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Chu CM, Sabbineni B, Cen HH, Hu X, Sun WG, Brownrigg GP, Xia YH, Rogalski J, Johnson JD. Signal transduction pathways controlling Ins2 gene activity and beta cell state transitions. iScience 2025; 28:112015. [PMID: 40144638 PMCID: PMC11938086 DOI: 10.1016/j.isci.2025.112015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/19/2024] [Accepted: 02/10/2025] [Indexed: 03/28/2025] Open
Abstract
Pancreatic β cells exist in low and high insulin gene activity states that are dynamic on a scale of hours to days. Here, we used live 3D imaging, mass spectrometry proteomics, and targeted perturbations of β cell signaling to comprehensively investigate Ins2(GFP)HIGH and Ins2(GFP)LOW β cell states. We identified the two Ins2 gene activity states in intact isolated islets and showed that cells in the same state were more likely to be nearer to each other. We report the proteomes of pure β cells to a depth of 5555 proteins and show that β cells with high Ins2 gene activity had reduced β cell immaturity factors, as well as increased translation. We identified activators of cAMP signaling (GLP1, IBMX) as powerful drivers of Ins2(GFP)LOW to Ins2(GFP)HIGH transitions. Okadaic acid and cyclosporine A had the opposite effects. This study provides new insight into the proteomic profiles and regulation of β cell states.
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Affiliation(s)
- Chieh Min Chu
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia and the Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
| | - Bhavya Sabbineni
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia and the Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
| | - Haoning Howard Cen
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia and the Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
| | - Xiaoke Hu
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia and the Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
| | - WenQing Grace Sun
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia and the Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
| | - George P. Brownrigg
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia and the Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
| | - Yi Han Xia
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia and the Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
| | - Jason Rogalski
- Proteomics and Metabolomics Core Facility, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - James D. Johnson
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia and the Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
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Okuyama T, Tsuno T, Inoue R, Fukushima S, Kyohara M, Matsumura A, Miyashita D, Nishiyama K, Takano Y, Togashi Y, Meguro-Horike M, Horike SI, Kin T, Shapiro AJ, Yanagisawa H, Terauchi Y, Shirakawa J. The matricellular protein Fibulin-5 regulates β-cell proliferation in an autocrine/paracrine manner. iScience 2025; 28:111856. [PMID: 39995864 PMCID: PMC11848788 DOI: 10.1016/j.isci.2025.111856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 11/20/2024] [Accepted: 01/17/2025] [Indexed: 02/26/2025] Open
Abstract
The matricellular protein Fibulin-5 (Fbln5) is a secreted protein that is essential for elastic fiber formation, and pancreatic islets are usually surrounded by the extracellular matrix (ECM), which includes elastic fibers. However, much uncertainty remains regarding the function of the ECM and its components in β-cells. Here, we describe the role of Fbln5 in β-cell replication. Fbln5 expression was increased upon glucose stimulation in β-cells of mouse and human islets. β-Cell-specific Fbln5-knockout (βFbln5KO) mice exhibit significantly reduced β-cell proliferation in vivo but not in vitro. Secreted extracellular Fbln5 enhances β-cell replication. Fbln5-deficient β-cells exhibit the downregulated expression of the gene encoding Polo-like kinase 1 (PLK1), which is accompanied by ERK-mediated FoxM1 nuclear export. These data suggest that Fbln5 is secreted from β-cells in response to glucose and plays important roles in the appropriate maintenance of β-cell functions in an autocrine or paracrine manner.
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Affiliation(s)
- Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Takahiro Tsuno
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Ryota Inoue
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Setsuko Fukushima
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Anzu Matsumura
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Daisuke Miyashita
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Kuniyuki Nishiyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Yusuke Takano
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Makiko Meguro-Horike
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan
| | - Shin-ichi Horike
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan
| | - Tatsuya Kin
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - A.M. James Shapiro
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Hiromi Yanagisawa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Jun Shirakawa
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
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Magnuson MA, Osipovich AB. Ca 2+ signaling and metabolic stress-induced pancreatic β-cell failure. Front Endocrinol (Lausanne) 2024; 15:1412411. [PMID: 39015185 PMCID: PMC11250477 DOI: 10.3389/fendo.2024.1412411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 06/10/2024] [Indexed: 07/18/2024] Open
Abstract
Early in the development of Type 2 diabetes (T2D), metabolic stress brought on by insulin resistance and nutrient overload causes β-cell hyperstimulation. Herein we summarize recent studies that have explored the premise that an increase in the intracellular Ca2+ concentration ([Ca2+]i), brought on by persistent metabolic stimulation of β-cells, causes β-cell dysfunction and failure by adversely affecting β-cell function, structure, and identity. This mini-review builds on several recent reviews that also describe how excess [Ca2+]i impairs β-cell function.
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Affiliation(s)
- Mark A. Magnuson
- Department of Molecular Physiology and Biophysics and Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, United States
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Rossi MR, Mazzali M, de Sousa MV. Post-transplant diabetes mellitus: risk factors and outcomes in a 5-year follow-up. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2024; 5:1336896. [PMID: 38352660 PMCID: PMC10863447 DOI: 10.3389/fcdhc.2024.1336896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 01/10/2024] [Indexed: 02/16/2024]
Abstract
Introduction Kidney transplantation is associated with an increased risk of posttransplant diabetes mellitus (PTDM), impacting recipient and graft survivals. The incidence of PTDM ranges from 15% to 30%, with most cases occurring in the first year post-transplant. Some clinical and laboratory characteristics pre- and post-transplant may be associated with a higher PTDM incidence in a more extended follow-up period. This study aimed to analyze the prevalence of PTDM among renal transplant recipients without previous DM diagnosis during a five-year post-transplant follow-up, as well as clinical and laboratory characteristics associated with a higher incidence of PTDM during this period. Material and methods Single-center retrospective cohort including kidney transplant recipients older than 18 years with a functioning graft over six months of follow-up between January and December 2018. Exclusion criteria were recipients younger than 18 years at kidney transplantation, previous diabetes mellitus diagnosis, and death with a functioning graft or graft failure within six months post-transplant. Results From 117 kidney transplants performed during the period, 71 (60.7%) fulfilled the inclusion criteria, 18 (25.3%) had PTDM diagnosis, and most (n=16, 88.9%) during the 1st year post-transplant. The need for insulin therapy during the hospital stay was significantly higher in the PTDM group (n=11, 61.1% vs. n=14, 26.4%, PTDM vs. non-PTDM). Other PTDM risk factors, such as older age, high body mass index, HLA mismatches, and cytomegalovirus or hepatitis C virus infections, were not associated with PTDM occurrence in this series. During 5-year post-transplant follow-up, the graft function remained stable in both groups. Conclusion The accumulated incidence of PTDM in this series was similar to the reported in other studies. The perioperative hyperglycemia with the need for treatment with insulin before hospital discharge was associated with PTDM.
