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Uniyal P, Panwar S, Bhatt A, Marianesan AB, Kumar R, Singh TG, Tyagi Y, Bushi G, Gaidhane AM, Kumar B. An update on current type 2 diabetes mellitus (T2DM) druggable targets and drugs targeting them. Mol Divers 2025:10.1007/s11030-025-11149-y. [PMID: 40080341 DOI: 10.1007/s11030-025-11149-y] [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: 12/19/2024] [Accepted: 02/24/2025] [Indexed: 03/15/2025]
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia and affects millions of people globally. Even after advancement and development in medical science, it is a big task to achieve victory over type 2 diabetes mellitus (T2DM). T2DM can be a reason for fatal events like stroke, cardiac failure, nephropathy, and retinopathy. Many advanced antidiabetic drugs have been introduced in the market in the past two decades, leading researchers to hunt for new target proteins and their potential modulators that can help develop newer antidiabetic drugs. This review article comprises a broad literature of the latest developments in the management of T2DM concerning new target proteins, their inhibitors, or drugs from the clinical arena employed for the successful management of symptoms of T2DM using mono, dual, or triple combination medication therapy. The review categorizes antidiabetic drugs into three general classes that include conventional drug targets, currently explored targets, and upcoming emerging targets. The review aims to merge information on the medicines affecting these targets, their mechanisms, followed by the chemical structures, and recent advancements.
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Affiliation(s)
- Prerna Uniyal
- School of Pharmacy, Graphic Era Hill University, Bell Road, Clement Town, Dehradun, Uttarakhand, India
| | - Surbhi Panwar
- School of Pharmacy, Graphic Era Hill University, Bell Road, Clement Town, Dehradun, Uttarakhand, India
| | - Akanksha Bhatt
- School of Pharmacy, Graphic Era Hill University, Bell Road, Clement Town, Dehradun, Uttarakhand, India
| | - Arockia Babu Marianesan
- Institute of Pharmaceutical Research, GLA University, 17, Km Stone, National Highway #2, Delhi-Mathura Road, Mathura, India
| | - Roshan Kumar
- Department of Microbiology, Graphic Era (Deemed to be University), Clement Town, Dehradun, 248002, India
| | - Thakur Gurjeet Singh
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
| | - Yogita Tyagi
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Premanagar, Dehradun, Uttarakhand, 248007, India
| | - Ganesh Bushi
- Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Abhay M Gaidhane
- School of Epidemiology and Public Health, Jawaharlal Nehru Medical College, and Global Health Academy, Datta Meghe Institute of Higher Education, Wardha, India
| | - Bhupinder Kumar
- Department of Pharmaceutical Sciences, Hemvati Nandan Bahuguna Garhwal University (Central University), Dist. Garhwal, Srinagar, Uttarakhand, 246174, India.
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2
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Zhang F, Wu Z, Su Q, Sa R, Zhang Y, Zhang X, Hou S, Gui L. Effect of different Lys/Met ratios in a low-protein diet on the meat quality of Tibetan sheep: A transcriptomics- and metabolomics-based analysis. Food Res Int 2025; 204:115893. [PMID: 39986761 DOI: 10.1016/j.foodres.2025.115893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 01/23/2025] [Accepted: 01/29/2025] [Indexed: 02/24/2025]
Abstract
This study integrated the the effects of dietary Lys/Met ratio in a low protein diet on the meat quality in Tibetan sheep. A total of 90 weaned Tibetan sheep, 2 months old with initial weight of 15.37 ± 0.92 kg were randomly divided into 3 treatments, which were supplemented with Lys/Met ratio at 3 (LP-H), 2 (LP-M), and 1 (LP-L) in the basal diet (10 % crude protein), respectively. After slaughter (150 days of age), the growth performances and meat quality of longissimus dorsi muscle were evaluated. The LP-L group showed significantly higher final body weight compared to the LP-M group (P < 0.05). Serum albumin and total protein levels were significantly higher in the LP-L group than in the LP-H group (P < 0.05). Furthermore, meat from the LP-L group had significantly higher protein, calcium, and vitamin E content compared to the LP-M group (P < 0.05). Transcriptomic analysis revealed 3,479 differentially expressed genes enriched in pathways related to muscle growth, energy metabolism, and signaling transduction. Metabolomic analysis identified 771 differential metabolites, significantly enriched in ABC transporters, beta-alanine metabolism, and taste transduction pathways. Integrated analysis highlighted the upregulation of the ABCD4 gene and L-valine metabolite in the LP-L group, contributing to improved phenotypic traits. These findings provide molecular insights into the regulatory mechanisms underlying the effects of dietary Lys/Met ratios on Tibetan sheep meat quality and offer a basis for developing nutritional strategies to enhance premium meat production.
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Affiliation(s)
- Fengshuo Zhang
- College of Agriculture and Animal Husbandry, Qinghai University, China
| | - Zhenling Wu
- College of Agriculture and Animal Husbandry, Qinghai University, China
| | - Quyangangmao Su
- College of Agriculture and Animal Husbandry, Qinghai University, China
| | - Rengeerli Sa
- College of Agriculture and Animal Husbandry, Qinghai University, China
| | - Yu Zhang
- College of Agriculture and Animal Husbandry, Qinghai University, China
| | - Xianhua Zhang
- College of Agriculture and Animal Husbandry, Qinghai University, China
| | - Shengzhen Hou
- College of Agriculture and Animal Husbandry, Qinghai University, China
| | - Linsheng Gui
- College of Agriculture and Animal Husbandry, Qinghai University, China.
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3
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Cheng CH, Hao WR, Cheng TH. Unveiling mitochondrial mysteries: Exploring novel tRNA variants in type 2 diabetes mellitus. World J Diabetes 2025; 16:98798. [PMID: 39817212 PMCID: PMC11718450 DOI: 10.4239/wjd.v16.i1.98798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 10/21/2024] [Accepted: 11/08/2024] [Indexed: 11/29/2024] Open
Abstract
The recent study of Ding et al provides valuable insights into the functional implications of novel mitochondrial tRNATrp and tRNASer(AGY) variants in type 2 diabetes mellitus (T2DM). This editorial explores their findings, highlighting the role of mitochondrial dysfunction in the pathogenesis of T2DM. By examining the molecular mechanisms through which these tRNA variants contribute to disease progression, the study introduces new targets for therapeutic strategies. We discuss the broader implications of these results, emphasizing the importance of understanding mitochondrial genetics in addressing T2DM.
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Affiliation(s)
- Chun-Han Cheng
- Department of Medical Education, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Wen-Rui Hao
- Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Ministry of Health and Welfare, Taipei Medical University, New Taipei 23561, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11002, Taiwan
| | - Tzu-Hurng Cheng
- Department of Biochemistry, School of Medicine, College of Medicine, China Medical University, Taichung 404328, Taiwan
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4
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Langlois A, Pinget M, Kessler L, Bouzakri K. Islet Transplantation: Current Limitations and Challenges for Successful Outcomes. Cells 2024; 13:1783. [PMID: 39513890 PMCID: PMC11544954 DOI: 10.3390/cells13211783] [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: 09/26/2024] [Revised: 10/22/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
Islet transplantation is a promising approach for treating patients with unstable T1DM. However, it is confronted with numerous obstacles throughout the various stages of the transplantation procedure. Significant progress has been made over the last 25 years in understanding the mechanisms behind the loss of functional islet mass and in developing protective strategies. Nevertheless, at present, two to three pancreases are still needed to treat a single patient, which limits the maximal number of patients who can benefit from islet transplantation. Thus, this publication provides an overview of recent scientific findings on the various issues affecting islet transplantation. Specifically, we will focus on the understanding of the mechanisms involved and the strategies developed to alleviate these problems from the isolation stage to the post-transplantation phase. Finally, we hope that this review will highlight new avenues of action, enabling us to propose pancreatic islet transplantation to a maximum number of patients with T1DM.
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Affiliation(s)
- Allan Langlois
- UR «Diabète et Thérapeutiques», Centre Européen d’Étude du Diabète, Université de Strasbourg, Boulevard René Leriche, 67200 Strasbourg, France; (A.L.); (M.P.)
| | - Michel Pinget
- UR «Diabète et Thérapeutiques», Centre Européen d’Étude du Diabète, Université de Strasbourg, Boulevard René Leriche, 67200 Strasbourg, France; (A.L.); (M.P.)
| | - Laurence Kessler
- Department of Endocrinology, Diabetes and Nutrition, University Hospital of Strasbourg, 67200 Strasbourg, France;
- Inserm UMR 1260, Nanomédicine Regenerative, University of Strasbourg, 67085 Strasbourg, France
| | - Karim Bouzakri
- UR «Diabète et Thérapeutiques», Centre Européen d’Étude du Diabète, Université de Strasbourg, Boulevard René Leriche, 67200 Strasbourg, France; (A.L.); (M.P.)
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Yue L, Li J, Yao M, Song S, Zhang X, Wang Y. Cutting edge of immune response and immunosuppressants in allogeneic and xenogeneic islet transplantation. Front Immunol 2024; 15:1455691. [PMID: 39346923 PMCID: PMC11427288 DOI: 10.3389/fimmu.2024.1455691] [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: 06/27/2024] [Accepted: 08/27/2024] [Indexed: 10/01/2024] Open
Abstract
As an effective treatment for diabetes, islet transplantation has garnered significant attention and research in recent years. However, immune rejection and the toxicity of immunosuppressive drugs remain critical factors influencing the success of islet transplantation. While immunosuppressants are essential in reducing immune rejection reactions and can significantly improve the survival rate of islet transplants, improper use of these drugs can markedly increase mortality rates following transplantation. Additionally, the current availability of islet organ donations fails to meet the demand for organ transplants, making xenotransplantation a crucial method for addressing organ shortages. This review will cover the following three aspects: 1) the immune responses occurring during allogeneic islet transplantation, including three stages: inflammation and IBMIR, allogeneic immune response, and autoimmune recurrence; 2) commonly used immunosuppressants in allogeneic islet transplantation, including calcineurin inhibitors (Cyclosporine A, Tacrolimus), mycophenolate mofetil, glucocorticoids, and Bortezomib; and 3) early and late immune responses in xenogeneic islet transplantation and the immune effects of triple therapy (ECDI-fixed donor spleen cells (ECDI-SP) + anti-CD20 + Sirolimus) on xenotransplantation.
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Affiliation(s)
- Liting Yue
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Jisong Li
- Department of Gastrointestinal Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Mingjun Yao
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Siyuan Song
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Xiaoqin Zhang
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yi Wang
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, Chengdu, China
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Duță C, Muscurel C, Dogaru CB, Stoian I. Ferroptosis-A Shared Mechanism for Parkinson's Disease and Type 2 Diabetes. Int J Mol Sci 2024; 25:8838. [PMID: 39201524 PMCID: PMC11354749 DOI: 10.3390/ijms25168838] [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: 06/30/2024] [Revised: 07/31/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Type 2 diabetes (T2D) and Parkinson's disease (PD) are the two most frequent age-related chronic diseases. There are many similarities between the two diseases: both are chronic diseases; both are the result of a decrease in a specific substance-insulin in T2D and dopamine in PD; and both are caused by the destruction of specific cells-beta pancreatic cells in T2D and dopaminergic neurons in PD. Recent epidemiological and experimental studies have found that there are common underlying mechanisms in the pathophysiology of T2D and PD: chronic inflammation, mitochondrial dysfunction, impaired protein handling and ferroptosis. Epidemiological research has indicated that there is a higher risk of PD in individuals with T2D. Moreover, clinical studies have observed that the symptoms of Parkinson's disease worsen significantly after the onset of T2D. This article provides an up-to-date review on the intricate interplay between oxidative stress, reactive oxygen species (ROS) and ferroptosis in PD and T2D. By understanding the shared molecular pathways and how they can be modulated, we can develop more effective therapies, or we can repurpose existing drugs to improve patient outcomes in both disorders.
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Lo CH, O’Connor LM, Loi GWZ, Saipuljumri EN, Indajang J, Lopes KM, Shirihai OS, Grinstaff MW, Zeng J. Acidic Nanoparticles Restore Lysosomal Acidification and Rescue Metabolic Dysfunction in Pancreatic β-Cells under Lipotoxic Conditions. ACS NANO 2024; 18:15452-15467. [PMID: 38830624 PMCID: PMC11192035 DOI: 10.1021/acsnano.3c09206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 05/09/2024] [Accepted: 05/16/2024] [Indexed: 06/05/2024]
Abstract
Type 2 diabetes (T2D), a prevalent metabolic disorder lacking effective treatments, is associated with lysosomal acidification dysfunction, as well as autophagic and mitochondrial impairments. Here, we report a series of biodegradable poly(butylene tetrafluorosuccinate-co-succinate) polyesters, comprising a 1,4-butanediol linker and varying ratios of tetrafluorosuccinic acid (TFSA) and succinic acid as components, to engineer lysosome-acidifying nanoparticles (NPs). The synthesized NPs are spherical with diameters of ≈100 nm and have low polydispersity and good stability. Notably, TFSA NPs, which are composed entirely of TFSA, exhibit the strongest degradation capability and superior acidifying properties. We further reveal significant downregulation of lysosomal vacuolar (H+)-ATPase subunits, which are responsible for maintaining lysosomal acidification, in human T2D pancreatic islets, INS-1 β-cells under chronic lipotoxic conditions, and pancreatic tissues of high-fat-diet (HFD) mice. Treatment with TFSA NPs restores lysosomal acidification, autophagic function, and mitochondrial activity, thereby improving the pancreatic function in INS-1 cells and HFD mice with lipid overload. Importantly, the administration of TFSA NPs to HFD mice reduces insulin resistance and improves glucose clearance. These findings highlight the therapeutic potential of lysosome-acidifying TFSA NPs for T2D.
