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Quezada E, Knoch KP, Vasiljevic J, Seiler A, Pal A, Gunasekaran A, Münster C, Friedland D, Schöniger E, Sönmez A, Roch P, Wegbrod C, Ganß K, Kipke N, Alberti S, Nano R, Piemonti L, Aust D, Weitz J, Distler M, Solimena M. Aldolase-regulated G3BP1/2 + condensates control insulin mRNA storage in beta cells. EMBO J 2025:10.1038/s44318-025-00448-7. [PMID: 40355555 DOI: 10.1038/s44318-025-00448-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 03/13/2025] [Accepted: 04/02/2025] [Indexed: 05/14/2025] Open
Abstract
Upregulation of insulin mRNA translation upon hyperglycemia in pancreatic islet β-cells involves several RNA-binding proteins. Here, we found that G3BP1, a stress granule marker downregulated in islets of subjects with type 2 diabetes, binds to insulin mRNA in glucose concentration-dependent manner. We show in mouse insulinoma MIN6-K8 cells exposed to fasting glucose levels that G3BP1 and its paralog G3BP2 colocalize to cytosolic condensates with eIF3b, phospho-AMPKαThr172 and Ins1/2 mRNA. Glucose stimulation dissolves G3BP1+/2+ condensates with cytosolic redistribution of their components. The aldolase inhibitor aldometanib prevents the glucose- and pyruvate-induced dissolution of G3BP1+/2+ condensates, increases phospho-AMPKαThr172 levels and reduces those of phospho-mTORSer2448. G3BP1 or G3BP2 depletion precludes condensate assembly. KO of G3BP1 decreases Ins1/2 mRNA abundance and translation as well as proinsulin levels, and impaires glucose-stimulated insulin secretion. Further, other insulin secretagogues such as exendin-4 and palmitate, but not high KCl, prompts the dissolution of G3BP1+/2+ condensates. G3BP1+/2+/Ins mRNA+ condensates are also found in primary mouse and human β-cells. Hence, G3BP1+/2+ condensates represent a conserved glycolysis/aldolase-regulated compartment for the physiological storage and protection of insulin mRNA in resting β-cells.
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Affiliation(s)
- Esteban Quezada
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Klaus-Peter Knoch
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Jovana Vasiljevic
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Annika Seiler
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Akshaye Pal
- Max Planck Institute of Molecular Cell Biology and Genetics, 01307, Dresden, Germany
| | - Abishek Gunasekaran
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Carla Münster
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Daniela Friedland
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Eyke Schöniger
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Anke Sönmez
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Pascal Roch
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Carolin Wegbrod
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Katharina Ganß
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Nicole Kipke
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Simon Alberti
- Biotechnology Center (BIOTEC), Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden, Germany
| | - Rita Nano
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Daniela Aust
- Department of Pathology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden Germany, TU Dresden, Dresden, Germany
| | - Jürgen Weitz
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - Marius Distler
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - Michele Solimena
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
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Cho H, Ha SE, Singh R, Kim D, Ro S. microRNAs in Type 1 Diabetes: Roles, Pathological Mechanisms, and Therapeutic Potential. Int J Mol Sci 2025; 26:3301. [PMID: 40244147 PMCID: PMC11990060 DOI: 10.3390/ijms26073301] [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: 02/21/2025] [Revised: 03/26/2025] [Accepted: 03/28/2025] [Indexed: 04/18/2025] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the progressive destruction of pancreatic β-cells, leading to insulin deficiency. The primary drivers of β-cell destruction in T1D involve autoimmune-mediated processes that trigger chronic inflammation and ultimately β-cell loss. Regulatory microRNAs (miRNAs) play a crucial role in modulating these processes by regulating gene expression through post-transcriptional suppression of target mRNAs. Dysregulated miRNAs have been implicated in T1D pathogenesis, serving as both potential diagnostic biomarkers and therapeutic targets. This review explores the role of miRNAs in T1D, highlighting their involvement in disease mechanisms across both rodent models and human patients. While current antidiabetic therapies manage T1D symptoms, they do not prevent β-cell destruction, leaving patients reliant on lifelong insulin therapy. By summarizing key miRNA expression profiles in diabetic animal models and patients, this review explores the potential of miRNA-based therapies to restore β-cell function and halt or slow the progression of the disease.
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Affiliation(s)
| | | | | | | | - Seungil Ro
- Department of Physiology & Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (H.C.); (S.E.H.); (R.S.); (D.K.)
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Naatz A, Bohl KS, Jones Lipinski RA, Nord JA, Gehant AL, Hansen PA, Smith BC, Corbett JA. Role of SIRT3 in the regulation of Gadd45α expression and DNA repair in β-cells. J Biol Chem 2025; 301:108451. [PMID: 40147772 PMCID: PMC12051128 DOI: 10.1016/j.jbc.2025.108451] [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: 10/21/2024] [Revised: 03/09/2025] [Accepted: 03/22/2025] [Indexed: 03/29/2025] Open
Abstract
In previous studies, we have shown that growth arrest and DNA damage (Gadd) 45α is required for the repair of nitric oxide-mediated DNA damage in β-cells. Gadd45α expression is stimulated by nitric oxide and requires forkhead box protein (Fox) O1 and NAD+-dependent deacetylase activity. Based on inhibitor studies, we attributed this activity to Sirtuin (SIRT)1; however, the inhibitors used in this previous study also attenuate the deacetylase activity of SIRT2, 3, and 6. We now provide experimental evidence that SIRT1 is dispensable for β-cell expression of Gadd45α and that the mitochondrial localized isoform SIRT3, is required for DNA repair in β-cells. We show that siRNA knockdown of Sirt3 attenuates nitric oxide-stimulated Gadd45α mRNA accumulation in both wildtype and Sirt1-/- INS 832/13 cells as well as isolated rat islets and that SIRT3 inhibition increases FoxO1 acetylation and attenuates DNA repair in response to nitric oxide. While SIRT3 is predominantly localized to mitochondria, a small fraction is localized in the nucleus of insulin-containing cells and functions to participate in the regulation of FoxO1-dependent, nitric oxide-stimulated DNA repair.
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Affiliation(s)
- Aaron Naatz
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Kelsey S Bohl
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | | | - Joshua A Nord
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Alyssa L Gehant
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Polly A Hansen
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Brian C Smith
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - John A Corbett
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
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Gao M, Liu Q, Zhang L, Tabak F, Hua Y, Shao W, Li Y, Qian L, Liu Y. Identification of crucial extracellular genes as potential biomarkers in newly diagnosed Type 1 diabetes via integrated bioinformatics analysis. PeerJ 2025; 13:e18660. [PMID: 39802181 PMCID: PMC11725270 DOI: 10.7717/peerj.18660] [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: 07/30/2024] [Accepted: 11/17/2024] [Indexed: 01/16/2025] Open
Abstract
Purpose In this study, we aimed to study the role of extracellular proteins as biomarkers associated with newly diagnosed Type 1 diabetes (NT1D) diagnosis and prognosis. Patients and Methods We retrieved and analyzed the GSE55098 microarray dataset from the Gene Expression Omnibus (GEO) database. Using R software, we screened out the extracellular protein-differentially expressed genes (EP-DEGs) through several protein-related databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were applied to describe the role and function of these EP-DEGs. We used the STRING database to construct the interaction of proteins, Cytoscape software to visualize the protein-protein interaction (PPI) networks, and its plugin CytoHubba to identify the crucial genes between PPI networks. Finally, we used the comparative toxicogenomics database (CTD) to evaluate the connection between NT1D with the potential crucial genes and we validated our conclusions with another dataset (GSE33440) and some clinical samples. Results We identified 422 DEGs and 122 EP-DEGs from a dataset that includes (12) NT1D patients compared with (10) healthy people. Protein digestion and absorption, toll-like receptor signaling, and T cell receptor signaling were the most meaningful pathways defined by KEGG enrichment analyses. We recognized nine important extracellular genes: GZMB, CCL4, TNF, MMP9, CCL5, IFNG, CXCL1, GNLY, and LCN2. CTD analyses showed that LCN2, IFNG, and TNF had higher levels in NT1D and hypoglycemia; while TNF, IFNG and MMP9 increased in hyperglycemia. Further verification showed that LCN2, MMP9, TNF and IFNG were elevated in NT1D patients. Conclusion The nine identified key extracellular genes, particularly LCN2, IFNG, TNF, and MMP9, may be potential diagnostic biomarkers for NT1D. Our findings provide new insights into the molecular mechanisms and novel therapeutic targets of NT1D.
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Affiliation(s)
- Ming Gao
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Qing Liu
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Lingyu Zhang
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Fatema Tabak
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yifei Hua
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Wei Shao
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yangyang Li
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Li Qian
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yu Liu
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
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Yu J, Lalwani A, Gunton JE. β-Cell Deletion of Hypoxia-Inducible Factor 1α (HIF-1α) Increases Pancreatic β-Cell Susceptibility to Streptozotocin. Int J Mol Sci 2024; 25:13451. [PMID: 39769216 PMCID: PMC11676740 DOI: 10.3390/ijms252413451] [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: 11/05/2024] [Revised: 12/05/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Type 1 diabetes (T1D) is caused by the immune-mediated loss of pancreatic β-cells. Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor which is crucial for cellular responses to low oxygen. Here, we investigate the role of β-cell HIF-1α in β-cell death and diabetes after exposure to multiple low-dose streptozotocin (MLDS). MDLS triggers auto-immunity in susceptible animal models, such as non-obese diabetic (NOD) mice. These experiments used a novel mouse model with β-cell-specific deletion of HIF-1α on a NOD background (BIN mice). Mice were given 20 mg/kg MLDS for 5 consecutive days. Following MLDS, 100% of BIN mice developed frank diabetes versus 33% of floxed-control (FC) littermates and 17% of NOD controls (p < 0.001). BIN mice had obvious loss of β-cell mass (p < 0.0001) and increased necrotic areas within islets (p < 0.001). To confirm that diabetes was T1D, adoptive transfers of splenocytes from diabetic BIN and FC mice were performed on NOD-SCID (Severe Combined ImmunoDeficiency) recipients. All mice receiving BIN-splenocytes developed frank diabetes, confirming that MLDS induced true T1D. Interestingly, diabetes developed significantly faster in BIN-adoptive transfer mice compared to mice which developed diabetes after receiving an FC-adoptive transfer. These studies demonstrate the importance of β-cell HIF-1α in the preservation of β-cell mass and avoidance of auto-immunity.
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Affiliation(s)
- Josephine Yu
- Centre for Diabetes, Obesity and Endocrinology (CDOE), The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia
| | - Amit Lalwani
- Centre for Diabetes, Obesity and Endocrinology (CDOE), The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2145, Australia
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Jenny E. Gunton
- Centre for Diabetes, Obesity and Endocrinology (CDOE), The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2145, Australia
- Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW 2145, Australia
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Pei R, Wang J, He P, Yu Q, Zhang S, Shi G, Liu G, Li X. Risk factors for type 2 diabetes mellitus in Chinese rheumatoid arthritis patients from 2018 to 2022: a real-world, single-center, retrospective study. Front Immunol 2024; 15:1445639. [PMID: 39430749 PMCID: PMC11486693 DOI: 10.3389/fimmu.2024.1445639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 09/12/2024] [Indexed: 10/22/2024] Open
Abstract
Introduction In patients with rheumatoid arthritis (RA), the increased risk of concomitant type 2 diabetes mellitus (T2D) is an important contributor to increased mortality and decreased quality of life; however, the mechanisms and pathogenetic factors remain unknown. Methods In this study, we aimed to assess the risk factors for T2D in patients with RA. We recruited 206 healthy controls and 488 patients with RA, 160 of whom had comorbid T2D. General clinical information, disease characteristics, and circulating lymphocyte levels detected using modified flow cytometry were collected from all participants. Logistic regression models adjusted for confounders were fitted to estimate the risk factors of T2D in patients with RA. Results The incidence of RA in patients with T2D was 15.6%. Patients with RA and T2D had a longer disease duration, higher BMI, and a higher incidence of hypertension and a family history of diabetes than those with RA but no T2D. The absolute numbers of T helper 2 cell (Th2) and Regulatory T cells (Treg) decreased in patients with RA and T2D, which led to an increase in the ratios of Th1/Th2 and Th17/Treg cells. Multivariate logistic regression analysis showed that a family history of diabetes, a higher incidence of hypertension, higher neutrophil-lymphocyte ratio (NLR) levels, lower platelet-lymphocyte ratio (PLR) levels, and fewer circulating Th2 and Treg cells were associated with an increased risk of T2D in patients with RA. Discussion The levels of peripheral lymphocytes, especially Th2 and Treg cells, are closely related to the occurrence of T2D in patients with RA; however, the influence of body mass index (BMI), family history of diabetes, and systemic inflammation should not be ignored.
