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Giroud J, Combémorel E, Pourtier A, Abbadie C, Pluquet O. Unraveling the functional and molecular interplay between cellular senescence and the unfolded protein response. Am J Physiol Cell Physiol 2025; 328:C1764-C1782. [PMID: 40257464 DOI: 10.1152/ajpcell.00091.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 02/12/2025] [Accepted: 04/14/2025] [Indexed: 04/22/2025]
Abstract
Senescence is a complex cellular state that can be considered as a stress response phenotype. A decade ago, we suggested the intricate connections between unfolded protein response (UPR) signaling and the development of the senescent phenotype. Over the past ten years, significant advances have been made in understanding the multifaceted role of the UPR in regulating cellular senescence, highlighting its contribution to biological processes such as oxidative stress and autophagy. In this updated review, we expand these interconnections with the benefit of new insights, and we suggest that targeting specific components of the UPR could provide novel therapeutic strategies to mitigate the deleterious effects of senescence, with significant implications for age-related pathologies and geroscience.
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Affiliation(s)
- Joëlle Giroud
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Emilie Combémorel
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Albin Pourtier
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Corinne Abbadie
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Olivier Pluquet
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
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Lin KA, Su CC, Liu SH, Lee KI, Fang KM, Tang CH, Kuo CY, Chang KC, Ke JA, Huang CF, Chen YW, Yang CY. Antimony induces mitochondria-dependent and ER stress-triggered apoptosis via the oxidative stress-activated JNK signaling pathway in pancreatic islet β-cells. Toxicology 2025; 516:154188. [PMID: 40368022 DOI: 10.1016/j.tox.2025.154188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 04/30/2025] [Accepted: 05/11/2025] [Indexed: 05/16/2025]
Abstract
Antimony (Sb), a silvery-white metal, is a heavy metal of particular prevalence that has the ability to result in adverse effects in humans through environmental exposure resulting from natural processes and human activities. Epidemiological studies have suggested that Sb has an association with the potential for diabetes mellitus (DM) development. However, the mechanisms by which Sb exerts toxicological effects on pancreatic islet β-cells are still not clear. In this investigation, Sb exposure significantly inhibited rat pancreatic islet β-cell-derived RIN-m5F cell viability and insulin secretion, while inducing mitochondria-dependent apoptotic signals, inclusive of increased apoptotic cell populations, caspase-3 activity, the expression of PARP and caspase-3/-7/-9, and mitochondrial dysfunction. RIN-m5F cells exposure to Sb also led to the triggering of endoplasmic reticulum (ER) stress via the induction of a number of vital molecules, including CHOP, XBP-1s, and caspase-12. In Sb-exposed RIN-m5F cells, 4-PBA pretreatment (an inhibitor of ER stress) significantly suppressed protein expression related to ER stress and events of an apoptotic nature. Furthermore, exposure to Sb resulted in the significant activation of AMPKα, ERK1/2, and JNK signaling, as well as reactive oxygen species (ROS) generation. Pretreatment with SP600125 (an inhibitor of JNK) and antioxidant NAC, but not PD98059 (an inhibitor of ERK) or compound C (an inhibitor of AMPK), effectively abrogated the cytotoxicity, ER stress responses, mitochondrial dysfunction, apoptotic events, insulin secretion inhibition, and JNK activation in Sb-exposed rat pancreatic islet β-cells. However, SP600125 did not prevent ROS generation, which was inhibited by the antioxidant NAC. Collectively, the results demonstrate exposure to Sb to exert β-cell cytotoxicity through oxidative stress-activated JNK signaling downstream-regulated mitochondria-dependent and ER stress-triggered cell apoptotic pathways, eventually resulting in the death of rat pancreatic islet β-cells.
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Affiliation(s)
- Ken-An Lin
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404, Taiwan
| | - Chin-Chuan Su
- Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua County, Changhua County 500, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Kuan-I Lee
- Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan
| | - Kai-Min Fang
- Department of Otolaryngology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
| | - Chih-Hsin Tang
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404, Taiwan
| | - Chun-Ying Kuo
- Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua County, Changhua County 500, Taiwan
| | - Kai-Chih Chang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan
| | - Jun-An Ke
- Department of Medical Education, Changhua Christian Hospital Changhua City 500, Taiwan
| | - Chun-Fa Huang
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan; Department of Nursing, College of Medical and Health Science, Asia University, Taichung 413, Taiwan
| | - Ya-Wen Chen
- Department of Physiology, School of Medicine, College of Medicine, China Medical University, Taichung 404, Taiwan.
| | - Ching-Yao Yang
- Department of Surgery, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan.
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MacDonald TL, Ryback B, Aparecida da Silva Pereira J, Wei S, Mendez B, Cai EP, Ishikawa Y, Arbeau M, Weir G, Bonner-Weir S, Kissler S, Yi P. Renalase inhibition defends against acute and chronic β cell stress by regulating cell metabolism. Mol Metab 2025; 95:102115. [PMID: 39988068 PMCID: PMC11981795 DOI: 10.1016/j.molmet.2025.102115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 02/18/2025] [Accepted: 02/18/2025] [Indexed: 02/25/2025] Open
Abstract
OBJECTIVE Renalase (Rnls) is annotated as an oxidase enzyme. It has been implicated in Type 1 diabetes (T1D) risk via genome-wide association studies (GWAS). We previously discovered through CRISPR screening and validation experiments that Rnls inhibition prevents or delays T1D in multiple mouse models of diabetes in vivo, and protects pancreatic β cells against autoimmune killing, ER and oxidative stress in vitro. The molecular biochemistry and functions of Rnls are largely uncharted. Here we studied the mechanisms of Rnls inhibition that underlie β cell protection during diabetogenic stress. METHODS Akita mice were treated with oral Pargyline (PG) in vivo to bind and inhibit Rnls, and pancreas or islets were harvested for β cell mass and β cell function analyses. Genetic and pharmacological tools were used to inhibit Rnls in β cell lines. RNA sequencing, metabolomics and metabolic function experiments were conducted in vitro in NIT-1 mouse β cell lines and human stem cell-derived β cells. RESULTS In vivo, PG improved glycemia and mildly preserved β cell mass and function in females. Genetic strategies to mutate (Rnlsmut) or knockout (Rnls KO) Rnls induced a robust metabolic shift towards glycolysis in both mouse and human β cell lines, in vitro. Stress protection was abolished when glycolysis was blocked with 2-deoxyglucose (2-DG). Pharmacological Rnls inhibition with PG did not strongly mimic these newly identified metabolic mechanisms. CONCLUSIONS Our work illustrates a role for Rnls in regulating cell metabolism. We show that inhibiting Rnls protects against chronic stress in vivo, and shields against acute stress in β cell lines in vitro by rewiring cell metabolism towards glycolysis.
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Affiliation(s)
- Tara L MacDonald
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, USA; Section for Immunobiology, Joslin Diabetes Center, Boston, USA; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, Harvard Medical School, Boston, MA, USA.
| | - Birgitta Ryback
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA
| | - Jéssica Aparecida da Silva Pereira
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Siying Wei
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Bryhan Mendez
- Section for Immunobiology, Joslin Diabetes Center, Boston, USA
| | - Erica P Cai
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Yuki Ishikawa
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Meagan Arbeau
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Gordon Weir
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Diabetes Program, Harvard Stem Cell Institute, Cambridge, MA, USA
| | - Susan Bonner-Weir
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Diabetes Program, Harvard Stem Cell Institute, Cambridge, MA, USA
| | - Stephan Kissler
- Section for Immunobiology, Joslin Diabetes Center, Boston, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Diabetes Program, Harvard Stem Cell Institute, Cambridge, MA, USA
| | - Peng Yi
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Diabetes Program, Harvard Stem Cell Institute, Cambridge, MA, USA.
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Panzhinskiy E, Skovsø S, Cen HH, Rahardjo A, Zhang JA, Chu KY, MacDonald K, Soukhatcheva G, Dionne DA, Hallmaier-Wacker LK, Wildi JS, Marcil S, Noursadeghi N, Taghizadeh F, Verchere CB, Jan E, Johnson JD. Eukaryotic translation initiation factor 2A protects pancreatic beta cells during endoplasmic reticulum stress while rescuing global translation inhibition. Diabetologia 2025:10.1007/s00125-025-06431-5. [PMID: 40304759 DOI: 10.1007/s00125-025-06431-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 12/03/2024] [Indexed: 05/02/2025]
Abstract
AIMS/HYPOTHESIS The endoplasmic reticulum (ER) stress-induced unfolded protein response helps determine beta cell survival rate in diabetes. The alternative eukaryotic translation initiation factor 2A (EIF2A) has been proposed to mediate translation initiation independent of the α subunit of EIF2 (EIF2S1) during cellular stress, but its role in beta cells has not been comprehensively examined. METHODS For in vitro experiments, we used MIN6 cells, primary mouse pancreatic islets, and human islets obtained under informed consent. Thapsigargin (1 µmol/l) or palmitate complexed with BSA (0.5 mmol/l) was used to induce ER stress. Transient transfection and lentiviral infection were used for transgene delivery. For in vivo experiments, adeno-associated viral particles expressing EIF2A or GFP under the control of a rat insulin promoter were delivered via intraductal injection to 6-week-old female Akita mice randomised into three groups (two cohorts, n=10-11). Tail blood was collected for blood glucose measurements for single time points as well as during glucose and insulin tolerance tests. RESULTS EIF2A protein abundance and specificity was high in human and mouse islets relative to other tissues. We used STRING and AlphaFold pulldown to predict interacting proteins and binding partners, verifying EIF1AX with co-immunoprecipitation. Both thapsigargin and palmitate significantly increased EIF2A mRNA and EIF2A protein levels in MIN6 cells, mouse islets and human islets. Knockdowns of EIF2A, the related factor EIF2D or both EIF2A and EIF2D were not sufficient to cause apoptosis. On the other hand, transient or stable EIF2A overexpression protected MIN6 cells, primary mouse islets and human islets from ER stress-induced, caspase-3-dependent apoptosis. Mechanistically, EIF2A overexpression decreased endoplasmic reticulum to nucleus signalling 1 (ERN1, also known as inositol-requiring enzyme 1 α or IRE1α) expression in thapsigargin-treated MIN6 cells or human islets. In vivo, beta cell-specific EIF2A viral overexpression reduced ER stress and improved insulin secretion and glucose tolerance in Ins2Akita/WT mice. EIF2A overexpression significantly increased expression of genes involved in mRNA translation and reduced expression of pro-apoptotic genes (e.g. Aldh1a3). Proteomic analysis of EIF2A-overexpressing human islets revealed significant changes in pathways associated with ribosomes and protein processing in ER. Remarkably, the decrease in global protein synthesis during unfolded protein response was prevented by EIF2A, despite ER stress-induced EIF2S1 phosphorylation. The protective effects of EIF2A were additive to those of ISRIB, a drug that counteracts the effects of EIF2S1 phosphorylation. Cells overexpressing EIF2A showed higher expression of translation factor EIF2B5, which may contribute to the lack of translational inhibition in these cells. CONCLUSIONS/INTERPRETATION We conclude that EIF2A is a novel target for beta cell protection and the circumvention of EIF2S1-mediated translational repression.
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Affiliation(s)
- Evgeniy Panzhinskiy
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
| | - Søs Skovsø
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Haoning Howard Cen
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Amanda Rahardjo
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Jiashuo Aaron Zhang
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Kwan Yi Chu
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Kate MacDonald
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Galina Soukhatcheva
- BC Children'S Hospital Research Institute, Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Derek A Dionne
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Luisa K Hallmaier-Wacker
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Jennifer S Wildi
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Stephanie Marcil
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Nilou Noursadeghi
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Farnaz Taghizadeh
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - C Bruce Verchere
- BC Children'S Hospital Research Institute, Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Eric Jan
- Life Sciences Institute, Department of Biochemistry, University of British Columbia, Vancouver, BC, Canada.
| | - James D Johnson
- Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
- Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
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Hu R, Yagan M, Wang Y, Tong X, Hamilton N, Doss TD, Liu J, Xu Y, Simmons AJ, Lau KS, Stein R, Kaverina I, Coate KC, Liu Q, Gu G. Diabetes-associated MYT1 and MYT3 regulate human β-cell insulin secretion and survival via other diabetes-risk genes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.24.639737. [PMID: 40060649 PMCID: PMC11888307 DOI: 10.1101/2025.02.24.639737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/18/2025]
Abstract
Genetic and environmental factors together cause islet β-cell failure, leading to Type 2 diabetes (T2D). Yet how they integrate to regulate β-cells remains largely unclear. Here, we examined how two members of the Myelin transcription factor family (MYT1, 2, and 3) prevent human β-cell failure under obesity-related stress. We have reported that obesity-related nutrient levels induce these factors. They prevent β-cell failure in mouse islets and human β-cell lines. Their variants are all associated with human T2D, and their downregulation accompanies β-cell dysfunction. By knocking down MYT1 or MYT3 separately in primary human donor islets, we show here that they have overlapping but distinct functions. Under normal culture conditions, MYT1 - knockdown (KD) causes β-cell death, while MYT3 - KD compromises glucose-stimulated insulin secretion. Under obesity-induced metabolic stress in vivo , MYT3 - KD also causes β-cell death. Accordingly, these TFs regulate common and unique genes, with MYT1 - KD de-regulating several genes in cell death and Ca 2+ binding, while MYT3-KD de-regulating genes involved in mitochondria, ER, etc. Intriguingly, the MYT1 and MYT3-regulated genes are enriched for T2D-associated genes. These findings suggest that the MYT TFs complement each other to serve as a node that integrates genetic and environmental factors to prevent β-cell failure and T2D. Research in Context It is now known that: All MYT TFs (including MYT1, 2, 3) are associated with the risk of T2D, and their downregulation accompanies β-cell failure during human T2D development.besity-related high glucose/free fatty acids regulate the levels and/or nuclear localization of MYT1 and MYT3 in primary human β-cells, implying them as integrators of genetic and nutrition factors to determine the risk of β-cell failure and T2D.Myt TFs, via coregulators including Sin3, work together to prevent postnatal β-cell failure in mice and the death of a human β-cell line, suggesting they are essential switches for β-cell protection.The key remaining question is: How do these TFs regulate primary human β-cell failure in response to different nutritional signals?Our new findings are: Reduced MYT1 or MYT3 expression levels in primary human islets via knockdown compromised β-cell survival or secretion, respectively, under normal physiology.MYT3-knockdown compromises human β-cell survival in obesity.MYT1/MYT3-regulated genes are enriched for those associated with T2D risk.Impact: Manipulating MYT TF activities, via modulating their associations with coregulators, could be explored to attenuate β-cell failure and risk of T2D.