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Affiliation(s)
- Chih Hung Lo
- Lee
Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
| | - Lance M. O’Connor
- College
of Biological Sciences, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Gavin Wen Zhao Loi
- Lee
Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
| | | | - Jonathan Indajang
- Meinig
School of Biomedical Engineering, Cornell
University, Ithaca, New York 14853, United States
| | - Kaitlynn M. Lopes
- Department
of Chemistry, Boston University, Boston, Massachusetts 02215, United States
| | - Orian S. Shirihai
- Division
of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90045, United States
- Department
of Molecular and Medical Pharmacology, University
of California, Los Angeles, Los
Angeles, California 90095, United States
| | - Mark W. Grinstaff
- Department
of Chemistry, Boston University, Boston, Massachusetts 02215, United States
- Department
of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, United States
| | - Jialiu Zeng
- Lee
Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
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8
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Xu B, Chen ZX, Zhou WJ, Su J, Zhou Q. Associations between blood manganese levels and sarcopenia in adults: insights from the National Health and Nutrition Examination Survey. Front Public Health 2024; 12:1351479. [PMID: 38803810 PMCID: PMC11128573 DOI: 10.3389/fpubh.2024.1351479] [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: 12/06/2023] [Accepted: 04/01/2024] [Indexed: 05/29/2024] Open
Abstract
Background While increasing concerns arise about the health effects of environmental pollutants, the relationship between blood manganese (Mn) and sarcopenia has yet to be fully explored in the general population. Objective This study aims to investigate the association between blood manganese (Mn) levels and sarcopenia in adults. Methods In our study, we evaluated 8,135 individuals aged 18-59 years, utilizing data from the National Health and Nutrition Examination Survey (NHANES) spanning 2011 to 2018. We employed generalized additive model (GAM) to discern potential non-linear relationships and utilized the two-piecewise linear regression model to probe the association between blood Mn levels and sarcopenia. Results After adjusting for potential confounders, we identified non-linear association between blood Mn levels and sarcopenia, with an inflection point at 13.45 μg/L. The effect sizes and the confidence intervals on the left and right sides of the inflection point were 1.006 (0.996 to 1.048) and 1.082 (1.043 to 1.122), respectively. Subgroup analysis showed that the effect sizes of blood Mn on sarcopenia have significant differences in gender and different BMI groups. Conclusion Our results showed that a reverse U-shaped curve between blood Mn levels and sarcopenia, with an identified the inflection point at blood Mn level of 13.45 μg/L.
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Affiliation(s)
| | | | | | | | - Qiang Zhou
- Department of Orthopedic Surgery, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou, Zhejiang, China
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Yamagata K, Tsuyama T, Sato Y. Roles of β-Cell Hypoxia in the Progression of Type 2 Diabetes. Int J Mol Sci 2024; 25:4186. [PMID: 38673770 PMCID: PMC11050445 DOI: 10.3390/ijms25084186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Revised: 04/05/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Type 2 diabetes is a chronic disease marked by hyperglycemia; impaired insulin secretion by pancreatic β-cells is a hallmark of this disease. Recent studies have shown that hypoxia occurs in the β-cells of patients with type 2 diabetes and hypoxia, in turn, contributes to the insulin secretion defect and β-cell loss through various mechanisms, including the activation of hypoxia-inducible factors, induction of transcriptional repressors, and activation of AMP-activated protein kinase. This review focuses on advances in our understanding of the contribution of β-cell hypoxia to the development of β-cell dysfunction in type 2 diabetes. A better understanding of β-cell hypoxia might be useful in the development of new strategies for treating type 2 diabetes.
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Affiliation(s)
- Kazuya Yamagata
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
- Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
| | - Tomonori Tsuyama
- Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
| | - Yoshifumi Sato
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
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Aoyagi K, Nishiwaki C, Nakamichi Y, Yamashita SI, Kanki T, Ohara-Imaizumi M. Imeglimin mitigates the accumulation of dysfunctional mitochondria to restore insulin secretion and suppress apoptosis of pancreatic β-cells from db/db mice. Sci Rep 2024; 14:6178. [PMID: 38485716 PMCID: PMC10940628 DOI: 10.1038/s41598-024-56769-w] [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: 10/11/2023] [Accepted: 03/11/2024] [Indexed: 03/18/2024] Open
Abstract
Mitochondrial dysfunction in pancreatic β-cells leads to impaired glucose-stimulated insulin secretion (GSIS) and type 2 diabetes (T2D), highlighting the importance of autophagic elimination of dysfunctional mitochondria (mitophagy) in mitochondrial quality control (mQC). Imeglimin, a new oral anti-diabetic drug that improves hyperglycemia and GSIS, may enhance mitochondrial activity. However, chronic imeglimin treatment's effects on mQC in diabetic β-cells are unknown. Here, we compared imeglimin, structurally similar anti-diabetic drug metformin, and insulin for their effects on clearance of dysfunctional mitochondria through mitophagy in pancreatic β-cells from diabetic model db/db mice and mitophagy reporter (CMMR) mice. Pancreatic islets from db/db mice showed aberrant accumulation of dysfunctional mitochondria and excessive production of reactive oxygen species (ROS) along with markedly elevated mitophagy, suggesting that the generation of dysfunctional mitochondria overwhelmed the mitophagic capacity in db/db β-cells. Treatment with imeglimin or insulin, but not metformin, reduced ROS production and the numbers of dysfunctional mitochondria, and normalized mitophagic activity in db/db β-cells. Concomitantly, imeglimin and insulin, but not metformin, restored the secreted insulin level and reduced β-cell apoptosis in db/db mice. In conclusion, imeglimin mitigated accumulation of dysfunctional mitochondria through mitophagy in diabetic mice, and may contribute to preserving β-cell function and effective glycemic control in T2D.
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Affiliation(s)
- Kyota Aoyagi
- Department of Cellular Biochemistry, Kyorin University School of Medicine, Mitaka, Tokyo, 181-8611, Japan
| | - Chiyono Nishiwaki
- Department of Cellular Biochemistry, Kyorin University School of Medicine, Mitaka, Tokyo, 181-8611, Japan
| | - Yoko Nakamichi
- Department of Cellular Biochemistry, Kyorin University School of Medicine, Mitaka, Tokyo, 181-8611, Japan
| | - Shun-Ichi Yamashita
- Department of Cellular Physiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Tomotake Kanki
- Department of Cellular Physiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Mica Ohara-Imaizumi
- Department of Cellular Biochemistry, Kyorin University School of Medicine, Mitaka, Tokyo, 181-8611, Japan.
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Pearce B, Pearce K. Mitochondrial dysfunction and diabetes in South Africa: A review. ENDOCRINE AND METABOLIC SCIENCE 2024; 14:100157. [DOI: 10.1016/j.endmts.2024.100157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025] Open
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12
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Lin QR, Jia LQ, Lei M, Gao D, Zhang N, Sha L, Liu XH, Liu YD. Natural products as pharmacological modulators of mitochondrial dysfunctions for the treatment of diabetes and its complications: An update since 2010. Pharmacol Res 2024; 200:107054. [PMID: 38181858 DOI: 10.1016/j.phrs.2023.107054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 12/12/2023] [Accepted: 12/31/2023] [Indexed: 01/07/2024]
Abstract
Diabetes, characterized as a well-known chronic metabolic syndrome, with its associated complications pose a substantial and escalating health and healthcare challenge on a global scale. Current strategies addressing diabetes are mainly symptomatic and there are fewer available curative pharmaceuticals for diabetic complications. Thus, there is an urgent need to identify novel pharmacological targets and agents. The impaired mitochondria have been associated with the etiology of diabetes and its complications, and the intervention of mitochondrial dysfunction represents an attractive breakthrough point for the treatments of diabetes and its complications. Natural products (NPs), with multicenter characteristics, multi-pharmacological activities and lower toxicity, have been caught attentions as the modulators of mitochondrial functions in the therapeutical filed of diabetes and its complications. This review mainly summarizes the recent progresses on the potential of 39 NPs and 2 plant-extracted mixtures to improve mitochondrial dysfunction against diabetes and its complications. It is expected that this work may be useful to accelerate the development of innovative drugs originated from NPs and improve upcoming therapeutics in diabetes and its complications.
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Affiliation(s)
- Qian-Ru Lin
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, China
| | - Lian-Qun Jia
- Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 116600, China
| | - Ming Lei
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China
| | - Di Gao
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, China
| | - Nan Zhang
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, China
| | - Lei Sha
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, China
| | - Xu-Han Liu
- Department of Endocrinology, Dalian Municipal Central Hospital, Dalian, Liaoning 116033, China.
| | - Yu-Dan Liu
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, China.
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Veluthakal R, Esparza D, Hoolachan JM, Balakrishnan R, Ahn M, Oh E, Jayasena CS, Thurmond DC. Mitochondrial Dysfunction, Oxidative Stress, and Inter-Organ Miscommunications in T2D Progression. Int J Mol Sci 2024; 25:1504. [PMID: 38338783 PMCID: PMC10855860 DOI: 10.3390/ijms25031504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/15/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Type 2 diabetes (T2D) is a heterogenous disease, and conventionally, peripheral insulin resistance (IR) was thought to precede islet β-cell dysfunction, promoting progression from prediabetes to T2D. New evidence suggests that T2D-lean individuals experience early β-cell dysfunction without significant IR. Regardless of the primary event (i.e., IR vs. β-cell dysfunction) that contributes to dysglycemia, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may be a driver of T2D onset and progression. Oxidative stress, defined as the generation of reactive oxygen species (ROS), is mediated by hyperglycemia alone or in combination with lipids. Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress promotes inter-tissue mis-communication, and new evidence suggests that this is mediated via extracellular vesicles (EVs), including mitochondria containing EVs. Under metabolic-related stress conditions, EV-mediated cross-talk between β-cells and skeletal muscle likely trigger mitochondrial anomalies leading to prediabetes and T2D. This article reviews the underlying molecular mechanisms in ROS-related pathogenesis of prediabetes, including mitophagy and mitochondrial dynamics due to oxidative stress. Further, this review will describe the potential of various therapeutic avenues for attenuating oxidative damage, reversing prediabetes and preventing progression to T2D.
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Affiliation(s)
- Rajakrishnan Veluthakal
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Beckman Research Institute, 1500 E. Duarte Rd, Duarte, CA 91010, USA; (D.E.); (J.M.H.); (R.B.); (M.A.); (E.O.); (C.S.J.)
| | | | | | | | | | | | | | - Debbie C. Thurmond
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Beckman Research Institute, 1500 E. Duarte Rd, Duarte, CA 91010, USA; (D.E.); (J.M.H.); (R.B.); (M.A.); (E.O.); (C.S.J.)
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14
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Yazıcı D, Demir SÇ, Sezer H. Insulin Resistance, Obesity, and Lipotoxicity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:391-430. [PMID: 39287860 DOI: 10.1007/978-3-031-63657-8_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Lipotoxicity, originally used to describe the destructive effects of excess fat accumulation on glucose metabolism, causes functional impairments in several metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas, and muscle. Ectopic lipid accumulation in the kidneys, liver, and heart has important clinical counterparts like diabetic nephropathy in type 2 diabetes mellitus, obesity-related glomerulopathy, nonalcoholic fatty liver disease, and cardiomyopathy. Insulin resistance due to lipotoxicity indirectly lead to reproductive system disorders, like polycystic ovary syndrome. Lipotoxicity has roles in insulin resistance and pancreatic beta-cell dysfunction. Increased circulating levels of lipids and the metabolic alterations in fatty acid utilization and intracellular signaling have been related to insulin resistance in muscle and liver. Different pathways, like novel protein kinase c pathways and the JNK-1 pathway, are involved as the mechanisms of how lipotoxicity leads to insulin resistance in nonadipose tissue organs, such as liver and muscle. Mitochondrial dysfunction plays a role in the pathogenesis of insulin resistance. Endoplasmic reticulum stress, through mainly increased oxidative stress, also plays an important role in the etiology of insulin resistance, especially seen in non-alcoholic fatty liver disease. Visceral adiposity and insulin resistance both increase the cardiometabolic risk, and lipotoxicity seems to play a crucial role in the pathophysiology of these associations.
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Affiliation(s)
- Dilek Yazıcı
- Koç University Medical School, Section of Endocrinology and Metabolism, Koç University Hospital, Topkapi, Istanbul, Turkey.
| | - Selin Çakmak Demir
- Koç University Medical School, Section of Endocrinology and Metabolism, Koç University Hospital, Topkapi, Istanbul, Turkey
| | - Havva Sezer
- Koç University Medical School, Section of Endocrinology and Metabolism, Koç University Hospital, Topkapi, Istanbul, Turkey
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15
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Swain J, Jadhao P, Sravya SL, Teli B, Lavanya K, Singh J, Sahoo A, Das S. Mitochondrial Dysfunction and Imeglimin: A New Ray of Hope for the Treatment of Type-2 Diabetes Mellitus. Mini Rev Med Chem 2024; 24:1575-1589. [PMID: 37861052 DOI: 10.2174/0113895575260225230921062013] [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: 05/01/2023] [Revised: 07/03/2023] [Accepted: 07/26/2023] [Indexed: 10/21/2023]
Abstract
Diabetes is a rapidly growing health challenge and epidemic in many developing countries, including India. India, being the diabetes capital of the world, has the dubious dual distinction of being the leading nations for both undernutrition and overnutrition. Diabetes prevalence has increased in both rural and urban areas, affected the younger population and increased the risk of complications and economic burden. These alarming statistics ring an alarm bell to achieve glycemic targets in the affected population in order to decrease diabetes-related morbidity and mortality. In the recent years, diabetes pathophysiology has been extended from an ominous triad through octet and dirty dozen etc. There is a new scope to target multiple pathways at the molecular level to achieve a better glycemic target and further prevent micro- and macrovascular complications. Mitochondrial dysfunction has a pivotal role in both β-cell failure and insulin resistance. Hence, targeting this molecular pathway may help with both insulin secretion and peripheral tissue sensitization to insulin. Imeglimin is the latest addition to our anti-diabetic armamentarium. As imeglimin targets, this root cause of defective energy metabolism and insulin resistance makes it a new add-on therapy in different diabetic regimes to achieve the proper glycemic targets. Its good tolerability and efficacy profiles in recent studies shows a new ray of hope in the journey to curtail diabetes-related morbidity.