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Affiliation(s)
- Ruomeng Pei
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- School of Management, Shanxi Medical University, Taiyuan, China
- Institute of Medical Data Science, Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Big Data for Clinical Decision, Shanxi Medical University, Taiyuan, China
| | - Jia Wang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Peifeng He
- School of Management, Shanxi Medical University, Taiyuan, China
- Institute of Medical Data Science, Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Big Data for Clinical Decision, Shanxi Medical University, Taiyuan, China
- Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Qi Yu
- School of Management, Shanxi Medical University, Taiyuan, China
- Institute of Medical Data Science, Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Big Data for Clinical Decision, Shanxi Medical University, Taiyuan, China
- Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Shengxiao Zhang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Gaoxiang Shi
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Institute of Medical Data Science, Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Big Data for Clinical Decision, Shanxi Medical University, Taiyuan, China
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Geliang Liu
- School of Management, Shanxi Medical University, Taiyuan, China
- Institute of Medical Data Science, Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Big Data for Clinical Decision, Shanxi Medical University, Taiyuan, China
| | - Xiaofeng Li
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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Mekuanint A, Ambachew S, Worede A, Asrie F, Sinishaw MA, Gelaw Y, Dagnew M, Gelaw A, Negash M, Kassa E, Bizuneh S, Wudineh D, Dimah B, Abebe W, Chane E, Fetene G. Assessment of abnormal liver function tests and associated factors among COVID-19-infected patients in Addis Ababa, Ethiopia, 2022: a facility-based comparative cross-sectional study. BMJ Open 2024; 14:e076647. [PMID: 39260868 PMCID: PMC11409313 DOI: 10.1136/bmjopen-2023-076647] [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: 06/16/2023] [Accepted: 07/19/2024] [Indexed: 09/13/2024] Open
Abstract
OBJECTIVE Liver function test (LFT) abnormalities are higher in patients with severe COVID-19. Most of the studies on this theme were conducted in foreign nations, and the association with LFT abnormalities was not sufficiently addressed in the study areas. Therefore, the current study aimed to investigate the effects of COVID-19 infection on liver function of patients. SETTING A facility-based comparative cross-sectional study was carried out from 10 April to 15 June 2022, among COVID-19 infected individuals admitted in Eka Kotebe General Hospital and Saint Petrous Specialized Hospitals, Addis Ababa, 2022. PARTICIPANTS A total of 284 confirmed COVID-19-positive and COVID-19-negative controls matched by gender and age were included in the present study. RESULTS Among SARS-COV-2 positive groups, 63 (44.4%) had one or more LFT abnormalities. The most common elevated level of the LFTs among patients with COVID-19 were gamma-glutamyl transferase (GGT) 50 (35.2%), while the most common lowered level was albumin 58 (40.8%). The mean values of aspartate aminotransferase (AST) (35.4±26.9 vs 22.9±12.6, p<0.001) were significantly different between patients with COVID-19 and the COVID-19-free groups. Being COVID-19-positive was significantly associated with an elevated level of AST (AOR=3.0, 95% CI 1.2 to 7.4) and GGT (AOR=4.55, 95% CI 2.02 to 10.3). Being male was significantly associated with an elevated level of total bilirubin (BILT, AOR=2.41, 95% CI 1.2 to 4.9) and direct bilirubin (BILD, AOR=3.7, 95% CI 1.72 to 8.2), and also severe stage of COVID-19 was associated with hypoalbuminaemia (AOR=3.3, 95% CI 1.4 to 7.9). SARS-COV-2 infection was independently associated with LFT abnormality. CONCLUSION Patients with COVID-19 had decreased albumin levels, and elevated AST, GGT, BILT and BILD levels.
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Affiliation(s)
- Amare Mekuanint
- Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Sintayehu Ambachew
- Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Abebaw Worede
- Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Fikir Asrie
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Mulusew Alemneh Sinishaw
- Department of Clinical Chemistry, College of Medicine and Health Science, Bahir Dar University, Bahir Dar, Ethiopia
| | - Yemataw Gelaw
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Mulat Dagnew
- Department of Medical Microbiology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Aschalew Gelaw
- Department of Medical Microbiology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Markos Negash
- Department of Immunology and Molecular Biology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Eyuel Kassa
- University of Gondar Comprehensive Specialized Hospital Laboratory, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Segenet Bizuneh
- Department of Internal Medicine, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Dessalew Wudineh
- Department of Medical Laboratory Sciences, Institute of Health Sciences, Mizan Tepi University, Mizan Tepi, Ethiopia
| | - Belayneh Dimah
- Department of Microbiology, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia
| | - Wagaw Abebe
- Department of Medical Laboratory Sciences, College of Health Sciences, Woldia University, Woldia, Ethiopia
| | - Elias Chane
- Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Getnet Fetene
- Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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Hu X, Lin H, Qian S, Xu Z, Li Z, Qian S, Yang F, Hou H, Xie Q, Wu W, Hu C, Abou-Elnour A, He Y, Huang Y. A novel experimental mouse model of diabetic nonalcoholic steatohepatitis: A critical role for acid-sensitive Ion Channel 1a. Biomed Pharmacother 2024; 178:117184. [PMID: 39142252 DOI: 10.1016/j.biopha.2024.117184] [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: 06/02/2024] [Revised: 07/17/2024] [Accepted: 07/22/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND A two-way relationship exists between type 2 diabetes (T2DM) and human nonalcoholic steatohepatitis (NASH). Several diabetic NASH models have the disadvantages of long cycles or inconsistent with the actual incidence of human disease, which would be costly and time-consuming to investigate disease pathogenesis and develop drugs. Therefore, there is an urgent need to establish a diabetic NASH mouse model. METHODS The combination between Fructose-palmitate-cholesterol diet (FPC) and Streptozotocin (STZ) (FPC+STZ) was used to construct diabetic NASH mouse model. The in vivo effects of silencing acid-sensitive Ion Channel 1a (ASIC1a) were examined with an adeno-associated virus 9 (AAV9) carrying ASIC1a short hairpin RNA (shRNA) in FPC+STZ model. RESULTS The mice fed with FPC for 12 weeks had insulin resistance, hyperinsulinemia, lipid accumulation, and increased hepatic levels of inflammatory factors. However, it still did not develop remarkable liver fibrosis. Most interestingly, noticeable fibrotic scars were observed in the liver of mice from FPC+STZ group. Furthermore, insulin therapy significantly ameliorated FPC+STZ-induced NASH-related liver fibrosis, indicating that hyperglycemia is of great significance in NASH development and progression. Importantly, ASIC1a was found to be involved in the pathogenesis of diabetic NASH as demonstrated that silencing ASIC1a in HSCs significantly ameliorated FPC+STZ-induced NASH fibrosis. Mechanistically, ASIC1a interacted with Poly Adp-adenosine ribose polymerase (PARP1) to promote HSC activation by inducing autophagy. CONCLUSION A FPC diet combined with an injection of STZ induces a diabetic NASH mouse model in a shorter period. Targeting ASIC1a may provide a novel therapeutic target for the treatment of diabetic NASH.
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Affiliation(s)
- Xiaojie Hu
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Huimin Lin
- Department of Pharmacy, the Second Affiliated Hospital of Anhui Medical University, China
| | - Shengying Qian
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Zhou Xu
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Zihao Li
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Shishun Qian
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Furong Yang
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hui Hou
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qinxiu Xie
- Department of Infection, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wenyong Wu
- Hospital of The Second People's Hospital of Anhui Province, Hefei, China
| | - Chengmu Hu
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Amira Abou-Elnour
- School of International Education, Anhui Medical University, Hefei, China
| | - Yong He
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
| | - Yan Huang
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China.
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9
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Petropavlovskaia M, Assouline-Thomas B, Cuerquis J, Zhao J, Violette-Deslauriers S, Nano E, Eliopoulos N, Rosenberg L. Characterization of MSCs expressing islet neogenesis associated protein (INGAP): INGAP secretion and cell survival in vitro and in vivo. Heliyon 2024; 10:e35372. [PMID: 39170459 PMCID: PMC11336584 DOI: 10.1016/j.heliyon.2024.e35372] [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: 11/21/2023] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 08/23/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are emerging as a new therapy for diabetes. Here we investigate the properties of MSCs engineered to express Islet Neogenesis Associated Protein (INGAP) previously shown to reverse diabetes in animal models and evaluate their potential for anti-diabetic applications in mice. Mouse bone marrow-derived MSCs retrovirally transduced to co-express INGAP, Firefly Luciferase and EGFP (INGAP-MSCs), were characterized in vitro and implanted intraperitoneally (IP) into non-diabetic and diabetic C57BL/6 mice (Streptozotocin model) and tracked by live bioluminescence imaging (BLI). Distribution and survival of IP injected INGAP-MSCs differed between diabetic and non-diabetic mice, with a rapid clearance of cells in the latter, and a stronger retention (up to 4 weeks) in diabetic mice concurring with homing towards the pancreas. Interestingly, INGAP-MSCs inhibited the progression of hyperglycemia starting at day 3 and lasting for the entire 6 weeks of the study. Pursuing greater retention, we investigated the survival of INGAP-MSCs in hydrogel matrices. When mixed with Matrigel™ and injected subcutaneously into non-diabetic mice, INGAP-MSCs remained in the implant up to 16 weeks. In vitro tests in three matrices (Matrigel™, Type I Collagen and VitroGel®-MSC) demonstrated that INGAP-MSCs survive and secrete INGAP, with best results at the density of 1-2 x 106 cells/mL. However, all matrices induced spontaneous adipogenic differentiation of INGAP-MSCs in vitro and in vivo, which requires further investigation of its potential impact on MSC therapeutic properties. In summary, based on their ability to stop the rise in hyperglycemia in STZ-treated mice, INGAP-MSCs are a promising therapeutic tool against diabetes but require further research to improve cell delivery and survival.
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Affiliation(s)
- Maria Petropavlovskaia
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
- Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| | | | - Jessica Cuerquis
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
| | - Jing Zhao
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
| | - Shaun Violette-Deslauriers
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
- Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| | - Eni Nano
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
- Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| | - Nicoletta Eliopoulos
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
- Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| | - Lawrence Rosenberg
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
- Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
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10
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Alazmi A, Bashiru MB, Viktor S, Erjavec M. Psychological variables and lifestyle in children with type1 diabetes and their parents: A systematic review. Clin Child Psychol Psychiatry 2024; 29:1174-1194. [PMID: 37249210 PMCID: PMC11188552 DOI: 10.1177/13591045231177115] [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] [Indexed: 05/31/2023]
Abstract
Diabetes may impact physical and psychosocial well-being; the diabetes incidence has seen a drastic increase globally. There is also a rise in poor mental health and well-being in children with and without chronic illness; problems are being seen at a younger age. The objective of this review was to understand the determinants of these problems in a family context. We conducted a systematic review to investigate what lifestyle and psychological factors influence children with Type 1 diabetes and their parents. A focused literature search was performed using a combination of keywords that covered the relevant terminology for diabetes, target population, and associated emotional distress, using electronic bibliographic databases containing publications until May 2022. Methodological quality was assessed using the Quality Assessment Tools for Quantitative Studies. Twenty articles met the inclusion criteria. Quality scores were weak because of a lack of comparison groups, information about the type of therapy, or adequate sample sizes. Many of the studies included a wide age range in their sample. The majority of the studies reported that parents and their children showed depression symptoms, fear of hypoglycaemia, and higher parenting stress. We conclude that sufficiently powered studies employing appropriate control groups and measures are needed to elucidate the psychological variables associated with Type1 diabetes in children and the effects on parents, especially considering primary-age children who are increasingly reported to suffer from poor mental health, and its implications. This should help to introduce better targeted interventions and improve behavioural outcomes.
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Affiliation(s)
- Afrah Alazmi
- School of Human and Behavioural Sciences, Bangor University, Bangor, UK
| | | | - Simon Viktor
- School of Human and Behavioural Sciences, Bangor University, Bangor, UK
| | - Mihela Erjavec
- School of Human and Behavioural Sciences, Bangor University, Bangor, UK
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11
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Sharifi S, Yamamoto T, Zeug A, Elsner M, Avezov E, Mehmeti I. Non-esterified fatty acid palmitate facilitates oxidative endoplasmic reticulum stress and apoptosis of β-cells by upregulating ERO-1α expression. Redox Biol 2024; 73:103170. [PMID: 38692092 PMCID: PMC11070623 DOI: 10.1016/j.redox.2024.103170] [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: 04/11/2024] [Revised: 04/24/2024] [Accepted: 04/26/2024] [Indexed: 05/03/2024] Open
Abstract
Adipose tissue-derived non-esterified saturated long-chain fatty acid palmitate (PA) decisively contributes to β-cell demise in type 2 diabetes mellitus in part through the excessive generation of hydrogen peroxide (H2O2). The endoplasmic reticulum (ER) as the primary site of oxidative protein folding could represent a significant source of H2O2. Both ER-oxidoreductin-1 (ERO-1) isoenzymes, ERO-1α and ERO-1β, catalyse oxidative protein folding within the ER, generating equimolar amounts of H2O2 for every disulphide bond formed. However, whether ERO-1-derived H2O2 constitutes a potential source of cytotoxic luminal H2O2 under lipotoxic conditions is still unknown. Here, we demonstrate that both ERO-1 isoforms are expressed in pancreatic β-cells, but interestingly, PA only significantly induces ERO-1α. Its specific deletion significantly attenuates PA-mediated oxidative ER stress and subsequent β-cell death by decreasing PA-mediated ER-luminal and mitochondrial H2O2 accumulation, by counteracting the dysregulation of ER Ca2+ homeostasis, and by mitigating the reduction of mitochondrial membrane potential and lowered ATP content. Moreover, ablation of ERO-1α alleviated PA-induced hyperoxidation of the ER redox milieu. Importantly, ablation of ERO-1α did not affect the insulin secretory capacity, the unfolded protein response, or ER redox homeostasis under steady-state conditions. The involvement of ERO-1α-derived H2O2 in PA-mediated β-cell lipotoxicity was corroborated by the overexpression of a redox-active ERO-1α underscoring the proapoptotic activity of ERO-1α in pancreatic β-cells. Overall, our findings highlight the critical role of ERO-1α-derived H2O2 in lipotoxic ER stress and β-cell failure.
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Affiliation(s)
- Sarah Sharifi
- Institute of Clinical Biochemistry, Hannover Medical School, 30625, Hannover, Germany
| | - Tomoko Yamamoto
- Institute of Clinical Biochemistry, Hannover Medical School, 30625, Hannover, Germany
| | - Andre Zeug
- Institute for Neurophysiology, Hannover Medical School, 30625, Hannover, Germany
| | - Matthias Elsner
- Institute of Clinical Biochemistry, Hannover Medical School, 30625, Hannover, Germany
| | - Edward Avezov
- Department of Clinical Neurosciences and UK Dementia Research Institute, University of Cambridge, CB2 0AH Cambridge, UK
| | - Ilir Mehmeti
- Institute of Clinical Biochemistry, Hannover Medical School, 30625, Hannover, Germany.
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12
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Koufakis T, Patoulias D, Zografou I, Papanas N, Popovic DS. Drawing lines in the sand: The growing threat of obesity in type 1 diabetes. World J Diabetes 2024; 15:823-827. [PMID: 38766422 PMCID: PMC11099370 DOI: 10.4239/wjd.v15.i5.823] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 01/31/2024] [Accepted: 03/12/2024] [Indexed: 05/10/2024] Open
Abstract
In this editorial, we comment on the article by Zeng et al published in the recent issue of the World Journal of Diabetes in 2024. We focus on the epidemiological, pathophysiological, and clinical interplay between obesity and type 1 diabetes mellitus (T1DM). Overweight and obesity represent a growing threat for modern societies and people with T1DM could not be an exception to this rule. Chronic exogenous insulin administration, genetic and epigenetic factors, and psy-chosocial and behavioral parameters, along with the modern way of life that incorporates unhealthy eating patterns and physical inactivity, set the stage for the increasing obesity rates in T1DM. As our knowledge of the underlying mechanisms that lead to the development of obesity and hyperglycemia expands, it becomes clear that there are overlap zones in the pathophysiology of the two main types of diabetes. Stereotypes regarding strict dividing lines between "autoimmune" and "metabolic" phenotypes increase the risk of trapping physicians into ineffective therapeutic approaches, instead of individualized diabetes care. In this context, the use of adjuncts to insulin therapy that have the potential to alleviate cardiorenal risk and decrease body weight can reduce the burden of obesity in patients with T1DM.