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Hansen MS, Pokharel P, Piganelli J, Sussel L. The Chicken or the Egg Dilemma: Understanding the Interplay between the Immune System and the β Cell in Type 1 Diabetes. Cold Spring Harb Perspect Med 2025; 15:a041591. [PMID: 38951031 PMCID: PMC11960692 DOI: 10.1101/cshperspect.a041591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
In this review, we explore the complex interplay between the immune system and pancreatic β cells in the context of type 1 diabetes (T1D). While T1D is predominantly considered a T-cell-mediated autoimmune disease, the inability of human leukocyte antigen (HLA)-risk alleles alone to explain disease development suggests a role for β cells in initiating and/or propagating disease. This review delves into the vulnerability of β cells, emphasizing their susceptibility to endoplasmic reticulum (ER) stress and protein modifications, which may give rise to neoantigens. Additionally, we discuss the role of viral infections as contributors to T1D onset, and of genetic factors with dual impacts on the immune system and β cells. A greater understanding of the interplay between environmental triggers, autoimmunity, and the β cell will not only lead to insight as to why the islet β cells are specifically targeted by the immune system in T1D but may also reveal potential novel therapeutic interventions.
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Affiliation(s)
- Maria Skjøtt Hansen
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
| | - Pravil Pokharel
- Division of Endocrinology Diabetes and Metabolism, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
| | - Jon Piganelli
- Division of Endocrinology Diabetes and Metabolism, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
| | - Lori Sussel
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
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Sastre J, Pérez S, Sabater L, Rius-Pérez S. Redox signaling in the pancreas in health and disease. Physiol Rev 2025; 105:593-650. [PMID: 39324871 DOI: 10.1152/physrev.00044.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024] Open
Abstract
This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.
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Affiliation(s)
- Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Hospital Clínico, Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
- Department of Cell Biology, Functional Biology and Physical Anthropology, Faculty of Biology, University of Valencia, Valencia, Spain
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8
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He Z, Liu Q, Wang Y, Zhao B, Zhang L, Yang X, Wang Z. The role of endoplasmic reticulum stress in type 2 diabetes mellitus mechanisms and impact on islet function. PeerJ 2025; 13:e19192. [PMID: 40166045 PMCID: PMC11956770 DOI: 10.7717/peerj.19192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 02/26/2025] [Indexed: 04/02/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a globally prevalent metabolic disorder characterized by insulin resistance and dysfunction of islet cells. Endoplasmic reticulum (ER) stress plays a crucial role in the pathogenesis and progression of T2DM, especially in the function and survival of β-cells. β-cells are particularly sensitive to ER stress because they require substantial insulin synthesis and secretion energy. In the early stages of T2DM, the increased demand for insulin exacerbates β-cell ER stress. Although the unfolded protein response (UPR) can temporarily alleviate this stress, prolonged or excessive stress leads to pancreatic cell dysfunction and apoptosis, resulting in insufficient insulin secretion. This review explores the mechanisms of ER stress in T2DM, particularly its impact on islet cells. We discuss how ER stress activates UPR signaling pathways to regulate protein folding and degradation, but when stress becomes excessive, these pathways may contribute to β-cell death. A deeper understanding of how ER stress impacts islet cells could lead to the development of novel T2DM treatment strategies aimed at improving islet function and slowing disease progression.
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Affiliation(s)
- Zhaxicao He
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Qian Liu
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Yan Wang
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Bing Zhao
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Lumei Zhang
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Xia Yang
- Tianshui Hospital of Traditional Chinese Medicine, Tianshui, China
| | - Zhigang Wang
- Gansu University of Chinese Medicine, Lanzhou, China
- Tianshui Hospital of Traditional Chinese Medicine, Tianshui, China
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Saxena S, Liebscher S. Boosting the X factor: Increasing XBP1s-mediated ER stress signaling protects motor neurons in ALS/FTD. Mol Ther 2025; 33:844-846. [PMID: 39999835 PMCID: PMC11897750 DOI: 10.1016/j.ymthe.2025.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/04/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Affiliation(s)
- Smita Saxena
- Department of Physical Medicine & Rehabilitation, University of Missouri, Columbia, MO, USA; NextGen Precision Health, University of Missouri, Columbia, MO, USA.
| | - Sabine Liebscher
- Institute of Clinical Neuroimmunology, University Hospital Munich & BioMedical Center, Ludwig Maximilians University Munich, Martinsried, Germany; Institute of Neurobiochemistry, Medical University of Innsbruck, Innsbruck, Austria.
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10
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Mladenov M, Sazdova I, Hadzi-Petrushev N, Konakchieva R, Gagov H. The Role of Reductive Stress in the Pathogenesis of Endocrine-Related Metabolic Diseases and Cancer. Int J Mol Sci 2025; 26:1910. [PMID: 40076537 PMCID: PMC11899626 DOI: 10.3390/ijms26051910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/14/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
Reductive stress (RS), characterized by excessive accumulation of reducing equivalents such as NADH and NADPH, is emerging as a key factor in metabolic disorders and cancer. While oxidative stress (OS) has been widely studied, RS and its complex interplay with endocrine regulation remain less understood. This review explores molecular circuits of bidirectional crosstalk between metabolic hormones and RS, focusing on their role in diabetes, obesity, cardiovascular diseases, and cancer. RS disrupts insulin secretion and signaling, exacerbates metabolic inflammation, and contributes to adipose tissue dysfunction, ultimately promoting insulin resistance. In cardiovascular diseases, RS alters vascular smooth muscle cell function and myocardial metabolism, influencing ischemia-reperfusion injury outcomes. In cancer, RS plays a dual role: it enhances tumor survival by buffering OS and promoting metabolic reprogramming, yet excessive RS can trigger proteotoxicity and mitochondrial dysfunction, leading to apoptosis. Recent studies have identified RS-targeting strategies, including redox-modulating therapies, nanomedicine, and drug repurposing, offering potential for novel treatments. However, challenges remain, particularly in distinguishing physiological RS from pathological conditions and in overcoming therapy-induced resistance. Future research should focus on developing selective RS biomarkers, optimizing therapeutic interventions, and exploring the role of RS in immune and endocrine regulation.
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Affiliation(s)
- Mitko Mladenov
- Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (M.M.); (N.H.-P.)
- Department of Fundamental and Applied Physiology, Russian States Medical University, 117997 Moscow, Russia
| | - Iliyana Sazdova
- Department of Animal and Human Physiology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 1164 Sofia, Bulgaria;
| | - Nikola Hadzi-Petrushev
- Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (M.M.); (N.H.-P.)
| | - Rossitza Konakchieva
- Department of Cell and Developmental Biology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 1164 Sofia, Bulgaria;
| | - Hristo Gagov
- Department of Animal and Human Physiology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 1164 Sofia, Bulgaria;
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11
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Huang Y, He J, Wang Y, Li L, Lin S. Nitrogen source type modulates heat stress response in coral symbiont ( Cladocopium goreaui). Appl Environ Microbiol 2025; 91:e0059124. [PMID: 39772785 PMCID: PMC11837503 DOI: 10.1128/aem.00591-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 10/09/2024] [Indexed: 01/11/2025] Open
Abstract
Ocean warming due to climate change endangers coral reefs, and regional nitrogen overloading exacerbates the vulnerability of reef-building corals as the dual stress disrupts coral-Symbiodiniaceae mutualism. Different forms of nitrogen may create different interactive effects with thermal stress, but the underlying mechanisms remain elusive. To address the gap, we measured and compared the physiological and transcriptional responses of the Symbiodiniaceae Cladocopium goreaui to heat stress (31°C) when supplied with different types of nitrogen (nitrate, ammonium, or urea). Under heat stress (HS), cell proliferation and photosynthesis of C. goreaui declined, while cell size, lipid storage, and total antioxidant capacity increased, both to varied extents depending on the nitrogen type. Nitrate-cultured cells exhibited the most robust acclimation to HS, as evidenced by the fewest differentially expressed genes (DEGs) and less ROS accumulation, possibly due to activated nitrate reduction and enhanced ascorbate biogenesis. Ammonium-grown cultures exhibited higher algal proliferation and ROS scavenging capacity due to enhanced carotenoid and ascorbate quenching, but potentially reduced host recognizability due to the downregulation of N-glycan biosynthesis genes. Urea utilization led to the greatest ROS accumulation as genes involved in photorespiration, plant respiratory burst oxidase (RBOH), and protein refolding were markedly upregulated, but the greatest cutdown in photosynthate potentially available to corals as evidenced by photoinhibition and selfish lipid storage, indicating detrimental effects of urea overloading. The differential warming nitrogen-type interactive effects documented here has significant implication in coral-Symbiodiniaceae mutualism, which requires further research.IMPORTANCERegional nitrogen pollution exacerbates coral vulnerability to globally rising sea-surface temperature, with different nitrogen types exerting different interactive effects. How this occurs is poorly understood and understudied. This study explored the underlying mechanism by comparing physiological and transcriptional responses of a coral symbiont to heat stress under different nitrogen supplies (nitrate, ammonium, and urea). The results showed some common, significant responses to heat stress as well as some unique, N-source dependent responses. These findings underscore that nitrogen eutrophication is not all the same, the form of nitrogen pollution should be considered in coral conservation, and special attention should be given to urea pollution.
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Affiliation(s)
- Yulin Huang
- State Key Laboratory of Marine Environmental Science, College of Ocean and Earth Sciences, Xiamen University, Xiamen, Fujian, China
| | - Jiamin He
- State Key Laboratory of Marine Environmental Science, College of Ocean and Earth Sciences, Xiamen University, Xiamen, Fujian, China
| | - Yujie Wang
- State Key Laboratory of Marine Environmental Science, College of Ocean and Earth Sciences, Xiamen University, Xiamen, Fujian, China
| | - Ling Li
- State Key Laboratory of Marine Environmental Science, College of Ocean and Earth Sciences, Xiamen University, Xiamen, Fujian, China
| | - Senjie Lin
- Department of Marine Sciences, University of Connecticut, Groton, Connecticut, USA
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12
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Pinheiro-Machado E, de Haan BJ, Engelse MA, Smink AM. Secretome Analysis of Human and Rat Pancreatic Islets Co-Cultured with Adipose-Derived Stromal Cells Reveals a Signature with Enhanced Regenerative Capacities. Cells 2025; 14:302. [PMID: 39996773 PMCID: PMC11854805 DOI: 10.3390/cells14040302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 02/06/2025] [Accepted: 02/14/2025] [Indexed: 02/26/2025] Open
Abstract
Pancreatic islet transplantation (PIT) is a promising treatment for type 1 diabetes (T1D) but faces challenges pre- and post-transplantation. Co-transplantation with mesenchymal stromal cells (MSCs), known for their regenerative properties, has shown potential in improving PIT outcomes. This study examined the secretome of islets cultured alone compared to the secretomes of islets co-cultured with adipose-derived stromal cells (ASCs), a subtype of MSCs, under transplantation-relevant stressors: normoxia, cytokines, high glucose, hypoxia, and combined hypoxia and high glucose. Islet co-culture with ASCs significantly altered the proteome, affecting pathways related to energy metabolism, angiogenesis, extracellular matrix organization, and immune modulation. Key signaling molecules (e.g., VEGF, PDGF, bFGF, Collagen I alpha 1, IL-1α, and IL-10) were differentially regulated depending on culture conditions and ASC presence. Functional assays demonstrated that the co-culture secretome could enhance angiogenesis, collagen deposition, and immune modulation, depending on the stress conditions. These findings highlight possible mechanisms through which ASCs may support islet survival and function, offering insights into overcoming PIT challenges. Moreover, this work contributes to identifying biomarkers of the post-transplantation microenvironment, advancing therapeutic strategies for T1D and regenerative medicine.
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Affiliation(s)
- Erika Pinheiro-Machado
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Bart J. de Haan
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Marten A. Engelse
- Leiden Transplant Center, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Alexandra M. Smink
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
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13
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Liu Y, Yang X, Zhou J, Yang H, Yang R, Zhu P, Zhou R, Wu T, Gao Y, Ye Z, Li X, Liu R, Zhang W, Zhou H, Li Q. OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in mice. Nat Commun 2024; 15:10479. [PMID: 39622811 PMCID: PMC11612026 DOI: 10.1038/s41467-024-54905-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 11/25/2024] [Indexed: 12/06/2024] Open
Abstract
Proinsulin translation and folding is crucial for glucose homeostasis. However, islet β-cell control of Proinsulin translation remains incompletely understood. Here, we identify OSGEP, an enzyme responsible for t6A37 modification of tRNANNU that tunes glucose metabolism in β-cells. Global Osgep deletion causes glucose intolerance, while β-cell-specific deletion induces hyperglycemia and glucose intolerance due to impaired insulin activity. Transcriptomics and proteomics reveal activation of the unfolded protein response (UPR) and apoptosis signaling pathways in Osgep-deficient islets, linked to an increase in misfolded Proinsulin from reduced t6A37 modification. Osgep overexpression in pancreas rescues insulin secretion and mitigates diabetes in high-fat diet mice. Osgep enhances translational fidelity and alleviates UPR signaling, highlighting its potential as a therapeutic target for diabetes. Individuals carrying the C allele at rs74512655, which promotes OSGEP transcription, may show reduced susceptibility to T2DM. These findings show OSGEP is essential for islet β-cells and a potential diabetes therapy target.
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Affiliation(s)
- Yujie Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
- Department of Pharmacy, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xuechun Yang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Jian Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Haijun Yang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Ruimeng Yang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Peng Zhu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Rong Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Tianyuan Wu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Yongchao Gao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Zhi Ye
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, 410008, China
| | - Xi Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Rong Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Honghao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Qing Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, China.
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410078, China.
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China.