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Affiliation(s)
- Jayshree Swain
- Department of Endocrinology, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, India
| | - Pooja Jadhao
- Department of Endocrinology, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, India
| | - S L Sravya
- Department of Endocrinology, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, India
| | - Brij Teli
- Department of Endocrinology, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, India
| | - Kasukurti Lavanya
- Department of Endocrinology, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, India
| | - Jaspreet Singh
- Department of Endocrinology, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, India
| | - Abhay Sahoo
- Department of Endocrinology, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, India
| | - Srijit Das
- Department of Human & Clinical Anatomy, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat 123, Sultanate of Oman
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16
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Lin J, Lan Y, Xiang D, Ma R, Chen Q, Ding K, Lu J. IL-33 promotes pancreatic β-cell survival and insulin secretion under diabetogenic conditions through PPARγ. Eur J Pharmacol 2023; 959:176059. [PMID: 37758011 DOI: 10.1016/j.ejphar.2023.176059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 08/01/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023]
Abstract
Pancreatic β-cell dysfunction plays a vital role in the development of diabetes. IL-33 exerts anti-diabetic effects via its anti-inflammatory properties and has been demonstrated to increase insulin secretion in animal models. However, IL-33, as a pleiotropic cytokine, may also exert a deleterious effect on β-cells, which has not been rigorously studied. In the present study, we found that IL-33 promoted cell survival and insulin secretion in MIN6 (a mouse pancreatic β-cell line) cells under diabetogenic conditions. IL-33 increased the expression of its receptor ST2 and the transcription factor PPARγ, whereas PPARγ inhibition impaired IL-33-mediated β-cell survival and insulin release. IL-33 did not repress the expression of pro-inflammatory mediators, including Tf, Icam1, Cxcl10, and Il1b, whereas it significantly reduced the expression of Ccl2. IL-33 decreased TNF-α secretion and increased IL-10 secretion; these effects were completely reversed by PPARγ inhibition. IL-33 increased glucose uptake and expression of Glut2. It upregulated the expression of glycolytic enzyme genes, namely, Pkm2, Hk2, Gpi1, and Tpi, and downregulated the expression of Gck, Ldha, and Mct4. However, it did not alter hexokinase activity. Moreover, IL-33 increased the number and activity of mitochondria, accompanied by increased ATP production and reduced accumulation of ROS. IL-33 upregulated the expression of PGC-1α and cytochrome c, and mitochondrial fission- and fusion-associated genes, including Mfn1, Mfn2, and Dnm1l. IL-33-mediated mitochondrial homeostasis was partially reversed by PPARγ inhibition. Altogether, IL-33 protects β-cell survival and insulin secretion that could be partially driven via PPARγ, which regulates glucose uptake and promotes mitochondrial function and anti-inflammatory responses.
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Affiliation(s)
- Jian Lin
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Yan Lan
- Department of Pharmacy, Huangshi Central Hospital, Huangshi, China
| | - Daochun Xiang
- The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Ma
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Qianjiang Chen
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Ke Ding
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Jingli Lu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China.
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17
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Saucedo R, Ortega-Camarillo C, Ferreira-Hermosillo A, Díaz-Velázquez MF, Meixueiro-Calderón C, Valencia-Ortega J. Role of Oxidative Stress and Inflammation in Gestational Diabetes Mellitus. Antioxidants (Basel) 2023; 12:1812. [PMID: 37891891 PMCID: PMC10604289 DOI: 10.3390/antiox12101812] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/21/2023] [Accepted: 09/27/2023] [Indexed: 10/29/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications. It is related to several gestational and fetal adverse outcomes. Moreover, women with GDM and their infants have a high risk of developing type 2 diabetes in the future. The pathogenesis of GDM is not completely understood; nevertheless, two factors that contribute to its development are oxidative stress and inflammation. Oxidative stress and inflammation are related; reactive oxygen species (ROS) production can activate inflammatory cells and enhance the production of inflammatory mediators. Inflammation, in turn, leads to an increased ROS release, causing a vicious circle to ensue. Inflammatory responses can be achieved via the activation of the NF-κB signaling pathway. Herein, we review the English literature regarding oxidative stress and inflammation evaluated simultaneously in the same population, attempting to identify mechanisms through which these factors contribute to the development of GDM. Furthermore, the modulation of oxidative stress and inflammation by different therapies used in women with GDM and in cell models of GDM is included in the review. Probiotics and nutrient supplementations have been shown to reduce biomarkers of inflammation and oxidative stress in vitro and in women with GDM.
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Affiliation(s)
- Renata Saucedo
- Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (R.S.); (A.F.-H.)
| | - Clara Ortega-Camarillo
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico;
| | - Aldo Ferreira-Hermosillo
- Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (R.S.); (A.F.-H.)
| | - Mary Flor Díaz-Velázquez
- Hospital de Gineco Obstetricia 3, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City 02990, Mexico;
| | | | - Jorge Valencia-Ortega
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 11000, Mexico
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18
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Lang AL, Nissanka N, Louzada RA, Tamayo A, Pereira E, Moraes CT, Caicedo A. A Defect in Mitochondrial Complex III but Not in Complexes I or IV Causes Early β-Cell Dysfunction and Hyperglycemia in Mice. Diabetes 2023; 72:1262-1276. [PMID: 37343239 PMCID: PMC10451017 DOI: 10.2337/db22-0728] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 06/04/2023] [Indexed: 06/23/2023]
Abstract
Mitochondrial metabolism and oxidative respiration are crucial for pancreatic β-cell function and stimulus secretion coupling. Oxidative phosphorylation (OxPhos) produces ATP and other metabolites that potentiate insulin secretion. However, the contribution of individual OxPhos complexes to β-cell function is unknown. We generated β-cell-specific, inducible OxPhos complex knock-out (KO) mouse models to investigate the effects of disrupting complex I, complex III, or complex IV on β-cell function. Although all KO models had similar mitochondrial respiratory defects, complex III caused early hyperglycemia, glucose intolerance, and loss of glucose-stimulated insulin secretion in vivo. However, ex vivo insulin secretion did not change. Complex I and IV KO models showed diabetic phenotypes much later. Mitochondrial Ca2+ responses to glucose stimulation 3 weeks after gene deletion ranged from not affected to severely disrupted, depending on the complex targeted, supporting the unique roles of each complex in β-cell signaling. Mitochondrial antioxidant enzyme immunostaining increased in islets from complex III KO, but not from complex I or IV KO mice, indicating that severe diabetic phenotype in the complex III-deficient mice is causing alterations in cellular redox status. The present study highlights that defects in individual OxPhos complexes lead to different pathogenic outcomes. ARTICLE HIGHLIGHTS Mitochondrial metabolism is critical for β-cell insulin secretion, and mitochondrial dysfunction is involved in type 2 diabetes pathogenesis. We determined whether individual oxidative phosphorylation complexes contribute uniquely to β-cell function. Compared with loss of complex I and IV, loss of complex III resulted in severe in vivo hyperglycemia and altered β-cell redox status. Loss of complex III altered cytosolic and mitochondrial Ca2+ signaling and increased expression of glycolytic enzymes. Individual complexes contribute differently to β-cell function. This underscores the role of mitochondrial oxidative phosphorylation complex defects in diabetes pathogenesis.
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Affiliation(s)
- Anna L. Lang
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL
| | - Nadee Nissanka
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL
| | - Ruy A. Louzada
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Alejandro Tamayo
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
- Department of Molecular Cell and Developmental Biology, University of Miami Miller School of Medicine, Miami, FL
| | - Elizabeth Pereira
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Carlos T. Moraes
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL
| | - Alejandro Caicedo
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
- Department of Molecular Cell and Developmental Biology, University of Miami Miller School of Medicine, Miami, FL
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19
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Pugliese LA, De Lorenzi V, Bernardi M, Ghignoli S, Tesi M, Marchetti P, Pesce L, Cardarelli F. Unveiling nanoscale optical signatures of cytokine-induced β-cell dysfunction. Sci Rep 2023; 13:13342. [PMID: 37587148 PMCID: PMC10432522 DOI: 10.1038/s41598-023-40272-9] [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: 05/11/2023] [Accepted: 08/08/2023] [Indexed: 08/18/2023] Open
Abstract
Pro-inflammatory cytokines contribute to β-cell failure in both Type-1 and Type-2 Diabetes. Data collected so far allowed to dissect the genomic, transcriptomic, proteomic and biochemical landscape underlying cytokine-induced β-cell progression through dysfunction. Yet, no report thus far complemented such molecular information with the direct optical nanoscopy of the β-cell subcellular environment. Here we tackle this issue in Insulinoma 1E (INS-1E) β-cells by label-free fluorescence lifetime imaging microscopy (FLIM) and fluorescence-based super resolution imaging by expansion microscopy (ExM). It is found that 24-h exposure to IL-1β and IFN-γ is associated with a neat modification of the FLIM signature of cell autofluorescence due to the increase of either enzyme-bound NAD(P)H molecules and of oxidized lipid species. At the same time, ExM-based direct imaging unveils neat alteration of mitochondrial morphology (i.e. ~ 80% increase of mitochondrial circularity), marked degranulation (i.e. ~ 40% loss of insulin granules, with mis-localization of the surviving pool), appearance of F-actin-positive membrane blebs and an hitherto unknown extensive fragmentation of the microtubules network (e.g. ~ 37% reduction in the number of branches). Reported observations provide an optical-microscopy framework to interpret the amount of molecular information collected so far on β-cell dysfunction and pave the way to future ex-vivo and in-vivo investigations.
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Affiliation(s)
- Licia Anna Pugliese
- NEST Laboratory - Scuola Normale Superiore, Piazza San Silvestro 12, Pisa, Italy.
| | - Valentina De Lorenzi
- NEST Laboratory - Scuola Normale Superiore, Piazza San Silvestro 12, Pisa, Italy
| | - Mario Bernardi
- NEST Laboratory - Scuola Normale Superiore, Piazza San Silvestro 12, Pisa, Italy
| | - Samuele Ghignoli
- NEST Laboratory - Scuola Normale Superiore, Piazza San Silvestro 12, Pisa, Italy
| | - Marta Tesi
- Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, Italy
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, Italy
| | - Luca Pesce
- NEST Laboratory - Scuola Normale Superiore, Piazza San Silvestro 12, Pisa, Italy.
| | - Francesco Cardarelli
- NEST Laboratory - Scuola Normale Superiore, Piazza San Silvestro 12, Pisa, Italy.
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20
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Son J, Accili D. Reversing pancreatic β-cell dedifferentiation in the treatment of type 2 diabetes. Exp Mol Med 2023; 55:1652-1658. [PMID: 37524865 PMCID: PMC10474037 DOI: 10.1038/s12276-023-01043-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 03/29/2023] [Accepted: 04/24/2023] [Indexed: 08/02/2023] Open
Abstract
The maintenance of glucose homeostasis is fundamental for survival and health. Diabetes develops when glucose homeostasis fails. Type 2 diabetes (T2D) is characterized by insulin resistance and pancreatic β-cell failure. The failure of β-cells to compensate for insulin resistance results in hyperglycemia, which in turn drives altered lipid metabolism and β-cell failure. Thus, insulin secretion by pancreatic β-cells is a primary component of glucose homeostasis. Impaired β-cell function and reduced β-cell mass are found in diabetes. Both features stem from a failure to maintain β-cell identity, which causes β-cells to dedifferentiate into nonfunctional endocrine progenitor-like cells or to trans-differentiate into other endocrine cell types. In this regard, one of the key issues in achieving disease modification is how to reestablish β-cell identity. In this review, we focus on the causes and implications of β-cell failure, as well as its potential reversibility as a T2D treatment.
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Affiliation(s)
- Jinsook Son
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
| | - Domenico Accili
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
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21
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Pelligra A, Mrugala J, Griess K, Kirschner P, Nortmann O, Bartosinska B, Köster A, Krupenko NI, Gebel D, Westhoff P, Steckel B, Eberhard D, Herebian D, Belgardt BF, Schrader J, Weber APM, Krupenko SA, Lammert E. Pancreatic islet protection at the expense of secretory function involves serine-linked mitochondrial one-carbon metabolism. Cell Rep 2023; 42:112615. [PMID: 37294632 PMCID: PMC10592470 DOI: 10.1016/j.celrep.2023.112615] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 03/30/2023] [Accepted: 05/23/2023] [Indexed: 06/11/2023] Open
Abstract
Type 2 diabetes is characterized by insulin hypersecretion followed by reduced glucose-stimulated insulin secretion (GSIS). Here we show that acute stimulation of pancreatic islets with the insulin secretagogue dextrorphan (DXO) or glibenclamide enhances GSIS, whereas chronic treatment with high concentrations of these drugs reduce GSIS but protect islets from cell death. Bulk RNA sequencing of islets shows increased expression of genes for serine-linked mitochondrial one-carbon metabolism (OCM) after chronic, but not acute, stimulation. In chronically stimulated islets, more glucose is metabolized to serine than to citrate, and the mitochondrial ATP/ADP ratio decreases, whereas the NADPH/NADP+ ratio increases. Activating transcription factor-4 (Atf4) is required and sufficient to activate serine-linked mitochondrial OCM genes in islets, with gain- and loss-of-function experiments showing that Atf4 reduces GSIS and is required, but not sufficient, for full DXO-mediated islet protection. In sum, we identify a reversible metabolic pathway that provides islet protection at the expense of secretory function.
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Affiliation(s)
- Angela Pelligra
- Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Jessica Mrugala
- Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany; Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Kerstin Griess
- Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Philip Kirschner
- Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Oliver Nortmann
- Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Barbara Bartosinska
- Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Andrea Köster
- Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Natalia I Krupenko
- University of North Carolina (UNC) Nutrition Research Institute, UNC Chapel Hill, Chapel Hill, NC, USA
| | - Dominik Gebel
- Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Philipp Westhoff
- Institute of Plant Biochemistry, Cluster of Excellence on Plant Science (CEPLAS), Heinrich Heine University, 40225 Düsseldorf, Germany; Cluster of Excellence on Plant Science (CEPLAS), Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Bodo Steckel
- Department of Molecular Cardiology, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Daniel Eberhard
- Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany; Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Diran Herebian
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Bengt-Frederik Belgardt
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Jürgen Schrader
- Department of Molecular Cardiology, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Andreas P M Weber
- Institute of Plant Biochemistry, Cluster of Excellence on Plant Science (CEPLAS), Heinrich Heine University, 40225 Düsseldorf, Germany; Cluster of Excellence on Plant Science (CEPLAS), Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Sergey A Krupenko
- University of North Carolina (UNC) Nutrition Research Institute, UNC Chapel Hill, Chapel Hill, NC, USA
| | - Eckhard Lammert
- Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany; Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, 85764 Neuherberg, Germany.