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Affiliation(s)
- Theocharis Koufakis
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Dimitrios Patoulias
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Ioanna Zografou
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis 68100, Greece
| | - Djordje S Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Center of Vojvodina, Medical Faculty, University of Novi Sad, Novi Sad 21000, Serbia
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Liu X, Qin H, Liu Y, Ma J, Li Y, He Y, Zhu H, Mao L. The biological functions and pathological mechanisms of CASK in various diseases. Heliyon 2024; 10:e28863. [PMID: 38638974 PMCID: PMC11024568 DOI: 10.1016/j.heliyon.2024.e28863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 03/21/2024] [Accepted: 03/26/2024] [Indexed: 04/20/2024] Open
Abstract
Background As a scaffold protein, calcium/calmodulin-dependent serine protein kinase (CASK) has been extensively studied in a variety of tissues throughout the body. The Cask gene is ubiquitous in several tissues, such as the neurons, islets, heart, kidneys and sperm, and is mostly localised in the cytoplasm adjacent to the basement membrane. CASK binds to a variety of proteins through its domains to exerting its biological activity. Scope of review Here, we discuss the role of CASK in multiple tissues throughout the body. The role of different CASK domains in regulating neuronal development, neurotransmitter release and synaptic vesicle secretion was emphasised; the regulatory mechanism of CASK on the function of pancreatic islet β cells was analysed; the role of CASK in cardiac physiology, kidney and sperm development was discussed; and the role of CASK in different tumours was compared. Finally, we clarify the importance of the Cask gene in the body, and how deletion or mutation of the Cask gene can have adverse consequences. Major conclusions CASK is a conserved gene with similar roles in various tissues. The function of the Cask gene in the nervous system is mainly involved in the development of the nervous system and the release of neurotransmitters. In the endocrine system, an involvement of CASK has been reported in the process of insulin vesicle transport. CASK is also involved in cardiomyocyte ion channel regulation, kidney and sperm development, and tumour proliferation. CASK is an indispensable gene for the whole body, and CASK mutations can cause foetal malformations or death at birth. In this review, we summarise the biological functions and pathological mechanisms of CASK in various systems, thereby providing a basis for further in-depth studies of CASK functions.
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Affiliation(s)
- Xingjing Liu
- Department of Endocrinology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Haonan Qin
- Department of Orthopedics, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Yuanyuan Liu
- Department of Endocrinology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Jingjing Ma
- Department of Endocrinology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Yiming Li
- Department of Endocrinology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Yu He
- Department of Endocrinology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Huimin Zhu
- Department of Electrophysiology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Li Mao
- Department of Endocrinology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
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14
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Zhang J, Chen W, Chen G, Flannick J, Fikse E, Smerin G, Degner K, Yang Y, Xu C, Consortium AMP-T2D-GENES, Li Y, Hanover JA, Simonds WF. Ancestry-specific high-risk gene variant profiling unmasks diabetes-associated genes. Hum Mol Genet 2024; 33:655-666. [PMID: 36255737 PMCID: PMC11000659 DOI: 10.1093/hmg/ddac255] [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: 05/04/2022] [Revised: 09/28/2022] [Accepted: 10/10/2022] [Indexed: 11/15/2022] Open
Abstract
How ancestry-associated genetic variance affects disparities in the risk of polygenic diseases and influences the identification of disease-associated genes warrants a deeper understanding. We hypothesized that the discovery of genes associated with polygenic diseases may be limited by the overreliance on single-nucleotide polymorphism (SNP)-based genomic investigation, as most significant variants identified in genome-wide SNP association studies map to introns and intergenic regions of the genome. To overcome such potential limitations, we developed a gene-constrained, function-based analytical method centered on high-risk variants (hrV) that encode frameshifts, stopgains or splice site disruption. We analyzed the total number of hrV per gene in populations of different ancestry, representing a total of 185 934 subjects. Using this analysis, we developed a quantitative index of hrV (hrVI) across 20 428 genes within each population. We then applied hrVI analysis to the discovery of genes associated with type 2 diabetes mellitus (T2DM), a polygenic disease with ancestry-related disparity. HrVI profiling and gene-to-gene comparisons of ancestry-specific hrV between the case (20 781 subjects) and control (24 440 subjects) populations in the T2DM national repository identified 57 genes associated with T2DM, 40 of which were discoverable only by ancestry-specific analysis. These results illustrate how a function-based, ancestry-specific analysis of genetic variations can accelerate the identification of genes associated with polygenic diseases. Besides T2DM, such analysis may facilitate our understanding of the genetic basis for other polygenic diseases that are also greatly influenced by environmental and behavioral factors, such as obesity, hypertension and Alzheimer's disease.
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Affiliation(s)
- Jianhua Zhang
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - Weiping Chen
- Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
- Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - Guanjie Chen
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD 20892, United States
| | - Jason Flannick
- Metabolism Program, Broad Institute, Cambridge, MA 02142, United States
| | - Emma Fikse
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - Glenda Smerin
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - Katherine Degner
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - Yanqin Yang
- Laboratory of Transplantation Genomics, National Heart Lung and Blood Institute; National Institutes of Health, Bethesda, MD 20892, United States
| | - Catherine Xu
- Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | | | - Yulong Li
- Milton S. Hershey Medical Center, Division of Endocrinology, Diabetes and Metabolism, Penn State University, Hershey, PA 17033, United States
| | - John A Hanover
- Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - William F Simonds
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
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Li F, Liu X, Zhao L, Wang H, Zhang L, Xing W, Cui J. Vitamin B6 Turnover Predicts Long-term Mortality Risk in Patients with Type 2 Diabetes. Curr Dev Nutr 2024; 8:102073. [PMID: 38312433 PMCID: PMC10830545 DOI: 10.1016/j.cdnut.2023.102073] [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: 11/27/2023] [Revised: 12/20/2023] [Accepted: 12/21/2023] [Indexed: 02/06/2024] Open
Abstract
Background Inflammation can increase vitamin B6 uptake and catabolism. Higher vitamin B6 turnover [4-pyridoxic acid (4-PA)/pyridoxal 5'-phosphate (PLP) ratio], was associated with mortality risk in the general population. Objectives We aimed to investigate the association between 4-PA/PLP and long-term mortality in patients with type 2 diabetes mellitus (T2DM), an inflammatory disease. Methods In this prospective cohort study from the National Health and Nutrition Examination Survey (NHANES) cycles 2005-2010, the concentrations of 4-PA and PLP in plasma were measured using high-performance liquid chromatography, with mortality data updated to 31 December 2019. We included 2074 patients with T2DM aged between 20 and 85 y at baseline. Results There were 739 deaths among 2279 patients with T2DM with a median follow-up of 11.83 y. In the age- and sex-adjusted COX model (model 1), 4-PA/PLP was positively associated with mortality in patients with T2DM [hazard ratio (HR) and 95% confidence interval (CI) highest compared with lowest quartiles: 35.55 (18.29, 69.09); P < 0.001], and in model 3, which was adjusted for demographics as well as inflammation, nutrition, and renal function, high 4-PA/PLP concentrations remained an independent risk factor for mortality in patients with T2DM [HR (95% CI) highest compared with lowest quartiles: 5.03 (2.46, 10.30); P < 0.001]. In restricted cubic spline (RCS), the link between 4-PA/PLP and all-cause mortality displays a positive correlation. Patients with died within the previous 2 y were excluded, the sensitivity analysis had no effect on the association between 4-PA/PLP and mortality in patients with T2DM. Finally, comparable results were found in subgroup analyses of specific-cause mortality. Conclusion Higher vitamin B6 turnover is associated with long-term mortality risk in patients with T2DM. 4-PA/PLP may serve as a convenient prognostic marker in T2DM management.
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Affiliation(s)
| | | | | | - Hongyi Wang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Lili Zhang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Weiwei Xing
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Jiuwei Cui
- Cancer Center, The First Hospital of Jilin University, Changchun, China
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16
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Yildirim V, Sheraton VM, Brands R, Crielaard L, Quax R, van Riel NA, Stronks K, Nicolaou M, Sloot PM. A data-driven computational model for obesity-driven diabetes onset and remission through weight loss. iScience 2023; 26:108324. [PMID: 38026205 PMCID: PMC10665812 DOI: 10.1016/j.isci.2023.108324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 08/22/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
Obesity is a major risk factor for the development of type 2 diabetes (T2D), where a sustained weight loss may result in T2D remission in individuals with obesity. To design effective and feasible intervention strategies to prevent or reverse T2D, it is imperative to study the progression of T2D and remission together. Unfortunately, this is not possible through experimental and observational studies. To address this issue, we introduce a data-driven computational model and use human data to investigate the progression of T2D with obesity and remission through weight loss on the same timeline. We identify thresholds for the emergence of T2D and necessary conditions for remission. We explain why remission is only possible within a window of opportunity and the way that window depends on the progression history of T2D, individual's metabolic state, and calorie restrictions. These findings can help to optimize therapeutic intervention strategies for T2D prevention or treatment.
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Affiliation(s)
- Vehpi Yildirim
- Department of Public and Occupational Health, Amsterdam University Medical Centers, University of Amsterdam, 1081 BT Amsterdam, the Netherlands
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
| | - Vivek M. Sheraton
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
- Computational Science Lab, University of Amsterdam, 1098 XH Amsterdam, the Netherlands
- Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, 1100 DD Amsterdam, the Netherlands
| | - Ruud Brands
- AMRIF B.V., Agro Business Park, 6708 PW Wageningen, the Netherlands
- Institute for Risk Assessment Sciences, Utrecht University, 3584 CL Utrecht, the Netherlands
| | - Loes Crielaard
- Department of Public and Occupational Health, Amsterdam University Medical Centers, University of Amsterdam, 1081 BT Amsterdam, the Netherlands
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
| | - Rick Quax
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
- Computational Science Lab, University of Amsterdam, 1098 XH Amsterdam, the Netherlands
| | - Natal A.W. van Riel
- Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, the Netherlands
- Department of Experimental and Vascular Medicine, Amsterdam University Medical Centers, 1100 DD Amsterdam, the Netherlands
| | - Karien Stronks
- Department of Public and Occupational Health, Amsterdam University Medical Centers, University of Amsterdam, 1081 BT Amsterdam, the Netherlands
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
| | - Mary Nicolaou
- Department of Public and Occupational Health, Amsterdam University Medical Centers, University of Amsterdam, 1081 BT Amsterdam, the Netherlands
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
| | - Peter M.A. Sloot
- Institute for Advanced Study, University of Amsterdam, 1012 GC Amsterdam, the Netherlands
- Computational Science Lab, University of Amsterdam, 1098 XH Amsterdam, the Netherlands
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Gonuguntla S, Humphrey RK, Gorantla A, Hao E, Jhala US. Stress-induced pseudokinase TRB3 augments IL1β signaling by interacting with Flightless homolog 1. J Biol Chem 2023; 299:104803. [PMID: 37172723 PMCID: PMC10432976 DOI: 10.1016/j.jbc.2023.104803] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 04/20/2023] [Accepted: 04/22/2023] [Indexed: 05/15/2023] Open
Abstract
Interleukin-1β is one of the most potent inducers of beta cell inflammation in the lead-up to type 1 diabetes. We have previously reported that IL1β-stimulated pancreatic islets from mice with genetic ablation of stress-induced pseudokinase TRB3(TRB3KO) show attenuated activation kinetics for the MAP3K MLK3 and JNK stress kinases. However, JNK signaling constitutes only a portion of the cytokine-induced inflammatory response. Here we report that TRB3KO islets also show a decrease in amplitude and duration of IL1β-induced phosphorylation of TAK1 and IKK, kinases that drive the potent NF-κB proinflammatory signaling pathway. We observed that TRB3KO islets display decreased cytokine-induced beta cell death, preceded by a decrease in select downstream NF-κB targets, including iNOS/NOS2 (inducible nitric oxide synthase), a mediator of beta cell dysfunction and death. Thus, loss of TRB3 attenuates both pathways required for a cytokine-inducible, proapoptotic response in beta cells. In order to better understand the molecular basis of TRB3-enhanced, post-receptor IL1β signaling, we interrogated the TRB3 interactome using coimmunoprecipitation followed by mass spectrometry to identify immunomodulatory protein Flightless homolog 1 (Fli1) as a novel, TRB3-interacting protein. We show that TRB3 binds and disrupts Fli1-dependent sequestration of MyD88, thereby increasing availability of this most proximal adaptor required for IL1β receptor-dependent signaling. Fli1 sequesters MyD88 in a multiprotein complex resulting in a brake on the assembly of downstream signaling complexes. By interacting with Fli1, we propose that TRB3 lifts the brake on IL1β signaling to augment the proinflammatory response in beta cells.
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Affiliation(s)
- Sumati Gonuguntla
- Pediatric Diabetes Research Center, University of California San Diego, La Jolla, California, USA
| | - Rohan K Humphrey
- Pediatric Diabetes Research Center, University of California San Diego, La Jolla, California, USA
| | - Akshita Gorantla
- Pediatric Diabetes Research Center, University of California San Diego, La Jolla, California, USA
| | - Ergeng Hao
- Pediatric Diabetes Research Center, University of California San Diego, La Jolla, California, USA
| | - Ulupi S Jhala
- Pediatric Diabetes Research Center, University of California San Diego, La Jolla, California, USA.
