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Combined Effects of Multiple Stresses on Pancreatic Human Islet β-Cell Response: New Insights into the Pathways Involved

ABSTRACT: This study used multiple common chemical stresses in human islets, mimicking the conditions experienced by dysfunctional β-cells. Proteomic alterations upon exposure of human islets to these stressors were profiled with TMT-based quantitative proteomics and further verified using label-free quantitative proteomics. The differentially expressed proteins under stress conditions were selected for in-depth bioinformatic analysis.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Cell Culture

SUBMITTER: Mehari Weldemariam

LAB HEAD: Qibin Zhang

PROVIDER: PXD034608 | Pride | 2024-01-26

REPOSITORIES: pride

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			Action	DRS
	HumanIslet_15spd_LFQ_Indv_400ng_24Indvand3Pool_20220122.msf	Msf
	HumanIslet_15spd_LFQ_Indv_400ng_24Indvand3Pool_20220122.pdResult	Other
	HumanIslet_15spd_LFQ_Indv_400ng_batch1_Cont-1.raw	Raw
	HumanIslet_15spd_LFQ_Indv_400ng_batch1_Cyto-1.raw	Raw
	HumanIslet_15spd_LFQ_Indv_400ng_batch1_CytoGlu-1.raw	Raw

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Publications

Effects of multiple stressors on pancreatic human islets proteome reveal new insights into the pathways involved.

Weldemariam Mehari Muuz MM Sudhir Putty-Reddy PR Woo Jongmin J Zhang Qibin Q

Proteomics 20230724 19

Pancreatic β-cell dysfunction is an early hallmark of type 1 diabetes mellitus. Among the potentially critical factors that cause β-cell dysfunction are cytokine attack, glucotoxicity, induction of endoplasmic reticulum (ER) or mitochondria stress. However, the exact molecular mechanism underlying β-cell's inability to maintain glucose homeostasis under severe stresses is unknown. This study used proinflammatory cytokines, thapsigargin, and rotenone in the presence of high concentration glucose ...[more]

PMID: 37489002

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Palmitoylation couples insulin hypersecretion with β-cell failure in diabetes

Project description:Hyperinsulinemia often precedes type 2 diabetes but its role in disease progression is unknown. Palmitoylation, a protein modification implicated in regulated exocytosis, is reversed by acyl-protein thioesterase 1 (APT1). We found altered APT1 biology in pancreatic islets from humans with type 2 diabetes, and APT1 knockdown in nondiabetic human islets caused insulin hypersecretion. Chow fed global and islet specific APT1 knockout mice had enhanced glucose tolerance due to islet autonomous increased glucose-stimulated insulin secretion. APT1 deficiency did not affect islet calcium dynamics but prolonged insulin granule fusion. Using palmitoylation proteomics, we identified Scamp1 as an APT1 substrate that localized to insulin secretory granules. Knockdown of Scamp1 caused insulin hypersecretion. APT1 deficient insulinoma cells subjected to nutrient excess had increased apoptosis, and expression of a mutated Scamp1 incapable of being palmitoylated in APT1 deficient cells rescued insulin hypersecretion and nutrient induced apoptosis. Compared to APT1 sufficient controls, high fat fed islet specific APT1 knockout mice and global APT1 deficient db/db mice showed increased -cell failure. These findings suggest that the depalmitoylation enzyme APT1 is regulated in human islets, and that APT1 deficiency causes insulin hypersecretion leading to -cell failure, modeling the evolution of some forms of human type 2 diabetes.

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Identification of HIPs in the islets of mice and non-diabetic human donors

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The human and mouse islet peptidome: effects of obesity and type 2 diabetes

Project description:To characterise the impact of metabolic disease on the peptidome of human and mouse pancreatic islets and the contribution of intra-islet glucagon-like peptide 1 (GLP-1) receptor signalling.