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22
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Granata S, Mercuri S, Troise D, Gesualdo L, Stallone G, Zaza G. mTOR-inhibitors and post-transplant diabetes mellitus: a link still debated in kidney transplantation. Front Med (Lausanne) 2023; 10:1168967. [PMID: 37250653 PMCID: PMC10213242 DOI: 10.3389/fmed.2023.1168967] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 04/25/2023] [Indexed: 05/31/2023] Open
Abstract
The mammalian target of rapamycin inhibitors (mTOR-Is, Sirolimus, and Everolimus) are immunosuppressive drugs widely employed in kidney transplantation. Their main mechanism of action includes the inhibition of a serine/threonine kinase with a pivotal role in cellular metabolism and in various eukaryotic biological functions (including proteins and lipids synthesis, autophagy, cell survival, cytoskeleton organization, lipogenesis, and gluconeogenesis). Moreover, as well described, the inhibition of the mTOR pathway may also contribute to the development of the post-transplant diabetes mellitus (PTDM), a major clinical complication that may dramatically impact allograft survival (by accelerating the development of the chronic allograft damage) and increase the risk of severe systemic comorbidities. Several factors may contribute to this condition, but the reduction of the beta-cell mass, the impairment of the insulin secretion and resistance, and the induction of glucose intolerance may play a pivotal role. However, although the results of several in vitro and in animal models, the real impact of mTOR-Is on PTDM is still debated and the entire biological machinery is poorly recognized. Therefore, to better elucidate the impact of the mTOR-Is on the risk of PTDM in kidney transplant recipients and to potentially uncover future research topics (particularly for the clinical translational research), we decided to review the available literature evidence regarding this important clinical association. In our opinion, based on the published reports, we cannot draw any conclusion and PTDM remains a challenge. However, also in this case, the administration of the lowest possible dose of mTOR-I should also be recommended.
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Affiliation(s)
- Simona Granata
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Silvia Mercuri
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Dario Troise
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Zaza
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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Ma P, Yu F, Zhong Y, Xu L, Xiao P. Protective effects of flavonoids in Coreopsis tinctoria Nutt. in a mouse model of type 2 diabetes. JOURNAL OF ETHNOPHARMACOLOGY 2023; 307:116214. [PMID: 36736673 DOI: 10.1016/j.jep.2023.116214] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 12/29/2022] [Accepted: 01/25/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Coreopsis tinctoria Nutt., a popular tea drink used in the Xinjiang region of China, has been traditionally used to treat diabetes and chronic metabolic diseases in China, Portugal, and North America. The bioactive extraction and potential mechanism have not been fully elucidated until now. AIM OF THE STUDY Traditional herbal medicines usually share network targets due to multicomponent therapeutics. Therefore, we tried to explore the protective effects of C. tinctoria on diabetes and the related molecular mechanism. MATERIALS AND METHODS A flavonoid-rich fraction of C. tinctoria (CTF) was prepared. After 15 weeks of continuous treatment with CTF, the blood glucose and blood lipid levels of experimental mice were evaluated. Tissue was collected for differentially expressed genes (DEGs), bioinformatics analysis, RT‒PCR and Western blot for target-related DEGs. RESULTS After 15 weeks of continuous treatment with CTF, db/db mice showed reversed levels of glucose, insulin, glucagon and glycated hemoglobin A1c. CTF treatment also regulated total cholesterol, triglycerides, low density lipoprotein, nonesterified fatty acid, alanine transaminase, and aspartate transaminase. Major metabolic pathways were found to be dysregulated in the liver using a combined analysis of transcriptomics and network pharmacology. CTF treatment regulated 48.2% of 6357 dysregulated genes in db/db mice. The mitochondrial electron transport chain and tricarboxylic acid cycle were mainly affected. The sequencing data showed that fifty-nine predicted target genes for CTF were reverse regulated. Together with 1528 coexpressed genes, these genes reflected the main characteristics of the whole perturbed transcriptomic profile, i.e., dysregulated mitochondrial metabolism. The important genes of the target and coexpressed genes were further verified at the gene and protein levels. CONCLUSIONS The results confirm that the metabolic changes induced by hyperglycemia are closely related to mitochondrial metabolism in the liver. CTF alters a core gene set that exerts regulatory effects at the biological pathway level in db/db mice. In conclusion, our data reveal that an important molecular event for CTF treatment is the regulation of mitochondrial metabolism and support the idea that herbs or natural compounds are potential therapeutic substances for mitochondrial dysfunction-related diabetes.
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Affiliation(s)
- Pei Ma
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, 100193, China.
| | - Fan Yu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, 100193, China.
| | - Yi Zhong
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, 100193, China.
| | - Lijia Xu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, 100193, China.
| | - Peigen Xiao
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, 100193, China.
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Huang M, Coral D, Ardalani H, Spegel P, Saadat A, Claussnitzer M, Mulder H, Franks PW, Kalamajski S. Identification of a weight loss-associated causal eQTL in MTIF3 and the effects of MTIF3 deficiency on human adipocyte function. eLife 2023; 12:84168. [PMID: 36876906 PMCID: PMC10023155 DOI: 10.7554/elife.84168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 03/05/2023] [Indexed: 03/07/2023] Open
Abstract
Genetic variation at the MTIF3 (Mitochondrial Translational Initiation Factor 3) locus has been robustly associated with obesity in humans, but the functional basis behind this association is not known. Here, we applied luciferase reporter assay to map potential functional variants in the haplotype block tagged by rs1885988 and used CRISPR-Cas9 to edit the potential functional variants to confirm the regulatory effects on MTIF3 expression. We further conducted functional studies on MTIF3-deficient differentiated human white adipocyte cell line (hWAs-iCas9), generated through inducible expression of CRISPR-Cas9 combined with delivery of synthetic MTIF3-targeting guide RNA. We demonstrate that rs67785913-centered DNA fragment (in LD with rs1885988, r2 > 0.8) enhances transcription in a luciferase reporter assay, and CRISPR-Cas9-edited rs67785913 CTCT cells show significantly higher MTIF3 expression than rs67785913 CT cells. Perturbed MTIF3 expression led to reduced mitochondrial respiration and endogenous fatty acid oxidation, as well as altered expression of mitochondrial DNA-encoded genes and proteins, and disturbed mitochondrial OXPHOS complex assembly. Furthermore, after glucose restriction, the MTIF3 knockout cells retained more triglycerides than control cells. This study demonstrates an adipocyte function-specific role of MTIF3, which originates in the maintenance of mitochondrial function, providing potential explanations for why MTIF3 genetic variation at rs67785913 is associated with body corpulence and response to weight loss interventions.
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Affiliation(s)
- Mi Huang
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Clinical Research Centre, Lund UniversityMalmöSweden
| | - Daniel Coral
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Clinical Research Centre, Lund UniversityMalmöSweden
| | - Hamidreza Ardalani
- Department of Chemistry, Centre for Analysis and Synthesis, Lund UniversityLundSweden
| | - Peter Spegel
- Department of Chemistry, Centre for Analysis and Synthesis, Lund UniversityLundSweden
| | - Alham Saadat
- Metabolism Program, Broad Institute of MIT and HarvardCambridgeUnited States
| | - Melina Claussnitzer
- Metabolism Program, Broad Institute of MIT and HarvardCambridgeUnited States
| | - Hindrik Mulder
- Unit of Molecular Metabolism, Department of Clinical Sciences, Clinical Research Centre, Lund UniversityMalmöSweden
| | - Paul W Franks
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Clinical Research Centre, Lund UniversityMalmöSweden
- Department of Nutrition, Harvard T.H. Chan School of Public HealthBostonUnited States
| | - Sebastian Kalamajski
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Clinical Research Centre, Lund UniversityMalmöSweden
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25
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Subash-Babu P, Abdulaziz AlSedairy S, Abdulaziz Binobead M, Alshatwi AA. Luteolin-7-O-rutinoside Protects RIN-5F Cells from High-Glucose-Induced Toxicity, Improves Glucose Homeostasis in L6 Myotubes, and Prevents Onset of Type 2 Diabetes. Metabolites 2023; 13:metabo13020269. [PMID: 36837888 PMCID: PMC9965038 DOI: 10.3390/metabo13020269] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/01/2023] [Accepted: 02/04/2023] [Indexed: 02/16/2023] Open
Abstract
Luteolin-7-O-rutinoside (lut-7-O-rutin), a flavonoid commonly present in Mentha longifolia L. and Olea europaea L. leaves has been used as a flavoring agent with some biological activity. The present study is the first attempt to analyze the protective effect of lut-7-O-rutin on high-glucose-induced toxicity to RIN-5F cells in vitro. We found that lut-7-O-rutin improved insulin secretion in both normal and high-glucose conditions in a dose-dependent manner, without toxicity observed. In addition, 20 µmol of lut-7-O-rutin improves insulin sensitization and glucose uptake significantly (p ≤ 0.01) in L6 myotubes cultured in a high-glucose medium. Lut-7-O-rutin has shown a significant (p ≤ 0.05) effect on glucose uptake in L6 myotubes compared to the reference drug, rosiglitazone (20 µmol). Gene expression analysis confirmed significantly lowered CYP1A, TNF-α, and NF-κb expressions in RIN-5F cells, and increased mitochondrial thermogenesis-related LPL, Ucp-1 and PPARγC1A mRNA expressions in L6 myotubes after 24 h of lut-7-O-rutin treatment. The levels of signaling proteins associated with intracellular glucose uptakes, such as cAMP, ChREBP-1, and AMPK, were significantly increased in L6 myotubes. In addition, the levels of the conversion rate of glucose to lactate and fatty acids were raised in insulin-stimulated conditions; the rate of glycerol conversion was found to be higher at the basal level in L6 myotubes. In conclusion, lut-7-O-rutin protects RIN-5F cells from high-glucose-induced toxicity, stimulates insulin secretion, and promotes glucose absorption and homeostasis via molecular mechanisms.
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26
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Papadakos SP, Dedes N, Gkolemi N, Machairas N, Theocharis S. The EPH/Ephrin System in Pancreatic Ductal Adenocarcinoma (PDAC): From Pathogenesis to Treatment. Int J Mol Sci 2023; 24:3015. [PMID: 36769332 PMCID: PMC9917762 DOI: 10.3390/ijms24033015] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 01/09/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a major concern for health care systems worldwide, since its mortality remains unaltered despite the surge in cutting-edge science. The EPH/ephrin signaling system was first investigated in the 1980s. EPH/ephrins have been shown to exert bidirectional signaling and cell-to-cell communication, influencing cellular morphology, adhesion, migration and invasion. Recent studies have highlighted the critical role of the EPH/ephrin system in various physiologic processes, including cellular proliferation, survival, synaptic plasticity and angiogenesis. Thus, it has become evident that the EPH/ephrin signaling system may have compelling effects on cell homeostasis that contribute to carcinogenesis. In particular, the EPH/ephrins have an impact on pancreatic morphogenesis and development, whereas several EPHs and ephrins are altered in PDAC. Several clinical and preclinical studies have attempted to elucidate the effects of the EPH/ephrin pathway, with multilayered effects on PDAC development. These studies have highlighted its highly promising role in the diagnosis, prognosis and therapeutic management of PDAC. The aim of this review is to explore the obscure aspects of the EPH/ephrin system concerning the development, physiology and homeostasis of the pancreas.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Nikolaos Dedes
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Nikolina Gkolemi
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Nikolaos Machairas
- Second Department of Propaedeutic Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 Athens, Greece
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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27
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Onikanni SA, Lawal B, Oyinloye BE, Ajiboye BO, Ulziijargal S, Wang CH, Emran TB, Simal-Gandara J. Mitochondrial defects in pancreatic beta-cell dysfunction and neurodegenerative diseases: Pathogenesis and therapeutic applications. Life Sci 2023; 312:121247. [PMID: 36450327 DOI: 10.1016/j.lfs.2022.121247] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/12/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022]
Abstract
Mitochondria malfunction is linked to the development of β-cell failure and a variety of neurodegenerative disorders. Pancreatic β-cells are normally configured to detect glucose and other food secretagogues in order to adjust insulin exocytosis and maintain glucose homeostasis. As a result of the increased glucose level, mitochondria metabolites and nucleotides are produced, which operate in concert with cytosolic Ca2+ to stimulate insulin secretion. Furthermore, mitochondria are the primary generators of adenosine triphosphate (ATP), reactive oxygen species (ROS), and apoptosis regulation. Mitochondria are concentrated in synapses, and any substantial changes in synaptic mitochondria location, shape, quantity, or function might cause oxidative stress, resulting in faulty synaptic transmission, a symptom of various degenerative disorders at an early stage. However, a greater understanding of the role of mitochondria in the etiology of β-cell dysfunction and neurodegenerative disorder should pave the way for a more effective approach to addressing these health issues. This review looks at the widespread occurrence of mitochondria depletion in humans, and its significance to mitochondria biogenesis in signaling and mitophagy. Proper understanding of the processes might be extremely beneficial in ameliorating the rising worries about mitochondria biogenesis and triggering mitophagy to remove depleted mitochondria, therefore reducing disease pathogenesis.