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14
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Zaidalkilani AT, Al‐kuraishy HM, Fahad EH, Al‐Gareeb AI, Elewa YHA, Zahran MH, Alexiou A, Papadakis M, AL‐Farga A, Batiha GE. Autophagy modulators in type 2 diabetes: A new perspective. J Diabetes 2024; 16:e70010. [PMID: 39676616 PMCID: PMC11647182 DOI: 10.1111/1753-0407.70010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 05/31/2024] [Accepted: 08/27/2024] [Indexed: 12/17/2024] Open
Abstract
Type 2 diabetes (T2D) is a chronic metabolic disorder caused by defective insulin signaling, insulin resistance, and impairment of insulin secretion. Autophagy is a conserved lysosomal-dependent catabolic cellular pathway involved in the pathogenesis of T2D and its complications. Basal autophagy regulates pancreatic β-cell function by enhancing insulin release and peripheral insulin sensitivity. Therefore, defective autophagy is associated with impairment of pancreatic β-cell function and the development of insulin rersistance (IR). However, over-activated autophagy increases apoptosis of pancreatic β-cells leading to pancreatic β-cell dysfunction. Hence, autophagy plays a double-edged sword role in T2D. Therefore, the use of autophagy modulators including inhibitors and activators may affect the pathogenesis of T2D. Hence, this review aims to clarify the potential role of autophagy inhibitors and activators in T2D.
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Affiliation(s)
- Ayah Talal Zaidalkilani
- Department of Nutrition, Faculty of Pharmacy and Medical SciencesUniversity of PetraAmmanJordan
| | - Hayder M. Al‐kuraishy
- Department of Clinical Pharmacology and MedicineCollege of Medicine, Al‐Mustansiriyah UniversityBaghdadIraq
| | - Esraa H. Fahad
- Department of Pharmacology and ToxicologyCollege of Pharmacy, Mustansiriyah UniversityBaghdadIraq
| | - Ali I. Al‐Gareeb
- Department of Clinical Pharmacology and MedicineCollege of Medicine, Al‐Mustansiriyah UniversityBaghdadIraq
| | - Yaser Hosny Ali Elewa
- Department of Histology and Cytology, Faculty of Veterinary MedicineZagazig UniversityZagazigEgypt
- Faculty of Veterinary MedicineHokkaido UniversitySapporoJapan
| | | | - Athanasios Alexiou
- University Centre for Research & Development, Chandigarh UniversityMohaliPunjabIndia
- Department of Research & DevelopmentFunogenAthensGreece
- Department of Research & DevelopmentAFNP MedWienAustria
- Department of Science and EngineeringNovel Global Community Educational FoundationHebershamNew South WalesAustralia
| | - Marios Papadakis
- Department of Surgery IIUniversity Hospital Witten‐HerdeckeWuppertalGermany
| | - Ammar AL‐Farga
- Department of BiochemistryCollege of Science University of JeddahJeddahSaudi Arabia
| | - Gaber El‐Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary MedicineDamanhur UniversityDamanhurAlBeheiraEgypt
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15
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Klyosova E, Azarova I, Petrukhina I, Khabibulin R, Polonikov A. The rs2341471-G/G genotype of activating transcription factor 6 (ATF6) is the risk factor of type 2 diabetes in subjects with obesity or overweight. Int J Obes (Lond) 2024; 48:1638-1649. [PMID: 39134692 DOI: 10.1038/s41366-024-01604-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 07/17/2024] [Accepted: 08/06/2024] [Indexed: 08/28/2024]
Abstract
BACKGROUND Numerous studies have demonstrated that the onset of type 2 diabetes (T2D) is linked to the reduction in ß-cell mass caused by apoptosis, a process initiated by endoplasmic reticulum (ER) stress. The aim of this study was to investigate the associations between single nucleotide polymorphisms (SNPs) in the ATF6 gene (activating transcription factor 6), a key sensor of ER stress, and T2D susceptibility. METHODS The study involved 3229 unrelated individuals, including 1569 patients with T2D and 1660 healthy controls from Central Russia. Four functionally significant intronic SNPs, namely rs931778, rs90559, rs2341471, and rs7517862, were genotyped using the MassARRAY-4 system. RESULTS The rs2341471-G/G genotype of ATF6 was found to be associated with an increased risk of T2D (OR = 1.61, 95% CI 1.37-1.90, PFDR < 0.0001). However, a BMI-stratified analysis showed that this genotype and haplotypes CGGA and TAGA are associated with T2D risk exclusively in subjects with obesity or overweight (PFDR < 0.05). Despite these patients being found to have higher consumption of high-carbohydrate and high-calorie diets compared to normal-weight individuals (P < 0.0001), the influence of the rs7517862 polymorphism on T2D risk was observed independently of these dietary habits. Functional SNP annotation revealed the following: (1) the rs2341471-G allele is associated with increased ATF6 expression; (2) the SNP is located in a region exhibiting enhancer activity epigenetically regulated in pancreatic islets; (3) the rs2341471-G was predicted to create binding sites for 18 activating transcription factors that are part of gene-regulatory networks controlling glucose metabolism and maintaining proteostasis. CONCLUSIONS The present study revealed, for the first time, a strong association between the rs2341471-G/G ATF6 genotype and an increased risk of type 2 diabetes in people with obesity or overweight, regardless of known dietary risk factors. Further research is needed to support the potential of silencing the ATF6 gene as a means for the treatment and prevention of type 2 diabetes.
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Affiliation(s)
- Elena Klyosova
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041, Kursk, Russia
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, 305041, Kursk, Russia
| | - Iuliia Azarova
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041, Kursk, Russia
- Department of Biological Chemistry, Kursk State Medical University, 3 Karl Marx Street, 305041, Kursk, Russia
| | - Irina Petrukhina
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041, Kursk, Russia
| | - Ramis Khabibulin
- Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041, Kursk, Russia
| | - Alexey Polonikov
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, 305041, Kursk, Russia.
- Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041, Kursk, Russia.
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16
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DiGuilio A, Cheng B, Zhong F, Jha R, Wan Y, Anghel S, Hu H, Shishkova E, Ji Z, Coon JJ, Keenan RJ. The prolyl isomerase FKBP11 is a secretory translocon accessory factor. Mol Biol Cell 2024; 35:ar135. [PMID: 39259761 PMCID: PMC11617091 DOI: 10.1091/mbc.e24-07-0305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 08/29/2024] [Accepted: 09/02/2024] [Indexed: 09/13/2024] Open
Abstract
Eukaryotic cells encode thousands of secretory and membrane proteins, many of which are cotranslationally translocated into the endoplasmic reticulum (ER). Nascent polypeptides entering the ER encounter a network of molecular chaperones and enzymes that facilitate their folding. A rate-limiting step for some proteins is the trans-to-cis isomerization of the peptide bond between proline and the residue preceding it. The human ER contains six prolyl isomerases, but the function, organization, and substrate range of these proteins is not clear. Here we show that the metazoan-specific, prolyl isomerase FKBP11 binds to ribosome-translocon complexes (RTCs) in the ER membrane, dependent on its single transmembrane domain and a conserved, positively charged region at its cytosolic C-terminus. High-throughput mRNA sequencing shows selective engagement with ribosomes synthesizing secretory and membrane proteins with long translocated segments, and functional analysis shows reduced stability of two such proteins, EpCAM and PTTG1IP, in cells depleted of FKBP11. We propose that FKBP11 is a translocon accessory factor that acts on a broad range of soluble secretory and transmembrane proteins during their synthesis at the ER.
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Affiliation(s)
- Amanda DiGuilio
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637
| | - Ben Cheng
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637
| | - Frank Zhong
- Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637
| | - Roshan Jha
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637
| | - Yu Wan
- Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60628
| | - S. Andrei Anghel
- Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637
| | - Hong Hu
- Center for Research Informatics, The University of Chicago, Chicago, IL 60637
| | - Evgenia Shishkova
- National Center for Quantitative Biology of Complex Systems, Madison, WI 53706
- Department of Biomolecular Chemistry, University of Wisconsin–Madison, Madison, WI 53706
| | - Zhe Ji
- Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60628
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
| | - Joshua J. Coon
- National Center for Quantitative Biology of Complex Systems, Madison, WI 53706
- Department of Biomolecular Chemistry, University of Wisconsin–Madison, Madison, WI 53706
- Morgridge Institute for Research, Madison, WI 53515
- Department of Chemistry, University of Wisconsin–Madison, Madison, WI 53506
| | - Robert J. Keenan
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637
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17
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Tong X, Yagan M, Hu R, Nevills S, Doss TD, Stein RW, Balamurugan AN, Gu G. Metabolic Stress Levels Influence the Ability of Myelin Transcription Factors to Regulate β-Cell Identity and Survival. Diabetes 2024; 73:1662-1672. [PMID: 39058602 PMCID: PMC11417441 DOI: 10.2337/db23-0528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 07/14/2024] [Indexed: 07/28/2024]
Abstract
A hallmark of type 2 diabetes (T2D) is endocrine islet β-cell failure, which can occur via cell dysfunction, loss of identity, and/or death. How each is induced remains largely unknown. We used mouse β-cells deficient for myelin transcription factors (Myt TFs; including Myt1, -2, and -3) to address this question. We previously reported that inactivating all three Myt genes in pancreatic progenitor cells (MytPancΔ) caused β-cell failure and late-onset diabetes in mice. Their lower expression in human β-cells is correlated with β-cell dysfunction, and single nucleotide polymorphisms in MYT2 and MYT3 are associated with a higher risk of T2D. We now show that these Myt TF-deficient postnatal β-cells also dedifferentiate by reactivating several progenitor markers. Intriguingly, mosaic Myt TF inactivation in only a portion of islet β-cells did not result in overt diabetes, but this created a condition where Myt TF-deficient β-cells remained alive while activating several markers of Ppy-expressing islet cells. By transplanting MytPancΔ islets into the anterior eye chambers of immune-compromised mice, we directly show that glycemic and obesity-related conditions influence cell fate, with euglycemia inducing several Ppy+ cell markers and hyperglycemia and insulin resistance inducing additional cell death. These findings suggest that the observed β-cell defects in T2D depend not only on their inherent genetic/epigenetic defects but also on the metabolic load. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Xin Tong
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Mahircan Yagan
- Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN
- Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN
| | - Ruiying Hu
- Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN
- Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN
| | - Simone Nevills
- Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN
- Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN
| | - Teri D. Doss
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Roland W. Stein
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Appakalai N. Balamurugan
- Center for Clinical and Translational Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH
| | - Guoqiang Gu
- Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN
- Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN
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Rashwan AM, Abumandour MMA, Kandyel R, Choudhary OP, Soliman RM, El Sharaby A, Nomir AG. Implications of endoplasmic reticulum stress and beta-cell loss in immunodeficient diabetic NRG-Akita mice for understanding monogenic diabetes. Int J Surg 2024; 110:6231-6242. [PMID: 38329104 PMCID: PMC11486971 DOI: 10.1097/js9.0000000000001148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 01/26/2024] [Indexed: 02/09/2024]
Abstract
BACKGROUND Immunodeficient mice models have become increasingly important as in vivo models engrafted with human cells or tissues for research. The NOD-Rag1 null Ins2 Akita Il2r null (NRG-Akita) mice is a model combined with immunodeficient NRG and monogenic diabetes Akita mice that develop spontaneous hyperglycemia with progressive loss of pancreatic insulin-producing beta-cells with age. This model is one of the monogenic diabetic models, which has been providing a powerful platform for transplantation experiments of stem cells-generated human β-cells. This research aimed to provide insights into the mechanisms underlying this monogenic diabetes, which remains incompletely understood. METHODS Histological and immunofluorescence analyses were conducted on endocrine pancreatic islets to compare NRG wild-type (Wt) controls with NRG-Akita mice. Our investigation focused on assessing the expression of endocrine hormones, transcription factors, proliferation, ER stress, and apoptosis. RESULTS Histological analyses on NRG-Akita mice revealed smaller islets at 6-weeks-old, due to fewer β-cells in the islets, compared to NRG-Wt controls, which further progressed with age. The proliferation rate decreased, and apoptosis was abundant in β-cells in NRG-Akita mice. Interestingly, our mechanistic analyses revealed that β-cells in NRG-Akita mice progressively accumulated the endoplasmic reticulum (ER) stresses, leading to a decreased expression of pivotal β-cell transcriptional factor PDX1. CONCLUSIONS Altogether, our mechanistic insight into β-cell loss in this model could shed light on essential links between ER stress, proliferation, and cell identity, which might open the door to new therapeutic strategies for various diseases since ER stress is one of the most common features not only in diabetes but also in other degenerative diseases.
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Affiliation(s)
- Ahmed M. Rashwan
- Department of Anatomy and Embryology
- Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Japan
| | | | - Ramadan Kandyel
- Department of Zoology, Faculty of Science, Tanta University, Tanta, Egypt
- Department of Biology, Faculty of Arts and Sciences, Najran University, Najran, Saudi Arabia
| | - Om P. Choudhary
- Department of Veterinary Anatomy, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University, Rampura Phul, Bathinda, Punjab, India
| | - Rofaida M. Soliman
- Department of Animal Medicine, Faculty of Veterinary Medicine, Damanhour University, Damanhour
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19
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Gulen B, Blevins A, Kinch LN, Servage KA, Stewart NM, Gray HF, Casey AK, Orth K. FicD sensitizes cellular response to glucose fluctuations in mouse embryonic fibroblasts. Proc Natl Acad Sci U S A 2024; 121:e2400781121. [PMID: 39259589 PMCID: PMC11420183 DOI: 10.1073/pnas.2400781121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 08/07/2024] [Indexed: 09/13/2024] Open
Abstract
During homeostasis, the endoplasmic reticulum (ER) maintains productive transmembrane and secretory protein folding that is vital for proper cellular function. The ER-resident HSP70 chaperone, binding immunoglobulin protein (BiP), plays a pivotal role in sensing ER stress to activate the unfolded protein response (UPR). BiP function is regulated by the bifunctional enzyme filamentation induced by cyclic-AMP domain protein (FicD) that mediates AMPylation and deAMPylation of BiP in response to changes in ER stress. AMPylated BiP acts as a molecular rheostat to regulate UPR signaling, yet little is known about the molecular consequences of FicD loss. In this study, we investigate the role of FicD in mouse embryonic fibroblast (MEF) response to pharmacologically and metabolically induced ER stress. We find differential BiP AMPylation signatures when comparing robust chemical ER stress inducers to physiological glucose starvation stress and recovery. Wildtype MEFs respond to pharmacological ER stress by down-regulating BiP AMPylation. Conversely, BiP AMPylation in wildtype MEFs increases upon metabolic stress induced by glucose starvation. Deletion of FicD results in widespread gene expression changes under baseline growth conditions. In addition, FicD null MEFs exhibit dampened UPR signaling, altered cell stress recovery response, and unconstrained protein secretion. Taken together, our findings indicate that FicD is important for tampering UPR signaling, stress recovery, and the maintenance of secretory protein homeostasis.