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18
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Wang J, Qi Z, Wu Y, Wang A, Liu Q, Zou F, Wang B, Qi S, Cao J, Hu C, Shi C, Liang Q, Wang L, Liu J, Wang W, Liu Q. Discovery of IHMT-MST1-39 as a novel MST1 kinase inhibitor and AMPK activator for the treatment of diabetes mellitus. Signal Transduct Target Ther 2023; 8:143. [PMID: 37015918 PMCID: PMC10073293 DOI: 10.1038/s41392-023-01352-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 01/03/2023] [Accepted: 02/01/2023] [Indexed: 04/06/2023] Open
Abstract
Insulin-producing pancreatic β cell death is the fundamental cause of type 1 diabetes (T1D) and a contributing factor to type 2 diabetes (T2D). Moreover, metabolic disorder is another hallmark of T2D. Mammalian sterile 20-like kinase 1 (MST1) contributes to the progression of diabetes mellitus through apoptosis induction and acceleration of pancreatic β cell dysfunction. AMP-activated protein kinase (AMPK) is an energy sensing kinase and its activation has been suggested as a treatment option for metabolic diseases. Thus, pharmacological inhibition of MST1 and activation of AMPK simultaneously represents a promising approach for diabetes therapy. Here, we discovered a novel selective MST1 kinase inhibitor IHMT-MST1-39, which exhibits anti-apoptosis efficacy and improves the survival of pancreatic β cells under diabetogenic conditions, as well as primary pancreatic islets in an ex vivo disease model. Mechanistically, IHMT-MST1-39 activated AMPK signaling pathway in hepatocytes in vitro, combination of IHMT-MST1-39 and metformin synergistically prevented hyperglycemia and significantly ameliorated glucose tolerance and insulin resistance in diabetic mice. Taken together, IHMT-MST1-39 is a promising anti-diabetic candidate as a single agent or in combination therapy for both T1D and T2D.
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Affiliation(s)
- Junjie Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Ziping Qi
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Yun Wu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Aoli Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Qingwang Liu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Fengming Zou
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Beilei Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Shuang Qi
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Jiangyan Cao
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Chen Hu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Chenliang Shi
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Qianmao Liang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Li Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Jing Liu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.
| | - Wenchao Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.
| | - Qingsong Liu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China.
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.
- Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, P. R. China.
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Kulkarni A, Muralidharan C, May SC, Tersey SA, Mirmira RG. Inside the β Cell: Molecular Stress Response Pathways in Diabetes Pathogenesis. Endocrinology 2022; 164:bqac184. [PMID: 36317483 PMCID: PMC9667558 DOI: 10.1210/endocr/bqac184] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Indexed: 11/05/2022]
Abstract
The pathogeneses of the 2 major forms of diabetes, type 1 and type 2, differ with respect to their major molecular insults (loss of immune tolerance and onset of tissue insulin resistance, respectively). However, evidence suggests that dysfunction and/or death of insulin-producing β-cells is common to virtually all forms of diabetes. Although the mechanisms underlying β-cell dysfunction remain incompletely characterized, recent years have witnessed major advances in our understanding of the molecular pathways that contribute to the demise of the β-cell. Cellular and environmental factors contribute to β-cell dysfunction/loss through the activation of molecular pathways that exacerbate endoplasmic reticulum stress, the integrated stress response, oxidative stress, and impaired autophagy. Whereas many of these stress responsive pathways are interconnected, their individual contributions to glucose homeostasis and β-cell health have been elucidated through the development and interrogation of animal models. In these studies, genetic models and pharmacological compounds have enabled the identification of genes and proteins specifically involved in β-cell dysfunction during diabetes pathogenesis. Here, we review the critical stress response pathways that are activated in β cells in the context of the animal models.
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Affiliation(s)
- Abhishek Kulkarni
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| | - Charanya Muralidharan
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| | - Sarah C May
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| | - Sarah A Tersey
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| | - Raghavendra G Mirmira
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
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20
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Dalcin LDL, Fagundes-Triches DLG, de Queiroz AA, Torres AHF, França DCH, Soares TA, Ramos LCDS, Antônio CRSS, Fujimori M, França EL, Honorio-França AC. Resistin Modulates the Functional Activity of Colostral Macrophages from Mothers with Obesity and Diabetes. Biomedicines 2022; 10:2332. [PMID: 36289594 PMCID: PMC9598095 DOI: 10.3390/biomedicines10102332] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/15/2022] [Accepted: 09/16/2022] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Obesity and diabetes are major public health problems. Resistin is an adipokine that links the two diseases. There are few reports regarding colostrum cells and resistin from mothers with obesity and diabetes. Thus, this study aimed to determine the functional activity of macrophages present in the breast milk and colostrum of diabetic mothers with obesity and the effects of resistin on these cells. METHODS The women were divided according to BMI and glycemic status into normal weight non-diabetic, obese non-diabetic, normal weight type 2 diabetic, or obese type 2 diabetic groups. ELISA determined the resistin in colostrum. The cell subsets and apoptosis were determined by flow cytometry and the functional activity of cells by fluorescence microscopy. RESULTS The resistin levels were higher in the colostrum from diabetic mothers with obesity. The frequencies of CD14+ cells and cells expressing CD95+, independent of resistin treatment, were higher in the colostrum from diabetic mothers with obesity. The frequency of cells expressing CD14+CD95+ was higher in cells not treated with resistin in the colostrum from diabetic mothers with obesity. Apoptosis, irrespective of the presence of resistin, increased, whereas microbicidal activity decreased in cells from diabetic mothers with obesity. CONCLUSION The data suggest that hyperglycemia associated with low-grade inflammation caused by obesity affects the percentage of cells expressing CD14+CD95+, death by apoptosis, and microbicidal indices; meanwhile, resistin restored the microbicidal activity of colostrum cells.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Eduardo Luzia França
- Institute of Biological and Health Science, Federal University of Mato Grosso, Av. Valdon Varjão, 6390, Barra do Garças 78698-091, Mato Grosso, Brazil
| | - Adenilda Cristina Honorio-França
- Institute of Biological and Health Science, Federal University of Mato Grosso, Av. Valdon Varjão, 6390, Barra do Garças 78698-091, Mato Grosso, Brazil
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21
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Li J, Zhou L, Gong H. New insights and advances of sodium-glucose cotransporter 2 inhibitors in heart failure. Front Cardiovasc Med 2022; 9:903902. [PMID: 36186974 PMCID: PMC9520058 DOI: 10.3389/fcvm.2022.903902] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 08/15/2022] [Indexed: 11/30/2022] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are newly emerging insulin-independent anti-hyperglycemic agents that work independently of β-cells. Quite a few large-scale clinical trials have proven the cardiovascular protective function of SGLT2is in both diabetic and non-diabetic patients. By searching all relevant terms related to our topics over the previous 3 years, including all the names of agents and their brands in PubMed, here we review the mechanisms underlying the improvement of heart failure. We also discuss the interaction of various mechanisms proposed by diverse works of literature, including corresponding and opposing viewpoints to support each subtopic. The regulation of diuresis, sodium excretion, weight loss, better blood pressure control, stimulation of hematocrit and erythropoietin, metabolism remodeling, protection from structural dysregulation, and other potential mechanisms of SGLT2i contributing to heart failure improvement have all been discussed in this manuscript. Although some remain debatable or even contradictory, those newly emerging agents hold great promise for the future in cardiology-related therapies, and more research needs to be conducted to confirm their functionality, particularly in metabolism, Na+-H+ exchange protein, and myeloid angiogenic cells.
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Affiliation(s)
- Juexing Li
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
- Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lei Zhou
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
- Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hui Gong
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
- Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
- *Correspondence: Hui Gong
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22
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Da Porto A, Tascini C, Colussi G, Peghin M, Graziano E, De Carlo C, Bulfone L, Antonello M, Sozio E, Fabris M, Curcio F, Pucillo C, Catena C, Sechi LA. Relationship between cytokine release and stress hyperglycemia in patients hospitalized with COVID-19 infection. Front Med (Lausanne) 2022; 9:988686. [PMID: 36059840 PMCID: PMC9437426 DOI: 10.3389/fmed.2022.988686] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 08/04/2022] [Indexed: 01/08/2023] Open
Abstract
Introduction Stress hyperglycemia is a frequent finding in patients with COVID-19 infection and could affect the outcome of disease. Cytokines released in response to infection could have adverse effects on insulin sensitivity and pancreatic beta-cell function. The aim of the study was to examine the relationships of stress hyperglycemia with cytokines and clinical outcomes in hospitalized patients with COVID-19. Methods In a cross-sectional analysis of 150 patients hospitalized for COVID-19 infection who were included in the GIRA-COVID database, we identified patients with stress hyperglycemia by calculation of the Stress Hyperglycemia Ratio (SHR) and use of a cut-off of 1.14. Plasma levels of cytokines principally involved in COVID-19 infection-related cytokine storm were measured. Outcome variables were use of mechanical ventilation and death within 60 days from hospital admission. Results Patients with SHR > 1.14 had significantly higher plasma insulin, HOMA-index, and levels of interleukin-10 (IL-10), interleukin-10/tumor necrosis factor-a ratio (IL-10/TNF-α), and CXC motif chemokine ligand 10 (CXCL10) than patients with SHR ≤ 1.14. IL-10, IL-10/TNF-α ratio, CXCL10, and IFN-γ were significantly and directly related with SHR in univariate analysis and multivariate logistic regression models showed that IL-10, IL-10/TNF-α ratio, and CXCL10 were independently associated with SHR>1.14. In a multivariate logistic model, stress hyperglycemia predicted use of mechanical ventilation (OR 2.453; CI 1.078–6.012) and death (OR 2.281; CI 1.049–7.369) independently of diabetes and other major confounders. Conclusions In patients hospitalized for COVID-19 infection, stress hyperglycemia is associated with worse clinical outcomes and is independently related to levels of cytokines that might impair glucose homeostasis.
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Affiliation(s)
- Andrea Da Porto
- Division of Internal Medicine, Department of Medicine, University of Udine, Udine, Italy
- *Correspondence: Andrea Da Porto
| | - Carlo Tascini
- Division of Infectious Diseases, Department of Medicine, University of Udine, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine, Italy
| | - Gianluca Colussi
- Division of Internal Medicine, Department of Medicine, University of Udine, Udine, Italy
| | - Maddalena Peghin
- Division of Infectious Diseases, Department of Medicine, University of Udine, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine, Italy
| | - Elena Graziano
- Division of Infectious Diseases, Department of Medicine, University of Udine, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine, Italy
| | - Chiara De Carlo
- Division of Infectious Diseases, Department of Medicine, University of Udine, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine, Italy
| | - Luca Bulfone
- Division of Internal Medicine, Department of Medicine, University of Udine, Udine, Italy
| | - Martina Antonello
- Division of Internal Medicine, Department of Medicine, University of Udine, Udine, Italy
| | - Emanuela Sozio
- Division of Infectious Diseases, Department of Medicine, University of Udine, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine, Italy
| | - Martina Fabris
- Division of Laboratory Medicine, University of Udine, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine, Italy
| | - Francesco Curcio
- Division of Laboratory Medicine, University of Udine, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine, Italy
| | - Carlo Pucillo
- Laboratory of Immunology, Department of Medicine, University of Udine, Udine, Italy
| | - Cristiana Catena
- Division of Internal Medicine, Department of Medicine, University of Udine, Udine, Italy
| | - Leonardo A. Sechi
- Division of Internal Medicine, Department of Medicine, University of Udine, Udine, Italy
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23
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Sinha T, Mishra SS, Singh S, Panda AC. PanCircBase: An online resource for the exploration of circular RNAs in pancreatic islets. Front Cell Dev Biol 2022; 10:942762. [PMID: 36060809 PMCID: PMC9437246 DOI: 10.3389/fcell.2022.942762] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/11/2022] [Indexed: 11/13/2022] Open
Abstract
Circular RNAs (circRNAs) are a novel class of covalently closed RNA molecules that recently emerged as a critical regulator of gene expression in development and diseases. Recent research has highlighted the importance of novel circRNAs in the biosynthesis and secretion of insulin from β-cells of pancreatic islets. However, all circRNAs expressed in pancreatic islets or β-cells are not readily available in the database. In this study, we analyzed publicly available RNA-sequencing datasets of the pancreatic islets to catalog all circRNAs expressed in pancreatic islets to construct the PanCircBase (https://www.pancircbase.net/) database that provides the following resources: 1) pancreatic islet circRNA annotation details (genomic position, host gene, exon information, splice length, sequence, other database IDs, cross-species conservation), 2) divergent primers for PCR analysis of circRNAs, 3) siRNAs for silencing of target circRNAs, 4) miRNAs associated with circRNAs, 5) possible protein-coding circRNAs and their polypeptides. In summary, this is a comprehensive online resource for exploring circRNA expression and its possible function in pancreatic β-cells.
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Affiliation(s)
- Tanvi Sinha
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, India
- Regional Center for Biotechnology, Faridabad, India
| | | | - Suman Singh
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, India
- Regional Center for Biotechnology, Faridabad, India
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24
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Ben Nasr M, D’Addio F, Montefusco L, Usuelli V, Loretelli C, Rossi A, Pastore I, Abdelsalam A, Maestroni A, Dell’Acqua M, Ippolito E, Assi E, Seelam AJ, Fiorina RM, Chebat E, Morpurgo P, Lunati ME, Bolla AM, Abdi R, Bonventre JV, Rusconi S, Riva A, Corradi D, Santus P, Clark P, Nebuloni M, Baldi G, Finzi G, Folli F, Zuccotti GV, Galli M, Herold KC, Fiorina P. Indirect and Direct Effects of SARS-CoV-2 on Human Pancreatic Islets. Diabetes 2022; 71:1579-1590. [PMID: 35499468 PMCID: PMC9490452 DOI: 10.2337/db21-0926] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 04/04/2022] [Indexed: 01/08/2023]
Abstract
Recent studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may induce metabolic distress, leading to hyperglycemia in patients affected by coronavirus disease 19 (COVID-19). We investigated the potential indirect and direct effects of SARS-CoV-2 on human pancreatic islets in 10 patients who became hyperglycemic after COVID-19. Although there was no evidence of peripheral anti-islet autoimmunity, the serum of these patients displayed toxicity on human pancreatic islets, which could be abrogated by the use of anti-interleukin-1β (IL-1β), anti-IL-6, and anti-tumor necrosis factor α, cytokines known to be highly upregulated during COVID-19. Interestingly, the receptors of those aforementioned cytokines were highly expressed on human pancreatic islets. An increase in peripheral unmethylated INS DNA, a marker of cell death, was evident in several patients with COVID-19. Pathology of the pancreas from deceased hyperglycemic patients who had COVID-19 revealed mild lymphocytic infiltration of pancreatic islets and pancreatic lymph nodes. Moreover, SARS-CoV-2-specific viral RNA, along with the presence of several immature insulin granules or proinsulin, was detected in postmortem pancreatic tissues, suggestive of β-cell-altered proinsulin processing, as well as β-cell degeneration and hyperstimulation. These data demonstrate that SARS-CoV-2 may negatively affect human pancreatic islet function and survival by creating inflammatory conditions, possibly with a direct tropism, which may in turn lead to metabolic abnormalities observed in patients with COVID-19.