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Affiliation(s)
- Sunday Amos Onikanni
- Graduate Institute of Biomedical Science, College of Medicine, China Medical University, Taichung, Taiwan; Department of Chemical Sciences, Biochemistry Unit, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria.
| | - Bashir Lawal
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Babatunji Emmanuel Oyinloye
- Department of Chemical Sciences, Biochemistry Unit, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria; Biotechnology and Structural Biology (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa; Institute of Drug Research and Development, SE Bogoro Center, Afe Babalola University, PMB 5454, Ado-Ekiti 360001, Nigeria
| | - Basiru Olaitan Ajiboye
- Institute of Drug Research and Development, SE Bogoro Center, Afe Babalola University, PMB 5454, Ado-Ekiti 360001, Nigeria; Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University of Technology, Oye-Ekiti, Ekiti State, Nigeria
| | - Sukhbat Ulziijargal
- Graduate Institute of Biomedical Science, College of Medicine, China Medical University, Taichung, Taiwan
| | - Chih-Hao Wang
- Graduate Institute of Biomedical Science, College of Medicine, China Medical University, Taichung, Taiwan
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh; Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh.
| | - Jesus Simal-Gandara
- Universidade de Vigo, Nutrition and Bromatology Group, Analytical Chemistry and Food Science Department, Faculty of Science, E32004 Ourense, Spain.
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28
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Pires Da Silva J, Wargny M, Raffin J, Croyal M, Duparc T, Combes G, Genoux A, Perret B, Vellas B, Guyonnet S, Thalamas C, Langin D, Moro C, Viguerie N, Rolland Y, Barreto PDS, Cariou B, Martinez LO. Plasma level of ATPase inhibitory factor 1 (IF1) is associated with type 2 diabetes risk in humans: A prospective cohort study. DIABETES & METABOLISM 2023; 49:101391. [PMID: 36174852 DOI: 10.1016/j.diabet.2022.101391] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/15/2022] [Accepted: 09/22/2022] [Indexed: 01/28/2023]
Abstract
AIM Mitochondrial dysfunction is associated with the development of type 2 diabetes mellitus (T2DM). It is thus of clinical relevance to identify plasma biomarkers of mitochondrial dysfunction associated with the risk of T2DM. ATPase inhibitory factor 1 (IF1) endogenously inhibits mitochondrial ATP synthase activity. Here, we analyzed association of the plasma IF1 level with markers of glucose homeostasis and with the conversion to new-onset diabetes (NOD) in individuals with prediabetes. METHODS In the IT-DIAB prospective study, the baseline plasma level of IF1 was measured in 307 participants with prediabetes. The primary outcome was the incidence of NOD within five years of follow-up. Cross-sectional analysis of the IF1 level was also done in two independent interventional studies. Correlations between plasma IF1 and metabolic parameters at baseline were assessed by Spearman's correlation coefficients, and the association with the risk of NOD was determined using Cox proportional-hazards models. RESULTS In IT-DIAB, the mean IF1 plasma level was lower in participants who developed NOD than in those who did not (537 ± 248 versus 621 ± 313 ng/mL, P = 0.01). The plasma IF1 level negatively correlated with clinical variables associated with obesity and insulin resistance, including the body mass index (r = -0.20, P = 0.0005) and homeostasis model assessment of insulin resistance (HOMA-IR). (r = -0.37, P < 0.0001). Conversely, IF1 was positively associated with plasma markers of cardiometabolic health, such as HDL-C (r = 0.63, P < 0.0001) and apoA-I (r = 0.33, P < 0.0001). These correlations were confirmed in cross-sectional analyses. In IT-DIAB, the IF1 level was significantly associated with a lower risk of T2DM after adjustment for age, sex, and fasting plasma glucose (HR [95% CI] per 1 SD = 0.76 [0.62; 0.94], P = 0.012). CONCLUSION We identified for the first time the mitochondrial-related biomarker IF1 as being associated with the risk of T2DM.
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Affiliation(s)
- Julie Pires Da Silva
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France
| | - Matthieu Wargny
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, 44000 Nantes, France; Nantes Université, CHU Nantes, Pôle Hospitalo-Universitaire 11 : Santé Publique, Clinique des données, INSERM, CIC 1413, F-44000 Nantes, France
| | - Jérémy Raffin
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France
| | - Mikaël Croyal
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, 44000 Nantes, France; Nantes Université, CHU Nantes, CNRS, Inserm, BioCore, US16, SFR Bonamy, F-44000 Nantes, France; CRNH-Ouest Mass Spectrometry Core Facility, 44000 Nantes, France
| | - Thibaut Duparc
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France
| | - Guillaume Combes
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France
| | - Annelise Genoux
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France; Service de Biochimie, Pôle de biologie, Hôpital de Purpan, CHU de Toulouse, Toulouse, France
| | - Bertrand Perret
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France; Service de Biochimie, Pôle de biologie, Hôpital de Purpan, CHU de Toulouse, Toulouse, France
| | - Bruno Vellas
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France; CERPOP UMR 1295, University of Toulouse III, INSERM, UPS, Toulouse, France
| | - Sophie Guyonnet
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France; CERPOP UMR 1295, University of Toulouse III, INSERM, UPS, Toulouse, France
| | - Claire Thalamas
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France; Clinical Investigation Center, Université de Toulouse, INSERM, Université Toulouse III-Paul Sabatier, Toulouse University Hospitals, CIC1436, F-CRIN/FORCE Network, Toulouse, France
| | - Dominique Langin
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France; Service de Biochimie, Pôle de biologie, Hôpital de Purpan, CHU de Toulouse, Toulouse, France; Institut Universitaire de France (IUF), Paris, France
| | - Cédric Moro
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France
| | - Nathalie Viguerie
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France
| | - Yves Rolland
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France; CERPOP UMR 1295, University of Toulouse III, INSERM, UPS, Toulouse, France
| | - Philipe de Souto Barreto
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France; CERPOP UMR 1295, University of Toulouse III, INSERM, UPS, Toulouse, France
| | - Bertrand Cariou
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, 44000 Nantes, France
| | - Laurent O Martinez
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.
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- Members are listed in the acknowledgements
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Onikanni SA, Lawal B, Bakare OS, Ajiboye BO, Ojo OA, Farasani A, Kabrah SM, Batiha GES, Conte-Junior CA. Cancer of the Liver and its Relationship with Diabetes mellitus. Technol Cancer Res Treat 2022; 21:15330338221119743. [PMID: 36533882 PMCID: PMC9772979 DOI: 10.1177/15330338221119743] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
A high increase witnessed in type II diabetes mellitus (T2DM) globally has increasingly posed a serious threat to global increases in liver cancer with the association between diabetes mellitus type II and the survival rate in liver cancer patients showing unstable findings. An increase in the development and progression of chronic liver disease from diabetes mellitus patients may be connected to cancer of the liver with several links such as Hepatitis B and C virus and heavy consumption of alcohol. The link between T2DM patients and liver cancer is centered on non-alcoholic fatty liver disease (NAFLD) which could be a serious threat globally if not clinically addressed. Several reports identified metformin treatment as linked to a lower risk of liver cancer prognosis while insulin treatment or sulphonylureas posed a serious threat. Mechanistically, the biological linkage between diabetes type II mellitus and liver cancer are still complex to understand with only the existence of a relationship between NAFLD and high level of energy intake and diabetes mellitus induces hepatic damage, increased liver weight thereby causes multiple pro-inflammatory cytokines that lead to the development of liver cancer. Therefore, this review gives an account of the pathophysiological importance of liver cancer position with T2DM, with the role of NAFLD as an important factor that bridges them.
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Affiliation(s)
- Sunday Amos Onikanni
- Department of Chemical Sciences, Biochemistry Unit, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria,College of Medicine, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan,Sunday Amos Onikanni, College of Medicine, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
| | - Bashir Lawal
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei,Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei
| | | | - Basiru Olaitan Ajiboye
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Ekiti State, Nigeria
| | - Oluwafemi Adeleke Ojo
- Phytomedicine, Molecular Toxicology, and Computational Biochemistry Research Laboratory (PMTCB-RL), Department of Biochemistry, Bowen University, Iwo, 232101, Nigeria
| | - Abdullah Farasani
- Biomedical Research Unit, Medical Research Center, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia,Department of Medical Laboratory Technology, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Saeed M Kabrah
- Department of Laboratory Medicine Faculty of Applied medical sciences, Umm Al-Qura University, Kingdom of Saudi Arabia
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, AlBeheira, Egypt
| | - Carlos Adam Conte-Junior
- Analytical and Molecular Laboratorial Center (CLAn), Institute of Chemistry (IQ), Federal University of Rio de Janeiro (UFRJ), Cidade Universitária, Rio de Janeiro, RJ, 21941-909, Brazil
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30
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Haythorne E, Lloyd M, Walsby-Tickle J, Tarasov AI, Sandbrink J, Portillo I, Exposito RT, Sachse G, Cyranka M, Rohm M, Rorsman P, McCullagh J, Ashcroft FM. Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells. Nat Commun 2022; 13:6754. [PMID: 36376280 PMCID: PMC9663558 DOI: 10.1038/s41467-022-34095-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 10/13/2022] [Indexed: 11/16/2022] Open
Abstract
Chronic hyperglycaemia causes a dramatic decrease in mitochondrial metabolism and insulin content in pancreatic β-cells. This underlies the progressive decline in β-cell function in diabetes. However, the molecular mechanisms by which hyperglycaemia produces these effects remain unresolved. Using isolated islets and INS-1 cells, we show here that one or more glycolytic metabolites downstream of phosphofructokinase and upstream of GAPDH mediates the effects of chronic hyperglycemia. This metabolite stimulates marked upregulation of mTORC1 and concomitant downregulation of AMPK. Increased mTORC1 activity causes inhibition of pyruvate dehydrogenase which reduces pyruvate entry into the tricarboxylic acid cycle and partially accounts for the hyperglycaemia-induced reduction in oxidative phosphorylation and insulin secretion. In addition, hyperglycaemia (or diabetes) dramatically inhibits GAPDH activity, thereby impairing glucose metabolism. Our data also reveal that restricting glucose metabolism during hyperglycaemia prevents these changes and thus may be of therapeutic benefit. In summary, we have identified a pathway by which chronic hyperglycaemia reduces β-cell function.
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Affiliation(s)
- Elizabeth Haythorne
- Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
| | - Matthew Lloyd
- Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK
| | - John Walsby-Tickle
- Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
| | - Andrei I Tarasov
- School of Biomedical Sciences, Ulster University, Coleraine, BT52 1SA, Northern Ireland, UK
| | - Jonas Sandbrink
- Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK
| | - Idoia Portillo
- Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK
| | - Raul Terron Exposito
- Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK
- Institute for Diabetes and Cancer (IDC), Helmholtz Center, Munich, Neuherberg, 85764, Germany
| | - Gregor Sachse
- Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK
- Brandenburg Medical School (Theodor Fontane), ZTM-BB, Brandenburg a. d. H, 14770, Germany
| | - Malgorzata Cyranka
- Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK
| | - Maria Rohm
- Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK
- Institute for Diabetes and Cancer (IDC), Helmholtz Center, Munich, Neuherberg, 85764, Germany
| | - Patrik Rorsman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK
| | - James McCullagh
- Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
| | - Frances M Ashcroft
- Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
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The human batokine EPDR1 regulates β-cell metabolism and function. Mol Metab 2022; 66:101629. [PMID: 36343918 PMCID: PMC9663883 DOI: 10.1016/j.molmet.2022.101629] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 10/14/2022] [Accepted: 11/01/2022] [Indexed: 11/08/2022] Open
Abstract
OBJECTIVE Ependymin-Related Protein 1 (EPDR1) was recently identified as a secreted human batokine regulating mitochondrial respiration linked to thermogenesis in brown fat. Despite that EPDR1 is expressed in human pancreatic β-cells and that glucose-stimulated mitochondrial metabolism is critical for stimulus-secretion coupling in β-cells, the role of EPDR1 in β-cell metabolism and function has not been investigated. METHODS EPDR1 mRNA levels in human pancreatic islets from non-diabetic (ND) and type 2 diabetes (T2D) subjects were assessed. Human islets, EndoC-βH1 and INS1 832/13 cells were transfected with scramble (control) and EPDR1 siRNAs (EPDR1-KD) or treated with human EPDR1 protein, and glucose-stimulated insulin secretion (GSIS) assessed by ELISA. Mitochondrial metabolism was investigated by extracellular flux analyzer, confocal microscopy and mass spectrometry-based metabolomics analysis. RESULTS EPDR1 mRNA expression was upregulated in human islets from T2D and obese donors and positively correlated to BMI of donors. In T2D donors, EPDR1 mRNA levels negatively correlated with HbA1c and positively correlated with GSIS. EPDR1 silencing in human islets and β-cell lines reduced GSIS whereas treatment with human EPDR1 protein increased GSIS. Epdr1 silencing in INS1 832/13 cells reduced glucose- and pyruvate- but not K+-stimulated insulin secretion. Metabolomics analysis in Epdr1-KD INS1 832/13 cells suggests diversion of glucose-derived pyruvate to lactate production and decreased malate-aspartate shuttle and the tricarboxylic acid (TCA) cycle activity. The glucose-stimulated rise in mitochondrial respiration and ATP/ADP-ratio was impaired in Epdr1-deficient cells. CONCLUSION These results suggests that to maintain glucose homeostasis in obese people, upregulation of EPDR1 may improve β-cell function via channelling glycolysis-derived pyruvate to the mitochondrial TCA cycle.
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Dogra S, Das D, Maity SK, Paul A, Rawat P, Daniel PV, Das K, Mitra S, Chakrabarti P, Mondal P. Liver-Derived S100A6 Propels β-Cell Dysfunction in NAFLD. Diabetes 2022; 71:2284-2296. [PMID: 35899967 DOI: 10.2337/db22-0056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an independent predictor of systemic insulin resistance and type 2 diabetes mellitus (T2DM). However, converse correlates between excess liver fat content and β-cell function remain equivocal. Specifically, how the accumulation of liver fat consequent to the enhanced de novo lipogenesis (DNL) leads to pancreatic β-cell failure and eventually to T2DM is elusive. Here, we have identified that low-molecular-weight calcium-binding protein S100A6, or calcyclin, inhibits glucose-stimulated insulin secretion (GSIS) from β cells through activation of the receptor for the advanced glycation end products and diminution of mitochondrial respiration. Serum S100A6 level is elevated both in human patients with NAFLD and in a high-fat diet-induced mouse model of NAFLD. Although serum S100A6 levels are negatively associated with β-cell insulin secretory capacity in human patients, depletion of hepatic S100A6 improves GSIS and glycemia in mice, suggesting that S100A6 contributes to the pathophysiology of diabetes in NAFLD. Moreover, transcriptional induction of hepatic S100A6 is driven by the potent regulator of DNL, carbohydrate response element-binding protein (ChREBP), and ectopic expression of ChREBP in the liver suppresses GSIS in a S100A6-sensitive manner. Together, these data suggest elevated serum levels of S100A6 may serve as a biomarker in identifying patients with NAFLD with a heightened risk of developing β-cell dysfunction. Overall, our data implicate S100A6 as, to our knowledge, a hitherto unknown hepatokine to be activated by ChREBP and that participates in the hepato-pancreatic communication to impair insulin secretion and drive the development of T2DM in NAFLD.