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Affiliation(s)
- Burak Gulen
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
- HHMI, Dallas, TX 75390
| | - Aubrie Blevins
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Lisa N Kinch
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
- HHMI, Dallas, TX 75390
| | - Kelly A Servage
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
- HHMI, Dallas, TX 75390
| | - Nathan M Stewart
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
- HHMI, Dallas, TX 75390
| | - Hillery F Gray
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
- HHMI, Dallas, TX 75390
| | - Amanda K Casey
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
- HHMI, Dallas, TX 75390
| | - Kim Orth
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
- HHMI, Dallas, TX 75390
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390
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20
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Sak F, Sengul F, Vatansev H. The Role of Endoplasmic Reticulum Stress in Metabolic Diseases. Metab Syndr Relat Disord 2024; 22:487-493. [PMID: 38666441 DOI: 10.1089/met.2024.0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2024] Open
Abstract
The endoplasmic reticulum (ER), the center of protein folding, also controls the cell's life-and-death signaling mechanisms. ER stress caused by unfolded or misfolded proteins leads to the activation of the unfolded protein response (UPR) in the cell. The UPR utilizes three main signaling pathways to restore disrupted ER homeostasis. These signaling pathways are protein kinase R-like endoplasmic reticulum kinase, inositol-requiring enzyme 1, and activating transcription factor 6. Studies have reported that ER stress (ERS) plays a role in the pathogenesis of metabolic disorders such as diabetes, obesity, atherosclerosis, and nonalcoholic liver disease. This review will briefly discuss the ERS response in these metabolic diseases.
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Affiliation(s)
- Firdevs Sak
- Faculty of Medicine, Department of Medical Biochemistry, University of Selçuk, Konya, Turkey
| | - Fatma Sengul
- Faculty of Pharmacy, Department of Biochemistry, University of Adiyaman, Adiyaman, Turkey
| | - Husamettin Vatansev
- Faculty of Medicine, Department of Medical Biochemistry, University of Selçuk, Konya, Turkey
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21
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Zhu S, Waeckel-Énée E, Oshima M, Moser A, Bessard MA, Gdoura A, Roger K, Mode N, Lipecka J, Yilmaz A, Bertocci B, Diana J, Saintpierre B, Guerrera IC, Scharfmann R, Francesconi S, Mauvais FX, van Endert P. Islet cell stress induced by insulin-degrading enzyme deficiency promotes regeneration and protection from autoimmune diabetes. iScience 2024; 27:109929. [PMID: 38799566 PMCID: PMC11126816 DOI: 10.1016/j.isci.2024.109929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 03/08/2024] [Accepted: 05/03/2024] [Indexed: 05/29/2024] Open
Abstract
Tuning of protein homeostasis through mobilization of the unfolded protein response (UPR) is key to the capacity of pancreatic beta cells to cope with variable demand for insulin. Here, we asked how insulin-degrading enzyme (IDE) affects beta cell adaptation to metabolic and immune stress. C57BL/6 and autoimmune non-obese diabetic (NOD) mice lacking IDE were exposed to proteotoxic, metabolic, and immune stress. IDE deficiency induced a low-level UPR with islet hypertrophy at the steady state, rapamycin-sensitive beta cell proliferation enhanced by proteotoxic stress, and beta cell decompensation upon high-fat feeding. IDE deficiency also enhanced the UPR triggered by proteotoxic stress in human EndoC-βH1 cells. In Ide-/- NOD mice, islet inflammation specifically induced regenerating islet-derived protein 2, a protein attenuating autoimmune inflammation. These findings establish a role of IDE in islet cell protein homeostasis, demonstrate how its absence induces metabolic decompensation despite beta cell proliferation, and UPR-independent islet regeneration in the presence of inflammation.
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Affiliation(s)
- Shuaishuai Zhu
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France
| | | | - Masaya Oshima
- Université Paris Cité, CNRS, INSERM, Institut Cochin, F-75014 Paris, France
| | - Anna Moser
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France
| | - Marie-Andrée Bessard
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France
| | - Abdelaziz Gdoura
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France
| | - Kevin Roger
- Université Paris Cité, INSERM, CNRS, Structure Fédérative de Recherche Necker, Proteomics Platform, F-75015 Paris, France
| | - Nina Mode
- Université Paris Cité, CNRS, INSERM, Institut Cochin, F-75014 Paris, France
| | - Joanna Lipecka
- Université Paris Cité, INSERM, CNRS, Structure Fédérative de Recherche Necker, Proteomics Platform, F-75015 Paris, France
| | - Ayse Yilmaz
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France
| | - Barbara Bertocci
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France
| | - Julien Diana
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France
| | | | - Ida Chiara Guerrera
- Université Paris Cité, INSERM, CNRS, Structure Fédérative de Recherche Necker, Proteomics Platform, F-75015 Paris, France
| | - Raphael Scharfmann
- Université Paris Cité, CNRS, INSERM, Institut Cochin, F-75014 Paris, France
| | - Stefania Francesconi
- Genome Dynamics Unit, Institut Pasteur, Centre National de la Recherche Scientifique, UMR3525, F-75015 Paris, France
| | - François-Xavier Mauvais
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France
- Service de Physiologie – Explorations Fonctionnelles Pédiatriques, AP-HP, Hôpital Universitaire Robert Debré, F-75019 Paris, France
| | - Peter van Endert
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France
- Service Immunologie Biologique, AP-HP, Hôpital Universitaire Necker-Enfants Malades, F-75015 Paris, France
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22
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MacDonald T, Ryback B, da Silva Pereira JA, Wei S, Mendez B, Cai E, Ishikawa Y, Weir G, Bonner-Weir S, Kissler S, Yi P. Renalase inhibition regulates β cell metabolism to defend against acute and chronic stress. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.11.598322. [PMID: 38915698 PMCID: PMC11195134 DOI: 10.1101/2024.06.11.598322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Renalase (Rnls), annotated as an oxidase enzyme, is a GWAS gene associated with Type 1 Diabetes (T1D) risk. We previously discovered that Rnls inhibition delays diabetes onset in mouse models of T1D in vivo , and protects pancreatic β cells against autoimmune killing, ER and oxidative stress in vitro . The molecular biochemistry and functions of Rnls are entirely uncharted. Here we find that Rnls inhibition defends against loss of β cell mass and islet dysfunction in chronically stressed Akita mice in vivo . We used RNA sequencing, untargeted and targeted metabolomics and metabolic function experiments in mouse and human β cells and discovered a robust and conserved metabolic shift towards glycolysis, amino acid abundance and GSH synthesis to counter protein misfolding stress, in vitro . Our work illustrates a function for Rnls in mammalian cells, and suggests an axis by which manipulating intrinsic properties of β cells can rewire metabolism to protect against diabetogenic stress.
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23
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Kim DS, Song L, Gou W, Kim J, Liu B, Wei H, Muise-Helmericks RC, Li Z, Wang H. GRP94 is an IGF-1R chaperone and regulates beta cell death in diabetes. Cell Death Dis 2024; 15:374. [PMID: 38811543 PMCID: PMC11137047 DOI: 10.1038/s41419-024-06754-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 05/10/2024] [Accepted: 05/16/2024] [Indexed: 05/31/2024]
Abstract
High workload-induced cellular stress can cause pancreatic islet β cell death and dysfunction, or β cell failure, a hallmark of type 2 diabetes mellitus. Thus, activation of molecular chaperones and other stress-response genes prevents β cell failure. To this end, we have shown that deletion of the glucose-regulated protein 94 (GRP94) in Pdx1+ pancreatic progenitor cells led to pancreas hypoplasia and reduced β cell mass during pancreas development in mice. Here, we show that GRP94 was involved in β cell adaption and compensation (or failure) in islets from leptin receptor-deficient (db/db) mice in an age-dependent manner. GRP94-deficient cells were more susceptible to cell death induced by various diabetogenic stress conditions. We also identified a new client of GRP94, insulin-like growth factor-1 receptor (IGF-1R), a critical factor for β cell survival and function that may mediate the effect of GRP94 in the pathogenesis of diabetes. This study has identified essential functions of GRP94 in β cell failure related to diabetes.
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Affiliation(s)
- Do-Sung Kim
- Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Lili Song
- Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Wenyu Gou
- Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Jisun Kim
- Microbiology and Immunology, Medical University of South Carolina, Charleson, SC, 29425, USA
| | - Bei Liu
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center-James, Columbus, OH, 43210, USA
| | - Hua Wei
- Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Robin C Muise-Helmericks
- Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Zihai Li
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center-James, Columbus, OH, 43210, USA
| | - Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA.
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA.
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24
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Dobson JR, Jacobson DA. Disrupted Endoplasmic Reticulum Ca 2+ Handling: A Harβinger of β-Cell Failure. BIOLOGY 2024; 13:379. [PMID: 38927260 PMCID: PMC11200644 DOI: 10.3390/biology13060379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/17/2024] [Accepted: 05/17/2024] [Indexed: 06/28/2024]
Abstract
The β-cell workload increases in the setting of insulin resistance and reduced β-cell mass, which occurs in type 2 and type 1 diabetes, respectively. The prolonged elevation of insulin production and secretion during the pathogenesis of diabetes results in β-cell ER stress. The depletion of β-cell Ca2+ER during ER stress activates the unfolded protein response, leading to β-cell dysfunction. Ca2+ER is involved in many pathways that are critical to β-cell function, such as protein processing, tuning organelle and cytosolic Ca2+ handling, and modulating lipid homeostasis. Mutations that promote β-cell ER stress and deplete Ca2+ER stores are associated with or cause diabetes (e.g., mutations in ryanodine receptors and insulin). Thus, improving β-cell Ca2+ER handling and reducing ER stress under diabetogenic conditions could preserve β-cell function and delay or prevent the onset of diabetes. This review focuses on how mechanisms that control β-cell Ca2+ER are perturbed during the pathogenesis of diabetes and contribute to β-cell failure.
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Affiliation(s)
| | - David A. Jacobson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA;
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25
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Mbara KC, Fotsing MC, Ndinteh DT, Mbeb CN, Nwagwu CS, Khan R, Mokhetho KC, Baijnath H, Nlooto M, Mokhele S, Leonard CM, Tembu VJ, Tarirai C. Endoplasmic reticulum stress in pancreatic β-cell dysfunction: The potential therapeutic role of dietary flavonoids. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2024; 6:100184. [PMID: 38846008 PMCID: PMC11153890 DOI: 10.1016/j.crphar.2024.100184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 05/21/2024] [Accepted: 05/22/2024] [Indexed: 06/09/2024] Open
Abstract
Diabetes mellitus (DM) is a global health burden that is characterized by the loss or dysfunction of pancreatic β-cells. In pancreatic β-cells, endoplasmic reticulum (ER) stress is a fact of life that contributes to β-cell loss or dysfunction. Despite recent advances in research, the existing treatment approaches such as lifestyle modification and use of conventional therapeutics could not prevent the loss or dysfunction of pancreatic β-cells to abrogate the disease progression. Therefore, targeting ER stress and the consequent unfolded protein response (UPR) in pancreatic β-cells may be a potential therapeutic strategy for diabetes treatment. Dietary phytochemicals have therapeutic applications in human health owing to their broad spectrum of biochemical and pharmacological activities. Flavonoids, which are commonly obtained from fruits and vegetables worldwide, have shown promising prospects in alleviating ER stress. Dietary flavonoids including quercetin, kaempferol, myricetin, isorhamnetin, fisetin, icariin, apigenin, apigetrin, vitexin, baicalein, baicalin, nobiletin hesperidin, naringenin, epigallocatechin 3-O-gallate hesperidin (EGCG), tectorigenin, liquiritigenin, and acacetin have shown inhibitory effects on ER stress in pancreatic β-cells. Dietary flavonoids modulate ER stress signaling components, chaperone proteins, transcription factors, oxidative stress, autophagy, apoptosis, and inflammatory responses to exert their pharmacological effects on pancreatic β-cells ER stress. This review focuses on the role of dietary flavonoids as potential therapeutic adjuvants in preserving pancreatic β-cells from ER stress. Highlights of the underlying mechanisms of action are also presented as well as possible strategies for clinical translation in the management of DM.