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Abderahmene A, Khalij Y, Moussa A, Ammar M, Ellouz A, Amor D, Abbes H, Ganouni MR, Sahtout W, Chouchene S, Omezzine A, Zellama D, Bouslama A. The pharmacogenetics of tacrolimus in renal transplant patients: association with tremors, new-onset diabetes and other clinical events. THE PHARMACOGENOMICS JOURNAL 2024; 24:3. [PMID: 38253626 DOI: 10.1038/s41397-024-00323-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024]
Abstract
Our study is the first study to investigate the effect of SNPs in CYP3A5, CYP3A4, ABCB1 and POR genes on the incidence of tremors, nephrotoxicity, and diabetes mellitus. A total of 223 renal transplant patients receiving tacrolimus and mycophenolate mofetil (MMF) were recruited. Both adults and children patients participated in the study. Genotyping was performed using PROFLEX-PCR followed by RFLP. MPA and tacrolimus plasma concentrations were measured by immunoassay. The AUC0-12h of MMF was estimated by a Bayesian method. We found a statistically significant association between the CYP3A5*3 and CYP3A4*1B genotypes and the tacrolimus exposure. We found a lower occurrence of nephrotoxicity (p = 0.03), tremor (p = 0.01), and new-onset diabetes (p = 0.002) associated with CYP3A5*1 allele. The CYP3A4*1B allele was significantly associated with a lower occurrence of new-onset diabetes (p = 0.026). The CYP3A5*1 allele was significantly associated with an increased risk of acute and chronic rejection (p = 0.03 and p < 0.001, respectively). Our results support the usefulness of tacrolimus pharmacokinetics in pre-kidney transplant assessments.
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Affiliation(s)
- Amani Abderahmene
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia.
| | - Yassine Khalij
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Amira Moussa
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Meriam Ammar
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Amel Ellouz
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Dorra Amor
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Houwaida Abbes
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Mohamed Rayen Ganouni
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Wissal Sahtout
- Nephrology Department, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
| | - Saoussen Chouchene
- Hematology Department, Fattouma Bourguiba University Hospital, 5000, Monastir, Tunisia
| | - Asma Omezzine
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Dorsaf Zellama
- Nephrology Department, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
| | - Ali Bouslama
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
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Abstract
Heart transplantation (HT) remains the best treatment of patients with severe heart failure who are deemed to be transplant candidates. The authors discuss postoperative management of the HT recipient by system, emphasizing areas where care might differ from other cardiac surgery patients. Working together, critical care physicians, heart transplant surgeons and cardiologists, advanced practice providers, pharmacists, transplant coordinators, nursing staff, physical therapists, occupational therapists, rehabilitation specialists, nutritionists, health psychologists, social workers, and the patient and their loved ones partner to increase the likelihood of a successful outcome.
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Affiliation(s)
- Gozde Demiralp
- Division of Critical Care Medicine, Department of Anesthesiology, University of Wisconsin School of Medicine & Public Health, 600 Highland Avenue, B6/319 CSC, Madison, WI 53792, USA
| | - Robert T Arrigo
- Division of Critical Care Medicine, Department of Anesthesiology, University of Wisconsin School of Medicine & Public Health, 600 Highland Avenue, Mail Code 3272, Madison, WI 53792, USA; Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, University of Wisconsin School of Medicine & Public Health, 600 Highland Avenue, Mail Code 3272, Madison, WI 53792, USA
| | - Christopher Cassara
- Division of Critical Care Medicine, Department of Anesthesiology, University of Wisconsin School of Medicine & Public Health, 600 Highland Avenue, Mail Code 3272, Madison, WI 53792, USA; Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, University of Wisconsin School of Medicine & Public Health, 600 Highland Avenue, Mail Code 3272, Madison, WI 53792, USA
| | - Maryl R Johnson
- Heart Failure and Transplant Cardiology, University of Wisconsin School of Medicine & Public Health, 600 Highland Avenue, E5/582 CSC, Mail Code 5710, Madison, WI 53792, USA.
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Liu T, Ma Y, Zhao H, Wang P, Niu Y, Hu Y, Shen X, Zhang M, Yan B, Yu J. Hawthorn leaves flavonoids attenuate cardiac remodeling induced by simulated microgravity. PHARMACEUTICAL BIOLOGY 2023; 61:683-695. [PMID: 37096968 PMCID: PMC10132252 DOI: 10.1080/13880209.2023.2203194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
CONTEXT Hawthorn leaves are a kind of widely used medicinal plant in China. The major ingredient, hawthorn leaves flavonoids (HLF), have cardiotonic, cardioprotective, and vascular protective effects. OBJECTIVE The study evaluated the protective role of HLF in cardiac remodelling and the underlying mechanisms under simulated microgravity by hindlimb unloading rats. MATERIALS AND METHODS Adult male Sprague-Dawley rats were divided into control, HLF, HU (hindlimb unloading) and HU + HLF groups (n = 8). After HU and daily intragastric administration at the dose of 100 mg/kg/d for 8 weeks, cardiac function and structure were evaluated by biochemical indices and histopathology. We identified the main active compounds and mechanisms involved in the cardioprotective effects of HLF via bioinformatics and molecular docking analysis, and relative signalling pathway activity was verified by Western blot. RESULTS HLF treatment could reverse the HU-induced decline in LV-EF (HU, 55.13% ± 0.98% vs. HU + HLF, 71.16% ± 5.08%), LV-FS (HU, 29.44% ± 0.67% vs. HU + HLF, 41.62% ± 4.34%) and LV mass (HU, 667.99 ± 65.69 mg vs. HU + HLF, 840.02 ± 73.00 mg). Furthermore, HLF treatment significantly increased NPRA expression by 135.39%, PKG by 51.27%, decreased PDE5A by 20.03%, NFATc1 by 41.68% and Rcan1.4 by 54.22%. CONCLUSIONS HLF plays a protective effect on HU-induced cardiac remodelling by enhancing NPRA-cGMP-PKG pathway and suppressing the calcineurin-NFAT pathway, which provides a theoretical basis for use in clinical therapies.