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Affiliation(s)
- Surbhi Dogra
- School of Basic Sciences, Indian Institute of Technology-Mandi
| | - Debajyoti Das
- Division of Cell Biology and Physiology, Council of Scientific & Industrial Research-Indian Institute of Chemical Biology, Kolkata
| | - Sujay K Maity
- Division of Cell Biology and Physiology, Council of Scientific & Industrial Research-Indian Institute of Chemical Biology, Kolkata
| | - Avishek Paul
- Division of Cell Biology and Physiology, Council of Scientific & Industrial Research-Indian Institute of Chemical Biology, Kolkata
| | - Priya Rawat
- School of Basic Sciences, Indian Institute of Technology-Mandi
| | | | - Kausik Das
- Department of Hepatology, Institute of Post-Graduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, India
| | - Souveek Mitra
- Department of Hepatology, Institute of Post-Graduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, India
| | - Partha Chakrabarti
- Division of Cell Biology and Physiology, Council of Scientific & Industrial Research-Indian Institute of Chemical Biology, Kolkata
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33
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The Role of Galectin 3 in the Pathogenesis of Diabetes Mellitus: Focus on Β-Cell Function and Survival. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2022. [DOI: 10.2478/sjecr-2022-0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Abstract
Galectin 3 is a lectin expressed in many tissues with a significant biological role in physiological and pathological processes. Our review aims to sublimate the effects of galectin 3 on the β-cells function and survival. Data about the effect of galectin 3 on β- cells are scarce and contradictory. Several studies have shown that reduced activity of the galectin 3 gene reduces the risk of developing type 1 diabetes in an experimental model of diabetes in galectin 3 deficient mice. On the other side, in an experimental model of type 1 diabetes with mice with selectively enhanced expression of galectin 3 in β-cells, was shown that increased expression of this lectin has a protective role. Unlike type 1 diabetes where the autoimmune process plays a dominant role in pathogenesis, the pathogenesis of type 2 diabetes is multifactorial. One of the main factors which contribute to type 2 diabetes, the insulin resistance, is related to the concentration of soluble galectin 3. The effect of galectin 3 is very important for β-cell function. When a harmful factor acts on a β-cell, its intracellular concentration increases to preserve the function of β-cells and prevent their apoptosis, by blocking the internal path of apoptosis. However, excessive accumulation of galectin 3 inside the cell leads to its secretion, which encourages tissue inflammation. Based on all the above, galectin 3 has a double effect on β-cells.
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34
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Jeyagaran A, Lu CE, Zbinden A, Birkenfeld AL, Brucker SY, Layland SL. Type 1 diabetes and engineering enhanced islet transplantation. Adv Drug Deliv Rev 2022; 189:114481. [PMID: 36002043 PMCID: PMC9531713 DOI: 10.1016/j.addr.2022.114481] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 01/24/2023]
Abstract
The development of new therapeutic approaches to treat type 1 diabetes mellitus (T1D) relies on the precise understanding and deciphering of insulin-secreting β-cell biology, as well as the mechanisms responsible for their autoimmune destruction. β-cell or islet transplantation is viewed as a potential long-term therapy for the millions of patients with diabetes. To advance the field of insulin-secreting cell transplantation, two main research areas are currently investigated by the scientific community: (1) the identification of the developmental pathways that drive the differentiation of stem cells into insulin-producing cells, providing an inexhaustible source of cells; and (2) transplantation strategies and engineered transplants to provide protection and enhance the functionality of transplanted cells. In this review, we discuss the biology of pancreatic β-cells, pathology of T1D and current state of β-cell differentiation. We give a comprehensive view and discuss the different possibilities to engineer enhanced insulin-secreting cell/islet transplantation from a translational perspective.
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Affiliation(s)
- Abiramy Jeyagaran
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; NMI Natural and Medical Sciences Institute at the University Tübingen, 72770 Reutlingen, Germany
| | - Chuan-En Lu
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Aline Zbinden
- Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, German Center for Diabetes Research (DZD e.V.), Munich, Germany
| | - Sara Y Brucker
- Department of Women's Health, Eberhard Karls University, 72076 Tübingen, Germany
| | - Shannon L Layland
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Department of Women's Health, Eberhard Karls University, 72076 Tübingen, Germany.
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35
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So S, Lee S, Lee Y, Han J, Kang S, Choi J, Kim B, Kim D, Yoo HJ, Shim IK, Oh JY, Lee YN, Kim SC, Kang E. Dysfunctional pancreatic cells differentiated from induced pluripotent stem cells with mitochondrial DNA mutations. BMB Rep 2022; 55:453-458. [PMID: 35651332 PMCID: PMC9537029 DOI: 10.5483/bmbrep.2022.55.9.023] [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: 02/10/2022] [Revised: 03/30/2022] [Accepted: 05/04/2022] [Indexed: 11/20/2022] Open
Abstract
Diabetes mellitus (DM) is a serious disease in which blood sugar levels rise abnormally because of failed insulin production or decreased insulin sensitivity. Although many studies are being conducted for the treatment or early diagnosis of DM, it is not fully understood how mitochondrial genome (mtDNA) abnormalities appear in patients with DM. Here, we induced iPSCs from fibroblasts, PBMCs, or pancreatic cells of three patients with type 2 DM (T2D) and three patients with non-diabetes counterpart. The mtDNA mutations were detected randomly without any tendency among tissues or patients. In T2D patients, 62% (21/34) of iPSC clones harbored multiple mtDNA mutations, of which 37% were homoplasmy at the 100% mutation level compared to only 8% in non-diabetes. We next selected iPSC clones that were a wild type or carried mutations and differentiated into pancreatic cells. Oxygen consumption rates were significantly lower in cells carrying mutant mtDNA. Additionally, the mutant cells exhibited decreased production of insulin and reduced secretion of insulin in response to glucose. Overall, the results suggest that screening mtDNA mutations in iPSCs from patients with T2D is an essential step before pancreatic cell differentiation for disease modeling or autologous cell therapy. [BMB Reports 2022; 55(9): 453-458].
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Affiliation(s)
- Seongjun So
- Department of Convergence Medicine & Stem Cell Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
- Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam 13488, Korea
| | - Song Lee
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Yeonmi Lee
- Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam 13488, Korea
| | - Jongsuk Han
- Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam 13488, Korea
| | - Soonsuk Kang
- Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam 13488, Korea
| | - Jiwan Choi
- Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam 13488, Korea
| | - Bitnara Kim
- Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam 13488, Korea
| | - Deokhoon Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Hyun-Ju Yoo
- Department of Convergence Medicine & Stem Cell Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - In-Kyong Shim
- Department of Convergence Medicine & Stem Cell Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Ju-Yun Oh
- Department of Convergence Medicine & Stem Cell Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Yu-Na Lee
- Department of Convergence Medicine & Stem Cell Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Song-Cheol Kim
- Department of Convergence Medicine & Stem Cell Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Eunju Kang
- Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam 13488, Korea
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36
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Tani H, Ishikawa K, Tamashiro H, Ogasawara E, Yasukawa T, Matsuda S, Shimizu A, Kang D, Hayashi JI, Wei FY, Nakada K. Aberrant RNA processing contributes to the pathogenesis of mitochondrial diseases in trans-mitochondrial mouse model carrying mitochondrial tRNALeu(UUR) with a pathogenic A2748G mutation. Nucleic Acids Res 2022; 50:9382-9396. [PMID: 35998911 PMCID: PMC9458463 DOI: 10.1093/nar/gkac699] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 07/13/2022] [Accepted: 08/04/2022] [Indexed: 12/24/2022] Open
Abstract
Mitochondrial tRNAs are indispensable for the intra-mitochondrial translation of genes related to respiratory subunits, and mutations in mitochondrial tRNA genes have been identified in various disease patients. However, the molecular mechanism underlying pathogenesis remains unclear due to the lack of animal models. Here, we established a mouse model, designated 'mito-mice tRNALeu(UUR)2748', that carries a pathogenic A2748G mutation in the tRNALeu(UUR) gene of mitochondrial DNA (mtDNA). The A2748G mutation is orthologous to the human A3302G mutation found in patients with mitochondrial diseases and diabetes. A2748G mtDNA was maternally inherited, equally distributed among tissues in individual mice, and its abundance did not change with age. At the molecular level, A2748G mutation is associated with aberrant processing of precursor mRNA containing tRNALeu(UUR) and mt-ND1, leading to a marked decrease in the steady-levels of ND1 protein and Complex I activity in tissues. Mito-mice tRNALeu(UUR)2748 with ≥50% A2748G mtDNA exhibited age-dependent metabolic defects including hyperglycemia, insulin insensitivity, and hepatic steatosis, resembling symptoms of patients carrying the A3302G mutation. This work demonstrates a valuable mouse model with an inheritable pathological A2748G mutation in mt-tRNALeu(UUR) that shows metabolic syndrome-like phenotypes at high heteroplasmy level. Furthermore, our findings provide molecular basis for understanding A3302G mutation-mediated mitochondrial disorders.
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Affiliation(s)
- Haruna Tani
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan,Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Kaori Ishikawa
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan,Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan
| | - Hiroaki Tamashiro
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan
| | - Emi Ogasawara
- Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
| | - Takehiro Yasukawa
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan,Department of Pathology and Oncology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Shigeru Matsuda
- Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai, Miyagi 980-8575, Japan,Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Akinori Shimizu
- Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University, Jonan-ku, Fukuoka, Fukuoka 814-0180, Japan
| | - Dongchon Kang
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan,Kashiigaoka Rehabilitation Hospital, Higashi-ku, Fukuoka, Fukuoka 813-0002, Japan
| | - Jun-Ichi Hayashi
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan
| | - Fan-Yan Wei
- Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Kazuto Nakada
- To whom correspondence should be addressed. Tel: +81 29 853 6694; Fax: +81 29 853 6614;
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37
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Cornell D, Miwa S, Georgiou M, Anderson SJ, Honkanen-Scott M, Shaw JAM, Arden C. Pseudoislet Aggregation of Pancreatic β-Cells Improves Glucose Stimulated Insulin Secretion by Altering Glucose Metabolism and Increasing ATP Production. Cells 2022; 11:cells11152330. [PMID: 35954174 PMCID: PMC9367366 DOI: 10.3390/cells11152330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/19/2022] [Accepted: 07/26/2022] [Indexed: 11/20/2022] Open
Abstract
Appropriate glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells is an essential component of blood glucose homeostasis. Configuration of β-cells as 3D pseudoislets (PI) improves the GSIS response compared to 2D monolayer (ML) culture. The aim of this study was to determine the underlying mechanisms. MIN6 β-cells were grown as ML or PI for 5 days. Human islets were isolated from patients without diabetes. Function was assessed by GSIS and metabolic capacity using the Seahorse bioanalyser. Connexin 36 was downregulated using inducible shRNA. Culturing MIN6 as PI improved GSIS. MIN6 PI showed higher glucose-stimulated oxygen consumption (OCR) and extracellular acidification (ECAR) rates. Further analysis showed the higher ECAR was, at least in part, a consequence of increased glycolysis. Intact human islets also showed glucose-stimulated increases in both OCR and ECAR rates, although the latter was smaller in magnitude compared to MIN6 PI. The higher rates of glucose-stimulated ATP production in MIN6 PI were consistent with increased enzyme activity of key glycolytic and TCA cycle enzymes. There was no impact of connexin 36 knockdown on GSIS or ATP production. Configuration of β-cells as PI improves GSIS by increasing the metabolic capacity of the cells, allowing higher ATP production in response to glucose.
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Affiliation(s)
- Deborah Cornell
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK; (D.C.); (S.M.); (M.G.)
| | - Satomi Miwa
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK; (D.C.); (S.M.); (M.G.)
| | - Merilin Georgiou
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK; (D.C.); (S.M.); (M.G.)
| | - Scott James Anderson
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK; (S.J.A.); (M.H.-S.); (J.A.M.S.)
| | - Minna Honkanen-Scott
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK; (S.J.A.); (M.H.-S.); (J.A.M.S.)
| | - James A. M. Shaw
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK; (S.J.A.); (M.H.-S.); (J.A.M.S.)
| | - Catherine Arden
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK; (D.C.); (S.M.); (M.G.)
- Correspondence: ; Tel.: +44-191-2088798
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38
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Hong HJ, Joung KH, Kim YK, Choi MJ, Kang SG, Kim JT, Kang YE, Chang JY, Moon JH, Jun S, Ro HJ, Lee Y, Kim H, Park JH, Kang BE, Jo Y, Choi H, Ryu D, Lee CH, Kim H, Park KS, Kim HJ, Shong M. Mitoribosome insufficiency in β cells is associated with type 2 diabetes-like islet failure. EXPERIMENTAL & MOLECULAR MEDICINE 2022; 54:932-945. [PMID: 35804190 PMCID: PMC9355985 DOI: 10.1038/s12276-022-00797-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 02/22/2022] [Accepted: 03/14/2022] [Indexed: 12/04/2022]
Abstract
Genetic variations in mitoribosomal subunits and mitochondrial transcription factors are related to type 2 diabetes. However, the role of islet mitoribosomes in the development of type 2 diabetes has not been determined. We investigated the effects of the mitoribosomal gene on β-cell function and glucose homeostasis. Mitoribosomal gene expression was analyzed in datasets from the NCBI GEO website (GSE25724, GSE76894, and GSE76895) and the European Nucleotide Archive (ERP017126), which contain the transcriptomes of type 2 diabetic and nondiabetic organ donors. We found deregulation of most mitoribosomal genes in islets from individuals with type 2 diabetes, including partial downregulation of CRIF1. The phenotypes of haploinsufficiency in a single mitoribosomal gene were examined using β-cell-specific Crif1 (Mrpl59) heterozygous-deficient mice. Crif1beta+/− mice had normal glucose tolerance, but their islets showed a loss of first-phase glucose-stimulated insulin secretion. They also showed increased β-cell mass associated with higher expression of Reg family genes. However, Crif1beta+/− mice showed earlier islet failure in response to high-fat feeding, which was exacerbated by aging. Haploinsufficiency of a single mitoribosomal gene predisposes rodents to glucose intolerance, which resembles the early stages of type 2 diabetes in humans. Disruptions in the mitochondrial protein synthesis machinery give rise to metabolic disturbances that lay the foundation for type 2 diabetes. As physiological glucose levels rise, the energy-generating machinery of the mitochondria responds with increased activity, which stimulates insulin secretion. Many proteins responsible for mitochondrial metabolism are produced by ribosomes within this cellular organelle. Researchers led by Hyun Jin Kim and Minho Shong at Chungnam National University, Daejon, South Korea, have determined that mutations affecting a mitochondrial ribosomal protein called CRIF1 can lead to impaired insulin release. Mice with reduced CRIF1 were initially healthy, but as they aged, exhibited signs of impaired pancreatic function similar to those seen in patients with early-stage diabetes. This process was accelerated by consumption of a high-fat diet, and the researchers propose that this mechanism may be directly relevant to human disease.