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Affiliation(s)
- Kingsley C. Mbara
- Nanomedicines Manufacturing, Biopharmaceutics and Diagnostics Research Laboratory, Department of Pharmaceutical Sciences, Tshwane University of Technology, Private Bag X680, Pretoria, 0001, South Africa
| | - Marthe C.D. Fotsing
- Drug Discovery and Smart Molecules Research Laboratory, Centre for Natural Products Research (CNPR), Department of Chemical Sciences, University of Johannesburg, Doornfontein, Johannesburg, 2028, South Africa
| | - Derek T. Ndinteh
- Drug Discovery and Smart Molecules Research Laboratory, Centre for Natural Products Research (CNPR), Department of Chemical Sciences, University of Johannesburg, Doornfontein, Johannesburg, 2028, South Africa
| | - Claudine N. Mbeb
- Nanomedicines Manufacturing, Biopharmaceutics and Diagnostics Research Laboratory, Department of Pharmaceutical Sciences, Tshwane University of Technology, Private Bag X680, Pretoria, 0001, South Africa
| | - Chinekwu S. Nwagwu
- Drug Delivery and Nanomedicines Research Laboratory, Department of Pharmaceutics, University of Nigeria, Nsukka, Enugu State, Nigeria
| | - Rene Khan
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban, South Africa
| | - Kopang C. Mokhetho
- Nanomedicines Manufacturing, Biopharmaceutics and Diagnostics Research Laboratory, Department of Pharmaceutical Sciences, Tshwane University of Technology, Private Bag X680, Pretoria, 0001, South Africa
| | - Himansu Baijnath
- Ward Herbarium, School of Life Sciences, University of KwaZulu-Natal, Durban, 4000, KwaZulu-Natal, South Africa
| | - Manimbulu Nlooto
- Department of Pharmaceutical Sciences, Healthcare Sciences, University of Limpopo, South Africa
| | - Shoeshoe Mokhele
- Department of Pharmaceutical Sciences, School of Pharmacy, Sefako Makgatho Health Sciences University, Pretoria, 0208, South Africa
| | - Carmen M. Leonard
- Nanomedicines Manufacturing, Biopharmaceutics and Diagnostics Research Laboratory, Department of Pharmaceutical Sciences, Tshwane University of Technology, Private Bag X680, Pretoria, 0001, South Africa
| | - Vuyelwa J. Tembu
- Natural Products Chemistry Research Laboratory, Department of Chemistry, Tshwane University of Technology, Private Bag X680, Pretoria, 0001, South Africa
| | - Clemence Tarirai
- Nanomedicines Manufacturing, Biopharmaceutics and Diagnostics Research Laboratory, Department of Pharmaceutical Sciences, Tshwane University of Technology, Private Bag X680, Pretoria, 0001, South Africa
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26
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Blanc M, Habbouche L, Xiao P, Lebeaupin C, Janona M, Vaillant N, Irondelle M, Gilleron J, Murcy F, Rousseau D, Luci C, Barouillet T, Marchetti S, Lacas-Gervais S, Yvan-Charvet L, Gual P, Cardozo AK, Bailly-Maitre B. Bax Inhibitor-1 preserves pancreatic β-cell proteostasis by limiting proinsulin misfolding and programmed cell death. Cell Death Dis 2024; 15:334. [PMID: 38744890 PMCID: PMC11094198 DOI: 10.1038/s41419-024-06701-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 04/17/2024] [Accepted: 04/22/2024] [Indexed: 05/16/2024]
Abstract
The prevalence of diabetes steadily increases worldwide mirroring the prevalence of obesity. Endoplasmic reticulum (ER) stress is activated in diabetes and contributes to β-cell dysfunction and apoptosis through the activation of a terminal unfolded protein response (UPR). Our results uncover a new role for Bax Inhibitor-One (BI-1), a negative regulator of inositol-requiring enzyme 1 (IRE1α) in preserving β-cell health against terminal UPR-induced apoptosis and pyroptosis in the context of supraphysiological loads of insulin production. BI-1-deficient mice experience a decline in endocrine pancreatic function in physiological and pathophysiological conditions, namely obesity induced by high-fat diet (HFD). We observed early-onset diabetes characterized by hyperglycemia, reduced serum insulin levels, β-cell loss, increased pancreatic lipases and pro-inflammatory cytokines, and the progression of metabolic dysfunction. Pancreatic section analysis revealed that BI-1 deletion overburdens unfolded proinsulin in the ER of β-cells, confirmed by ultrastructural signs of ER stress with overwhelmed IRE1α endoribonuclease (RNase) activity in freshly isolated islets. ER stress led to β-cell dysfunction and islet loss, due to an increase in immature proinsulin granules and defects in insulin crystallization with the presence of Rod-like granules. These results correlated with the induction of autophagy, ER phagy, and crinophagy quality control mechanisms, likely to alleviate the atypical accumulation of misfolded proinsulin in the ER. In fine, BI-1 in β-cells limited IRE1α RNase activity from triggering programmed β-cell death through apoptosis and pyroptosis (caspase-1, IL-1β) via NLRP3 inflammasome activation and metabolic dysfunction. Pharmaceutical IRE1α inhibition with STF-083010 reversed β-cell failure and normalized the metabolic phenotype. These results uncover a new protective role for BI-1 in pancreatic β-cell physiology as a stress integrator to modulate the UPR triggered by accumulating unfolded proinsulin in the ER, as well as autophagy and programmed cell death, with consequences on β-cell function and insulin secretion. In pancreatic β-cells, BI-1-/- deficiency perturbs proteostasis with proinsulin misfolding, ER stress, terminal UPR with overwhelmed IRE1α/XBP1s/CHOP activation, inflammation, β-cell programmed cell death, and diabetes.
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Affiliation(s)
- Marina Blanc
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Team "Hematometabolism and Metainflammation (HEMAMETABO), 06204, Nice, France
| | - Lama Habbouche
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Team "Hematometabolism and Metainflammation (HEMAMETABO), 06204, Nice, France
| | - Peng Xiao
- Inflammation and Cell Death Signalling group, Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles (ULB), Bruxelles, Belgique
| | - Cynthia Lebeaupin
- Degenerative Diseases Program, Sanford Burnham Prebys, La Jolla, CA, 92037, USA
| | - Marion Janona
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Team "Hematometabolism and Metainflammation (HEMAMETABO), 06204, Nice, France
| | - Nathalie Vaillant
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Team "Hematometabolism and Metainflammation (HEMAMETABO), 06204, Nice, France
| | - Marie Irondelle
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Team "Hematometabolism and Metainflammation (HEMAMETABO), 06204, Nice, France
| | - Jérôme Gilleron
- Université Côte d'Azur, Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Adipo-Cible Research Study Group, Centre Méditerranéen de Médecine Moléculaire (C3M), Team «Insulin Resistance in Obesity and type 2 Diabetes», Nice, France
| | - Florent Murcy
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Team "Hematometabolism and Metainflammation (HEMAMETABO), 06204, Nice, France
| | - Déborah Rousseau
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Team «Chronic Liver Diseases Associated with Obesity and Alcohol», Nice, France
| | - Carmelo Luci
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Team «Chronic Liver Diseases Associated with Obesity and Alcohol», Nice, France
| | - Thibault Barouillet
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Team "Hematometabolism and Metainflammation (HEMAMETABO), 06204, Nice, France
| | - Sandrine Marchetti
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Team «Metabolism, cancer and immune responses», Nice, France
| | - Sandra Lacas-Gervais
- Université Côte d'Azur, Centre Commun de Microscopie Appliquée, CCMA, Nice, France
| | - Laurent Yvan-Charvet
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Team "Hematometabolism and Metainflammation (HEMAMETABO), 06204, Nice, France
| | - Philippe Gual
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Team «Chronic Liver Diseases Associated with Obesity and Alcohol», Nice, France
| | - Alessandra K Cardozo
- Inflammation and Cell Death Signalling group, Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles (ULB), Bruxelles, Belgique
| | - Béatrice Bailly-Maitre
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Team "Hematometabolism and Metainflammation (HEMAMETABO), 06204, Nice, France.
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Pei X, Wang Z, He W, Li S, Chen X, Fan Z, Lan Y, Yuan L, Xu P. ER-tethered RNA-binding protein controls NADPH oxidase translation for hydrogen peroxide homeostasis. Redox Biol 2024; 71:103126. [PMID: 38503217 PMCID: PMC10963860 DOI: 10.1016/j.redox.2024.103126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 03/04/2024] [Accepted: 03/14/2024] [Indexed: 03/21/2024] Open
Abstract
Hydrogen peroxide (H2O2) functions as a signaling molecule in diverse cellular processes. While cells have evolved the capability to detect and manage changes in H2O2 levels, the mechanisms regulating key H2O2-producing enzymes to maintain optimal levels, especially in pancreatic beta cells with notably weak antioxidative defense, remain unclear. We found that the protein EI24 responds to changes in H2O2 concentration and regulates the production of H2O2 by controlling the translation of NOX4, an enzyme that is constitutively active, achieved by recruiting an RNA-binding protein, RTRAF, to the 3'-UTR of Nox4. Depleting EI24 results in RTRAF relocating into the nucleus, releasing the brake on NOX4 translation. The excessive production of H2O2 by liberated NOX4 further suppresses the translation of the key transcription factor MafA, ultimately preventing its binding to the Ins2 gene promoter and subsequent transcription of insulin. Treatment with a specific NOX4 inhibitor or the antioxidant NAC reversed these effects and alleviated the diabetic symptoms in beta-cell specific Ei24-KO mice. This study revealed a new mechanism through which cells regulate oxidative stress at the translational level, involving an ER-tethered RNA-binding protein that controls the expression of the key H2O2-producing enzyme NOX4.
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Affiliation(s)
- Xintong Pei
- Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Zhe Wang
- Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Wenting He
- Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Shunqin Li
- Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Xiaowei Chen
- Center for High Throughput Sequencing, Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Zhen Fan
- Center for High Throughput Sequencing, Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yongguang Lan
- Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Lin Yuan
- Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Pingyong Xu
- Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100101, China; Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
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Schauner R, Cress J, Hong C, Wald D, Ramakrishnan P. Single cell and bulk RNA expression analyses identify enhanced hexosamine biosynthetic pathway and O-GlcNAcylation in acute myeloid leukemia blasts and stem cells. Front Immunol 2024; 15:1327405. [PMID: 38601153 PMCID: PMC11004450 DOI: 10.3389/fimmu.2024.1327405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 03/13/2024] [Indexed: 04/12/2024] Open
Abstract
Introduction Acute myeloid leukemia (AML) is the most common acute leukemia in adults with an overall poor prognosis and high relapse rate. Multiple factors including genetic abnormalities, differentiation defects and altered cellular metabolism contribute to AML development and progression. Though the roles of oxidative phosphorylation and glycolysis are defined in AML, the role of the hexosamine biosynthetic pathway (HBP), which regulates the O-GlcNAcylation of cytoplasmic and nuclear proteins, remains poorly defined. Methods We studied the expression of the key enzymes involved in the HBP in AML blasts and stem cells by RNA sequencing at the single-cell and bulk level. We performed flow cytometry to study OGT protein expression and global O-GlcNAcylation. We studied the functional effects of inhibiting O-GlcNAcylation on transcriptional activation in AML cells by Western blotting and real time PCR and on cell cycle by flow cytometry. Results We found higher expression levels of the key enzymes in the HBP in AML as compared to healthy donors in whole blood. We observed elevated O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA) expression in AML stem and bulk cells as compared to normal hematopoietic stem and progenitor cells (HSPCs). We also found that both AML bulk cells and stem cells show significantly enhanced OGT protein expression and global O-GlcNAcylation as compared to normal HSPCs, validating our in silico findings. Gene set analysis showed substantial enrichment of the NF-κB pathway in AML cells expressing high OGT levels. Inhibition of O-GlcNAcylation decreased NF-κB nuclear translocation and the expression of selected NF-κB-dependent genes controlling cell cycle. It also blocked cell cycle progression suggesting a link between enhanced O-GlcNAcylation and NF-κB activation in AML cell survival and proliferation. Discussion Our study suggests the HBP may prove a potential target, alone or in combination with other therapeutic approaches, to impact both AML blasts and stem cells. Moreover, as insufficient targeting of AML stem cells by traditional chemotherapy is thought to lead to relapse, blocking HBP and O-GlcNAcylation in AML stem cells may represent a novel promising target to control relapse.
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Affiliation(s)
- Robert Schauner
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
- Department of Artificial Intelligence and Informatics, Mayo Clinic, Jacksonville, FL, United States
| | - Jordan Cress
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
| | - Changjin Hong
- Department of Artificial Intelligence and Informatics, Mayo Clinic, Jacksonville, FL, United States
| | - David Wald
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
- The Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United States
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Parameswaran Ramakrishnan
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
- The Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United States
- Department of Pathology, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, United States
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Gulen B, Kinch LN, Servage KA, Blevins A, Stewart NM, Gray HF, Casey AK, Orth K. FicD Sensitizes Cellular Response to Glucose Fluctuations in Mouse Embryonic Fibroblasts. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.22.576705. [PMID: 38328056 PMCID: PMC10849547 DOI: 10.1101/2024.01.22.576705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
During homeostasis, the endoplasmic reticulum (ER) maintains productive transmembrane and secretory protein folding that is vital for proper cellular function. The ER-resident HSP70 chaperone, BiP, plays a pivotal role in sensing ER stress to activate the unfolded protein response (UPR). BiP function is regulated by the bifunctional enzyme FicD that mediates AMPylation and deAMPylation of BiP in response to changes in ER stress. AMPylated BiP acts as a molecular rheostat to regulate UPR signaling, yet little is known about the molecular consequences of FicD loss. In this study, we investigate the role of FicD in mouse embryonic fibroblast (MEF) response to pharmacologically and metabolically induced ER stress. We find differential BiP AMPylation signatures when comparing robust chemical ER stress inducers to physiological glucose starvation stress and recovery. Wildtype MEFs respond to pharmacological ER stress by downregulating BiP AMPylation. Conversely, BiP AMPylation in wildtype MEFs increases upon metabolic stress induced by glucose starvation. Deletion of FicD results in widespread gene expression changes under baseline growth conditions. In addition, FicD null MEFs exhibit dampened UPR signaling, altered cell stress recovery response, and unconstrained protein secretion. Taken together, our findings indicate that FicD is important for tampering UPR signaling, stress recovery, and the maintenance of secretory protein homeostasis. Significance Statement The chaperone BiP plays a key quality control role in the endoplasmic reticulum, the cellular location for the production, folding, and transport of secreted proteins. The enzyme FicD regulates BiP's activity through AMPylation and deAMPylation. Our study unveils the importance of FicD in regulating BiP and the unfolded protein response (UPR) during stress. We identify distinct BiP AMPylation signatures for different stressors, highlighting FicD's nuanced control. Deletion of FicD causes widespread gene expression changes, disrupts UPR signaling, alters stress recovery, and perturbs protein secretion in cells. These observations underscore the pivotal contribution of FicD for preserving secretory protein homeostasis. Our findings deepen the understanding of FicD's role in maintaining cellular resilience and open avenues for therapeutic strategies targeting UPR-associated diseases.