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Affiliation(s)
- Tian Liu
- Clinical Experimental Center, Northwest University Affiliated Xi’an International Medical Center Hospital, Shaanxi, P.R.China
- Xi’an Engineering Technology Research Center for Cardiovascular Active Peptides, Shaanxi, P.R.China
| | - Yuqi Ma
- Endocrinology Department, Northwest University Affiliated Xi’an International Medical Center Hospital, Shaanxi, P. R.China
| | - Hui Zhao
- Clinical Experimental Center, Northwest University Affiliated Xi’an International Medical Center Hospital, Shaanxi, P.R.China
- Xi’an Engineering Technology Research Center for Cardiovascular Active Peptides, Shaanxi, P.R.China
| | - Pengli Wang
- Clinical Experimental Center, Northwest University Affiliated Xi’an International Medical Center Hospital, Shaanxi, P.R.China
- Xi’an Engineering Technology Research Center for Cardiovascular Active Peptides, Shaanxi, P.R.China
| | - Yan Niu
- Clinical Experimental Center, Northwest University Affiliated Xi’an International Medical Center Hospital, Shaanxi, P.R.China
- Xi’an Engineering Technology Research Center for Cardiovascular Active Peptides, Shaanxi, P.R.China
| | - Yuehuan Hu
- Clinical Experimental Center, Northwest University Affiliated Xi’an International Medical Center Hospital, Shaanxi, P.R.China
- Xi’an Engineering Technology Research Center for Cardiovascular Active Peptides, Shaanxi, P.R.China
| | - Xi Shen
- Clinical Experimental Center, Northwest University Affiliated Xi’an International Medical Center Hospital, Shaanxi, P.R.China
- Xi’an Engineering Technology Research Center for Cardiovascular Active Peptides, Shaanxi, P.R.China
| | - Mingxia Zhang
- Clinical Experimental Center, Northwest University Affiliated Xi’an International Medical Center Hospital, Shaanxi, P.R.China
- Xi’an Engineering Technology Research Center for Cardiovascular Active Peptides, Shaanxi, P.R.China
| | - Bing Yan
- Clinical Experimental Center, Northwest University Affiliated Xi’an International Medical Center Hospital, Shaanxi, P.R.China
- Xi’an Engineering Technology Research Center for Cardiovascular Active Peptides, Shaanxi, P.R.China
| | - Jun Yu
- Clinical Experimental Center, Northwest University Affiliated Xi’an International Medical Center Hospital, Shaanxi, P.R.China
- Xi’an Engineering Technology Research Center for Cardiovascular Active Peptides, Shaanxi, P.R.China
- CONTACT Jun Yu Clinical Experimental Center, Xi’an International Medical Center Hospital, No. 777 Xitai Road Xi’an, Shaanxi710100, P. R. China
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Nguyen HD. An evaluation of the effects of mixed heavy metals on prediabetes and type 2 diabetes: epidemiological and toxicogenomic analysis. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:82437-82457. [PMID: 37326729 DOI: 10.1007/s11356-023-28037-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 05/29/2023] [Indexed: 06/17/2023]
Abstract
The link between mixed heavy metals (mercury, lead, and cadmium), prediabetes, and type 2 diabetes mellitus (T2DM), especially molecular mechanisms, is poorly understood. Thus, we aimed to identify the association between mixed heavy metals and T2DM and its components using a data set from the Korean National Health and Nutrition Examination Survey. We further analyzed the main molecular mechanisms implicated in T2DM development induced by mixed heavy metals using in-silico analysis. Our findings observed that serum mercury was associated with prediabetes, elevated glucose, and ln2-transformed glucose when using different statistical methods. "AGE-RAGE signaling pathway in diabetic complications", "non-alcoholic fatty liver disease", "metabolic Syndrome X", and three miRNAs (hsa-miR-98-5p, hsa-let-7a-5p, and hsa-miR-34a-5p) were listed as the most important molecular mechanisms related to T2DM development caused by mixed heavy metals. These miRNA sponge structures were created and examined, and they may be beneficial in the treatment of T2DM. The predicted cutoff values for three heavy metal levels linked to T2DM and its components were specifically identified. Our results imply that chronic exposure to heavy metals, particularly mercury, may contribute to the development of T2DM. To understand the changes in the pathophysiology of T2DM brought on by a combination of heavy metals, more research is required.
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Affiliation(s)
- Hai Duc Nguyen
- Department of Pharmacy, College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, 57922, Jeonnam, Republic of Korea.