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Affiliation(s)
- Hyun Jung Hong
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 35015, Korea.,Department of Medical Science, Chungnam National University School of Medicine, Daejeon, 35015, Korea
| | - Kyong Hye Joung
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 35015, Korea.,Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Korea
| | - Yong Kyung Kim
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 35015, Korea
| | - Min Jeong Choi
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 35015, Korea
| | - Seul Gi Kang
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 35015, Korea
| | - Jung Tae Kim
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 35015, Korea.,Department of Medical Science, Chungnam National University School of Medicine, Daejeon, 35015, Korea
| | - Yea Eun Kang
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 35015, Korea.,Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Korea
| | - Joon Young Chang
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 35015, Korea.,Department of Medical Science, Chungnam National University School of Medicine, Daejeon, 35015, Korea
| | - Joon Ho Moon
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Korea
| | - Sangmi Jun
- Center for Research Equipment, Korea Basic Science Institute, Cheongju, 28119, Korea.,Convergent Research Center for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea
| | - Hyun-Joo Ro
- Center for Research Equipment, Korea Basic Science Institute, Cheongju, 28119, Korea.,Convergent Research Center for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea
| | - Yujeong Lee
- Center for Research Equipment, Korea Basic Science Institute, Cheongju, 28119, Korea.,Convergent Research Center for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea
| | - Hyeongseok Kim
- Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, 35015, Korea
| | - Jae-Hyung Park
- Department of Physiology, Keimyung University School of Medicine, Daegu, 704-200, Korea
| | - Baeki E Kang
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Korea
| | - Yunju Jo
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Korea
| | - Heejung Choi
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Korea
| | - Dongryeol Ryu
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Korea.,Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, Korea.,Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, 06351, Korea
| | - Chul-Ho Lee
- Animal Model Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Korea
| | - Hail Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Korea
| | - Kyu-Sang Park
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, 26426, Korea
| | - Hyun Jin Kim
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 35015, Korea. .,Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Korea.
| | - Minho Shong
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 35015, Korea. .,Department of Medical Science, Chungnam National University School of Medicine, Daejeon, 35015, Korea. .,Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Korea.
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Lipotoxicity in a Vicious Cycle of Pancreatic Beta Cell Exhaustion. Biomedicines 2022; 10:biomedicines10071627. [PMID: 35884932 PMCID: PMC9313354 DOI: 10.3390/biomedicines10071627] [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: 05/09/2022] [Revised: 07/05/2022] [Accepted: 07/05/2022] [Indexed: 02/07/2023] Open
Abstract
Hyperlipidemia is a common metabolic disorder in modern society and may precede hyperglycemia and diabetes by several years. Exactly how disorders of lipid and glucose metabolism are related is still a mystery in many respects. We analyze the effects of hyperlipidemia, particularly free fatty acids, on pancreatic beta cells and insulin secretion. We have developed a computational model to quantitatively estimate the effects of specific metabolic pathways on insulin secretion and to assess the effects of short- and long-term exposure of beta cells to elevated concentrations of free fatty acids. We show that the major trigger for insulin secretion is the anaplerotic pathway via the phosphoenolpyruvate cycle, which is affected by free fatty acids via uncoupling protein 2 and proton leak and is particularly destructive in long-term chronic exposure to free fatty acids, leading to increased insulin secretion at low blood glucose and inadequate insulin secretion at high blood glucose. This results in beta cells remaining highly active in the “resting” state at low glucose and being unable to respond to anaplerotic signals at high pyruvate levels, as is the case with high blood glucose. The observed fatty-acid-induced disruption of anaplerotic pathways makes sense in the context of the physiological role of insulin as one of the major anabolic hormones.
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Sobajima M, Miyake M, Hamada Y, Tsugawa K, Oyadomari M, Inoue R, Shirakawa J, Arima H, Oyadomari S. The multifaceted role of ATF4 in regulating glucose-stimulated insulin secretion. Biochem Biophys Res Commun 2022; 611:165-171. [PMID: 35489203 DOI: 10.1016/j.bbrc.2022.04.038] [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: 03/22/2022] [Accepted: 04/08/2022] [Indexed: 11/02/2022]
Abstract
Stress-inducible transcription factor ATF4 is essential for survival and identity of β-cell during stress conditions. However, the physiological role of ATF4 in β-cell function is not yet completely understood. To understand the role of ATF4 in glucose-stimulated insulin secretion (GSIS), β-cell-specific Atf4 knockout (βAtf4KO) mice were phenotypically characterized. Insulin secretion and mechanistic analyses were performed using islets from control Atf4f/f and βAtf4KO mice to assess key regulators for triggering and amplifying signals for GSIS. βAtf4KO mice displayed glucose intolerance due to reduced insulin secretion. Moreover, βAtf4KO islets exhibited a decrease in both the insulin content and first-phase insulin secretion. The analysis of βAtf4KO islets showed that ATF4 is required for insulin production and glucose-stimulated ATP and cAMP production. The results demonstrate that ATF4 contributes to the multifaceted regulatory process in GSIS even under stress-free conditions.
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Affiliation(s)
- Mitsuaki Sobajima
- Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Department of Molecular Physiology, Diabetes Therapeutics and Research Center, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, 371-8512, Japan
| | - Masato Miyake
- Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Department of Molecular Physiology, Diabetes Therapeutics and Research Center, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Yoshimasa Hamada
- Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Department of Molecular Physiology, Diabetes Therapeutics and Research Center, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Kazue Tsugawa
- Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Miho Oyadomari
- Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Ryota Inoue
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, 371-8512, Japan
| | - Jun Shirakawa
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, 371-8512, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan
| | - Seiichi Oyadomari
- Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Department of Molecular Physiology, Diabetes Therapeutics and Research Center, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
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41
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Yuan S, Ye Z, Li Y, Zou J, Wu M, Wang K, Liao W, Shen J. Hypoglycemic Effect of Nobiletin via Regulation of Islet β-Cell Mitophagy and Gut Microbiota Homeostasis in Streptozocin-Challenged Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:5805-5818. [PMID: 35522926 DOI: 10.1021/acs.jafc.2c00148] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Nobiletin is a natural nutrient (or polymethoxyflavonoid) in orange peels exerting a preventive effect against metabolic diseases. However, there are very few reports on the hypoglycemic effect of nobiletin. In the present study, the hypoglycemic effect of nobiletin was investigated using NIT-1 cells and streptozocin (STZ)-challenged mouse models. Our results indicated that nobiletin could significantly suppress the high blood glucose in STZ-challenged mice. In addition, nobiletin could effectively activate the mitophagy and inhibit the inflammatory pathways in NIT-1 cells. The mitochondria membrane potential dysbiosis induced by glucotoxicity in NIT-1 cells was restored after treatment by nobiletin. Further investigation revealed that the hypoglycemic effect of nobiletin was mainly through regulation of gut microbiota dysbiosis, activation of mitophagy flux, inhibition of inflammasome expression, and restoration of islet morphological destruction in the pancreas of STZ-challenged mice. Our study revealed that nobiletin could be used as a functional food or drug candidate for the treatment of diabetes.
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Affiliation(s)
- Sijie Yuan
- Department of Endocrinology and Metabolic Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510630, China
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Zichong Ye
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Ye Li
- Department of Endocrinology and Metabolic Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510630, China
| | - Jiaxuan Zou
- School of Biological Science, University of California Irvine, Irvine, California 92697, United States
| | - Mengting Wu
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Ke Wang
- Department of Food Science & Technology, National University of Singapore, Singapore 117542, Singapore
| | - Wenzhen Liao
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Jie Shen
- Department of Endocrinology and Metabolic Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510630, China
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42
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Is Type 2 Diabetes a Primary Mitochondrial Disorder? Cells 2022; 11:cells11101617. [PMID: 35626654 PMCID: PMC9140179 DOI: 10.3390/cells11101617] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/27/2022] [Accepted: 04/20/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus is the most common endocrine disturbance in inherited mitochondrial diseases. It is essential to increase awareness of the correct diagnosis and treatment of diabetes in these patients and screen for the condition in family members, as diabetes might appear with distinctive clinical features, complications and at different ages of onset. The severity of mitochondrial-related diabetes is likely to manifest on a large scale of phenotypes depending on the location of the mutation and whether the number of affected mitochondria copies (heteroplasmy) reaches a critical threshold. Regarding diabetes treatment, the first-choice treatment for type 2 diabetes (T2D), metformin, is not recommended because of the risk of lactic acidosis. The preferred treatment for diabetes in patients with mitochondrial disorders is SGLT-2i and mitochondrial GLP-1-related substances. The tight relationship between mitochondrial dysfunction, reduced glucose-stimulated insulin secretion (GSIS), and diabetes development in human patients is acknowledged. However, despite the well-characterized role of mitochondria in GSIS, there is a relative lack of data in humans implicating mitochondrial dysfunction as a primary defect in T2D. Our recent studies have provided data supporting the significant role of the mitochondrial respiratory-chain enzyme, cytochrome c oxidase (COX), in regulating GSIS in a rodent model of T2D, the Cohen diabetic sensitive (CDs) rat. The nutritionally induced diabetic CDs rat demonstrates several features of mitochondrial diseases: markedly reduced COX activity in several tissues, increased reactive oxygen production, decreased ATP generation, and increased lactate dehydrogenase expression in islets. Moreover, our data demonstrate that reduced islet-COX activity precedes the onset of diabetes, suggesting that islet-COX deficiency is the primary defect causing diabetes in this model. This review examines the possibility of including T2D as a primary mitochondrial-related disease. Understanding the critical interdependence between diabetes and mitochondrial dysfunction, centering on the role of COX, may open novel avenues to diagnose and treat diabetes in patients with mitochondrial diseases and mitochondrial dysfunction in diabetic patients.
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Ježek P, Holendová B, Jabůrek M, Dlasková A, Plecitá-Hlavatá L. Contribution of Mitochondria to Insulin Secretion by Various Secretagogues. Antioxid Redox Signal 2022; 36:920-952. [PMID: 34180254 PMCID: PMC9125579 DOI: 10.1089/ars.2021.0113] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Significance: Mitochondria determine glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells by elevating ATP synthesis. As the metabolic and redox hub, mitochondria provide numerous links to the plasma membrane channels, insulin granule vesicles (IGVs), cell redox, NADH, NADPH, and Ca2+ homeostasis, all affecting insulin secretion. Recent Advances: Mitochondrial redox signaling was implicated in several modes of insulin secretion (branched-chain ketoacid [BCKA]-, fatty acid [FA]-stimulated). Mitochondrial Ca2+ influx was found to enhance GSIS, reflecting cytosolic Ca2+ oscillations induced by action potential spikes (intermittent opening of voltage-dependent Ca2+ and K+ channels) or the superimposed Ca2+ release from the endoplasmic reticulum (ER). The ATPase inhibitory factor 1 (IF1) was reported to tune the glucose sensitivity range for GSIS. Mitochondrial protein kinase A was implicated in preventing the IF1-mediated inhibition of the ATP synthase. Critical Issues: It is unknown how the redox signal spreads up to the plasma membrane and what its targets are, what the differences in metabolic, redox, NADH/NADPH, and Ca2+ signaling, and homeostasis are between the first and second GSIS phase, and whether mitochondria can replace ER in the amplification of IGV exocytosis. Future Directions: Metabolomics studies performed to distinguish between the mitochondrial matrix and cytosolic metabolites will elucidate further details. Identifying the targets of cell signaling into mitochondria and of mitochondrial retrograde metabolic and redox signals to the cell will uncover further molecular mechanisms for insulin secretion stimulated by glucose, BCKAs, and FAs, and the amplification of secretion by glucagon-like peptide (GLP-1) and metabotropic receptors. They will identify the distinction between the hub β-cells and their followers in intact and diabetic states. Antioxid. Redox Signal. 36, 920-952.
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Affiliation(s)
- Petr Ježek
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Blanka Holendová
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Martin Jabůrek
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Andrea Dlasková
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Lydie Plecitá-Hlavatá
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
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Li A, Zhang X, Singla J, White K, Loconte V, Hu C, Zhang C, Li S, Li W, Francis JP, Wang C, Sali A, Sun L, He X, Stevens RC. Auto-segmentation and time-dependent systematic analysis of mesoscale cellular structure in β-cells during insulin secretion. PLoS One 2022; 17:e0265567. [PMID: 35324950 PMCID: PMC8947144 DOI: 10.1371/journal.pone.0265567] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 03/03/2022] [Indexed: 02/07/2023] Open
Abstract
The mesoscale description of the subcellular organization informs about cellular mechanisms in disease state. However, applications of soft X-ray tomography (SXT), an important approach for characterizing organelle organization, are limited by labor-intensive manual segmentation. Here we report a pipeline for automated segmentation and systematic analysis of SXT tomograms. Our approach combines semantic and first-applied instance segmentation to produce separate organelle masks with high Dice and Recall indexes, followed by analysis of organelle localization based on the radial distribution function. We demonstrated this technique by investigating the organization of INS-1E pancreatic β-cell organization under different treatments at multiple time points. Consistent with a previous analysis of a similar dataset, our results revealed the impact of glucose stimulation on the localization and molecular density of insulin vesicles and mitochondria. This pipeline can be extended to SXT tomograms of any cell type to shed light on the subcellular rearrangements under different drug treatments.