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Affiliation(s)
- Moufida Ben Nasr
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo and Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche (DIBIC), Università di Milano, Milan, Italy
- Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA
| | - Francesca D’Addio
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo and Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche (DIBIC), Università di Milano, Milan, Italy
- Division of Endocrinology, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli-Sacco, Milan, Italy
| | - Laura Montefusco
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo and Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche (DIBIC), Università di Milano, Milan, Italy
| | - Vera Usuelli
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo and Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche (DIBIC), Università di Milano, Milan, Italy
| | - Cristian Loretelli
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo and Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche (DIBIC), Università di Milano, Milan, Italy
| | - Antonio Rossi
- Division of Endocrinology, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli-Sacco, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli-Sacco, Milan, Italy
| | - Ahmed Abdelsalam
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo and Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche (DIBIC), Università di Milano, Milan, Italy
| | - Anna Maestroni
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo and Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche (DIBIC), Università di Milano, Milan, Italy
| | - Marco Dell’Acqua
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo and Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche (DIBIC), Università di Milano, Milan, Italy
- Division of Endocrinology, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli-Sacco, Milan, Italy
| | - Elio Ippolito
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo and Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche (DIBIC), Università di Milano, Milan, Italy
| | - Emma Assi
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo and Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche (DIBIC), Università di Milano, Milan, Italy
| | - Andy Joe Seelam
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo and Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche (DIBIC), Università di Milano, Milan, Italy
| | - Roberta Maria Fiorina
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo and Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche (DIBIC), Università di Milano, Milan, Italy
| | - Enrica Chebat
- Division of Endocrinology, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli-Sacco, Milan, Italy
| | - Paola Morpurgo
- Division of Endocrinology, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli-Sacco, Milan, Italy
| | - Maria Elena Lunati
- Division of Endocrinology, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli-Sacco, Milan, Italy
| | - Andrea Mario Bolla
- Division of Endocrinology, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli-Sacco, Milan, Italy
| | - Reza Abdi
- Transplantation Research Center and Nephrology Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Joseph V. Bonventre
- Transplantation Research Center and Nephrology Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Stefano Rusconi
- Infectious Diseases Unit, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Agostino Riva
- Infectious Diseases Unit, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Domenico Corradi
- Unit of Pathology, Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy
| | - Pierachille Santus
- Division of Respiratory Diseases, ASST Fatebenefratelli-Sacco, Milan, Italy
- Department of Biomedical and Clinical Sciences, DIBIC, Università di Milano, Milan, Italy
| | - Pamela Clark
- Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT
| | - Manuela Nebuloni
- Department of Biomedical and Clinical Sciences, DIBIC, Università di Milano, Milan, Italy
- Department of Pathology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Gabriella Baldi
- Endocrinology Laboratory, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Giovanna Finzi
- Department of Pathology, University Hospital ASST-Settelaghi, Varese, Italy
| | - Franco Folli
- Endocrinology and Metabolism, Department of Health Science, Università di Milano, ASST Santi Paolo e Carlo, Milan, Italy
| | | | - Massimo Galli
- Infectious Diseases Unit, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Kevan C. Herold
- Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT
| | - Paolo Fiorina
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo and Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche (DIBIC), Università di Milano, Milan, Italy
- Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA
- Division of Endocrinology, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli-Sacco, Milan, Italy
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25
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Abstract
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is a global pandemic impacting 254 million people in 190 countries. Comorbidities, particularly cardiovascular disease, diabetes, and hypertension, increase the risk of infection and poor outcomes. SARS-CoV-2 enters host cells through the angiotensin-converting enzyme-2 receptor, generating inflammation and cytokine storm, often resulting in multiorgan failure. The mechanisms and effects of COVID-19 on patients with high-risk diabetes are not yet completely understood. In this review, we discuss the variety of coronaviruses, structure of SARS-CoV-2, mutations in SARS-CoV-2 spike proteins, receptors associated with viral host entry, and disease progression. Furthermore, we focus on possible mechanisms of SARS-CoV-2 in diabetes, leading to inflammation and heart failure. Finally, we discuss existing therapeutic approaches, unanswered questions, and future directions.
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Affiliation(s)
- Chandrakala Aluganti Narasimhulu
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States
| | - Dinender K Singla
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States
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26
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Li Z, Pan X, Cai YD. Identification of Type 2 Diabetes Biomarkers From Mixed Single-Cell Sequencing Data With Feature Selection Methods. Front Bioeng Biotechnol 2022; 10:890901. [PMID: 35721855 PMCID: PMC9201257 DOI: 10.3389/fbioe.2022.890901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 04/04/2022] [Indexed: 11/18/2022] Open
Abstract
Diabetes is the most common disease and a major threat to human health. Type 2 diabetes (T2D) makes up about 90% of all cases. With the development of high-throughput sequencing technologies, more and more fundamental pathogenesis of T2D at genetic and transcriptomic levels has been revealed. The recent single-cell sequencing can further reveal the cellular heterogenicity of complex diseases in an unprecedented way. With the expectation on the molecular essence of T2D across multiple cell types, we investigated the expression profiling of more than 1,600 single cells (949 cells from T2D patients and 651 cells from normal controls) and identified the differential expression profiling and characteristics at the transcriptomics level that can distinguish such two groups of cells at the single-cell level. The expression profile was analyzed by several machine learning algorithms, including Monte Carlo feature selection, support vector machine, and repeated incremental pruning to produce error reduction (RIPPER). On one hand, some T2D-associated genes (MTND4P24, MTND2P28, and LOC100128906) were discovered. On the other hand, we revealed novel potential pathogenic mechanisms in a rule manner. They are induced by newly recognized genes and neglected by traditional bulk sequencing techniques. Particularly, the newly identified T2D genes were shown to follow specific quantitative rules with diabetes prediction potentials, and such rules further indicated several potential functional crosstalks involved in T2D.
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Affiliation(s)
- Zhandong Li
- College of Biological and Food Engineering, Jilin Engineering Normal University, Changchun, China
| | - Xiaoyong Pan
- Key Laboratory of System Control and Information Processing, Institute of Image Processing and Pattern Recognition, Ministry of Education of China, Shanghai Jiao Tong University, Shanghai, China
| | - Yu-Dong Cai
- School of Life Sciences, Shanghai University, Shanghai, China
- *Correspondence: Yu-Dong Cai,
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27
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Zhou Y, Takano T, Li X, Wang Y, Wang R, Zhu Z, Tanokura M, Miyakawa T, Hachimura S. β-elemene regulates M1-M2 macrophage balance through the ERK/JNK/P38 MAPK signaling pathway. Commun Biol 2022; 5:519. [PMID: 35641589 PMCID: PMC9156783 DOI: 10.1038/s42003-022-03369-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 04/14/2022] [Indexed: 02/06/2023] Open
Abstract
Macrophages are classified into classically activated M1 macrophages and alternatively activated M2 macrophages, and the two phenotypes of macrophages are present during the development of various chronic diseases, including obesity-induced inflammation. In the present study, β-elemene, which is contained in various plant substances, is predicted to treat high-fat diet (HFD)-induced macrophage dysfunction based on the Gene Expression Omnibus (GEO) database and experimental validation. β-elemene impacts the imbalance of M1-M2 macrophages by regulating pro-inflammatory cytokines in mouse white adipose tissue both in vitro and in vivo. In addition, the RAW 264 cell line, which are macrophages from mouse ascites, is used to identify the effects of β-elemene on inhibiting bacterial endotoxin lipopolysaccharide (LPS)-induced phosphorylation of mitogen-activated protein kinase (MAPK) pathways. These pathways both induce and are activated by pro-inflammatory cytokines, and they also participate in the process of obesity-induced inflammation. The results highlight that β-elemene may represent a possible macrophage-mediated therapeutic medicine.
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Affiliation(s)
- Yingyu Zhou
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Tomohiro Takano
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Xuyang Li
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Yimei Wang
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Rong Wang
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Zhangliang Zhu
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
- Key Laboratory of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, National Engineering Laboratory for Industrial Enzymes, Tianjin, 300457, P. R. China
| | - Masaru Tanokura
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan.
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan.
| | - Takuya Miyakawa
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan.
| | - Satoshi Hachimura
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan.
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan.
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28
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Hong H, He H, Lin X, Hayuehashi T, Xu J, Zhang J, Xu Y, Tong T, Lu Y, Zhou Z. Cadmium exposure suppresses insulin secretion through mtROS-mediated mitochondrial dysfunction and inflammatory response in pancreatic beta cells. J Trace Elem Med Biol 2022; 71:126952. [PMID: 35183883 DOI: 10.1016/j.jtemb.2022.126952] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 02/09/2022] [Accepted: 02/14/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Cadmium (Cd) exposure is a worldwide environmental threat to the public health and participates in the pathogenesis of multiple diseases. Epidemiologic research have established a direct relation between Cd exposure and diabetes development in humans. Although pancreatic β-cell dysfunction has been considered as the major culprit in the pathogenesis of diabetes, there is a paucity of studies to elucidate the molecular mechanism of Cd toxicity on β-cells. METHODS To unveil the toxic effect and its underlying mechanism of Cd exposure on β-cells, we used an in vitro MIN6 cell model of environment-relevant Cd exposure to elucidate the crucial role of mtROS-mediated mitochondrial dysfunction and inflammatory response in suppression of pancreatic β-cell insulin secretion. RESULTS We uncovered that Cd treatment suppresses cell viability and induces insulin secretion dysfunction in a dose-dependent manner. Moreover, Cd exposure elicits the inflammatory response, as indicated by increased IL-1β, IL-6 and TNF-α expressions. Significant elevations of intracellular ROS and mitochondrial ROS levels were detected as early as 3 h after Cd treatment. In mitochondrial function analysis, we demonstrated that Cd treatment induced mitochondrial dysfunction and disorder of mitochondrial fission indicated by the significant decline in ATP production, the marked depolarization of mitochondrial membrane potential, the decrease in mtDNA copy numbers, the suppressions of mitochondrial transcription factor A (Tfam) and mitochondrial fission-related gene Drp1 expressions. Pretreatment with TEMPO, a specific mitochondrial ROS (mtROS) scavenger, efficiently antagonizes Cd cytotoxicity, which is indicated by attenuating Cd-induced mitochondrial dysfunction, suppressing IL-1β, IL-6 and TNF-α expressions, ameliorating insulin production dysfunction and preserving cell viability in MIN6 cells. CONCLUSION Our study demonstrates that Cd exposure induces an inflammatory response through mtROS-mediated mitochondrial dysfunction. Antagonism of mtROS production might be an effective strategy to prevent pancreatic toxicity from environment-relevant Cd exposure.
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Affiliation(s)
- Huihui Hong
- Department of Environmental Medicine and Department of Emergency Medicine of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haotian He
- Department of Environmental Medicine and Department of Emergency Medicine of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiqin Lin
- Department of Environmental Medicine and Department of Emergency Medicine of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tali Hayuehashi
- Department of Environmental Medicine and Department of Emergency Medicine of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jia Xu
- Department of Emergency Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou, China
| | - Jingjing Zhang
- Department of Environmental Medicine and Department of Emergency Medicine of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yudong Xu
- Department of Environmental Medicine and Department of Emergency Medicine of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tong Tong
- Department of Environmental Medicine and Department of Emergency Medicine of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuanqiang Lu
- Department of Emergency Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou, China.
| | - Zhou Zhou
- Department of Environmental Medicine and Department of Emergency Medicine of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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29
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Huang G, Li M, Tian X, Jin Q, Mao Y, Li Y. The emerging roles of IL-36, IL-37, and IL-38 in diabetes mellitus and its complications. Endocr Metab Immune Disord Drug Targets 2022; 22:997-1008. [PMID: 35049442 DOI: 10.2174/1871530322666220113142533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/15/2021] [Accepted: 12/30/2021] [Indexed: 11/22/2022]
Abstract
Diabetes mellitus is a metabolic disease caused by a combination of genetics and environmental factors. The importance of the inflammatory response occurring in the pancreas and adipose tissue in the occurrence and progression of diabetes has been gradually accepted. Excess blood glucose and free fatty acids produce large amounts of inflammatory cytokines and chemokines through oxidative stress and endoplasmic reticulum stress. There is sufficient evidence that proinflammatory mediators, such as interleukin (IL)-1β, IL-6, macrophage chemotactic protein-1, and tumor necrosis factor-α, are engaged in the insulin resistance in peripheral adipose tissue and the apoptosis of pancreatic β-cells. IL-36, IL-37, and IL-38, as new members of the IL-1 family, play an indispensable effect in the regulation of immune system homeostasis and are involved in the pathogenesis of inflammatory and autoimmune diseases. Recently, the abnormal expression of IL-36, IL-37, and IL-38 in diabetes has been reported. In this review, we discuss the emerging functions, potential mechanisms, and future research directions on the role of IL-36, IL-37, and IL-38 in diabetes mellitus and its complications.
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Affiliation(s)
- Guoqing Huang
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China
| | - Mingcai Li
- School of Medicine, Ningbo University, Ningbo 315211, China
| | - Xiaoqing Tian
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China
| | - Qiankai Jin
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China
| | - Yushan Mao
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China
| | - Yan Li
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China
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30
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Yang Y, Chen Z, Zhao X, Xie H, Du L, Gao H, Xie C. Mechanisms of Kaempferol in the treatment of diabetes: A comprehensive and latest review. Front Endocrinol (Lausanne) 2022; 13:990299. [PMID: 36157449 PMCID: PMC9490412 DOI: 10.3389/fendo.2022.990299] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 08/17/2022] [Indexed: 01/07/2023] Open
Abstract
Obesity-insulin resistance-β-cells apoptosis" is an important trilogy of the pathogenesis of type 2 diabetes. With the global pandemic of obesity and diabetes, continuous research and development of new drugs focuses on the prevention of the pathological progress of these diseases. According to a recent study, the natural product kaempferol has excellent antidiabetic effects. Therefore, this review comprehensively summarized the frontier studies and pharmacological mechanisms of kaempferol in the treatment of diabetes. The successful research and development of kaempferol may yield a significant leap in the treatment of diabetes and its complications.