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Mu-U-Min RBA, Diane A, Allouch A, Al-Siddiqi HH. Ca 2+-Mediated Signaling Pathways: A Promising Target for the Successful Generation of Mature and Functional Stem Cell-Derived Pancreatic Beta Cells In Vitro. Biomedicines 2023; 11:1577. [PMID: 37371672 DOI: 10.3390/biomedicines11061577] [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: 04/17/2023] [Revised: 05/18/2023] [Accepted: 05/23/2023] [Indexed: 06/29/2023] Open
Abstract
Diabetes mellitus is a chronic disease affecting over 500 million adults globally and is mainly categorized as type 1 diabetes mellitus (T1DM), where pancreatic beta cells are destroyed, and type 2 diabetes mellitus (T2DM), characterized by beta cell dysfunction. This review highlights the importance of the divalent cation calcium (Ca2+) and its associated signaling pathways in the proper functioning of beta cells and underlines the effects of Ca2+ dysfunction on beta cell function and its implications for the onset of diabetes. Great interest and promise are held by human pluripotent stem cell (hPSC) technology to generate functional pancreatic beta cells from diabetic patient-derived stem cells to replace the dysfunctional cells, thereby compensating for insulin deficiency and reducing the comorbidities of the disease and its associated financial and social burden on the patient and society. Beta-like cells generated by most current differentiation protocols have blunted functionality compared to their adult human counterparts. The Ca2+ dynamics in stem cell-derived beta-like cells and adult beta cells are summarized in this review, revealing the importance of proper Ca2+ homeostasis in beta-cell function. Consequently, the importance of targeting Ca2+ function in differentiation protocols is suggested to improve current strategies to use hPSCs to generate mature and functional beta-like cells with a comparable glucose-stimulated insulin secretion (GSIS) profile to adult beta cells.
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Affiliation(s)
- Razik Bin Abdul Mu-U-Min
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Abdoulaye Diane
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Asma Allouch
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Heba H Al-Siddiqi
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
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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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11
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Kale A, Rogers NM. No Time to Die-How Islets Meet Their Demise in Transplantation. Cells 2023; 12:cells12050796. [PMID: 36899932 PMCID: PMC10000424 DOI: 10.3390/cells12050796] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/27/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Islet transplantation represents an effective treatment for patients with type 1 diabetes mellitus (T1DM) and severe hypoglycaemia unawareness, capable of circumventing impaired counterregulatory pathways that no longer provide protection against low blood glucose levels. The additional beneficial effect of normalizing metabolic glycaemic control is the minimisation of further complications related to T1DM and insulin administration. However, patients require allogeneic islets from up to three donors, and the long-term insulin independence is inferior to that achieved with solid organ (whole pancreas) transplantation. This is likely due to the fragility of islets caused by the isolation process, innate immune responses following portal infusion, auto- and allo-immune-mediated destruction and β-cell exhaustion following transplantation. This review covers the specific challenges related to islet vulnerability and dysfunction that affect long-term cell survival following transplantation.
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Affiliation(s)
- Atharva Kale
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Natasha M. Rogers
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
- Renal and Transplant Unit, Westmead Hospital, Westmead, NSW 2145, Australia
- Correspondence:
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12
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Gingerich MA, Liu X, Chai B, Pearson GL, Vincent MP, Stromer T, Zhu J, Sidarala V, Renberg A, Sahu D, Klionsky DJ, Schnell S, Soleimanpour SA. An intrinsically disordered protein region encoded by the human disease gene CLEC16A regulates mitophagy. Autophagy 2023; 19:525-543. [PMID: 35604110 PMCID: PMC9851259 DOI: 10.1080/15548627.2022.2080383] [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] [Indexed: 01/22/2023] Open
Abstract
CLEC16A regulates mitochondrial health through mitophagy and is associated with over 20 human diseases. However, the key structural and functional regions of CLEC16A, and their relevance for human disease, remain unknown. Here, we report that a disease-associated CLEC16A variant lacks a C-terminal intrinsically disordered protein region (IDPR) that is critical for mitochondrial quality control. IDPRs comprise nearly half of the human proteome, yet their mechanistic roles in human disease are poorly understood. Using carbon detect NMR, we find that the CLEC16A C terminus lacks secondary structure, validating the presence of an IDPR. Loss of the CLEC16A C-terminal IDPR in vivo impairs mitophagy, mitochondrial function, and glucose-stimulated insulin secretion, ultimately causing glucose intolerance. Deletion of the CLEC16A C-terminal IDPR increases CLEC16A ubiquitination and degradation, thus impairing assembly of the mitophagy regulatory machinery. Importantly, CLEC16A stability is dependent on proline bias within the C-terminal IDPR, but not amino acid sequence order or charge. Together, we elucidate how an IDPR in CLEC16A regulates mitophagy and implicate pathogenic human gene variants that disrupt IDPRs as novel contributors to diabetes and other CLEC16A-associated diseases.Abbreviations : CAS: carbon-detect amino-acid specific; IDPR: intrinsically disordered protein region; MEFs: mouse embryonic fibroblasts; NMR: nuclear magnetic resonance.
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Affiliation(s)
- Morgan A. Gingerich
- Department of Internal Medicine and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA,Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA
| | - Xueying Liu
- Department of Internal Medicine and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA,Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Biaoxin Chai
- Department of Internal Medicine and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Gemma L. Pearson
- Department of Internal Medicine and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Michael P. Vincent
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA,Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Tracy Stromer
- Department of Internal Medicine and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Jie Zhu
- Department of Internal Medicine and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Vaibhav Sidarala
- Department of Internal Medicine and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Aaron Renberg
- Department of Internal Medicine and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Debashish Sahu
- BioNMR Core Facility, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Daniel J. Klionsky
- Life Sciences Institute and Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Santiago Schnell
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA,Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Scott A. Soleimanpour
- Department of Internal Medicine and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA,Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA,Medicine Service, Endocrinology and Metabolism Section, VA Ann Arbor Health Care System, Ann Arbor, MI, USA,CONTACT Scott A. Soleimanpour Department of Internal Medicine and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Wall Street, Brehm Tower Room, Ann Arbor, MI, USA
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13
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Górska M, Kurnatowska I. Nutrition Disturbances and Metabolic Complications in Kidney Transplant Recipients: Etiology, Methods of Assessment and Prevention-A Review. Nutrients 2022; 14:nu14234996. [PMID: 36501026 PMCID: PMC9738485 DOI: 10.3390/nu14234996] [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: 10/31/2022] [Revised: 11/20/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022] Open
Abstract
Nutrition disturbances occur at all stages of chronic kidney disease and progress with the decrease of the kidney filtration rate. Kidney transplantation (KTx) as the best form of kidney replacement therapy poses various nutritional challenges. Prior to transplantation, recipients often present with mild to advanced nutrition disturbances. A functioning allograft not only relieves uremia, acidosis, and electrolyte disturbances, but also resumes other kidney functions such as erythropoietin production and vitamin D3 metabolism. KTx recipients represent a whole spectrum of undernutrition and obesity. Since following transplantation, patients are relieved of most dietary restrictions and appetite disturbances; they resume old nutrition habits that result in weight gain. The immunosuppressive regimen often predisposes them to dyslipidemia, glucose intolerance, and hypertension. Moreover, most recipients present with chronic kidney graft disease at long-term follow-ups, usually in stages G2-G3T. Therefore, the nutritional status of KTx patients requires careful monitoring. Appropriate dietary and lifestyle habits prevent nutrition disturbances and may improve kidney graft function. Despite many nutritional guidelines and recommendations targeted at chronic kidney disease, there are few targeted at KTx recipients. We aimed to provide a brief review of nutrition disturbances and known nutritional recommendations for kidney transplant recipients based on the current literature and dietary trends.
