Unravelling Post-transcriptional Regulators of IAPP turnover in Human Pancreatic Islets
Open AccessAbstractA hallmark of late-onset type-2 Diabetes mellitus (T2DM) is the formation of insoluble protein plaques or amyloidosis. Together with other factors, amyloidosis is linked to pancreatic β-cell failure and death, eventually leading to T2DM. Human islet amyloid polypeptide (hIAPP), or amylin is a major constituent of islet amyloid plaques. It is a small peptide hormone that consists of 37 amino acid residues and is secreted by pancreatic β-cells along with insulin in a 1:20 ratio. Insulin and hIAPP regulate blood glucose levels synergistically under normal conditions. Over the past 20 years, a plethora of studies have been done to understand the molecular mechanisms of intracellular and extracellular hIAPP aggregation and its cytotoxic effects on β-cells. These studies revealed that redox stress, inflammation and ionic disbalance are the main culprits in hIAPP-induced β-cell death. Toxic and aggregation prone species of hIAPP are an alarming issue in human health because hIAPP-derived plaques were found in over 90% of type-2 diabetic patients at postmortem together with the progressive β-cell loss. However, the cellular factors and mechanisms regulating hIAPP production under normal and ER stress conditions are still unclear. If and how cellular stress particularly ER-stress, affects synthesis of hIAPP is less clear, and hence was investigated in this master project. MicroRNAs (miRNAs) are ~22 nucleotide small non-coding RNA molecules implicated in the regulation of gene expression in eukaryotic cells. At present, there is a lack of studies and understanding in the field regarding a possible contribution and importance of miRNAs in the regulation of hIAPP translation in β-cells. Hence, the main goal of this master project was to determine the regulatory role of RISC complex and its constituents, micro-RNAs and Ago1/2 proteins, in hIAPP turnover (synthesis and release) in normal and ER-stressed human islets. Recent studies show correlation of pancreatic islet miRNAs with β-cell stress and the development of T2DM, implying the role of miRNAs in T2DM progression and possibly hIAPP-derived islet amyloidosis. Thus, identifying and clarifying regulatory roles of miRNAs in hIAPP translation in pancreatic β-cells can be an important first step in the prevention of islet amyloidosis and T2DM. In this project, I examined and identified posttranscriptional regulators of hIAPP translation in normal and ER stressed human islets, notably miRNAs and Ago1/2 proteins. High glucose and ER stress downregulated the miR-335 and several other miRNAs. This downregulation of miRNAs, likely prevents its binding to hIAPP mRNA 3’-UTR, thereby upregulating hIAPP translation that leads to its accumulation, intracellularly and extracellularly. Functional studies confirmed the importance of miR-335 and Ago2 protein in hIAPP synthesis and its release from human islet beta-cells. This regulatory (inhibitory) pathway of hIAPP synthesis by miRNAs/Ago2 complex could potentially serve as a novel, druggable target to limits hIAPP overproduction and aggregation, ultimately preventing hIAPP-induced β-cell demise and progression of T2DM.
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Kudaibergenova_gwu_0075M_15757.pdf | 2022-04-25 | Open Access |
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