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Affiliation(s)
- Yan Yang
- Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
| | - Zhengtao Chen
- Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoyan Zhao
- Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
| | - Hongyan Xie
- Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
| | - Lian Du
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hong Gao
- Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Hong Gao, ; Chunguang Xie,
| | - Chunguang Xie
- Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Hong Gao, ; Chunguang Xie,
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31
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Sukumaran V, Gurusamy N, Yalcin HC, Venkatesh S. Understanding diabetes-induced cardiomyopathy from the perspective of renin angiotensin aldosterone system. Pflugers Arch 2021; 474:63-81. [PMID: 34967935 DOI: 10.1007/s00424-021-02651-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 12/02/2021] [Accepted: 12/03/2021] [Indexed: 12/31/2022]
Abstract
Experimental and clinical evidence suggests that diabetic subjects are predisposed to a distinct cardiovascular dysfunction, known as diabetic cardiomyopathy (DCM), which could be an autonomous disease independent of concomitant micro and macrovascular disorders. DCM is one of the prominent causes of global morbidity and mortality and is on a rising trend with the increase in the prevalence of diabetes mellitus (DM). DCM is characterized by an early left ventricle diastolic dysfunction associated with the slow progression of cardiomyocyte hypertrophy leading to heart failure, which still has no effective therapy. Although the well-known "Renin Angiotensin Aldosterone System (RAAS)" inhibition is considered a gold-standard treatment in heart failure, its role in DCM is still unclear. At the cellular level of DCM, RAAS induces various secondary mechanisms, adding complications to poor prognosis and treatment of DCM. This review highlights the importance of RAAS signaling and its major secondary mechanisms involving inflammation, oxidative stress, mitochondrial dysfunction, and autophagy, their role in establishing DCM. In addition, studies lacking in the specific area of DCM are also highlighted. Therefore, understanding the complex role of RAAS in DCM may lead to the identification of better prognosis and therapeutic strategies in treating DCM.
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Affiliation(s)
| | - Narasimman Gurusamy
- Department of Bioscience Research, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Huseyin C Yalcin
- Biomedical Research Center, Qatar University, Al-Tarfa, 2371, Doha, Qatar
| | - Sundararajan Venkatesh
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers-New Jersey Medical School, Newark, NJ, USA
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32
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Purdel C, Ungurianu A, Margina D. Metabolic and Metabolomic Insights Regarding the Omega-3 PUFAs Intake in Type 1 Diabetes Mellitus. Front Mol Biosci 2021; 8:783065. [PMID: 34926582 PMCID: PMC8678113 DOI: 10.3389/fmolb.2021.783065] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 11/22/2021] [Indexed: 12/16/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is currently considered an autoimmune disease characterized by the destruction of pancreatic β-cells, insulin deficiency, and dysglycemia. Dietary factors, including omega-3 polyunsaturated fatty acids (ω-3 PUFAs), were reported to influence T1DM. Therefore, a better understanding of the potential role of ω-3 PUFAs in the development and progression of T1DM will help to improve the clinical management of the disease. In this review, we explored the current understanding of molecular mechanisms and signaling pathways induced by ω-3 PUFAs and the beneficial effects of ω-3 PUFAs intake in the prevention and treatment of T1DM, as well as the underlying possible metabolomic (lipidomics) changes.
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Affiliation(s)
- Carmen Purdel
- Department of Toxicology, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Anca Ungurianu
- Department of Biochemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Denisa Margina
- Department of Biochemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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33
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Lu H, Guo R, Zhang Y, Su S, Zhao Q, Yu Y, Shi H, Sun H, Zhang Y, Li S, Shi D, Chu X, Sun C. Inhibition of lncRNA TCONS_00077866 Ameliorates the High Stearic Acid Diet-Induced Mouse Pancreatic β-Cell Inflammatory Response by Increasing miR-297b-5p to Downregulate SAA3 Expression. Diabetes 2021; 70:2275-2288. [PMID: 34261739 DOI: 10.2337/db20-1079] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 07/06/2021] [Indexed: 11/13/2022]
Abstract
Long-term consumption of a high-fat diet increases the circulating concentration of stearic acid (SA), which has a potent toxic effect on β-cells, but the underlying molecular mechanisms of this action have not been fully elucidated. Here, we evaluated the role of long noncoding (lnc)RNA TCONS_00077866 (lnc866) in SA-induced β-cell inflammation. lnc866 was selected for study because lncRNA high-throughput sequencing analysis demonstrated it to have the largest fold-difference in expression of five lncRNAs that were affected by SA treatment. Knockdown of lnc866 by virus-mediated shRNA expression in mice or by Smart Silencer in mouse pancreatic β-TC6 cells significantly inhibited the SA-induced reduction in insulin secretion and β-cell inflammation. According to lncRNA-miRNAs-mRNA coexpression network analysis and luciferase reporter assays, lnc866 directly bound to miR-297b-5p, thereby preventing it from reducing the expression of its target serum amyloid A3 (SAA3). Furthermore, overexpression of miR-297b-5p or inhibition of SAA3 also had marked protective effects against the deleterious effects of SA in β-TC6 cells and mouse islets. In conclusion, lnc866 silencing ameliorates SA-induced β-cell inflammation by targeting the miR-297b-5p/SAA3 axis. lnc866 inhibition may represent a new strategy to protect β-cells against the effects of SA during the development of type 2 diabetes.
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MESH Headings
- Animals
- Cells, Cultured
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/pathology
- Diabetes Mellitus, Type 2/prevention & control
- Diet, High-Fat/adverse effects
- Down-Regulation/drug effects
- Gene Expression Regulation/drug effects
- HEK293 Cells
- Humans
- Inflammation/etiology
- Inflammation/genetics
- Inflammation/pathology
- Inflammation/prevention & control
- Insulin Secretion/drug effects
- Insulin-Secreting Cells/drug effects
- Insulin-Secreting Cells/metabolism
- Insulin-Secreting Cells/pathology
- Male
- Mice
- Mice, Inbred C57BL
- MicroRNAs/genetics
- Palmitic Acid/adverse effects
- Palmitic Acid/pharmacology
- Pancreatitis/etiology
- Pancreatitis/genetics
- Pancreatitis/pathology
- Pancreatitis/prevention & control
- RNA, Long Noncoding/antagonists & inhibitors
- RNA, Long Noncoding/genetics
- RNA, Small Interfering/pharmacology
- Serum Amyloid A Protein/genetics
- Stearic Acids/adverse effects
- Stearic Acids/pharmacology
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Affiliation(s)
- Huimin Lu
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Rui Guo
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Yunjin Zhang
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Shenghan Su
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Qingrui Zhao
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Yue Yu
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Hongbo Shi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Haoran Sun
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Yongjian Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Tumor Hospital of Harbin Medical University, Harbin, China
| | - Shenglong Li
- Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dan Shi
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Xia Chu
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
| | - Changhao Sun
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China
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34
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Javeed N, Her TK, Brown MR, Vanderboom P, Rakshit K, Egan AM, Vella A, Lanza I, Matveyenko AV. Pro-inflammatory β cell small extracellular vesicles induce β cell failure through activation of the CXCL10/CXCR3 axis in diabetes. Cell Rep 2021; 36:109613. [PMID: 34433033 PMCID: PMC8420815 DOI: 10.1016/j.celrep.2021.109613] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 06/04/2021] [Accepted: 08/05/2021] [Indexed: 12/13/2022] Open
Abstract
Coordinated communication among pancreatic islet cells is necessary for maintenance of glucose homeostasis. In diabetes, chronic exposure to pro-inflammatory cytokines has been shown to perturb β cell communication and function. Compelling evidence has implicated extracellular vesicles (EVs) in modulating physiological and pathological responses to β cell stress. We report that pro-inflammatory β cell small EVs (cytokine-exposed EVs [cytoEVs]) induce β cell dysfunction, promote a pro-inflammatory islet transcriptome, and enhance recruitment of CD8+ T cells and macrophages. Proteomic analysis of cytoEVs shows enrichment of the chemokine CXCL10, with surface topological analysis depicting CXCL10 as membrane bound on cytoEVs to facilitate direct binding to CXCR3 receptors on the surface of β cells. CXCR3 receptor inhibition reduced CXCL10-cytoEV binding and attenuated β cell dysfunction, inflammatory gene expression, and leukocyte recruitment to islets. This work implies a significant role of pro-inflammatory β cell-derived small EVs in modulating β cell function, global gene expression, and antigen presentation through activation of the CXCL10/CXCR3 axis.
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Affiliation(s)
- Naureen Javeed
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.
| | - Tracy K Her
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - Matthew R Brown
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - Patrick Vanderboom
- Division of Endocrinology, Diabetes, and Metabolism, Mayo Clinic, Rochester, MN 55905, USA
| | - Kuntol Rakshit
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - Aoife M Egan
- Division of Endocrinology, Diabetes, and Metabolism, Mayo Clinic, Rochester, MN 55905, USA
| | - Adrian Vella
- Division of Endocrinology, Diabetes, and Metabolism, Mayo Clinic, Rochester, MN 55905, USA
| | - Ian Lanza
- Division of Endocrinology, Diabetes, and Metabolism, Mayo Clinic, Rochester, MN 55905, USA
| | - Aleksey V Matveyenko
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA; Division of Endocrinology, Diabetes, and Metabolism, Mayo Clinic, Rochester, MN 55905, USA
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Untangling the genetic link between type 1 and type 2 diabetes using functional genomics. Sci Rep 2021; 11:13871. [PMID: 34230558 PMCID: PMC8260770 DOI: 10.1038/s41598-021-93346-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
There is evidence pointing towards shared etiological features between type 1 diabetes (T1D) and type 2 diabetes (T2D) despite both phenotypes being considered genetically distinct. However, the existence of shared genetic features for T1D and T2D remains complex and poorly defined. To better understand the link between T1D and T2D, we employed an integrated functional genomics approach involving extensive chromatin interaction data (Hi-C) and expression quantitative trait loci (eQTL) data to characterize the tissue-specific impacts of single nucleotide polymorphisms associated with T1D and T2D. We identified 195 pleiotropic genes that are modulated by tissue-specific spatial eQTLs associated with both T1D and T2D. The pleiotropic genes are enriched in inflammatory and metabolic pathways that include mitogen-activated protein kinase activity, pertussis toxin signaling, and the Parkinson's disease pathway. We identified 8 regulatory elements within the TCF7L2 locus that modulate transcript levels of genes involved in immune regulation as well as genes important in the etiology of T2D. Despite the observed gene and pathway overlaps, there was no significant genetic correlation between variant effects on T1D and T2D risk using European ancestral summary data. Collectively, our findings support the hypothesis that T1D and T2D specific genetic variants act through genetic regulatory mechanisms to alter the regulation of common genes, and genes that co-locate in biological pathways, to mediate pleiotropic effects on disease development. Crucially, a high risk genetic profile for T1D alters biological pathways that increase the risk of developing both T1D and T2D. The same is not true for genetic profiles that increase the risk of developing T2D. The conversion of information on genetic susceptibility to the protein pathways that are altered provides an important resource for repurposing or designing novel therapies for the management of diabetes.
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Ng XW, Chung YH, Piston DW. Intercellular Communication in the Islet of Langerhans in Health and Disease. Compr Physiol 2021; 11:2191-2225. [PMID: 34190340 PMCID: PMC8985231 DOI: 10.1002/cphy.c200026] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Blood glucose homeostasis requires proper function of pancreatic islets, which secrete insulin, glucagon, and somatostatin from the β-, α-, and δ-cells, respectively. Each islet cell type is equipped with intrinsic mechanisms for glucose sensing and secretory actions, but these intrinsic mechanisms alone cannot explain the observed secretory profiles from intact islets. Regulation of secretion involves interconnected mechanisms among and between islet cell types. Islet cells lose their normal functional signatures and secretory behaviors upon dispersal as compared to intact islets and in vivo. In dispersed islet cells, the glucose response of insulin secretion is attenuated from that seen from whole islets, coordinated oscillations in membrane potential and intracellular Ca2+ activity, as well as the two-phase insulin secretion profile, are missing, and glucagon secretion displays higher basal secretion profile and a reverse glucose-dependent response from that of intact islets. These observations highlight the critical roles of intercellular communication within the pancreatic islet, and how these communication pathways are crucial for proper hormonal and nonhormonal secretion and glucose homeostasis. Further, misregulated secretions of islet secretory products that arise from defective intercellular islet communication are implicated in diabetes. Intercellular communication within the islet environment comprises multiple mechanisms, including electrical synapses from gap junctional coupling, paracrine interactions among neighboring cells, and direct cell-to-cell contacts in the form of juxtacrine signaling. In this article, we describe the various mechanisms that contribute to proper islet function for each islet cell type and how intercellular islet communications are coordinated among the same and different islet cell types. © 2021 American Physiological Society. Compr Physiol 11:2191-2225, 2021.
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Affiliation(s)
- Xue W Ng
- Department of Cell Biology and Physiology, Washington University, St Louis, Missouri, USA
| | - Yong H Chung
- Department of Cell Biology and Physiology, Washington University, St Louis, Missouri, USA
| | - David W Piston
- Department of Cell Biology and Physiology, Washington University, St Louis, Missouri, USA
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Kumar V, Singh J, Bala K, Singh J. Association of Metallothionein 1A gene polymorphisms at rs11640851 and rs8052394 with risk of type 2 diabetes mellitus in Indian population. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100862] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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Choi EM, Suh KS, Yun SJ, Park J, Park SY, Chin SO, Chon S. Oleuropein attenuates the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-perturbing effects on pancreatic β-cells. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART A, TOXIC/HAZARDOUS SUBSTANCES & ENVIRONMENTAL ENGINEERING 2021; 56:752-761. [PMID: 33985414 DOI: 10.1080/10934529.2021.1923312] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 04/20/2021] [Accepted: 04/22/2021] [Indexed: 06/12/2023]
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an endocrine disrupting compound and persistent organic pollutant that has been associated with diabetes in several epidemiological studies. Oleuropein, a major phenolic compound in olive fruit, is a superior antioxidant and radical scavenger. This study aimed to examine the effects of oleuropein against TCDD-induced stress response in a pancreatic beta cell line, INS-1 cells. Cells were pre-incubated with various concentrations of oleuropein and then stimulated with TCDD (10 nM) for 48 hrs. When treated with TCDD, INS-1 cells produced robust amounts of prostaglandin E2 (PGE2) compared to the untreated control, and this increase was inhibited by oleuropein treatment. TCDD increased Ca2+-independent phospholipase A2 (iPLA2β) level, but had no effect on Group 10 secretory phospholipase A2 (PLA2G10) level, while oleuropein deceased the levels of iPLA2β and PLA2G10 in the presence of TCDD. Cyclooxygenase-1 (COX-1) was significantly increased by TCDD treatment and attenuated with oleuropein pretreatment. Oleuropein decreased TCDD-mediated production of JNK, TNF-α, and ROS. In addition, oleuropein increased Akt and GLUT2 levels suppressed by TCDD in INS-1 cells. Thus, the results suggest that oleuropein prevents pancreatic beta cell impairment by TCDD.
