, we selected the polyphenols, Caffeic acid ( Cheng et al, 2011 ; Chang et al, 2019 ), Myricetin ( Ono et al, 2003 , 2012 ; Shimmyo et al, 2008 ; DeToma et al, 2011 ; Zelus et al, 2012 ; Gargari et al, 2018 ; Dubey et al, 2021 ), Rosmarinic acid ( Ono et al, 2012 ; Sun et al, 2019 ), Curcumin ( Ono et al, 2004 ; Daval et al, 2010 ; Nedumpully-Govindan et al, 2016 ; Thapa et al, 2016 ), EGCG ( Bastianetto et al, 2006 ; Ehrnhoefer et al, 2008 ; Bieschke et al, 2010 ; Meng et al, 2010 ; Liu et al, 2011 ; Cao and Raleigh, 2012 ; Suzuki et al, 2012 ; Cheng et al, 2013 ; Hyung et al, 2013 ; Zhang et al, 2013 ; Wang Q. et al, 2014 ; Xu et al, 2016 ) and Silibinin ( Yin et al, 2011 ; Cheng B et al, 2012 ; Sciacca et al, 2017 ), as candidate inhibitors of Aβ40 and IAPP self-aggregation based on their known anti-aggregation activities in literature. Figure 5A demonstrates the chemical structures of the polyphenolic candidate inhibitors.…”

Urolithin B: Two-way attack on IAPP proteotoxicity with implications for diabetes

“…(Poly)phenols have been largely explored as a group of phytochemicals with potential to intervene in numerous diseases. Several molecules have been put forward as effective in suppressing IAPP aggregation ( 66 ), namely myricetin ( 67 ), resveratrol ( 24 ), and EGCG ( 20 ). Different (poly)phenols seem to act differently towards IAPP.…”

Human islet amyloid polypeptide: A therapeutic target for the management of type 2 diabetes mellitus

“…Several natural products and small molecules present abundantly in certain foods and plant materials have been substantially used in the past to manage T2DM [ 199 ]. Among these, natural products belonging to the flavonoid and curcuminoid families have been extensively assessed for their potential as hIAPP aggregation inhibitors ( Table S3 ) [ [200] , [201] , [202] , [203] , [204] , [205] , [206] , [207] , [208] , [209] , [210] , [211] , [212] , [213] , [214] , [215] , [216] , [217] , [218] , [219] , [220] , [221] , [222] , [223] , [224] , [225] , [226] , [227] , [228] , [229] , [230] , [231] ]. As mentioned earlier, most of these studies have been conducted using cell lines derived from pancreatic insulinoma of mouse or rat origin.…”

“…It reduces oxidative stress and the associated DNA and membrane damages and restores the mitochondrial membrane potential. Myricetin supplementation also restores the function of pancreatic islets exposed to hIAPP [ 206 ].…”