2021-08-24 | PXD026095 | Pride

Epigenetic regulation of the MEG3-DLK1 microRNA cluster in human Type 2 diabetic islets

Project description:Type 2 diabetes mellitus (T2DM) is a multi-factorial disease characterized by the inability of beta-cells in the endocrine pancreas to produce sufficient amounts of insulin to overcome insulin resistance in peripheral tissue. To investigate the function of miRNAs in T2DM, we sequenced the small RNAs of human islets cells from diabetic and non-diabetic organ donors and identified a cluster of miRNAs in an imprinted locus on human chromosome 14 to be dramatically down-regulated in T2DM islets. These miRNAs are highly and specifically expressed in human beta-cells. The down-regulation of this imprinted locus strongly correlates with increased methylation of its promoter in T2DM islets, providing evidence for an epigenetic modification that contributes to the pathogenesis of T2DM. Targets of the Chr 14q32 cluster of miRNAs were identified by high-throughput sequencing of cross-linked and immunoprecipitated RNA (HITS-CLIP) of Argonaute. We have also identified a unique class of sequences, termed chimeric reads, that represent an in vivo ligation of miRNAs and their targets while in complex with Argonaute, and which allow for the direct identification of miRNA:target relationships in vivo. There are three experiments in this submission. All are in human islets or islet cell types. The first is a comparison of miRNA levels in sorted alpha versus beta cells. There is one replicate for this experiment. The second experiment is to measure the expression of miRNAs in whole islets as a function of glucose levels. There are three levels and one replicate for each condition. The third exeriment is a comparison of whole islets taken from human donors that were suspected/confirmed Type 2 diabetic or considered controls. There are 3 controls and 4 T2D samples.

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2012-07-30 | E-MEXP-3691 | biostudies-arrayexpress

Wnt-modulated hiPSC-derived insulin-producing cells, adult human islet proteome

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2019-11-13 | PXD012081 | Pride

Multi-omics Study Reveals the Synergistic Anti-tumor Effects of Aspirin and Gemcitabine-based Chemotherapy on Pancreatic Cancer and the Underlying Mechanism

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Mapping of INS promoter interactions reveals its role in long-range regulation of SYT8 transcription

Project description:Insulin (INS) synthesis and secretion from pancreatic M-NM-2 cells are tightly regulated; their deregulation causes diabetes. Here we map INS-associated loci in human pancreatic islets by 4C and 3C techniques and show that the INS gene physically interacts with the SYT8 gene, located over 300 kb away. This interaction is elevated by glucose and accompanied by increases in SYT8 expression. Inactivation of the INS promoter by promoter-targeting siRNA reduces SYT8 gene expression. SYT8-INS interaction and SYT8 transcription are attenuated by CTCF depletion. Furthermore, SYT8 knockdown decreases insulin secretion in islets. These results reveal a non-redundant role for SYT8 in insulin secretion and indicate that the INS promoter acts from a distance to stimulate SYT8 transcription. This suggests a function for the INS promoter in coordinating insulin transcription and secretion through long-range regulation of SYT8 expression in human islets. Circular Chromosome Conformation Capture (4C)-Seq experiments to profile interactions of INS promoter in human pancreatic islets isolated from two donors: donor 1 and donor 2.

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2006-01-16 | E-MEXP-536 | biostudies-arrayexpress

Expression data from fresh and cultured islets at different glucose concentrations

Project description:M-NM-2-cell identity is determined by tightly regulated transcriptional networks that are modulated by extracellular cues, thereby ensuring M-NM-2-cell adaptation to the organismM-bM-^@M-^Ys insulin demands. We have observed in pancreatic islets that stimulatory glucose concentrations induced a gene profile that was similar to that of freshly isolated islets, indicating that glucose-elicited cues are involved in maintaining M-NM-2-cell identity. Low glucose induces the expression of ubiquitous genes involved in stress responses, nutrient sensing, and organelle biogenesis. By contrast, stimulatory glucose concentrations activate genes with a more restricted expression pattern (M-NM-2- and neuronal- cell identity). Consistently, glucose-induced genes are globally reduced in islets deficient with Hnf1a (MODY3), characterized by a deficient glucose metabolism. Of interest, a cell cycle gene module was the most enriched among the variable genes between intermediate and stimulatory glucose concentrations. Glucose regulation of the islet transcriptome was unexpectedly broadly maintained in islets from aged mice. However, the cell cycle gene module is selectively lost in old islets and the glucose activation of this module is not recovered even in the absence of the cell cycle inhibitor p16. We used microarrays to detail the global programme of gene expression regulated by glucose in young and aged pancreatic islets as well as freshly-isolated islets. Pancreatic islets from young and old mice were isolated and cultured at different glucose concentrations for RNA extraction and hybridization on Affymetrix microarrays. Islets were cultured at 3mM (G3), 5.5mM (G5), 11mM (G11) and 16mM (G16). Freshly-isolated islets (F) were also processed for RNA extraction . We also assessed the dynamic glucose regulation of gene expression at different time-points after an overnight at 3mM (T0): after 1h at 11mM (T1) and after 4h (T4).

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