Molecular Mechanisms of Amylin Turnover, Misfolding and Toxicity in the Pancreas

Abstract

Amyloidosis is a common pathological event in which proteins self-assemble into misfolded soluble and insoluble molecular forms, oligomers and fibrils that are often toxic to cells. Notably, aggregation-prone human islet amyloid polypeptide (hIAPP), or amylin, is a pancreatic hormone linked to islet β-cells demise in diabetics. The unifying mechanism by which amyloid proteins, including hIAPP, aggregate and kill cells is still matter of debate. The pathology of type-2 diabetes mellitus (T2DM) is characterized by extracellular and intracellular accumulation of toxic hIAPP species, soluble oligomers and insoluble fibrils in pancreatic human islets, eventually leading to loss of β-cell mass. This review focuses on molecular, biochemical and cell-biology studies exploring molecular mechanisms of hIAPP synthesis, trafficking and degradation in the pancreas. In addition to hIAPP turnover, the dynamics and the mechanisms of IAPP–membrane interactions; hIAPP aggregation and toxicity in vitro and in situ; and the regulatory role of diabetic factors, such as lipids and cholesterol, in these processes are also discussed.

Analyzing Gene Expression After Administration of Low‐Intensity Therapeutic Ultrasound in Human Islet Cells

“…Although no significant gene expression changes were observed in our sonogenetic studies, an interesting finding was that the ultrasound administration appeared to be more stimulatory to amylin and BiP as compared with the other two islet hormones, indicating a selective effect of ultrasound on islet gene expression. In agreement with this finding, our previous studies demonstrate concurrent increases in amylin and BiP mRNA levels in HG‐challenged pancreatic β‐cells 42 …”

“…In agreement with this finding, our previous studies demonstrate concurrent increases in amylin and BiP mRNA levels in HG-challenged pancreatic β-cells. 42 To evaluate cell viability post-ultrasound administration, we employed the 0.4% Trypan Blue Dye Exclusion Test, quantifying the number of live cells vs dead cells immediately after treatment. However, a limitation exists in the short assessment period, potentially not capturing delayed cell death pathways that become active several hours post-treatment.…”

Zinc and iron dynamics in human islet amyloid polypeptide-induced diabetes mouse model

“…The interaction of metal ions with hIAPP may also affect its structure, causing the formation of misfolded IAPP, which can undergo oligomer and amyloid formation 40,41 . There are several in vitro studies reporting on the effects of metal ions on the formation of soluble hIAPP oligomers and mature amyloid [42][43][44][45][46][47] ; however, there are limited information on this issue regarding the physiological conditions in studies using mouse models or human samples.…”

Big versus small: The impact of aggregate size in disease

“…However, it was later found that small oligomers were the most toxic species among the various intermediates. Amylin misfolding and aggregation are associated with a gradual loss of pancreatic cell function and mass in diabetic patients (Bhowmick et al, 2022). It causes cytotoxicity by inducing endoplasmic reticulum stress (C. Huang et al, 2007), oxidative stress (Zraika et al, 2009), mitochondrial malfunction (X.-L. Li, Chen, et al, 2011), inflammatory cytokine release (Westwell-Roper et al, 2011), and autophagy pathway disruption (J. F. Rivera et al, 2011).…”