Intra-islet insulin synthesis defects are associated with endoplasmic reticulum stress and loss of beta cell identity in human diabetes

Brusco, Noemi; Sebastiani, Guido; Giuseppe, Gianfranco Di; Licata, Giada; Grieco, Giuseppina Emanuela; Fignani, Daniela; Nigi, Laura; Formichi, Caterina; Aiello, Elena; Auddino, Stefano; Quero, Giuseppe; Cefalo, Consuelo; Cinti, Francesca; Mari, Andrea; Ferraro, Pietro Manuel; Pontecorvi, Alfredo; Alfieri, Sergio; Giaccari, Andrea; Dotta, Francesco; Mezza, Teresa

doi:10.1007/s00125-022-05814-2

Cited by 23 publications

(22 citation statements)

References 40 publications

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“…The study protocol (ClinicalTrials.gov NCT02175459) was approved by the Ethical Committee Fondazione Policlinico Universitario Agostino Gemelli IRCCS – Università Cattolica del Sacro Cuore (P/656/CE2010 and 22573/14), and all participants provided written informed consent, followed by a comprehensive medical evaluation, as previously described [46, 47]…”

Section: Methodsmentioning

confidence: 99%

Comprehensive IsomiR sequencing profile of human pancreatic islets and EndoC-βH1 beta-cells

Auddino,

Aiello,

Toniolli

et al. 2023

Preprint

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Aims/HypothesisMiRNAs play a crucial role in regulating the islet transcriptome, influencing beta cell functions and pathways. Emerging evidence suggests that during biogenesis a single miRNA locus can generate various sequences, known as isomiRNAs (isomiRs). However, a comprehensive profiling analysis of isomiRs in human pancreatic islets and beta cells is still lacking. This study aims to unveil the isomiRs expression profile in Laser Capture Microdissected (LCM) human pancreatic islets (HI) from non-diabetic donors and in the human beta cell line EndoC-βH1, in order to shed light on novel molecular mechanisms governing beta cell function.MethodsRNA was extracted from LCM HI deriving from n=19 non-diabetic donors and from EndoC-βH1 beta cells. Small RNA-seq was performed. Data were processed with the sRNAbench online pipeline for miRNAs/isomiRs quantification. Results were further validated using an external miRNA-seq database (isomiRdb).ResultsIn both HI and EndoC-βH1, isomiRs accounted for a substantial proportion of total miRNA reads (HI: 59.4+/-1.9%; EndoC-βH1: 43.8+/-0.6%). Among isomiRs, the most prevalent types were 3’-end modifications, including trimming (HI=71.8+/-2.8%; EndoC-βH1=55.8+/-1.0%) and extension (HI: 12.1+/-1.9%; EndoC-βH1: 17.4+/-0.9%), followed by non-templated addition (HI: 9.8+/-0.9%; EndoC-βH1: 14.0+/-1.2%). The analysis of the composition of the n=10 most expressed miRNAs highlighted a significant contribution of reads assigned to isomiRs. For instance, the most abundant miRNA, miR-375-3p, resulted from 59.7+/-2.4% of canonical and 40.3+/-2.4% of isomiRs in EndoC-βH1 and from 45.3+/-2.0% of canonical and 54.7+/-2.0% of isomiR reads in HI. Interestingly, miR-7-5p, a beta cell-specific miRNA, was predominantly expressed as an isomiR both in EndoC-βH1 (65.3+/-2.7%) and in HI (82.4+/-1.4%). To identify a reliable beta cell isomiR signature, common sequences detected in HI and EndoC-βH1 were filtered based on their contribution to total miRNA expression, ultimately resulting in a set of 46 isomiRs. The expression of the isomiR signature in beta cells was further evaluated using an external database, isomiRdb, which contains small-RNA sequencing data from 99 different human cell types. This analysis revealed a significant enrichment of 11 out of the 46 isomiRs in beta cells compared to other cell types. The signature was functionally characterized through regression analysis with clinical and metabolic parameters related to beta cell function in non-diabetic individuals, demonstrating a significant negative correlation between basal insulin secretion and isomiR-411-5p, but not with its corresponding canonical miRNA.Conclusion/InterpretationThis study provides a comprehensive profile of isomiR expression in pancreatic islets and beta cells, highlighting the potential significance of isomiRs as novel regulators of beta cell function.Graphical AbstractResearch in ContextWhat is already know about this subject?- isomiRs are sequence variants of microRNAs (miRNAs) and may have distinct functional role respect to the canonical sequence.- isomiRs show cell/tissue specificity and are involved in multiple disease contexts.What is the key question?- What is the profile of isomiRs in human pancreatic islets (HI) and in beta cells?- Do isomiRs have a functional role in beta cells?What are the new findings?- IsomiRs represent a relevant fraction of total miRNAs in HI and beta cells.- 3’end miRNA sequence modifications are the major fraction of isomiRs in beta cells.- A set of n=11 isomiRs, more expressed than their canonical miRNAs, are enriched in beta cells compared to the other human cell types.- Specific isomiRs are associated with beta cell glucose sensitivity and basal insulin secretion.How might this impact on clinical practice in the foreseeable future?- A comprehensive profile of isomiRs in beta cells may improve our understanding of molecular mechanisms driving beta cell function and dysfunction.- A highly detailed and granular view of miRNAs sequence variants and their expression levels may help in the design of novel therapeutic RNA-based strategies.

