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DIA-based Proteomic analysis of human islets with treatment of a PERK inhibitor

ABSTRACT: Partial downregulation of pancreatic endoplasmic reticulum kinase (PERK) activity recovered insulin content in human islets exposed to glucolipotoxicity (GLT), resulting in improved insulin secretion and glucose-lowering effects in a mouse model of type 2 diabetes. We conducted this study to elucidate the beta-cell enhancing mechanisms of PERK attenuation.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pancreatic Islet Cell

SUBMITTER: Dohyun Han

LAB HEAD: Dohyun Han

PROVIDER: PXD074587 | Pride | 2026-06-29

REPOSITORIES: Pride

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			Action	DRS
	20251223_DIA_JHS_panc_QC_1.raw	Raw
	20251223_DIA_JHS_panc_QC_2.raw	Raw
	20251223_DIA_JHS_panc_QC_3.raw	Raw
	20251224_DIA_JHS_panc_QC_10.raw	Raw
	20251224_DIA_JHS_panc_QC_11.raw	Raw

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Publications

Proteomic Analysis on Human Islets Suggests Nucleocytoplasmic Transport as a Mechanism of PERK Attenuation Effects in Diabetes.

Park Yeon Soo YS Yun Soeun S Sim Min Seop MS An Eun Jin EJ Lee Jin J Ha Eun Hee EH Jang Jin-Young JY Kwon Wooil W Han Dohyun D Jung Hye Seung HS

Molecular & cellular proteomics : MCP 20260518 6

Partial downregulation of pancreatic endoplasmic reticulum kinase (PERK) activity recovered insulin content in human islets exposed to glucolipotoxicity (GLT), resulting in improved insulin secretion and glucose-lowering effects in a mouse model of type 2 diabetes. We conducted this study to elucidate the beta-cell-enhancing mechanisms of PERK attenuation. Pancreatic islets isolated from non-diabetic living donors were divided into three groups: control, GLT mimicking diabetes conditions, and GL ...[more]

PMID: 42155730

Similar Datasets

Proteomic analysis on human islet with treatment of a PERK inhibitor

Project description:Partial downregulation of pancreatic endoplasmic reticulum kinase (PERK) activity recovered insulin content in human islets exposed to glucolipotoxicity (GLT), resulting in improved insulin secretion and glucose-lowering effects in a mouse model of type 2 diabetes. We conducted this study to elucidate the beta-cell enhancing mechanisms of PERK attenuation.

2026-06-29 | PXD066613 | Pride

5’tRNA-derived fragments modulate beta cell homeostasis and islet macrophage activation in type 2 diabetes – Mouse islets proteomics

Project description:During obesity and type 2 diabetes, pancreatic β-cells face chronic environmental stress, while islet-resident macrophages (iMACs) undergo metabolic reprogramming that exacerbates β-cell dysfunction. Stress-induced cleavage of tRNAs generates tRNA-derived fragments (tRFs), whose role in this context is not fully understood. We identify elevated levels of 5’tRFGlu(CTC) and 5’tRFGly(GCC) in β-cells and iMACs from db/db mice and in islets from type 2 diabetic (T2D) patients. Notably, 5’tRFGlu(CTC) is also induced under prediabetic conditions and inversely correlates with insulin secretion. Lipotoxic stress triggers their production via Angiogenin-mediated cleavage. Blocking 5’tRFGlu(CTC) in islets protects against β-cell apoptosis and restores insulin secretion under palmitate stress. Using a β-cell/macrophage co-culture system, we show that β-cell contact shapes a unique macrophage phenotype (iMAC-like) that shifts upon palmitate exposure—recapitulating in vivo observations. Inhibiting 5’tRFGlu(CTC) in iMAC-like cells prevents this activation switch, reduces β-cell stress, and improves insulin secretion. Mechanistically, 5’tRFGlu(CTC) interacts with RNA-binding proteins to regulate transcriptional and post-transcriptional pathways linked to immune activation, ECM remodeling, neurogenesis, and oxidative stress. Our study identifies 5’tRFs as key mediators of islet microenvironment remodeling in diabetes, offering new insights into intercellular stress signaling in metabolic disease.