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30
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Tanday N, Tarasov AI, Moffett RC, Flatt PR, Irwin N. Pancreatic islet cell plasticity: Pathogenic or therapeutically exploitable? Diabetes Obes Metab 2024; 26:16-31. [PMID: 37845573 DOI: 10.1111/dom.15300] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/07/2023] [Accepted: 09/18/2023] [Indexed: 10/18/2023]
Abstract
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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Affiliation(s)
- Neil Tanday
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
| | - Andrei I Tarasov
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
| | - R Charlotte Moffett
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
| | - Nigel Irwin
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
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31
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McLaughlin MR, Weaver SA, Syed F, Evans-Molina C. Advanced Imaging Techniques for the Characterization of Subcellular Organelle Structure in Pancreatic Islet β Cells. Compr Physiol 2023; 14:5243-5267. [PMID: 38158370 PMCID: PMC11490899 DOI: 10.1002/cphy.c230002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
Type 2 diabetes (T2D) affects more than 32.3 million individuals in the United States, creating an economic burden of nearly $966 billion in 2021. T2D results from a combination of insulin resistance and inadequate insulin secretion from the pancreatic β cell. However, genetic and physiologic data indicate that defects in β cell function are the chief determinant of whether an individual with insulin resistance will progress to a diagnosis of T2D. The subcellular organelles of the insulin secretory pathway, including the endoplasmic reticulum, Golgi apparatus, and secretory granules, play a critical role in maintaining the heavy biosynthetic burden of insulin production, processing, and secretion. In addition, the mitochondria enable the process of insulin release by integrating the metabolism of nutrients into energy output. Advanced imaging techniques are needed to determine how changes in the structure and composition of these organelles contribute to the loss of insulin secretory capacity in the β cell during T2D. Several microscopy techniques, including electron microscopy, fluorescence microscopy, and soft X-ray tomography, have been utilized to investigate the structure-function relationship within the β cell. In this overview article, we will detail the methodology, strengths, and weaknesses of each approach. © 2024 American Physiological Society. Compr Physiol 14:5243-5267, 2024.
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Affiliation(s)
- Madeline R. McLaughlin
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
| | - Staci A. Weaver
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- The Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Farooq Syed
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
- The Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Carmella Evans-Molina
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- The Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Roudebush VA Medical Center, Indianapolis, Indiana, USA
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Kim G, Lee J, Ha J, Kang I, Choe W. Endoplasmic Reticulum Stress and Its Impact on Adipogenesis: Molecular Mechanisms Implicated. Nutrients 2023; 15:5082. [PMID: 38140341 PMCID: PMC10745682 DOI: 10.3390/nu15245082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 11/30/2023] [Accepted: 12/09/2023] [Indexed: 12/24/2023] Open
Abstract
Endoplasmic reticulum (ER) stress plays a pivotal role in adipogenesis, which encompasses the differentiation of adipocytes and lipid accumulation. Sustained ER stress has the potential to disrupt the signaling of the unfolded protein response (UPR), thereby influencing adipogenesis. This comprehensive review illuminates the molecular mechanisms that underpin the interplay between ER stress and adipogenesis. We delve into the dysregulation of UPR pathways, namely, IRE1-XBP1, PERK and ATF6 in relation to adipocyte differentiation, lipid metabolism, and tissue inflammation. Moreover, we scrutinize how ER stress impacts key adipogenic transcription factors such as proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding proteins (C/EBPs) along with their interaction with other signaling pathways. The cellular ramifications include alterations in lipid metabolism, dysregulation of adipokines, and aged adipose tissue inflammation. We also discuss the potential roles the molecular chaperones cyclophilin A and cyclophilin B play in adipogenesis. By shedding light on the intricate relationship between ER stress and adipogenesis, this review paves the way for devising innovative therapeutic interventions.
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Affiliation(s)
- Gyuhui Kim
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (G.K.); (J.H.); (I.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jiyoon Lee
- Department of Biological Sciences, Franklin College of Arts and Sciences, University of Georgia, Athens, GA 30609, USA;
| | - Joohun Ha
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (G.K.); (J.H.); (I.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Insug Kang
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (G.K.); (J.H.); (I.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Wonchae Choe
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (G.K.); (J.H.); (I.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
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Li Z, Liu X, Zhang K, Zhao H, Luo P, Li D, Liu Z, Yuan H, Zhang B, Xie X, Shen C. Role and Mechanism of Endoplasmic Reticulum Stress in Mice Pancreatic Islet Dysfunction After Severe Burns. J Burn Care Res 2023; 44:1231-1240. [PMID: 36869805 DOI: 10.1093/jbcr/irad029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Indexed: 03/05/2023]
Abstract
This study attempted to investigate the role and mechanism of endoplasmic reticulum (ER) stress in the islet dysfunction in mice after severe burns. C57BL/6 mice were randomly divided into the sham group, burn group, and burn+4-phenylbutyric acid (4-PBA) group. Mice were burned with full thickness of 30% total surface area (TBSA), and 4-PBA solution was intraperitoneally injected into mice in burn+4-PBA group. Glucose-stimulated insulin secretion (GSIS), Fasting blood glucose (FBG) and glucose tolerance were detected 24 hours post severe burns. The ER stress-related pathway markers immunoglobulin binding protein (BIP), X-box binding protein 1 (XBP1), phosphorylation-PKR-like ER kinase (p-PERK), phosphorylation-eukaryotic translation initiation factor 2α (p-eIF2α), CHOP, activating transcription factor 6 (ATF6), apoptosis-related protein Cleaved-Caspase 3, and islet cell apoptosis were measured. Mice were characterized with elevated FBG, decreased glucose tolerance and GSIS levels post severe burns. The expression of BIP, XBP1, p-PERK, p-eIF2α, CHOP, ATF6, Cleaved-Caspase 3, and islet cell apoptosis were increased significantly after severe burns. 4-PBA treatment contributed to decreased FBG, improved glucose tolerance, increased GSIS, inhibited islet ER stress, and reduced pancreatic islet cell apoptosis in mice post severe burns. ER stress occurs in islets of severely burned mice, which leads to increased apoptosis of islet cells, thus resulting in islet dysfunction.
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Affiliation(s)
- Zhisheng Li
- Jinzhou Medical University, Jinzhou, China
- Department of Burns and Plastic Surgery, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xinzhu Liu
- Department of Burns and Plastic Surgery, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Kun Zhang
- Jinzhou Medical University, Jinzhou, China
- Department of Burns and Plastic Surgery, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Hongqing Zhao
- Jinzhou Medical University, Jinzhou, China
- Department of Burns and Plastic Surgery, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Peng Luo
- Department of Burns and Plastic Surgery, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Dawei Li
- Department of Burns and Plastic Surgery, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zhaoxing Liu
- Department of Burns and Plastic Surgery, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Huageng Yuan
- Department of Burns and Plastic Surgery, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Bohan Zhang
- Department of Burns and Plastic Surgery, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xiaoye Xie
- Department of Burns and Plastic Surgery, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Chuan'an Shen
- Department of Burns and Plastic Surgery, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
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Schembri Wismayer D, Laurenti MC, Song Y, Egan AM, Welch AA, Bailey KR, Cobelli C, Dalla Man C, Jensen MD, Vella A. Effects of acute changes in fasting glucose and free fatty acid concentrations on indices of β-cell function and glucose metabolism in subjects without diabetes. Am J Physiol Endocrinol Metab 2023; 325:E119-E131. [PMID: 37285600 PMCID: PMC10393375 DOI: 10.1152/ajpendo.00043.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 05/19/2023] [Accepted: 06/06/2023] [Indexed: 06/09/2023]
Abstract
Elevated fasting free fatty acids (FFAs) and fasting glucose are additively associated with impaired glucose tolerance (IGT) and decreased β-cell function [quantified as disposition index (DI)]. We sought to examine how changes in fasting FFA and glucose alter islet function. We studied 10 subjects with normal fasting glucose (NFG) and normal glucose tolerance (NGT) on two occasions. On one occasion, Intralipid and glucose were infused overnight to mimic conditions present in IFG/IGT. In addition, we studied seven subjects with IFG/IGT on two occasions. On one occasion, insulin was infused to lower overnight FFA and glucose concentrations to those observed in people with NFG/NGT. The following morning, a labeled mixed meal was used to measure postprandial glucose metabolism and β-cell function. Elevation of overnight fasting FFA and glucose in NFG/NGT did not alter peak or integrated glucose concentrations (2.0 ± 0.1 vs. 2.0 ± 0.1 Mol per 5 h, Saline vs. Intralipid/glucose, P = 0.55). Although overall β-cell function quantified by the Disposition Index was unchanged, the dynamic component of β-cell responsivity (ϕd) was decreased by Intralipid and glucose infusion (9 ± 1 vs. 16 ± 3 10-9, P = 0.02). In people with IFG/IGT, insulin did not alter postprandial glucose concentrations or indices of β-cell function. Endogenous glucose production and glucose disappearance were also unchanged in both groups. We conclude that acute, overnight changes in FFA, and glucose concentrations do not alter islet function or glucose metabolism in prediabetes.NEW & NOTEWORTHY This experiment studied the effect of changes in overnight concentrations of free fatty acids (FFAs) and glucose on β-cell function and glucose metabolism. In response to elevation of these metabolites, the dynamic component of the β-cell response to glucose was impaired. This suggests that in health overnight hyperglycemia and FFA elevation can deplete preformed insulin granules in the β-cell.
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Affiliation(s)
- Daniel Schembri Wismayer
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
| | - Marcello C Laurenti
- Biomedical Engineering and Physiology Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota, United States
| | - Yilin Song
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
| | - Aoife M Egan
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
| | - Andrew A Welch
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
| | - Kent R Bailey
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States
| | - Claudio Cobelli
- Department of Woman and Child's Health, University of Padova, Padova, Italy
| | - Chiara Dalla Man
- Department of Information Engineering, University of Padova, Padova, Italy
| | - Michael D Jensen
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
| | - Adrian Vella
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
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Klyosova E, Azarova I, Buikin S, Polonikov A. Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes Mellitus. Int J Mol Sci 2023; 24:12059. [PMID: 37569434 PMCID: PMC10418503 DOI: 10.3390/ijms241512059] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/12/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
Impaired redox homeostasis in the endoplasmic reticulum (ER) may contribute to proinsulin misfolding and thus to activate the unfolded protein response (UPR) and apoptotic pathways, culminating in pancreatic β-cell loss and type 2 diabetes (T2D). The present study was designed to identify differentially expressed genes (DEGs) encoding enzymes for glutathione metabolism and their impact on the expression levels of genes regulating protein folding and UPR in β-cells of T2D patients. The GEO transcriptome datasets of β-cells of diabetics and non-diabetics, GSE20966 and GSE81608, were analyzed for 142 genes of interest using limma and GREIN software, respectively. Diabetic β-cells showed dataset-specific patterns of DEGs (FDR ≤ 0.05) implicated in the regulation of glutathione metabolism (ANPEP, PGD, IDH2, and CTH), protein-folding (HSP90AB1, HSP90AA1, HSPA1B, HSPA8, BAG3, NDC1, NUP160, RLN1, and RPS19BP1), and unfolded protein response (CREB3L4, ERP27, and BID). The GCLC gene, encoding the catalytic subunit of glutamate-cysteine ligase, the first rate-limiting enzyme of glutathione biosynthesis, was moderately down-regulated in diabetic β-cells from both datasets (p ≤ 0.05). Regression analysis established that genes involved in the de novo synthesis of glutathione, GCLC, GCLM, and GSS affect the expression levels of genes encoding molecular chaperones and those involved in the UPR pathway. This study showed for the first time that diabetic β-cells exhibit alterations in the expression of genes regulating glutathione metabolism, protein-folding, and UPR and provided evidence for the molecular crosstalk between impaired redox homeostasis and abnormal protein folding, underlying ER stress in type 2 diabetes.
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Affiliation(s)
- Elena Klyosova
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia; (E.K.); (I.A.)
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
| | - Iuliia Azarova
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia; (E.K.); (I.A.)
- Department of Biological Chemistry, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
| | - Stepan Buikin
- Centre of Omics Technology, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya Street, 119991 Moscow, Russia;
- Department of Internal Diseases, Yaroslav the Wise Novgorod State University, 41 Bolshaya St. Petersburg Street, 173003 Veliky Novgorod, Russia
| | - Alexey Polonikov
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
- Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia
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36
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Zhu S, Waeckel-Énée E, Moser A, Bessard MA, Roger K, Lipecka J, Yilmaz A, Bertocci B, Diana J, Saintpierre B, Guerrera IC, Francesconi S, Mauvais FX, van Endert P. Pancreatic islet cell stress induced by insulin-degrading enzyme deficiency promotes islet regeneration and protection from autoimmune diabetes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.19.549693. [PMID: 37503145 PMCID: PMC10370150 DOI: 10.1101/2023.07.19.549693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Appropriate tuning of protein homeostasis through mobilization of the unfolded protein response (UPR) is key to the capacity of pancreatic beta cells to cope with highly variable demand for insulin synthesis. An efficient UPR ensures a sufficient beta cell mass and secretory output but can also affect beta cell resilience to autoimmune aggression. The factors regulating protein homeostasis in the face of metabolic and immune challenges are insufficiently understood. We examined beta cell adaptation to stress in mice deficient for insulin-degrading enzyme (IDE), a ubiquitous protease with high affinity for insulin and genetic association with type 2 diabetes. IDE deficiency induced a low-level UPR in both C57BL/6 and autoimmune non-obese diabetic (NOD) mice, associated with rapamycin-sensitive beta cell proliferation strongly enhanced by proteotoxic stress. Moreover, in NOD mice, IDE deficiency protected from spontaneous diabetes and triggered an additional independent pathway, conditional on the presence of islet inflammation but inhibited by proteotoxic stress, highlighted by strong upregulation of regenerating islet-derived protein 2, a protein attenuating autoimmune inflammation. Our findings establish a key role of IDE in islet cell protein homeostasis, identify a link between low-level UPR and proliferation, and reveal an UPR-independent anti-inflammatory islet cell response uncovered in the absence of IDE of potential interest in autoimmune diabetes.