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Section: Methodsmentioning

confidence: 99%

Comprehensive IsomiR sequencing profile of human pancreatic islets and EndoC-βH1 beta-cells

Auddino,

Aiello,

Toniolli

et al. 2023

Preprint

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“…Beyond this, the prolonged demand for insulin may deplete zinc levels, potentially inducing the loss of mature β‐cell markers such as MafA, Pax6 and Nkx6.2 43 . Analysis of islets from healthy, impaired glucose tolerant and T2DM donors confirms that increased insulin demand leads to activation of UPR and increased ER stress, with altered insulin synthesis/processing leading to β‐cell dedifferentiation 143 …”

Section: Molecular Mechanisms Driving Transdifferentiationmentioning

confidence: 98%

“…43 Analysis of islets from healthy, impaired glucose tolerant and T2DM donors confirms that increased insulin demand leads to activation of UPR and increased ER stress, with altered insulin synthesis/processing leading to β-cell dedifferentiation. 143 Small non-coding miRNAs regulate key steps in gene expression, either promoting mRNA degradation or inhibiting protein translation, thereby playing a role in maintaining β-cell identity via sustaining mature β-cell transcription factors. 144 Accordingly, in human T2DM there is evidence for altered expression of several miRNAs, which correlate with (mis)expression of β-cell disallowed genes.…”

Section: Molecular Mechanisms Driving Transdifferentiationmentioning

confidence: 99%

“…Beyond this, severe insulin deficiency appears sufficient to trigger the dedifferentiation of α-cells. 79,143 Intriguingly, somewhat similar to the effects on β-cell dedifferentiation and restoration of β-cell identity, sub-chronic administration of enzymatically stable GLP-1, GIP and Y1 receptor agonists stimulates αto β-cell transdifferentiation in STZ-induced insulin-deficient mice, 61,73,157 an enteroendocrine K-cellderived hormone co-secreted with GIP following nutrient ingestion 158 has also been shown to exert similar dual benefits on islet cell lineage alterations, 73 with the non-classical islet hormone vasopressin eliciting comparable benefits on both retention of β-cell identity 157 and stimulation of αto β-cell transdifferentiation. 66 Notably, a long-acting oxyntomodulin analogue, (D-Ser 2 )-Oxm[Lys 38 PAL], 159 has a demonstrable capacity to transform mature α-cells towards a β-cell-like phenotype.…”

Section: Strategies To Utilize Transdifferentiation In the Generation...mentioning

confidence: 99%

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Pancreatic islet cell plasticity: Pathogenic or therapeutically exploitable?

Tanday,

Tarasov,

Moffett

et al. 2023

Diabetes Obesity Metabolism

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The development of pancreatic islet endocrine cells is a tightly regulated process leading to the generation of distinct cell types harbouring different hormones in response to small changes in environmental stimuli. Cell differentiation is driven by transcription factors that are also critical for the maintenance of the mature islet cell phenotype. Alteration of the insulin‐secreting β‐cell transcription factor set by prolonged metabolic stress, associated with the pathogenesis of diabetes, obesity or pregnancy, results in the loss of β‐cell identity through de‐ or transdifferentiation. Importantly, the glucose‐lowering effects of approved and experimental antidiabetic agents, including glucagon‐like peptide‐1 mimetics, novel peptides and small molecules, have been associated with preventing or reversing β‐cell dedifferentiation or promoting the transdifferentiation of non‐β‐cells towards an insulin‐positive β‐cell‐like phenotype. Therefore, we review the manifestations of islet cell plasticity in various experimental settings and discuss the physiological and therapeutic sides of this phenomenon, focusing on strategies for preventing β‐cell loss or generating new β‐cells in diabetes. A better understanding of the molecular mechanisms underpinning islet cell plasticity is a prerequisite for more targeted therapies to help prevent β‐cell decline in diabetes.

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“…Interestingly, when the 10 −9 mM lipoic acid concentration was tested alone without the addition of IL-1β,insulin secretion was not restored, but, in fact, decreased significantly (68%) compared to the control condition [ 58 ]. The latter observation suggests that the effect of ALA on insulin secretion can change in relation to more complex intracellular dynamics [ 59 ].…”

Section: Ala and Glucose Metabolismmentioning

confidence: 99%

Alpha-Lipoic Acid and Glucose Metabolism: A Comprehensive Update on Biochemical and Therapeutic Features

et al. 2022

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Alpha-lipoic acid (ALA) is a natural compound with antioxidant and pro-oxidant properties which has effects on the regulation of insulin sensitivity and insulin secretion. ALA is widely prescribed in patients with diabetic polyneuropathy due to its positive effects on nerve conduction and alleviation of symptoms. It is, moreover, also prescribed in other insulin resistance conditions such as metabolic syndrome (SM), polycystic ovary syndrome (PCOS) and obesity. However, several cases of Insulin Autoimmune Syndrome (IAS) have been reported in subjects taking ALA. The aim of the present review is to describe the main chemical and biological functions of ALA in glucose metabolism, focusing on its antioxidant activity, its role in modulating insulin sensitivity and secretion and in symptomatic peripheral diabetic polyneuropathy. We also provide a potential explanation for increased risk for the development of IAS.

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Intra-islet insulin synthesis defects are associated with endoplasmic reticulum stress and loss of beta cell identity in human diabetes

Cited by 23 publications

References 40 publications

Comprehensive IsomiR sequencing profile of human pancreatic islets and EndoC-βH1 beta-cells

Comprehensive IsomiR sequencing profile of human pancreatic islets and EndoC-βH1 beta-cells

Pancreatic islet cell plasticity: Pathogenic or therapeutically exploitable?

Alpha-Lipoic Acid and Glucose Metabolism: A Comprehensive Update on Biochemical and Therapeutic Features

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