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14
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Wong TH, Ho CM, Hsu HH, Wu YM, Ho MC, Lee PH, Hu RH. Delayed Hepatocellular Carcinoma Recurrence After Liver Transplantation: Comprehensive Clinical Characterization of Case Series. J Hepatocell Carcinoma 2022; 9:1081-1091. [PMID: 36275405 PMCID: PMC9586169 DOI: 10.2147/jhc.s383474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 10/08/2022] [Indexed: 11/06/2022] Open
Abstract
PURPOSE Liver transplantation (LT) is the definite curative treatment for hepatocellular carcinoma (HCC), but recurrence can occur even under stringent criteria. "Delayed" HCC recurrence (>3 years after LT) is not common. Here, we present the clinical features of patients who developed delayed HCC recurrence after LT. PATIENTS AND METHODS We reviewed the data of eligible patients from February 1999 to December 2020 from medical records. RESULTS From among 195 (17%) HCC patients who received LT, 34 experienced HCC recurrence, with 5 (15%) delayed recurrence. These five explant tumors were staged T1b-T2, graded II-III, with two vascular invasion and four beyond the Milan criteria. The median time to recurrence was 6.1 years, with the longest interval being nearly 18 years. Recurrence patterns included two extrahepatic, one intrahepatic, and two mixed extrahepatic and intrahepatic recurrences. A drastic increase in serum alpha-fetoprotein levels was observed in four cases 1 year before recurrence. Management of recurrence included locoregional (surgssical resection in three, radiotherapy in three, transarterial chemoembolization in one, radiofrequency ablation in one) and systemic sorafenib use in three. Two patients died within 12-18 months, one died within 18-24 months, and two are still alive until the end of the study, with respective 13.5- and 16.5-month survival. CONCLUSION Delayed HCC recurrence could occur over 10 years. Therefore, continual surveillance for recurrence is justified, but biomarkers and intervals or intensities specific for delayed recurrence are not validated, which warrants further validation to facilitate personalized medical care.
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Affiliation(s)
- Ta-Hsiang Wong
- Department of Medical Education, National Taiwan University Hospital, Taipei, Taiwan
- School of Medicine, National Taiwan University, Taipei, Taiwan
| | - Cheng-Maw Ho
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsao-Hsun Hsu
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yao-Ming Wu
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ming-Chih Ho
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Po-Huang Lee
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Rey-Heng Hu
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- College of Medicine, National Taiwan University, Taipei, Taiwan
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15
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Zhao YH, Wu ZX, Zhao X, Jiang J, Jiang R. Low androgen level impairs erectile function of rat by regulating the Ng/CaN/AKT/eNOS pathway in penile corpus cavernosum. Andrology 2022; 10:1189-1196. [PMID: 35678097 DOI: 10.1111/andr.13202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/06/2022] [Accepted: 06/02/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND The mechanism by which low androgen status inhibit erectile function has not yet been clearly elucidated. Neurogranin (Ng) is a Ca2+ -sensitive calmodulin binding protein that is expressed in endothelial cells and regulates eNOS function. OBJECTIVES To investigate whether low androgen status inhibit erectile function by regulating the Ng/CaN/AKT/eNOS pathway in the penile cavernous tissue of rats. MATERIALS AND METHODS Thirty-six 8-week-old male Sprague-Dawley rats were randomly divided into six groups as follows (n = 6): 4-week control group (4w-control), 4-week castration group (4w-cast), 4-week castration+testosterone replacement group (4w-cast+T), 8-week control group (8w-control), 8-week castration group (8w-cast), and 8-week castration+testosterone replacement group (8w-cast+T). Four weeks and eight weeks after surgery, the ratio of the maximum intracavernous pressure/mean arterial pressure (ICPmax/MAP) was examined. The level of NO and the expression of Ng, calcineurin (CaN), AKT, p-AKT(S473), eNOS, and p-eNOS(Ser1177) in the penile cavernous tissue of each group were determined. RESULTS Ng and CaN were mainly expressed in the membrane and cytoplasm of endothelial cells and smooth muscle cells in the penile cavernous tissue of rats. The ICPmax/MAP and the concentration of NO in the cast group were significantly lower than those in the control group and cast+T replacement group (p < 0.01). The expression of Ng and the ratios of p-AKT/AKT and p-eNOS/eNOS in the penile cavernous tissue of rats in the cast group were significantly lower than those in the control group and cast+T replacement group (p < 0.01). The expression of CaN in the penile cavernous tissue of rats in the cast group was significantly increased compared with that in the control group and the cast+T replacement group (p < 0.01). CONCLUSION Inhibiting the expression of Ng and subsequently upregulating the expression of CaN in the rat penile cavernous tissue was one of the upstream mechanisms of low androgen status inhibiting erectile function by inhibiting the AKT/eNOS signaling pathway.