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37
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Holendova B, Plecita-Hlavata L. Cysteine residues in signal transduction and its relevance in pancreatic beta cells. Front Endocrinol (Lausanne) 2023; 14:1221520. [PMID: 37455926 PMCID: PMC10339824 DOI: 10.3389/fendo.2023.1221520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 06/13/2023] [Indexed: 07/18/2023] Open
Abstract
Cysteine is one of the least abundant but most conserved amino acid residues in proteins, playing a role in their structure, metal binding, catalysis, and redox chemistry. Thiols present in cysteines can be modified by post-translational modifications like sulfenylation, acylation, or glutathionylation, regulating protein activity and function and serving as signals. Their modification depends on their position in the structure, surrounding amino acids, solvent accessibility, pH, etc. The most studied modifications are the redox modifications by reactive oxygen, nitrogen, and sulfur species, leading to reversible changes that serve as cell signals or irreversible changes indicating oxidative stress and cell damage. Selected antioxidants undergoing reversible oxidative modifications like peroxiredoxin-thioredoxin system are involved in a redox-relay signaling that can propagate to target proteins. Cysteine thiols can also be modified by acyl moieties' addition (derived from lipid metabolism), resulting in protein functional modification or changes in protein anchoring in the membrane. In this review, we update the current knowledge on cysteine modifications and their consequences in pancreatic β-cells. Because β-cells exhibit well-balanced redox homeostasis, the redox modifications of cysteines here serve primarily for signaling purposes. Similarly, lipid metabolism provides regulatory intermediates that have been shown to be necessary in addition to redox modifications for proper β-cell function and, in particular, for efficient insulin secretion. On the contrary, the excess of reactive oxygen, nitrogen, and sulfur species and the imbalance of lipids under pathological conditions cause irreversible changes and contribute to oxidative stress leading to cell failure and the development of type 2 diabetes.
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Affiliation(s)
| | - Lydie Plecita-Hlavata
- Laboratory of Pancreatic Islet Research, Institute of Physiology, Czech Academy of Sciences, Prague, Czechia
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38
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Sugawara H, Imai J, Yamamoto J, Izumi T, Kawana Y, Endo A, Kohata M, Seike J, Kubo H, Komamura H, Munakata Y, Asai Y, Hosaka S, Sawada S, Kodama S, Takahashi K, Kaneko K, Katagiri H. A highly sensitive strategy for monitoring real-time proliferation of targeted cell types in vivo. Nat Commun 2023; 14:3253. [PMID: 37316473 DOI: 10.1038/s41467-023-38897-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 05/22/2023] [Indexed: 06/16/2023] Open
Abstract
Cell proliferation processes play pivotal roles in timely adaptation to many biological situations. Herein, we establish a highly sensitive and simple strategy by which time-series showing the proliferation of a targeted cell type can be quantitatively monitored in vivo in the same individuals. We generate mice expressing a secreted type of luciferase only in cells producing Cre under the control of the Ki67 promoter. Crossing these with tissue-specific Cre-expressing mice allows us to monitor the proliferation time course of pancreatic β-cells, which are few in number and weakly proliferative, by measuring plasma luciferase activity. Physiological time courses, during obesity development, pregnancy and juvenile growth, as well as diurnal variation, of β-cell proliferation, are clearly detected. Moreover, this strategy can be utilized for highly sensitive ex vivo screening for proliferative factors for targeted cells. Thus, these technologies may contribute to advancements in broad areas of biological and medical research.
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Affiliation(s)
- Hiroto Sugawara
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Junpei Yamamoto
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohito Izumi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yohei Kawana
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akira Endo
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masato Kohata
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Junro Seike
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Haremaru Kubo
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroshi Komamura
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuichiro Munakata
- Division of Metabolism and Diabetes, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Yoichiro Asai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shinichiro Hosaka
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shojiro Sawada
- Division of Metabolism and Diabetes, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Shinjiro Kodama
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kei Takahashi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keizo Kaneko
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
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ERTÜRK E, AKGÜN O, YILDIZ Y, ALPER KALKAN P, SALOMATINA OV, SALAKHUTDINOV NF, ULUKAYA E, ARI F. Soloxolone methyl induces apoptosis and oxidative/ER stress in breast cancer cells and target cancer stem cell population. Turk J Biol 2023; 47:247-261. [PMID: 38152618 PMCID: PMC10751089 DOI: 10.55730/1300-0152.2660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 08/31/2023] [Accepted: 06/05/2023] [Indexed: 12/29/2023] Open
Abstract
One of the most prevalent malignancies in women and one of the leading causes of cancer-related death is breast cancer. There is a need for new treatment approaches and drugs for breast cancer. Many studies show the high potential of triterpene compounds and their semisynthetic derivatives as anticancer agents due to their ability to induce apoptosis and suppress tumorigenesis. The effects of soloxolone methyl (SM), a semisynthetic derivative of 18-H-glycyrrhetinic acid, on the cytotoxicity and apoptosis of human breast cancer cell line (T-47D) and cancer stem cell (CSCs) population (mammospheres; CD44+/CD24-antigen) derived from breast cancer cells, were examined in this work. The ATP assay was used to determine SM growth-inhibitory effects. Fluorescent staining, caspase-cleaved cytokeratin 18, and flow cytometry analysis were used to determine the mode of the cell death. In addition, cell death was investigated at protein and gene levels by Western Blotting and PCR, respectively. SM resulted in cytotoxicity in a time and dose dependent manner via ROS production and ER stress in T-47D cells in 2 models. The mode of cell death was apoptosis, evidenced by phosphatidylserine exposure, caspase activation, and bax overexpression. In mammospheres as 3D model, SM decreased stem cell properties and induced cell death. Taken together, SM may be a promising agent in the treatment of breast cancer, especially due to its antigrowth activity on CSCs.
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Affiliation(s)
- Elif ERTÜRK
- Vocational School of Health Services, Bursa Uludağ University, Bursa,
Turkiye
| | - Oğuzhan AKGÜN
- Department of Biology, Faculty of Science and Arts, Bursa Uludağ University, Bursa,
Turkiye
| | - Yaren YILDIZ
- Department of Biology, Faculty of Science and Arts, Bursa Uludağ University, Bursa,
Turkiye
| | - Pınar ALPER KALKAN
- Department of Biology, Faculty of Science and Arts, Bursa Uludağ University, Bursa,
Turkiye
- Aziz Sancar Experimental Medicine Research Institute, Molecular Medicine, İstanbul University, İstanbul,
Turkiye
| | - Oksana V. SALOMATINA
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk,
Russia
| | - Nariman F. SALAKHUTDINOV
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk,
Russia
| | - Engin ULUKAYA
- Department of Clinical Biochemistry, Faculty of Medicine, İstinye University, İstanbul,
Turkiye
| | - Ferda ARI
- Department of Biology, Faculty of Science and Arts, Bursa Uludağ University, Bursa,
Turkiye
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40
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Park NW, Lee ES, Ha KB, Jo SH, Kim HM, Kwon MH, Chung CH. Umbelliferone Ameliorates Hepatic Steatosis and Lipid-Induced ER Stress in High-Fat Diet-Induced Obese Mice. Yonsei Med J 2023; 64:243-250. [PMID: 36996895 PMCID: PMC10067795 DOI: 10.3349/ymj.2022.0354] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 02/25/2023] [Accepted: 02/27/2023] [Indexed: 04/01/2023] Open
Abstract
PURPOSE Among the characteristics of non-alcoholic fatty liver disease (NAFLD), hepatic steatosis is due to excessive fat accumulation and causes liver damage and lipotoxicity, which are associated with insulin resistance, endoplasmic reticulum (ER) stress, and apoptosis. Umbelliferone (UMB) has various powerful pharmacological properties, such as antioxidant, anti-hyperglycemic, anti-viral, and anti-inflammatory effects. However, the mechanism of action in hepatic steatosis and lipid-induced ER stress is still unclear. Thus, the efficacy of UMB in hepatic steatosis and palmitate (PA)-induced hepatocellular lipotoxicity was evaluated in the present study. MATERIALS AND METHODS Male C57BL/6J mice (n=40) were divided into four groups: regular diet (RD), UMB-supplemented RD, high-fat diet (HFD), and UMB-supplemented HFD. All mice were fed orally for 12 weeks. In addition, the effects of UMB on lipotoxicity were investigated in AML12 cells treated with PA (250 µM) for 24 h; Western blot analysis was used to evaluate the changes in ER stress and apoptotic-associated proteins. RESULTS Administration with UMB in HFD-fed mice reduced lipid accumulation and hepatic triglyceride (TG) as well as serum insulin and glucose levels. In AML12 cells, UMB treatment reduced lipid accumulation as indicated by decreases in the levels of lipogenesis markers, such as SREBP1, FAS, PPAR-γ, and ADRP. Furthermore, UMB reduced both oxidative stress and ER stress-related cellular apoptosis. CONCLUSION UMB supplementation ameliorated hepatic steatosis and improved insulin resistance by inhibiting lipid accumulation and regulating ER stress. These findings strongly suggest that UMB may be a potential therapeutic compound against NAFLD.
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Affiliation(s)
- Na Won Park
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
- Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Eun Soo Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
- Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Kyung Bong Ha
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
- Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Su Ho Jo
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
- Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea
| | | | - Mi-Hye Kwon
- East Coast Life Sciences Institute, Gangneung-Wonju National University, Gangneung, Korea
| | - Choon Hee Chung
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
- Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea.
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41
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Lichti CF, Wan X. Using mass spectrometry to identify neoantigens in autoimmune diseases: The type 1 diabetes example. Semin Immunol 2023; 66:101730. [PMID: 36827760 PMCID: PMC10324092 DOI: 10.1016/j.smim.2023.101730] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 02/06/2023] [Accepted: 02/09/2023] [Indexed: 02/24/2023]
Abstract
In autoimmune diseases, recognition of self-antigens presented by major histocompatibility complex (MHC) molecules elicits unexpected attack of tissue by autoantibodies and/or autoreactive T cells. Post-translational modification (PTM) may alter the MHC-binding motif or TCR contact residues in a peptide antigen, transforming the tolerance to self to autoreactivity. Mass spectrometry-based immunopeptidomics provides a valuable mechanism for identifying MHC ligands that contain PTMs and can thus provide valuable insights into pathogenesis and therapeutics of autoimmune diseases. A plethora of PTMs have been implicated in this process, and this review highlights their formation and identification.
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Affiliation(s)
- Cheryl F Lichti
- Department of Pathology and Immunology, Division of Immunobiology, The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8118, St. Louis, MO 63110, USA.
| | - Xiaoxiao Wan
- Department of Pathology and Immunology, Division of Immunobiology, The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8118, St. Louis, MO 63110, USA.
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42
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Azarova I, Polonikov A, Klyosova E. Molecular Genetics of Abnormal Redox Homeostasis in Type 2 Diabetes Mellitus. Int J Mol Sci 2023; 24:4738. [PMID: 36902173 PMCID: PMC10003739 DOI: 10.3390/ijms24054738] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023] Open
Abstract
Numerous studies have shown that oxidative stress resulting from an imbalance between the production of free radicals and their neutralization by antioxidant enzymes is one of the major pathological disorders underlying the development and progression of type 2 diabetes (T2D). The present review summarizes the current state of the art advances in understanding the role of abnormal redox homeostasis in the molecular mechanisms of T2D and provides comprehensive information on the characteristics and biological functions of antioxidant and oxidative enzymes, as well as discusses genetic studies conducted so far in order to investigate the contribution of polymorphisms in genes encoding redox state-regulating enzymes to the disease pathogenesis.
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Affiliation(s)
- Iuliia Azarova
- Department of Biological Chemistry, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia
| | - Alexey Polonikov
- Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
| | - Elena Klyosova
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia
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43
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Di Giuseppe G, Ciccarelli G, Soldovieri L, Capece U, Cefalo CMA, Moffa S, Nista EC, Brunetti M, Cinti F, Gasbarrini A, Pontecorvi A, Giaccari A, Mezza T. First-phase insulin secretion: can its evaluation direct therapeutic approaches? Trends Endocrinol Metab 2023; 34:216-230. [PMID: 36858875 DOI: 10.1016/j.tem.2023.02.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/26/2023] [Accepted: 02/01/2023] [Indexed: 03/03/2023]
Abstract
Our work is aimed at unraveling the role of the first-phase insulin secretion in the natural history of type 2 diabetes mellitus (T2DM) and its interrelationship with insulin resistance and with β cell function and mass. Starting from pathophysiology, we investigate the impact of impaired secretion on glucose homeostasis and explore postmeal hyperglycemia as the main clinical feature, underlining its relevance in the management of the disease. We also review dietary and pharmacological approaches aimed at improving early secretory defects and restoring residual β cell function. Furthermore, we discuss possible approaches to detect early secretory defects in clinical practice. By providing a journey through human and animal data, we attempt a unification of the recent evidence in an effort to offer a new outlook on β cell secretion.
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Affiliation(s)
- Gianfranco Di Giuseppe
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Gea Ciccarelli
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Laura Soldovieri
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Umberto Capece
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Chiara M A Cefalo
- Department of Clinical and Molecular Medicine, University of Rome - Sapienza, Rome, Italy
| | - Simona Moffa
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Enrico C Nista
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy; Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Michela Brunetti
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesca Cinti
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Antonio Gasbarrini
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy; Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Alfredo Pontecorvi
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Andrea Giaccari
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Teresa Mezza
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy; Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
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Brusco N, Sebastiani G, Di Giuseppe G, Licata G, Grieco GE, Fignani D, Nigi L, Formichi C, Aiello E, Auddino S, Quero G, Cefalo CMA, Cinti F, Mari A, Ferraro PM, Pontecorvi A, Alfieri S, Giaccari A, Dotta F, Mezza T. Intra-islet insulin synthesis defects are associated with endoplasmic reticulum stress and loss of beta cell identity in human diabetes. Diabetologia 2023; 66:354-366. [PMID: 36280617 PMCID: PMC9807540 DOI: 10.1007/s00125-022-05814-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/07/2022] [Indexed: 01/07/2023]
Abstract
AIMS/HYPOTHESIS Endoplasmic reticulum (ER) stress and beta cell dedifferentiation both play leading roles in impaired insulin secretion in overt type 2 diabetes. Whether and how these factors are related in the natural history of the disease remains, however, unclear. METHODS In this study, we analysed pancreas biopsies from a cohort of metabolically characterised living donors to identify defects in in situ insulin synthesis and intra-islet expression of ER stress and beta cell phenotype markers. RESULTS We provide evidence that in situ altered insulin processing is closely connected to in vivo worsening of beta cell function. Further, activation of ER stress genes reflects the alteration of insulin processing in situ. Using a combination of 17 different markers, we characterised individual pancreatic islets from normal glucose tolerant, impaired glucose tolerant and type 2 diabetic participants and reconstructed disease progression. CONCLUSIONS/INTERPRETATION Our study suggests that increased beta cell workload is accompanied by a progressive increase in ER stress with defects in insulin synthesis and loss of beta cell identity.