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Affiliation(s)
- Angdi Li
- iHuman Institute, ShanghaiTech University, Shanghai, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xiangyi Zhang
- School of Information Science and Technology, ShanghaiTech University, Shanghai, China
| | - Jitin Singla
- Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA, United States of America
| | - Kate White
- Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA, United States of America
| | - Valentina Loconte
- iHuman Institute, ShanghaiTech University, Shanghai, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Chuanyang Hu
- School of Information Science and Technology, ShanghaiTech University, Shanghai, China
| | - Chuyu Zhang
- School of Information Science and Technology, ShanghaiTech University, Shanghai, China
| | - Shuailin Li
- School of Information Science and Technology, ShanghaiTech University, Shanghai, China
| | - Weimin Li
- iHuman Institute, ShanghaiTech University, Shanghai, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - John Paul Francis
- Department of Computer Science, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, United States of America
| | - Chenxi Wang
- iHuman Institute, ShanghaiTech University, Shanghai, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Andrej Sali
- California Institute for Quantitative Biosciences, Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, United States of America
| | - Liping Sun
- iHuman Institute, ShanghaiTech University, Shanghai, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Xuming He
- School of Information Science and Technology, ShanghaiTech University, Shanghai, China
- Shanghai Engineering Research Center of Intelligent Vision and Imaging, Shanghai, China
| | - Raymond C. Stevens
- iHuman Institute, ShanghaiTech University, Shanghai, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA, United States of America
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45
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Aharon-Hananel G, Romero-Afrima L, Saada A, Mantzur C, Raz I, Weksler-Zangen S. Cytochrome c Oxidase Activity as a Metabolic Regulator in Pancreatic Beta-Cells. Cells 2022; 11:cells11060929. [PMID: 35326380 PMCID: PMC8946064 DOI: 10.3390/cells11060929] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/01/2022] [Accepted: 03/03/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic β-cells couple glucose-stimulated insulin secretion (GSIS) with oxidative phosphorylation via cytochrome c oxidase (COX), a mitochondrial respiratory-chain enzyme. The Cohen diabetic-sensitive (CDs) rats exhibit hyperglycemia when fed a diabetogenic diet but maintain normoglycemia on a regular diet. We have previously reported a decreased COX activity in CDs rats and explored its relevance for type 2 diabetes (T2D). In this study, we investigated the relation between COX activity in islets, peripheral-blood mononuclear cells (PBMCs), and GSIS during diabetes development in CDs rats fed a diabetogenic diet for 4, 11, 20, and 30 days and during reversion to normoglycemia in hyperglycemic CDs rats fed a reversion diet for 7, 11, and 20 days. An oral glucose-tolerance test was performed at different periods of the diets measuring blood glucose and insulin concentrations. COX activity was determined in islets and PBMCs isolated from rats at the different periods of the diets. We demonstrated a progressive reduction in COX activity in CDs-islets that correlated positively with the decreasing GSIS (R2 = 0.9691, p < 0.001) and inversely with the elevation in blood glucose levels (R2 = 0.8396, p < 0.001). Hyperglycemia was initiated when islet COX activity decreased below 46%. The reversion diet restored >46% of the islet COX activity and GSIS while re-establishing normoglycemia. Interestingly, COX activity in PBMCs correlated significantly with islet COX activity (R2 = 0.8944, p < 0.001). Our data support islet COX activity as a major metabolic regulator of β-cells function. The correlation between COX activity in PBMCs and islets may serve as a noninvasive biomarker to monitor β-cell dysfunction in diabetes.
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Affiliation(s)
- Genya Aharon-Hananel
- The Hadassah Diabetes Center, Hadassah Medical Center, Jerusalem 9112102, Israel; (G.A.-H.); (L.R.-A.); (C.M.); (I.R.)
- Division of Endocrinology, Diabetes and Metabolism, The Chaim Sheba Medical Center, Tel Hashomer, Ramat-Gan 5266202, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- The Department of Genetics, Hadassah Medical Center, Jerusalem 9112102, Israel;
| | - Leonor Romero-Afrima
- The Hadassah Diabetes Center, Hadassah Medical Center, Jerusalem 9112102, Israel; (G.A.-H.); (L.R.-A.); (C.M.); (I.R.)
- The Department of Genetics, Hadassah Medical Center, Jerusalem 9112102, Israel;
| | - Ann Saada
- The Department of Genetics, Hadassah Medical Center, Jerusalem 9112102, Israel;
- Faculty of Medicine Hebrew, University of Jerusalem, Jerusalem 9112102, Israel
| | - Carmit Mantzur
- The Hadassah Diabetes Center, Hadassah Medical Center, Jerusalem 9112102, Israel; (G.A.-H.); (L.R.-A.); (C.M.); (I.R.)
| | - Itamar Raz
- The Hadassah Diabetes Center, Hadassah Medical Center, Jerusalem 9112102, Israel; (G.A.-H.); (L.R.-A.); (C.M.); (I.R.)
- Faculty of Medicine Hebrew, University of Jerusalem, Jerusalem 9112102, Israel
| | - Sarah Weksler-Zangen
- The Hadassah Diabetes Center, Hadassah Medical Center, Jerusalem 9112102, Israel; (G.A.-H.); (L.R.-A.); (C.M.); (I.R.)
- Faculty of Medicine Hebrew, University of Jerusalem, Jerusalem 9112102, Israel
- The Liver Research Laboratory, Hadassah Medical Center, Jerusalem 9112102, Israel
- Correspondence: ; Tel.: +972-50-5172008
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Paul A, Azhar S, Das PN, Bairagi N, Chatterjee S. Elucidating the metabolic characteristics of pancreatic β-cells from patients with type 2 diabetes (T2D) using a genome-scale metabolic modeling. Comput Biol Med 2022; 144:105365. [PMID: 35276551 DOI: 10.1016/j.compbiomed.2022.105365] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/24/2022] [Accepted: 02/27/2022] [Indexed: 11/27/2022]
Abstract
Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate insulin. Despite extensive research, the identity of factors contributing to the dysregulated metabolism-secretion coupling in the β-cells remains elusive. The present study attempts to capture some of these factors responsible for the impaired β-cell metabolism-secretion coupling that contributes to diabetes pathogenesis. The metabolic-flux profiles of pancreatic β-cells were predicted using genome-scale metabolic modeling for ten diabetic patients and ten control subjects. Analysis of these flux states shows reduction in the mitochondrial fatty acid oxidation and mitochondrial oxidative phosphorylation pathways, that leads to decreased insulin secretion in diabetes. We also observed elevated reactive oxygen species (ROS) generation through peroxisomal fatty acid β-oxidation. In addition, cellular antioxidant defense systems were found to be attenuated in diabetes. Our analysis also uncovered the possible changes in the plasma metabolites in diabetes due to the β-cells failure. These efforts subsequently led to the identification of seven metabolites associated with cardiovascular disease (CVD) pathogenesis, thus establishing its link as a secondary complication of diabetes.
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Affiliation(s)
- Abhijit Paul
- Complex Analysis Group, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, India
| | - Salman Azhar
- Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA; Division of Endocrinology, Gerontology and Metabolism, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Phonindra Nath Das
- Department of Mathematics, Ramakrishna Mission Vivekananda Centenary College, Rahara, Kolkata, 700118, India
| | - Nandadulal Bairagi
- Centre for Mathematical Biology and Ecology, Department of Mathematics, Jadavpur University, Kolkata, 700032, India
| | - Samrat Chatterjee
- Complex Analysis Group, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, India.
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Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives. Cells 2022; 11:cells11030552. [PMID: 35159361 PMCID: PMC8833991 DOI: 10.3390/cells11030552] [Citation(s) in RCA: 311] [Impact Index Per Article: 103.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 02/04/2023] Open
Abstract
Reactive oxygen and nitrogen species (RONS) are generated through various endogenous and exogenous processes; however, they are neutralized by enzymatic and non-enzymatic antioxidants. An imbalance between the generation and neutralization of oxidants results in the progression to oxidative stress (OS), which in turn gives rise to various diseases, disorders and aging. The characteristics of aging include the progressive loss of function in tissues and organs. The theory of aging explains that age-related functional losses are due to accumulation of reactive oxygen species (ROS), their subsequent damages and tissue deformities. Moreover, the diseases and disorders caused by OS include cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases and cancer. OS, induced by ROS, is neutralized by different enzymatic and non-enzymatic antioxidants and prevents cells, tissues and organs from damage. However, prolonged OS decreases the content of antioxidant status of cells by reducing the activities of reductants and antioxidative enzymes and gives rise to different pathological conditions. Therefore, the aim of the present review is to discuss the mechanism of ROS-induced OS signaling and their age-associated complications mediated through their toxic manifestations in order to devise effective preventive and curative natural therapeutic remedies.
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Loconte V, Singla J, Li A, Chen JH, Ekman A, McDermott G, Sali A, Le Gros M, White KL, Larabell CA. Soft X-ray tomography to map and quantify organelle interactions at the mesoscale. Structure 2022; 30:510-521.e3. [PMID: 35148829 PMCID: PMC9013509 DOI: 10.1016/j.str.2022.01.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/04/2021] [Accepted: 01/17/2022] [Indexed: 12/11/2022]
Abstract
Inter-organelle interactions are a vital part of normal cellular function; however, these have proven difficult to quantify due to the range of scales encountered in cell biology and the throughput limitations of traditional imaging approaches. Here, we demonstrate that soft X-ray tomography (SXT) can be used to rapidly map ultrastructural reorganization and inter-organelle interactions in intact cells. SXT takes advantage of the naturally occurring, differential X-ray absorption of the carbon-rich compounds in each organelle. Specifically, we use SXT to map the spatiotemporal evolution of insulin vesicles and their co-localization and interaction with mitochondria in pancreatic β cells during insulin secretion and in response to different stimuli. We quantify changes in the morphology, biochemical composition, and relative position of mitochondria and insulin vesicles. These findings highlight the importance of a comprehensive and unbiased mapping at the mesoscale to characterize cell reorganization that would be difficult to detect with other existing methodologies.
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Affiliation(s)
- Valentina Loconte
- iHuman Institute, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Jitin Singla
- Department of Chemistry, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA
| | - Angdi Li
- iHuman Institute, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Jian-Hua Chen
- Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Axel Ekman
- Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Gerry McDermott
- Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Andrej Sali
- Department of Bioengineering and Therapeutic Science, Department of Pharmaceutical Chemistry, California Institute of Quantitative Bioscience, University of California San Francisco, San Francisco, CA 94158, USA
| | - Mark Le Gros
- Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Kate L White
- Department of Chemistry, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA.
| | - Carolyn A Larabell
- Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
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Rodríguez-Comas J, Ramón-Azcón J. Islet-on-a-chip for the study of pancreatic β-cell function. IN VITRO MODELS 2022; 1:41-57. [PMID: 39872972 PMCID: PMC11749753 DOI: 10.1007/s44164-021-00005-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/25/2021] [Accepted: 11/08/2021] [Indexed: 01/30/2025]
Abstract
Diabetes mellitus is a significant public health problem worldwide. It encompasses a group of chronic disorders characterized by hyperglycemia, resulting from pancreatic islet dysfunction or as a consequence of insulin-producing β-cell death. Organ-on-a-chip platforms have emerged as technological systems combining cell biology, engineering, and biomaterial technological advances with microfluidics to recapitulate a specific organ's physiological or pathophysiological environment. These devices offer a novel model for the screening of pharmaceutical agents and to study a particular disease. In the field of diabetes, a variety of microfluidic devices have been introduced to recreate native islet microenvironments and to understand pancreatic β-cell kinetics in vitro. This kind of platforms has been shown fundamental for the study of the islet function and to assess the quality of these islets for subsequent in vivo transplantation. However, islet physiological systems are still limited compared to other organs and tissues, evidencing the difficulty to study this "organ" and the need for further technological advances. In this review, we summarize the current state of islet-on-a-chip platforms that have been developed so far. We recapitulate the most relevant studies involving pancreatic islets and microfluidics, focusing on the molecular and cellular-scale activities that underlie pancreatic β-cell function.
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Affiliation(s)
- Júlia Rodríguez-Comas
- Biosensors for Bioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac, 10-12, 08028 Barcelona, Spain
| | - Javier Ramón-Azcón
- Biosensors for Bioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac, 10-12, 08028 Barcelona, Spain
- ICREA-Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain
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Langlois A, Dumond A, Vion J, Pinget M, Bouzakri K. Crosstalk Communications Between Islets Cells and Insulin Target Tissue: The Hidden Face of Iceberg. Front Endocrinol (Lausanne) 2022; 13:836344. [PMID: 35185804 PMCID: PMC8851682 DOI: 10.3389/fendo.2022.836344] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/06/2022] [Indexed: 12/11/2022] Open
Abstract
The regulation of insulin secretion is under control of a complex inter-organ/cells crosstalk involving various metabolites and/or physical connections. In this review, we try to illustrate with current knowledge how β-cells communicate with other cell types and organs in physiological and pathological contexts. Moreover, this review will provide a better understanding of the microenvironment and of the context in which β-cells exist and how this can influence their survival and function. Recent studies showed that β-cell insulin secretion is regulated also by a direct and indirect inter-organ/inter-cellular communication involving various factors, illustrating the idea of "the hidden face of the iceberg". Moreover, any disruption on the physiological communication between β-cells and other cells or organs can participate on diabetes onset. Therefore, for new anti-diabetic treatments' development, it is necessary to consider the entire network of cells and organs involved in the regulation of β-cellular function and no longer just β-cell or pancreatic islet alone. In this context, we discuss here the intra-islet communication, the β-cell/skeletal muscle, β-cell/adipose tissue and β-cell/liver cross talk.
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