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Affiliation(s)
- Yu-Hao Zhao
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ze-Xiu Wu
- Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xin Zhao
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jun Jiang
- Department of Thyroid Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Rui Jiang
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Nephropathy Clinical Medical Research Center of Sichuan Province, Sichuan, China
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16
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Sidarala V, Zhu J, Levi-D'Ancona E, Pearson GL, Reck EC, Walker EM, Kaufman BA, Soleimanpour SA. Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis. Nat Commun 2022; 13:2340. [PMID: 35487893 PMCID: PMC9055072 DOI: 10.1038/s41467-022-29945-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 03/21/2022] [Indexed: 02/01/2023] Open
Abstract
The dynamin-like GTPases Mitofusin 1 and 2 (Mfn1 and Mfn2) are essential for mitochondrial function, which has been principally attributed to their regulation of fission/fusion dynamics. Here, we report that Mfn1 and 2 are critical for glucose-stimulated insulin secretion (GSIS) primarily through control of mitochondrial DNA (mtDNA) content. Whereas Mfn1 and Mfn2 individually were dispensable for glucose homeostasis, combined Mfn1/2 deletion in β-cells reduced mtDNA content, impaired mitochondrial morphology and networking, and decreased respiratory function, ultimately resulting in severe glucose intolerance. Importantly, gene dosage studies unexpectedly revealed that Mfn1/2 control of glucose homeostasis was dependent on maintenance of mtDNA content, rather than mitochondrial structure. Mfn1/2 maintain mtDNA content by regulating the expression of the crucial mitochondrial transcription factor Tfam, as Tfam overexpression ameliorated the reduction in mtDNA content and GSIS in Mfn1/2-deficient β-cells. Thus, the primary physiologic role of Mfn1 and 2 in β-cells is coupled to the preservation of mtDNA content rather than mitochondrial architecture, and Mfn1 and 2 may be promising targets to overcome mitochondrial dysfunction and restore glucose control in diabetes.
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Affiliation(s)
- Vaibhav Sidarala
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, United States
| | - Jie Zhu
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, United States
| | - Elena Levi-D'Ancona
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, United States
| | - Gemma L Pearson
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, United States
| | - Emma C Reck
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, United States
| | - Emily M Walker
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, United States
| | - Brett A Kaufman
- Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15260, United States
| | - Scott A Soleimanpour
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48105, United States.
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48105, United States.
- VA Ann Arbor Healthcare System, Ann Arbor, MI, 48105, United States.
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17
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Darden CM, Vasu S, Mattke J, Liu Y, Rhodes CJ, Naziruddin B, Lawrence MC. Calcineurin/NFATc2 and PI3K/AKT signaling maintains β-cell identity and function during metabolic and inflammatory stress. iScience 2022; 25:104125. [PMID: 35402865 PMCID: PMC8983383 DOI: 10.1016/j.isci.2022.104125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 12/02/2021] [Accepted: 03/16/2022] [Indexed: 11/19/2022] Open
Abstract
Pancreatic islets respond to metabolic and inflammatory stress by producing hormones and other factors that induce adaptive cellular and systemic responses. Here we show that intracellular Ca2+ ([Ca2+]i) and ROS signals generated by high glucose and cytokine-induced ER stress activate calcineurin (CN)/NFATc2 and PI3K/AKT to maintain β-cell identity and function. This was attributed in part by direct induction of the endocrine differentiation gene RFX6 and suppression of several β-cell "disallowed" genes, including MCT1. CN/NFATc2 targeted p300 and HDAC1 to RFX6 and MCT1 promoters to induce and suppress gene transcription, respectively. In contrast, prolonged exposure to stress, hyperstimulated [Ca2+]i, or perturbation of CN/NFATc2 resulted in downregulation of RFX6 and induction of MCT1. These findings reveal that CN/NFATc2 and PI3K/AKT maintain β-cell function during acute stress, but β-cells dedifferentiate to a dysfunctional state upon loss or exhaustion of Ca2+/CN/NFATc2 signaling. They further demonstrate the utility of targeting CN/NFATc2 to restore β-cell function.
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Affiliation(s)
- Carly M. Darden
- Islet Cell Laboratory, Baylor Scott & White Research Institute, Dallas, TX 75204, USA
- Institute of Biomedical Studies, Baylor University, Waco, TX 76706, USA
| | - Srividya Vasu
- Islet Cell Laboratory, Baylor Scott & White Research Institute, Dallas, TX 75204, USA
| | - Jordan Mattke
- Islet Cell Laboratory, Baylor Scott & White Research Institute, Dallas, TX 75204, USA
- Institute of Biomedical Studies, Baylor University, Waco, TX 76706, USA
| | - Yang Liu
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX 75246, USA
| | - Christopher J. Rhodes
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes & Metabolism, University of Chicago, Chicago, IL 60637, USA
- Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca Ltd, Gaithersburg, MD 20878, USA
| | - Bashoo Naziruddin
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX 75246, USA
| | - Michael C. Lawrence
- Islet Cell Laboratory, Baylor Scott & White Research Institute, Dallas, TX 75204, USA
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18
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Miranda JG, Schleicher WE, Wells KL, Ramirez DG, Landgrave SP, Benninger RKP. Dynamic changes in β-cell [Ca 2+] regulate NFAT activation, gene transcription, and islet gap junction communication. Mol Metab 2022; 57:101430. [PMID: 34979329 PMCID: PMC8804269 DOI: 10.1016/j.molmet.2021.101430] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 12/28/2021] [Accepted: 12/29/2021] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE Diabetes occurs because of insufficient insulin secretion due to β-cell dysfunction within the islet of Langerhans. Elevated glucose levels trigger β-cell membrane depolarization, action potential generation, and slow sustained free-Ca2+ ([Ca2+]) oscillations, which trigger insulin release. Nuclear factor of activated T-cell (NFAT) is a transcription factor, which is regulated by the increases in [Ca2+] and calceineurin (CaN) activation. NFAT regulation links cell activity with gene transcription in many systems and regulates proliferation and insulin granule biogenesis within the β-cell. However, the link between the regulation of β-cell electrical activity and oscillatory [Ca2+] dynamics with NFAT activation and downstream transcription is poorly understood. Here, we tested whether dynamic changes to β-cell electrical activity and [Ca2+] regulate NFAT activation and downstream transcription. METHODS In cell lines, mouse islets, and human islets, including those from donors with type 2 diabetes, we applied both agonists/antagonists of ion channels together with optogenetics to modulate β-cell electrical activity. We measured the dynamics of [Ca2+] and NFAT activation as well as performed whole transcriptome and functional analyses. RESULTS Both glucose-induced membrane depolarization and optogenetic stimulation triggered NFAT activation as well as increased the transcription of NFAT targets and intermediate early genes (IEGs). Importantly, slow, sustained [Ca2+] oscillation conditions led to NFAT activation and downstream transcription. In contrast, in human islets from donors with type2 diabetes, NFAT activation by glucose was diminished, but rescued upon pharmacological stimulation of electrical activity. NFAT activation regulated GJD2 expression and increased Cx36 gap junction permeability upon elevated oscillatory [Ca2+] dynamics. However, it is unclear if NFAT directly binds the GJD2 gene to regulate expression. CONCLUSIONS This study provides an insight into the specific patterns of electrical activity that regulate NFAT activation, gene transcription, and islet function. In addition, it provides information on how these factors are disrupted in diabetes.