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Affiliation(s)
- Noemi Brusco
- Diabetes and Metabolic Disease Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Guido Sebastiani
- Diabetes and Metabolic Disease Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Gianfranco Di Giuseppe
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Giada Licata
- Diabetes and Metabolic Disease Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Giuseppina E Grieco
- Diabetes and Metabolic Disease Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Daniela Fignani
- Diabetes and Metabolic Disease Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Laura Nigi
- Diabetes and Metabolic Disease Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Caterina Formichi
- Diabetes and Metabolic Disease Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Elena Aiello
- Diabetes and Metabolic Disease Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Stefano Auddino
- Diabetes and Metabolic Disease Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Giuseppe Quero
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy
- Pancreatic surgery unit, Pancreatic Advanced Research Center (CRMPG), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Chiara M A Cefalo
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Francesca Cinti
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padova, Italy
| | - Pietro M Ferraro
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy
- U.O.S. Terapia Conservativa della Malattia Renale Cronica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Alfredo Pontecorvi
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Sergio Alfieri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy
- Pancreatic surgery unit, Pancreatic Advanced Research Center (CRMPG), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Andrea Giaccari
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy.
| | - Francesco Dotta
- Diabetes and Metabolic Disease Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.
| | - Teresa Mezza
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
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45
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Wang L, Wang CC. Oxidative protein folding fidelity and redoxtasis in the endoplasmic reticulum. Trends Biochem Sci 2023; 48:40-52. [PMID: 35871147 DOI: 10.1016/j.tibs.2022.06.011] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 06/16/2022] [Accepted: 06/29/2022] [Indexed: 02/09/2023]
Abstract
In eukaryotic cells, oxidative protein folding occurs in the lumen of the endoplasmic reticulum (ER), catalyzed by ER sulfhydryl oxidase 1 (Ero1) and protein disulfide isomerase (PDI). The efficiency and fidelity of oxidative protein folding are vital for the function of secretory cells. Here, we summarize oxidative protein folding in yeast, plants, and mammals, and discuss how the conformation and activity of human Ero1-PDI machinery is regulated through various post-translational modifications (PTMs). We propose that oxidative protein folding fidelity and ER redox homeostasis are maintained by both the precise control of Ero1 oxidase activity and the division of labor between PDI family members. We also discuss how deregulated Ero1-PDI functions contribute to human diseases and can be leveraged for therapeutic interventions.
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Affiliation(s)
- Lei Wang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Chih-Chen Wang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
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46
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Tran DT, Pottekat A, Lee K, Raghunathan M, Loguercio S, Mir SA, Paton AW, Paton JC, Arvan P, Kaufman RJ, Itkin-Ansari P. Inflammatory Cytokines Rewire the Proinsulin Interaction Network in Human Islets. J Clin Endocrinol Metab 2022; 107:3100-3110. [PMID: 36017587 PMCID: PMC10233482 DOI: 10.1210/clinem/dgac493] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Indexed: 01/19/2023]
Abstract
CONTEXT Aberrant biosynthesis and secretion of the insulin precursor proinsulin occurs in both type I and type II diabetes. Inflammatory cytokines are implicated in pancreatic islet stress and dysfunction in both forms of diabetes, but the mechanisms remain unclear. OBJECTIVE We sought to determine the effect of the diabetes-associated cytokines on proinsulin folding, trafficking, secretion, and β-cell function. METHODS Human islets were treated with interleukin-1β and interferon-γ for 48 hours, followed by analysis of interleukin-6, nitrite, proinsulin and insulin release, RNA sequencing, and unbiased profiling of the proinsulin interactome by affinity purification-mass spectrometry. RESULTS Cytokine treatment induced secretion of interleukin-6, nitrites, and insulin, as well as aberrant release of proinsulin. RNA sequencing showed that cytokines upregulated genes involved in endoplasmic reticulum stress, and, consistent with this, affinity purification-mass spectrometry revealed cytokine induced proinsulin binding to multiple endoplasmic reticulum chaperones and oxidoreductases. Moreover, increased binding to the chaperone immunoglobulin binding protein was required to maintain proper proinsulin folding in the inflammatory environment. Cytokines also regulated novel interactions between proinsulin and type 1 and type 2 diabetes genome-wide association studies candidate proteins not previously known to interact with proinsulin (eg, Ataxin-2). Finally, cytokines induced proinsulin interactions with a cluster of microtubule motor proteins and chemical destabilization of microtubules with Nocodazole exacerbated cytokine induced proinsulin secretion. CONCLUSION Together, the data shed new light on mechanisms by which diabetes-associated cytokines dysregulate β-cell function. For the first time, we show that even short-term exposure to an inflammatory environment reshapes proinsulin interactions with critical chaperones and regulators of the secretory pathway.
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Affiliation(s)
- Duc T Tran
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- Plexium, San Diego, CA, USA
| | - Anita Pottekat
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- Illumina, San Diego, CA, USA
| | - Kouta Lee
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Megha Raghunathan
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | | | - Saiful A Mir
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- University of Calcutta, West Bengal, India
| | | | | | - Peter Arvan
- University of Michigan Medical School, Ann Arbor, MI, USA
| | - Randal J Kaufman
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
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47
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Integrated energy conversion units in nanoscale frameworks induce sustained generation and amplified lethality of singlet oxygen in oxidative therapy of tumor. VIEW 2022. [DOI: 10.1002/viw.20220051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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48
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Wang Q, Chi L. The Alterations and Roles of Glycosaminoglycans in Human Diseases. Polymers (Basel) 2022; 14:polym14225014. [PMID: 36433141 PMCID: PMC9694910 DOI: 10.3390/polym14225014] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/14/2022] [Accepted: 11/15/2022] [Indexed: 11/22/2022] Open
Abstract
Glycosaminoglycans (GAGs) are a heterogeneous family of linear polysaccharides which are composed of a repeating disaccharide unit. They are also linked to core proteins to form proteoglycans (PGs). GAGs/PGs are major components of the cell surface and the extracellular matrix (ECM), and they display critical roles in development, normal function, and damage response in the body. Some properties (such as expression quantity, molecular weight, and sulfation pattern) of GAGs may be altered under pathological conditions. Due to the close connection between these properties and the function of GAGs/PGs, the alterations are often associated with enormous changes in the physiological/pathological status of cells and organs. Therefore, these GAGs/PGs may serve as marker molecules of disease. This review aimed to investigate the structural alterations and roles of GAGs/PGs in a range of diseases, such as atherosclerosis, cancer, diabetes, neurodegenerative disease, and virus infection. It is hoped to provide a reference for disease diagnosis, monitoring, prognosis, and drug development.
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49
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Guevara-Olaya L, Chimal-Vega B, Castañeda-Sánchez CY, López-Cossio LY, Pulido-Capiz A, Galindo-Hernández O, Díaz-Molina R, Ruiz Esparza-Cisneros J, García-González V. LDL Promotes Disorders in β-Cell Cholesterol Metabolism, Implications on Insulin Cellular Communication Mediated by EVs. Metabolites 2022; 12:754. [PMID: 36005626 PMCID: PMC9415214 DOI: 10.3390/metabo12080754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/05/2022] [Accepted: 08/08/2022] [Indexed: 12/01/2022] Open
Abstract
Dyslipidemia is described as a hallmark of metabolic syndrome, promoting a stage of metabolic inflammation (metainflammation) that could lead to misbalances in energetic metabolism, contributing to insulin resistance, and modifying intracellular cholesterol pathways and the renin-angiotensin system (RAS) in pancreatic islets. Low-density lipoprotein (LDL) hypercholesterolemia could disrupt the tissue communication between Langerhans β-cells and hepatocytes, wherein extracellular vesicles (EVs) are secreted by β-cells, and exposition to LDL can impair these phenomena. β-cells activate compensatory mechanisms to maintain insulin and metabolic homeostasis; therefore, the work aimed to characterize the impact of LDL on β-cell cholesterol metabolism and the implication on insulin secretion, connected with the regulation of cellular communication mediated by EVs on hepatocytes. Our results suggest that β-cells can endocytose LDL, promoting an increase in de novo cholesterol synthesis targets. Notably, LDL treatment increased mRNA levels and insulin secretion; this hyperinsulinism condition was associated with the transcription factor PDX-1. However, a compensatory response that maintains basal levels of intracellular calcium was described, mediated by the overexpression of calcium targets PMCA1/4, SERCA2, and NCX1, together with the upregulation of the unfolded protein response (UPR) through the activation of IRE1 and PERK arms to maintain protein homeostasis. The LDL treatment induced metainflammation by IL-6, NF-κB, and COX-2 overexpression. Furthermore, LDL endocytosis triggered an imbalance of the RAS components. LDL treatment increased the intracellular levels of cholesterol on lipid droplets; the adaptive β-cell response was portrayed by the overexpression of cholesterol transporters ABCA1 and ABCG1. Therefore, lipotoxicity and hyperinsulinism induced by LDL were regulated by the natural compound auraptene, a geranyloxyn coumarin modulator of cholesterol-esterification by ACAT1 enzyme inhibition. EVs isolated from β-cells impaired insulin signaling via mTOR/p70S6Kα in hepatocytes, a phenomenon regulated by auraptene. Our results show that LDL overload plays a novel role in hyperinsulinism, mechanisms associated with a dysregulation of intracellular cholesterol, lipotoxicity, and the adaptive UPR, which may be regulated by coumarin-auraptene; these conditions explain the affectations that occur during the initial stages of insulin resistance.
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Affiliation(s)
- Lizbeth Guevara-Olaya
- Departamento de Bioquímica, Facultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali 21000, BC, Mexico
- Laboratorio Multidisciplinario de Estudios Metabólicos y Cáncer, Facultad de Medicina Mexicali, Universidad Autónoma de BC, Mexicali 21000, BC, Mexico
| | - Brenda Chimal-Vega
- Departamento de Bioquímica, Facultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali 21000, BC, Mexico
- Laboratorio Multidisciplinario de Estudios Metabólicos y Cáncer, Facultad de Medicina Mexicali, Universidad Autónoma de BC, Mexicali 21000, BC, Mexico
| | - César Yahel Castañeda-Sánchez
- Departamento de Bioquímica, Facultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali 21000, BC, Mexico
- Laboratorio Multidisciplinario de Estudios Metabólicos y Cáncer, Facultad de Medicina Mexicali, Universidad Autónoma de BC, Mexicali 21000, BC, Mexico
| | - Leslie Y. López-Cossio
- Departamento de Bioquímica, Facultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali 21000, BC, Mexico
- Laboratorio Multidisciplinario de Estudios Metabólicos y Cáncer, Facultad de Medicina Mexicali, Universidad Autónoma de BC, Mexicali 21000, BC, Mexico
| | - Angel Pulido-Capiz
- Departamento de Bioquímica, Facultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali 21000, BC, Mexico
- Laboratorio de Biología Molecular, Facultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali 21000, BC, Mexico
| | - Octavio Galindo-Hernández
- Departamento de Bioquímica, Facultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali 21000, BC, Mexico
- Laboratorio Multidisciplinario de Estudios Metabólicos y Cáncer, Facultad de Medicina Mexicali, Universidad Autónoma de BC, Mexicali 21000, BC, Mexico
| | - Raúl Díaz-Molina
- Departamento de Bioquímica, Facultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali 21000, BC, Mexico
- Laboratorio Multidisciplinario de Estudios Metabólicos y Cáncer, Facultad de Medicina Mexicali, Universidad Autónoma de BC, Mexicali 21000, BC, Mexico
| | | | - Victor García-González
- Departamento de Bioquímica, Facultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali 21000, BC, Mexico
- Laboratorio Multidisciplinario de Estudios Metabólicos y Cáncer, Facultad de Medicina Mexicali, Universidad Autónoma de BC, Mexicali 21000, BC, Mexico
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50
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Chen CW, Guan BJ, Alzahrani MR, Gao Z, Gao L, Bracey S, Wu J, Mbow CA, Jobava R, Haataja L, Zalavadia AH, Schaffer AE, Lee H, LaFramboise T, Bederman I, Arvan P, Mathews CE, Gerling IC, Kaestner KH, Tirosh B, Engin F, Hatzoglou M. Adaptation to chronic ER stress enforces pancreatic β-cell plasticity. Nat Commun 2022; 13:4621. [PMID: 35941159 PMCID: PMC9360004 DOI: 10.1038/s41467-022-32425-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/01/2022] [Indexed: 11/30/2022] Open
Abstract
Pancreatic β-cells are prone to endoplasmic reticulum (ER) stress due to their role in insulin secretion. They require sustainable and efficient adaptive stress responses to cope with this stress. Whether episodes of chronic stress directly compromise β-cell identity is unknown. We show here under reversible, chronic stress conditions β-cells undergo transcriptional and translational reprogramming associated with impaired expression of regulators of β-cell function and identity. Upon recovery from stress, β-cells regain their identity and function, indicating a high degree of adaptive plasticity. Remarkably, while β-cells show resilience to episodic ER stress, when episodes exceed a threshold, β-cell identity is gradually lost. Single cell RNA-sequencing analysis of islets from type 1 diabetes patients indicates severe deregulation of the chronic stress-adaptation program and reveals novel biomarkers of diabetes progression. Our results suggest β-cell adaptive exhaustion contributes to diabetes pathogenesis.
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Affiliation(s)
- Chien-Wen Chen
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
| | - Bo-Jhih Guan
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Mohammed R Alzahrani
- Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Zhaofeng Gao
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Long Gao
- Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Syrena Bracey
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Jing Wu
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Cheikh A Mbow
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Raul Jobava
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Leena Haataja
- The Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, MI, 48105, USA
| | - Ajay H Zalavadia
- Lerner Research Institute, Cleveland Clinic, 9620 Carnegie Ave N Bldg, Cleveland, OH, 44106, US
| | - Ashleigh E Schaffer
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Hugo Lee
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, 53706, USA
| | - Thomas LaFramboise
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Ilya Bederman
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Peter Arvan
- The Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, MI, 48105, USA
| | - Clayton E Mathews
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, US
| | - Ivan C Gerling
- Department of Medicine, University of Tennessee, Memphis, TN, US
| | - Klaus H Kaestner
- Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Boaz Tirosh
- Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 44106, USA
- The Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Feyza Engin
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, 53706, USA.
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, 53705, USA.
| | - Maria Hatzoglou
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
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