2026-03-12 | PXD065746 | Pride

RNA seq of pancreatic islets isolated from free fatty acid receptor 3 knockout (Ffar3 KO) and wildtype (Ffar3 WT) male mice

Project description:The short chain fatty acid (SCFA) receptor (free fatty acid receptor-3; FFAR3) is expressed in pancreatic beta cells; however, its role in insulin secretion is not clearly defined. Here, we examined the role of FFAR3 in insulin secretion. Using islets from global knockout FFAR3 (Ffar3-/-) mice, we explored the role of FFAR3 and ligand-induced FFAR3 signaling on glucose stimulated insulin secretion. RNA sequencing was also performed to gain greater insight into the impact of FFAR3 deletion on the islet transcriptome. First exploring insulin secretion, it was determined that Ffar3-/- islets secrete more insulin in a glucose-dependent manner as compared to wildtype (WT) islets. Next, exploring its primary endogenous ligand, propionate, and a specific agonist for FFAR3, signaling by FFAR3 inhibited glucose-dependent insulin secretion, which occurred through a GÎ±i/o pathway. To help understand these results, transcriptome analyses by RNA-sequencing of Ffar3-/- and WT islets observed multiple genes with well known roles in islet biology to be altered by genetic knockout of FFAR3. Our data shows that FFAR3 signaling mediates glucose stimulated insulin secretion through GÎ±i/o sensitive pathway. Future studies are needed to more rigorously define the role of FFAR3 by in vivo approaches. Analysis of total RNA from 3 biological replicates of pancreatic islets isolated from free fatty acid receptor 3 knockout (Ffar3 KO) and wildtype (Ffar3 WT) male mice

2016-07-03 | E-GEOD-67991 | biostudies-arrayexpress

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.

2013-12-01 | E-GEOD-52314 | biostudies-arrayexpress

Expression data comparing adult human islets to human embryonic stem cell-derived insulin-positive and insulin-negative cells

Project description:The study was completed to compare expression profiles of primary human beta cells (in the form of adult human islets), to the expression profile of hESC-derived beta-like cells. A HES3 line modified by homologous recombination to express GFP under the insulin promoter allowed us to FACS sort the hESC-derived cells into purified insulin-positive (presumably beta-like cells), and insulin-negative populations. Expression profile of adult human islets from cadaveric donors is compared to insulin-positive and insulin-negative populations of hESC-derived beta-like cells

2012-09-09 | E-GEOD-40709 | biostudies-arrayexpress

NOD Mouse Islet Peptide Content Identification

Project description:Beta-cells produce hybrid insulin peptides (HIPs) by linking insulin fragments to other peptides through peptide bonds. HIPs have unique amino acid sequences and are targeted by autoreactive T cells in type 1 diabetes (T1D). Individuals with recent-onset T1D have significantly higher levels of HIP-reactive T cells in their blood compared to non-diabetic control subjects. HIP-reactive T cells have also been found in the residual pancreatic islets of deceased T1D organ donors. In non-obese diabetic (NOD) mice, a major T1D animal model, several CD4 T cell clones that trigger diabetes have been shown to target HIPs. Through mass spectrometry, a subgroup of HIPs containing N-terminal amine groups of various peptides linked to aspartic acid residues of insulin C-peptide has been detected in NOD islets. Our research reveals that these HIPs form spontaneously in beta-cells via an aspartic anhydride intermediate mechanism. This process leads to the creation of a regular HIP with a standard peptide bond and a HIP-isomer (isoHIP) with an isopeptide bond linked to the carboxylic acid side-chain of the aspartic acid residue. Our mass spectrometric analyses confirmed the presence of both HIP isomers in murine islets, thereby validating the occurrence of this new reaction mechanism in beta-cells. The spontaneous formation of neoepitopes through the development of new peptide bonds within cells may contribute to the pathogenesis of T1D and other autoimmune diseases.

2023-11-16 | PXD041616 | Pride

Expression data from the transplanted mouse islets into hyperglycemic and normoglycemic mice at 6 hours post-transplantation

Project description:insulin treatment protects islets from the initial rapid loss that is usually observed after transplantation and positively affects the outcome of islet transplantation in Akita mice. To study the molecular mechanism underlying the improved islet survival, expression profile analyses was performed to analyze the differences between the grafts transplanted into hyperglycemic and normoglycemic mice at 6 hours post-transplantation Cells were harvested at grafts for RNA extraction and hybridization on Affymetrix microarrays. We performed gene expression profiles of the transplanted mouse islets into hyperglycemic and normoglycemic mice at 6 hours post-transplantation

2014-04-18 | E-GEOD-55764 | biostudies-arrayexpress

Transcription profiling of mouse PERK knockouts vs. wikd type

Project description:to study the proliferation of PERK knockout mice islets. The major changes are the proliferation genes Experiment Overall Design: 2days after birth, Experiment Overall Design: Collagenase P digestion Experiment Overall Design: cRNA label with Ambion kit Experiment Overall Design: Hybridization with Affymetrix mouse 430A chip

2008-06-14 | E-GEOD-6193 | biostudies-arrayexpress

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.

2023-11-05 | PXD038554 | Pride

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.

2011-02-22 | E-GEOD-25862 | biostudies-arrayexpress

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