Human Islet Amyloid Polypeptide Overexpression in INS-1E Cells Influences Amylin Oligomerization under ER Stress and Oxidative Stress

Abstract

Human amylin or islet amyloid polypeptide (hIAPP) is synthesized in the pancreatic β-cells and has been shown to contribute to the pathogenesis of type 2 diabetes (T2D) in vitro and in vivo. This study compared amylin oligomerization/expression and signal transduction under endoplasmic reticulum (ER) stress and oxidative stress. pCMV-hIAPP-overexpressing INS-1E cells presented different patterns of amylin oligomerization/expression under ER stress and oxidative stress. Amylin oligomerization/expression under ER stress showed three amylin oligomers of less than 15 kDa size in pCMV-hIAPP-overexpressing cells, while one band was detected under oxidative stress. Under ER stress conditions, HIF1α, p-ERK, CHOP, Cu/Zn-SOD, and Bax were significantly increased in pCMV-hIAPP-overexpressing cells compared to the pCMV-Entry-expressing cells (control), whereas p-Akt, p-mTOR, Mn-SOD, catalase, and Bcl-2 were significantly decreased. Under oxidative stress conditions, HIF1α, p-ERK, CHOP, Mn-SOD, catalase, and Bcl-2 were significantly reduced in pCMV-hIAPP-overexpressing cells compared to the control, whereas p-mTOR, Cu/Zn-SOD, and Bax were significantly increased. In mitochondrial oxidative phosphorylation (OXPHOS), the mitochondrial complex I and complex IV were significantly decreased under ER stress conditions and significantly increased under oxidative stress conditions in pCMV-hIAPP-overexpressing cells compared to the control. The present study results demonstrate that amylin undergoes oligomerization under ER stress in pCMV-hIAPP-overexpressing cells. In addition, human amylin overexpression under ER stress in the pancreatic β cells may enhance amylin protein aggregation, resulting in β-cell dysfunction.

Combined training and hormones/enzymes with insulinotropic actions in individuals with overweight and type 2 diabetes mellitus: A randomized controlled trial

“…The risk of developing Alzheimer's disease is increased in diabetes T2DM (Martinez‐Valbuena et al., 2019; Wijesekara et al., 2017). Lastly, baseline overexpressed amylin/IAPP has been related to systemic inflammation, impaired mitophagy (Hernandez et al., 2018), endoplasmic reticulum stress (Yoo & Joo, 2021), and cardiovascular risk (Despa et al., 2014).…”

The role of autophagy in insulin resistance and glucolipid metabolism and potential use of autophagy modulating natural products in the treatment of type 2 diabetes mellitus

“…121,122 Furthermore, the excessive accumulation of islet amyloid, a characteristic feature of human T2DM, has been shown to impair β-cell function. 123,124 However, autophagy has been found to play a beneficial role in mitigating the cytotoxic effects of human islet amyloid polypeptide. [125][126][127] Taken together, when activated, autophagy enhances both β-cell mass and functionality while protects these cells against inflammation, ultimately improving insulin secretion.…”

“…Additionally, autophagy's role in clearing damaged cellular components and reducing cellular stress helps alleviate the inflammatory state in the pancreas, further contributing to enhanced insulin secretion 121,122 . Furthermore, the excessive accumulation of islet amyloid, a characteristic feature of human T2DM, has been shown to impair β ‐cell function 123,124 . However, autophagy has been found to play a beneficial role in mitigating the cytotoxic effects of human islet amyloid polypeptide 125–127 .…”