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Affiliation(s)
- Eun Mi Choi
- Department of Endocrinology & Metabolism, Kyung Hee University Hospital, Seoul, Republic of Korea
| | - Kwang Sik Suh
- Department of Endocrinology & Metabolism, Kyung Hee University Hospital, Seoul, Republic of Korea
- Department of Endocrinology & Metabolism, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Soo Jin Yun
- Department of Endocrinology & Metabolism, Kyung Hee University Hospital, Seoul, Republic of Korea
- Department of Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Jinsun Park
- Department of Endocrinology & Metabolism, Kyung Hee University Hospital, Seoul, Republic of Korea
- Department of Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - So Young Park
- Department of Endocrinology & Metabolism, Kyung Hee University Hospital, Seoul, Republic of Korea
| | - Sang Ouk Chin
- Department of Endocrinology & Metabolism, Kyung Hee University Hospital, Seoul, Republic of Korea
- Department of Endocrinology & Metabolism, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Suk Chon
- Department of Endocrinology & Metabolism, Kyung Hee University Hospital, Seoul, Republic of Korea
- Department of Endocrinology & Metabolism, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
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Shokri-Mashhadi N, Tahmasebi M, Mohammadi-Asl J, Zakerkish M, Mohammadshahi M. The antioxidant and anti-inflammatory effects of astaxanthin supplementation on the expression of miR-146a and miR-126 in patients with type 2 diabetes mellitus: A randomised, double-blind, placebo-controlled clinical trial. Int J Clin Pract 2021; 75:e14022. [PMID: 33445213 DOI: 10.1111/ijcp.14022] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 12/26/2020] [Accepted: 01/11/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND The pathogenesis of type 2 diabetes mellitus (T2DM) is associated with chronic oxidative stress and inflammation. It is well known that the expression of some miRNAs such as miRNA-146a is upregulated in diabetic and hyperglycaemic patients, whereas circulating miRNA-126 is reduced. Therefore, we aimed to determine the effects of astaxanthin (AST) supplementation on the circulating malondialdehyde (MDA) and interleukin 6 (IL-6) levels, and the expression of miR-146a and miR-126 in patients with T2DM. METHODS This randomised, double-blind, placebo-controlled clinical trial was conducted in 44 patients with T2DM randomly receiving 8 mg/d of oral AST (n = 22) or placebo (n = 22) for 8 weeks. RESULTS We observed that AST supplementation could decrease plasma levels of MDA and IL-6 (P < .05) and decrease the expression level of miR-146a over time (fold change: -1/388) (P < .05). CONCLUSION AST supplementation might be beneficial for improving circulating MDA and IL-6 and the down-regulation of miR-146a. However, future investigations are suggested to confirm these results.
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Affiliation(s)
- Nafiseh Shokri-Mashhadi
- Department of Clinical Nutrition and Food Security Research Center, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
- Nutrition and Metabolic Diseases Research Center and Department of Nutrition, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Tahmasebi
- Department of Molecular Genetics, Faculty of Biosciences, Tarbiat Modares University, Tehran, Iran
- Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Iran
| | - Javad Mohammadi-Asl
- Deptment of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mehrnoosh Zakerkish
- Department of Endocrinology and Metabolism, Health Research Institute, Diabetes Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Majid Mohammadshahi
- Nutrition and Metabolic Diseases Research Center and Department of Nutrition, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Chinniah R, Sevak V, Pandi S, Ravi PM, Vijayan M, Kannan A, Karuppiah B. HLA-DRB1 genes and the expression dynamics of HLA CIITA determine the susceptibility to T2DM. Immunogenetics 2021; 73:291-305. [PMID: 33754173 DOI: 10.1007/s00251-021-01212-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/01/2021] [Indexed: 12/18/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a disease with polygenic inheritance. The expression of major histocompatibility complex class II genes are regulated by several trans-activators. We have studied the expression of HLA-DRB1, RFX, CIITA-P1, PIV transactivators, immunophenotyping of cells, SNPs in CIITA-168 (A/G) and IFN-γ + 874 (T/A) in T2DM patients and controls (n = 201 each). We observed increased frequencies of DRB1*03, DRB1*04 and DRB1*07 and decreased frequencies of DRB1*10, DRB1*14, and DRB1*15 alleles among patients. Significant up-regulations of HLA-DRB1 genes were observed in patients (p < 0.0001). Down-regulated expressions were documented in DRB1*03-homo (p < 0.002) and DRB1*04-homo (p < 0.009) patients. No significant differences were observed for CIITA-P1 expression except DRB1*04-pooled (p < 0.0113). The CIITA-PIV was up-regulated in overall (p < 0.0001), DRB1*03-pooled (p < 0.0006), DRB1*03-hetero (p < 0.0006) and DRB1*03-homo (p < 0.001) T2DM patients. However, significant down-regulations were documented for DRB1*04-pooled (p < 0.040), DRB1*04-hetero (p < 0.060), and DRB1*04-homo (p < 0.027) combinations. Further, significant down-regulations of RFX5 were observed in overall (p < 0.0006), DRB1*04-pooled (p < 0.0022), and DRB1*04-hetero (p < 0.0004) combinations. Immunophenotyping studies revealed significant increase of CD45+ CD14-, CD19+, CD14- and CD8 cells and elevated level of expression of IFN-γ (p < 0.0001) in patients. A significant increase of TT (p < 3.35 × 10-6) and decrease of TA (p < 4.57 × 10-4) genotypes of IFN-γ + 874 (T/A) and an increase of GG (p < 0.001) and decrease of AG (p < 8.24 × 10-5) genotypes of CIITA-168 A/G SNPs were observed. The combinatorial analysis revealed susceptible associations for DRB1*03 + AA, *03 + AG, *03 + GG and *04 + GG and protective associations for DRB1*10 + AG, *10 + GG, *15 + AG, and *14 + GG combinations. Thus, the present study corroborated the effect of differential expressions of promoters of risk alleles in the pathogenesis of T2DM.
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Affiliation(s)
- Rathika Chinniah
- Department of Immunology, School of Biological Sciences, Madurai, Tamil Nadu, 625021, India
| | - Vandit Sevak
- Department of Immunology, School of Biological Sciences, Madurai, Tamil Nadu, 625021, India
| | - Sasiharan Pandi
- Department of Immunology, School of Biological Sciences, Madurai, Tamil Nadu, 625021, India
| | - Padma Malini Ravi
- Department of Immunology, School of Biological Sciences, Madurai, Tamil Nadu, 625021, India
| | - Murali Vijayan
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
| | - Arun Kannan
- The Madurai Institute of Diabetes and Endocrine Practice Research, Madurai, Tamil Nadu, 625 001, India
| | - Balakrishnan Karuppiah
- Department of Immunology, School of Biological Sciences, Madurai, Tamil Nadu, 625021, India.
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Therapeutic potential of Nrf-2 pathway in the treatment of diabetic neuropathy and nephropathy. Mol Biol Rep 2021; 48:2761-2774. [PMID: 33754251 DOI: 10.1007/s11033-021-06257-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 02/26/2021] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes (T2D) is one of the most widely spread metabolic disordersand is also referred as a 'lifestyle' disorder. According toa study conducted by IDB, the number of individuals affected with diabetes is expected to increase from 463 to 700 million by the end of year 2045. Thus, there is a great need to developed targeted therapies that can maintain homeostasis of glucose levels and improving insulin sensitivity which can overcome hurdles associated with conventional medicine. Detailed analysis was conducted by analyzing various research and review papers which were searched using MEDLINE and EMBASE using various keywords. This search retrieved the most appropriate content on these molecules targeting Nrf-2 functions and Nrf-2 pathway associated with diabetic neuropathy and nephropathy. In this review article, we have highlighted the role of Nrf-2 in diabetic associated complications of neuropathy and nephropathy. Since hyperglycemia is associated with oxidative stress and inflammation, regulating Nrf-2 activity through various synthetic and natural activators whichmay provide therapeutic benefits for the treatment and mitigation of diabetic neuropathy and nephropathy as well. Based on the available literature on Nrf-2 activity and despite some controversies in the association of Nrf-2 activity and its therapeutic usage, it can be concluded that regulation of this pathway is a trigger in the development of diabetes-associated complications. Thus, targeting this pathway with various activators may emerge as a novel therapy in the treatment of diabetes and diabetes-associated complications. Nrf-2 activation leading to regulation of various downstream pathways responsible for managament of Diabetic neuropathy and nephropathy Legend: Activities regulated by the activation of Nrf-2 pathway by Natural and Synthetic activators. Various downstream signalling pathway are involved in increase (+) and decrease (-) in levels of Nrf-2 levels. Subsequently controlling various mechanism involved in the pathogenies of Diabetic neuropathy and nephropathy.
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Nano E, Petropavlovskaia M, Rosenberg L. Islet neogenesis associated protein (INGAP) protects pancreatic β cells from IL-1β and IFNγ-induced apoptosis. Cell Death Discov 2021; 7:56. [PMID: 33731692 PMCID: PMC7969959 DOI: 10.1038/s41420-021-00441-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/06/2021] [Accepted: 02/14/2021] [Indexed: 11/11/2022] Open
Abstract
The goal of this study was to determine whether recombinant Islet NeoGenesis Associated Protein (rINGAP) and its active core, a pentadecapeptide INGAP104-118 (Ingap-p), protect β cells against cytokine-induced death. INGAP has been shown to induce islet neogenesis in diabetic animals, to stimulate β-cell proliferation and differentiation, and to improve islet survival and function. Importantly, Ingap-p has shown promising results in clinical trials for diabetes (phase I/II). However, the full potential of INGAP and its mechanisms of action remain poorly understood. Using rat insulinoma cells RINm5F and INS-1 treated with interleukin-1β (IL-1β) and interferon-gamma (IFN-γ), we demonstrate here that both rINGAP and Ingap-p inhibit apoptosis, Caspase-3 activation, inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, and explore the related signaling pathways. As expected, IL-1β induced nuclear factor kappa B (NF-κB), p38, and JNK signaling, whereas interferon-gamma (IFN-γ) activated the JAK2/STAT1 pathway and potentiated the IL-1β effects. Both rINGAP and Ingap-p decreased phosphorylation of IKKα/β, IkBα, and p65, although p65 nuclear translocation was not inhibited. rINGAP, used for further analysis, also inhibited STAT3, p38, and JNK activation. Interestingly, all inhibitory effects of rINGAP were observed for the cytokine cocktail, not IL-1β alone, and were roughly equal to reversing the potentiating effects of INFγ. Furthermore, rINGAP had no effect on IL-1β/NF-κB-induced gene expression (e.g., Ccl2, Sod2) but downregulated several IFNγ-stimulated (Irf1, Socs1, Socs3) or IFNγ-potentiated (Nos2) genes. This, however, was observed again only for the cytokine cocktail, not IFNγ alone, and rINGAP did not inhibit the IFNγ-induced JAK2/STAT1 activation. Together, these intriguing results suggest that INGAP does not target either IL-1β or IFNγ individually but rather inhibits the signaling crosstalk between the two, the exact mechanism of which remains to be investigated. In summary, our study characterizes the anti-inflammatory effects of INGAP, both protein and peptide, and suggests a new therapeutic utility for INGAP in the treatment of diabetes.
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Affiliation(s)
- Eni Nano
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Department of Surgery, Faculty of Medicine, McGill University, 3755, Cote Ste-Catherine Rd, Montreal, QC, H3T 1E2, Canada
| | - Maria Petropavlovskaia
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Department of Surgery, Faculty of Medicine, McGill University, 3755, Cote Ste-Catherine Rd, Montreal, QC, H3T 1E2, Canada.
| | - Lawrence Rosenberg
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Department of Surgery, Faculty of Medicine, McGill University, 3755, Cote Ste-Catherine Rd, Montreal, QC, H3T 1E2, Canada
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Rezaeepoor M, Hoseini-Aghdam M, Sheikh V, Eftekharian MM, Behzad M. Evaluation of Interleukin-23 and JAKs/STATs/SOCSs/ROR-γt Expression in Type 2 Diabetes Mellitus Patients Treated With or Without Sitagliptin. J Interferon Cytokine Res 2020; 40:515-523. [PMID: 33136467 DOI: 10.1089/jir.2020.0113] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The production of interleukin-23 (IL-23) and the expression levels of related genes were evaluated in type 2 diabetes mellitus patients. The correlations between them were also determined. Thirty patients without sitagliptin (sitagliptin negative; SN), 30 patients with sitagliptin (sitagliptin positive; SP), and 30 healthy controls (HCs) were recruited. The level of IL-23 in the supernatant of anti CD3-activated peripheral blood mononuclear cells (PBMCs) was assessed using enzyme-linked immunosorbent assay. The expressions of IL-23, JAK1/JAK2/TYK2, STAT1/STAT3, ROR-γt, and SOCS1/SOCS3 in PBMCs were evaluated by real-time polymerase chain reaction. The production of IL-23 and the expressions of IL-23, JAK2, STAT3, and ROR-γt were observed to be enhanced in SN patients versus HCs, while the levels were decreased in SP patients versus SN patients (P < 0.05). SOCS1 and SOCS3 expressions were lower in SN patients than HCs, and their expressions were elevated in SP patients versus SN patients (P < 0.05). In SN patients, positive correlations between the IL-23 with fasting plasma glucose and HbA1c were observed, and JAK2/STAT3/ROR-γt were positively correlated with IL-23. JAK2, STAT3, and ROR-γt were positively related to each other and were negatively related to SOCS3. Enhanced IL-23/JAK2/STAT3/ROR-γt and reduced SOCS1/SOCS3 were found in SN patients. Sitagliptin may regulate the IL-23 and related gene expression.