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Affiliation(s)
- Jose G Miranda
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora CO, 80045, USA
| | - Wolfgang E Schleicher
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora CO, 80045, USA
| | - Kristen L Wells
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - David G Ramirez
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora CO, 80045, USA
| | - Samantha P Landgrave
- Program in Cell Biology, Stem Cell and Development, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Richard K P Benninger
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora CO, 80045, USA; Program in Cell Biology, Stem Cell and Development, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA; Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
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19
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James-Todd T, Ponzano M, Bellavia A, Williams PL, Cantonwine DE, Calafat AM, Hauser R, Quinn MR, Seely EW, McElrath TF. Urinary phthalate and DINCH metabolite concentrations and gradations of maternal glucose intolerance. ENVIRONMENT INTERNATIONAL 2022; 161:107099. [PMID: 35085932 PMCID: PMC10723583 DOI: 10.1016/j.envint.2022.107099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 11/22/2021] [Accepted: 01/12/2022] [Indexed: 05/05/2023]
Abstract
BACKGROUND Studies suggest a link between pregnancy phthalate exposures and gestational diabetes mellitus (GDM). Few studies have evaluated associations between phthalate biomarkers (individual or mixtures) with gradations of maternal glucose intolerance. METHODS In a subset of 606 women participating in LIFECODES pregnancy cohort, a combination of 50-gram 1-h non-fasting glucose load test (GLT) and 100-gram 3-h fasting oral glucose tolerance test was used to determine pregnancy glycemic status (median: 27 weeks gestation): normoglycemia (n = 136), impaired glucose tolerance (IGT) (n = 296), and GDM (n = 174). Nineteen metabolites of phthalates and their replacements were measured during each trimester. We used multivariable logistic regression models to evaluate associations between biomarkers (in quartiles) and maternal glycemic status (GDM v. normoglycemia and IGT v. normoglycemia), adjusting for potential confounders. We also used principal component analysis to evaluate associations jointly accounting for metabolites as chemical mixtures. RESULTS Higher 1st trimester mono-3-carboxypropyl phthalate (MCPP) was associated with decreased odds of GDM (Q4 v. Q1: 0.30; 95% CI: 0.13, 0.67) and IGT (Q4 v. Q1 OR: 0.37; 95% CI: 0.17, 0.79). Higher 2nd trimester mono-isobutyl phthalate (MiBP) was associated with increased IGT (Q4 v. Q1 OR: 2.07; 95% CI: 1.06, 4.07), and 2nd trimester mono-3-hydroxybutyl phthalate (MHBP) was non-monotonically associated with increased GDM (Q2 v. Q1 OR: 3.21; 95% CI: 1.54, 6.87). Mixture analyses showed similar associations (Q4 v. Q1 for 2nd trimester dibutyl phthalates metabotlites mixtures OR: 2.08; 95% CI: 1.04, 4.22). CONCLUSION Some phthalate biomarkershad trimester-specific associations with glycemic outcomes, with long and short term health implications.
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Affiliation(s)
- Tamarra James-Todd
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Division of Women's Health, Department of Medicine, Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02120, USA.
| | - Marta Ponzano
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Andrea Bellavia
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Paige L Williams
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - David E Cantonwine
- Division of Maternal Fetal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Antonia M Calafat
- Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA
| | - Russ Hauser
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Marlee R Quinn
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Ellen W Seely
- Division of Endocrine, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Thomas F McElrath
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Division of Maternal Fetal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
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20
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Calcineurin regulates the stability and activity of estrogen receptor α. Proc Natl Acad Sci U S A 2021; 118:2114258118. [PMID: 34711683 DOI: 10.1073/pnas.2114258118] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 08/27/2021] [Indexed: 12/14/2022] Open
Abstract
Estrogen receptor α (ER-α) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. However, the molecular mechanisms underlying the regulation of the cellular abundance and activity of ER-α remain unclear. We here show that the protein phosphatase calcineurin regulates both ER-α stability and activity in human breast cancer cells. Calcineurin depletion or inhibition down-regulated the abundance of ER-α by promoting its polyubiquitination and degradation. Calcineurin inhibition also promoted the binding of ER-α to the E3 ubiquitin ligase E6AP, and calcineurin mediated the dephosphorylation of ER-α at Ser294 in vitro. Moreover, the ER-α (S294A) mutant was more stable and activated the expression of ER-α target genes to a greater extent compared with the wild-type protein, whereas the extents of its interaction with E6AP and polyubiquitination were attenuated. These results suggest that the phosphorylation of ER-α at Ser294 promotes its binding to E6AP and consequent degradation. Calcineurin was also found to be required for the phosphorylation of ER-α at Ser118 by mechanistic target of rapamycin complex 1 and the consequent activation of ER-α in response to β-estradiol treatment. Our study thus indicates that calcineurin controls both the stability and activity of ER-α by regulating its phosphorylation at Ser294 and Ser118 Finally, the expression of the calcineurin A-α gene (PPP3CA) was associated with poor prognosis in ER-α-positive breast cancer patients treated with tamoxifen or other endocrine therapeutic agents. Calcineurin is thus a promising target for the development of therapies for ER-α-positive breast cancer.