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Affiliation(s)
- Mahsa Rezaeepoor
- Department of Immunology and School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mirhamed Hoseini-Aghdam
- Department of Immunology and School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Vida Sheikh
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Mahdi Behzad
- Department of Immunology and School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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Nakhleh A, Shehadeh N. Interactions between antihyperglycemic drugs and the renin-angiotensin system: Putative roles in COVID-19. A mini-review. Diabetes Metab Syndr 2020; 14:509-512. [PMID: 32388330 PMCID: PMC7198998 DOI: 10.1016/j.dsx.2020.04.040] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 04/26/2020] [Accepted: 04/27/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Diabetes mellitus is associated with a more severe course of coronavirus disease 2019 (COVID-19). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme II (ACE2) receptor for host cell entry. We aimed to assess the interactions between antihyperglycemic drugs and the renin-angiotensin system (RAS) and their putative roles in COVID-19. METHODS A literature search was performed using Pubmed to review the interrelationships between hyperglycemia, RAS and COVID-19, and the effects of antihyperglycemic medications. RESULTS The RAS has an essential role in glucose homeostasis and may have a role in COVID-19-induced lung injury. Some antihyperglycemic medications modulate RAS and might hypothetically alleviate the deleterious effect of angiotensin II on lung injury. Furthermore, most antihyperglycemic medications showed anti-inflammatory effects in animal models of lung injury. CONCLUSIONS Some antihyperglycemic medications might have protective effects against COVID-19-induced lung injury. Early insulin therapy seems very promising in alleviating lung injury.
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Affiliation(s)
- Afif Nakhleh
- Institute of Endocrinology, Diabetes and Metabolism, Rambam Health Care Campus, 8 HaAliya HaShniya St, Haifa, Israel.
| | - Naim Shehadeh
- Institute of Endocrinology, Diabetes and Metabolism, Rambam Health Care Campus, 8 HaAliya HaShniya St, Haifa, Israel
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Abadpour S, Tyrberg B, Schive SW, Huldt CW, Gennemark P, Ryberg E, Rydén-Bergsten T, Smith DM, Korsgren O, Skrtic S, Scholz H, Winzell MS. Inhibition of the prostaglandin D 2-GPR44/DP2 axis improves human islet survival and function. Diabetologia 2020; 63:1355-1367. [PMID: 32350565 PMCID: PMC7286861 DOI: 10.1007/s00125-020-05138-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 02/28/2020] [Indexed: 12/12/2022]
Abstract
AIMS/HYPOTHESIS Inflammatory signals and increased prostaglandin synthesis play a role during the development of diabetes. The prostaglandin D2 (PGD2) receptor, GPR44/DP2, is highly expressed in human islets and activation of the pathway results in impaired insulin secretion. The role of GPR44 activation on islet function and survival rate during chronic hyperglycaemic conditions is not known. In this study, we investigate GPR44 inhibition by using a selective GPR44 antagonist (AZ8154) in human islets both in vitro and in vivo in diabetic mice transplanted with human islets. METHODS Human islets were exposed to PGD2 or proinflammatory cytokines in vitro to investigate the effect of GPR44 inhibition on islet survival rate. In addition, the molecular mechanisms of GPR44 inhibition were investigated in human islets exposed to high concentrations of glucose (HG) and to IL-1β. For the in vivo part of the study, human islets were transplanted under the kidney capsule of immunodeficient diabetic mice and treated with 6, 60 or 100 mg/kg per day of a GPR44 antagonist starting from the transplantation day until day 4 (short-term study) or day 17 (long-term study) post transplantation. IVGTT was performed on mice at day 10 and day 15 post transplantation. After termination of the study, metabolic variables, circulating human proinflammatory cytokines, and hepatocyte growth factor (HGF) were analysed in the grafted human islets. RESULTS PGD2 or proinflammatory cytokines induced apoptosis in human islets whereas GPR44 inhibition reversed this effect. GPR44 inhibition antagonised the reduction in glucose-stimulated insulin secretion induced by HG and IL-1β in human islets. This was accompanied by activation of the Akt-glycogen synthase kinase 3β signalling pathway together with phosphorylation and inactivation of forkhead box O-1and upregulation of pancreatic and duodenal homeobox-1 and HGF. Administration of the GPR44 antagonist for up to 17 days to diabetic mice transplanted with a marginal number of human islets resulted in reduced fasting blood glucose and lower glucose excursions during IVGTT. Improved glucose regulation was supported by increased human C-peptide levels compared with the vehicle group at day 4 and throughout the treatment period. GPR44 inhibition reduced plasma levels of TNF-α and growth-regulated oncogene-α/chemokine (C-X-C motif) ligand 1 and increased the levels of HGF in human islets. CONCLUSIONS/INTERPRETATION Inhibition of GPR44 in human islets has the potential to improve islet function and survival rate under inflammatory and hyperglycaemic stress. This may have implications for better survival rate of islets following transplantation.
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Affiliation(s)
- Shadab Abadpour
- Department of Transplant Medicine and Institute for Surgical Research, Oslo University Hospital, Sognsvannsveien 20, 0027, Oslo, Norway
- Hybrid Technology Hub, Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Björn Tyrberg
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Peppredsleden 1, 431 83 Mölndal, Gothenburg, Sweden
| | - Simen W Schive
- Department of Transplant Medicine and Institute for Surgical Research, Oslo University Hospital, Sognsvannsveien 20, 0027, Oslo, Norway
| | - Charlotte Wennberg Huldt
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Peppredsleden 1, 431 83 Mölndal, Gothenburg, Sweden
| | - Peter Gennemark
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Peppredsleden 1, 431 83 Mölndal, Gothenburg, Sweden
- Department of Biomedical Engineering, University of Linköping, Linköping, Sweden
| | - Erik Ryberg
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Peppredsleden 1, 431 83 Mölndal, Gothenburg, Sweden
| | - Tina Rydén-Bergsten
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Peppredsleden 1, 431 83 Mölndal, Gothenburg, Sweden
| | - David M Smith
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Peppredsleden 1, 431 83 Mölndal, Gothenburg, Sweden
- Hit Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, University of Uppsala, Uppsala, Sweden
| | - Stanko Skrtic
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Peppredsleden 1, 431 83 Mölndal, Gothenburg, Sweden
- Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Hanne Scholz
- Department of Transplant Medicine and Institute for Surgical Research, Oslo University Hospital, Sognsvannsveien 20, 0027, Oslo, Norway.
- Hybrid Technology Hub, Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
| | - Maria Sörhede Winzell
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Peppredsleden 1, 431 83 Mölndal, Gothenburg, Sweden.
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Abstract
Islet dysfunction is a hallmark of type 2 diabetes mellitus (T2DM). Compelling evidence suggests that accumulation of islet amyloid in the islets of Langerhans significantly contribute to β-cell dysfunction and diabetes. Emerging evidence implicates a role for cystic fibrosis transmembrane-conductance regulator in the regulation of insulin secretion from pancreatic islets. Impaired first-phase insulin responses and glucose homeostasis have also been reported in cystic fibrosis patients. The transforming growth factor-β protein superfamily is central regulators of pancreatic cell function, and has a key role in pancreas development and pancreatic disease, including diabetes and islet dysfunction. It is also becoming clear that islet inflammation plays a key role in the development of islet dysfunction. Inflammatory changes, including accumulation of macrophages, have been documented in type 2 diabetic islets. Islet dysfunction leads to hyperglycemia and ultimately the development of diabetes. In this review, we describe these risk factors and their associations with islet dysfunction.
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Affiliation(s)
- Fei Hu
- Diabetes Research Center, School of Medicine, Ningbo University, Ningbo, China
| | - Xiaohui Qiu
- Department of nephrology, Ningbo Medical Center Li Huili Eastern Hospital Affiliated to Ningbo University
| | - Shizhong Bu
- Diabetes Research Center, School of Medicine, Ningbo University, Ningbo, China
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47
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Brioudes E, Alibashe-Ahmed M, Lavallard V, Berney T, Bosco D. Syndecan-4 is regulated by IL-1β in β-cells and human islets. Mol Cell Endocrinol 2020; 510:110815. [PMID: 32315719 DOI: 10.1016/j.mce.2020.110815] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 03/30/2020] [Accepted: 04/01/2020] [Indexed: 12/13/2022]
Abstract
Syndecans (SDC) are important multifunctional components of the extracellular matrix mainly described in endothelial cells. We studied the expression and regulation of SDC in cultured MIN6B1 cells and pancreatic islets. qRT-PCR revealed that syndecan-4 (SDC4) was the predominant isoform expressed in MIN6B1 cells and islets compared to other forms of SDC. Immunofluorescence in mouse and human pancreas sections revealed that SDC4 is mainly expressed in β-cells compared to other pancreatic cells. Exposure of MIN6B1 and human islets to IL-1β dose-dependently induced a rapid and transient expression of SDC4 while SRC and STAT3 inhibitors decreased this effect. Exposure of human islets to Il-1β caused an increase of SDC4 shedding, however treatment with STAT3 and SRC inhibitors inhibited this effect. These results indicate that SDC4 is upregulated by IL-1β through the SRC-STAT3 pathway and this pathway is also involved in SDC4 shedding in islets.
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Affiliation(s)
- Estelle Brioudes
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, 1211, Geneva 4, Geneva, Switzerland; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211, Geneva 4, Geneva, Switzerland.
| | - Mohamed Alibashe-Ahmed
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, 1211, Geneva 4, Geneva, Switzerland; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211, Geneva 4, Geneva, Switzerland
| | - Vanessa Lavallard
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, 1211, Geneva 4, Geneva, Switzerland; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211, Geneva 4, Geneva, Switzerland
| | - Thierry Berney
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, 1211, Geneva 4, Geneva, Switzerland; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211, Geneva 4, Geneva, Switzerland
| | - Domenico Bosco
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, 1211, Geneva 4, Geneva, Switzerland; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211, Geneva 4, Geneva, Switzerland
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48
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Nakhleh A, Shehadeh N. Glycemic control of type 2 diabetic patients with coronavirus disease during hospitalization: a proposal for early insulin therapy. Am J Physiol Endocrinol Metab 2020; 318:E835-E837. [PMID: 32401039 PMCID: PMC7237499 DOI: 10.1152/ajpendo.00163.2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Afif Nakhleh
- Institute of Endocrinology, Diabetes and Metabolism, Rambam Health Care Campus, Haifa, Israel
| | - Naim Shehadeh
- Institute of Endocrinology, Diabetes and Metabolism, Rambam Health Care Campus, Haifa, Israel
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49
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Awolade P, Cele N, Kerru N, Gummidi L, Oluwakemi E, Singh P. Therapeutic significance of β-glucuronidase activity and its inhibitors: A review. Eur J Med Chem 2020; 187:111921. [PMID: 31835168 PMCID: PMC7111419 DOI: 10.1016/j.ejmech.2019.111921] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 11/27/2019] [Accepted: 11/27/2019] [Indexed: 01/02/2023]
Abstract
The emergence of disease and dearth of effective pharmacological agents on most therapeutic fronts, constitutes a major threat to global public health and man's existence. Consequently, this has created an exigency in the search for new drugs with improved clinical utility or means of potentiating available ones. To this end, accumulating empirical evidence supports molecular target therapy as a plausible egress and, β-glucuronidase (βGLU) - a lysosomal acid hydrolase responsible for the catalytic deconjugation of β-d-glucuronides has emerged as a viable molecular target for several therapeutic applications. The enzyme's activity level in body fluids is also deemed a potential biomarker for the diagnosis of some pathological conditions. Moreover, due to its role in colon carcinogenesis and certain drug-induced dose-limiting toxicities, the development of potent inhibitors of βGLU in human intestinal microbiota has aroused increased attention over the years. Nevertheless, although our literature survey revealed both natural products and synthetic scaffolds as potential inhibitors of the enzyme, only few of these have found clinical utility, albeit with moderate to poor pharmacokinetic profile. Hence, in this review we present a compendium of exploits in the present millennium directed towards the inhibition of βGLU. The aim is to proffer a platform on which new scaffolds can be modelled for improved βGLU inhibitory potency and the development of new therapeutic agents in consequential.
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Affiliation(s)
- Paul Awolade
- School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa
| | - Nosipho Cele
- School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa
| | - Nagaraju Kerru
- School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa
| | - Lalitha Gummidi
- School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa
| | - Ebenezer Oluwakemi
- School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa
| | - Parvesh Singh
- School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa.
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50
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Amin K, Qadr SH, Hassan Hussein R, Ali KM, Rahman HS. Levels of cytokines and GADA in type I and II diabetic patients. Prim Care Diabetes 2020; 14:61-67. [PMID: 31014937 DOI: 10.1016/j.pcd.2019.03.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 03/16/2019] [Accepted: 03/25/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Diabetes Mellitus is described as a group of metabolic diseases in which the patient has higher blood glucose levels due to many causes. These include a defect in insulin secretion and failure of the body's cells to respond to the hormone. Cytokines and autoantibodies have a critical role in the pathogenesis of diabetes, especially type I. AIM OF THE STUDY The aim of this study was to measure the serum levels of interleukin-1 beta (IL-1 β), interleukin-3 (IL-3), interferon-gamma (INF- γ), and glutamic acid decarboxylase autoantibody (GADA) in patients with type I and type II diabetes mellitus. MATERIAL AND METHODS In this cross-sectional study, serum samples were taken from 250 individuals, including 100 samples from patients with type II diabetes mellitus, 100 samples from healthy controls, and 50 samples from patients with type I diabetes mellitus. Five milliliters of venous blood were taken from each individual and the samples were analyzed for cytokines (IL-1 β, IL-3, and INF- γ) and GABA using ELISA. RESULTS In the study, we found that the serum levels of IL-1 β were significantly higher in the healthy control group compared to the patients with type I and type II diabetes mellitus. The levels of IL-3 and INF- γ were significantly higher in type II diabetes mellitus, while GABA serum levels were higher in type I diabetes mellitus. CONCLUSION Our data showed that GADA is an important autoantibody, not only in type I but also in type II diabetes mellitus and can probably be used in the future for diagnosis of this disease. There was also a close association of GADA with systemic immunoregulation in type I and II diabetes mellitus. The relation of cytokines (IL-1 β, IL-3, and INF- γ) and GADA in patients with diabetes will also increase our understanding for the immunology of diabetes mellitus and to propose specific treatment on the basis of our findings. Our data also include correlation between age and the level of cytokines and GADA with different conclusion for each parameter.
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Affiliation(s)
- Kawa Amin
- Department of Medical Science, Respiratory Medicine and Allergology, Clinical Chemistry and Asthma Research Centre, Uppsala University and University Hospital, Uppsala, Sweden; Department of Microbiology/Immunology, College of Medicine, University of Sulaimani, Sulaimani, Iraq.
| | - Shnyar Hamid Qadr
- Department of Clinical Biochemistry, College of Pharmacy, University of Sulaimani, Iraq
| | | | - Kosar Muhammad Ali
- Department of Medicine, College of Medicine, University of Sulaimani, Sulaimani, Iraq
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