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21
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Zhang J, Chen H, Weng X, Liu H, Chen Z, Huang Q, Wang L, Liu X. RCAN1.4 attenuates renal fibrosis through inhibiting calcineurin-mediated nuclear translocation of NFAT2. Cell Death Discov 2021; 7:317. [PMID: 34707090 PMCID: PMC8551295 DOI: 10.1038/s41420-021-00713-8] [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: 05/31/2021] [Revised: 09/21/2021] [Accepted: 10/13/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) is thus deemed to a global health problem. Renal fibrosis, characterized by accumulation of extracellular matrix (ECM) components in the kidney, is considered a common pathway leading to CKD. Regulator of calcineurin1 (RCAN1), identified as a competitive endogenous inhibitor of the phosphatase calcineurin, participates in ECM deposition in various organs. However, the role of RCAN1 in renal fibrosis remains unclear. Here, unilateral ureteral obstruction (UUO), a well-known model to induce renal fibrosis in vivo, was performed on mice for a week. To overexpress RCAN1.4 in vivo, recombinant adeno-associated virus 9-packed RCAN1.4 over-expression plasm was employed in mice kidney. Lentivirus-packed RCAN1.4 over-expression plasm was employed to transfer into HK-2 and NRK-49F cells in vitro. The results indicated that RCAN1.4 expression was impaired both in UUO-induced renal fibrosis in vivo and TGF-β1-induced renal fibrosis in vitro. However, knocking in of RCAN1.4 suppressed the production of extracellular matrix (ECM) both in vivo and in vitro. Furthermore, in vitro, the apoptosis-related proteins, including the ratio of Bax/Bcl-2 and cleaved-caspase3, were elevated in cells transfected with RCAN1.4 overexpression plasmid. In addition, we found that RCAN1.4 could rugulated NFAT2 nuclear distribution by inhibiting calcineurin pathway. So overexpression of RCAN1.4 could reverse renal fibrosis, attenuate ECM related protein accumulation, promote apoptosis of myofibroblast via inhibiting Calcineurin/NFAT2 signaling pathway. Taken together, our study demonstrated that targeting RCAN1.4 may be therapeutic efficacy in renal fibrosis.
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Affiliation(s)
- Jianjian Zhang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Hui Chen
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Xiaodong Weng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Hao Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Zhiyuan Chen
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Qin Huang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 430060, Wuhan, Hubei, China.
| | - Lei Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
| | - Xiuheng Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
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22
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Kotha S, Lawendy B, Asim S, Gomes C, Yu J, Orchanian-Cheff A, Tomlinson G, Bhat M. Impact of immunosuppression on incidence of post-transplant diabetes mellitus in solid organ transplant recipients: Systematic review and meta-analysis. World J Transplant 2021; 11:432-442. [PMID: 34722172 PMCID: PMC8529944 DOI: 10.5500/wjt.v11.i10.432] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/27/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Solid organ transplantation is a life-saving intervention for end-stage organ disease. Post-transplant diabetes mellitus (PTDM) is a common complication in solid organ transplant recipients, and significantly compromises long-term survival beyond a year.
AIM To perform a systematic review and meta-analysis to estimate incidence of PTDM and compare the effects of the 3 major immunosuppressants on incidence of PTDM.
METHODS Two hundred and six eligible studies identified 75595 patients on Tacrolimus, 51242 on Cyclosporine and 3020 on Sirolimus. Random effects meta-analyses was used to calculate incidence.
RESULTS Network meta-analysis estimated the overall risk of developing PTDM was higher with tacrolimus (OR = 1.4 95%CI: 1.0–2.0) and sirolimus (OR = 1.8; 95%CI: 1.5–2.2) than with Cyclosporine. The overall incidence of PTDM at years 2-3 was 17% for kidney, 19% for liver and 22% for heart. The risk factors for PTDM most frequently identified in the primary studies were age, body mass index, hepatitis C, and African American descent.
CONCLUSION Tacrolimus tends to exhibit higher diabetogenicity in the short-term (2-3 years post-transplant), whereas sirolimus exhibits higher diabetogenicity in the long-term (5-10 years post-transplant). This study will aid clinicians in recognition of risk factors for PTDM and encourage careful evaluation of the risk/benefit of different immunosuppressant regimens in transplant recipients.
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Affiliation(s)
- Sreelakshmi Kotha
- Department of Gastroenterology, Guy's and St Thomas' Hospital, London SE1 7JD, United Kingdom
| | - Bishoy Lawendy
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Saira Asim
- Multi Organ Transplant Program, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Charlene Gomes
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Jeffrey Yu
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Ani Orchanian-Cheff
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - George Tomlinson
- Dalla Lana School of Public Health, Department of Medicine, University Health Network - Toronto General Hospital, University of Toronto, Toronto M5G 2C4, Canada
| | - Mamatha Bhat
- Multi-organ Transplant, Toronto General Hospital, Toronto M5G 2C4, Canada
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23
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Azhie A, Sheth P, Hammad A, Woo M, Bhat M. Metabolic Complications in Liver Transplantation Recipients: How We Can Optimize Long-Term Survival. Liver Transpl 2021; 27:1468-1478. [PMID: 34165872 DOI: 10.1002/lt.26219] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 06/14/2021] [Accepted: 06/17/2021] [Indexed: 12/27/2022]
Abstract
Liver transplantation (LT) recipients have experienced a significant improvement in short-term survival during the past 3 decades attributed to advancements in surgical techniques, perioperative management, and effective immunosuppressive regimens. However, long-term survival is affected by a high incidence of metabolic disorders and their consequences, including cardiovascular disease (CVD) and malignancies. Pretransplant metabolic impairments especially in those with nonalcoholic steatohepatitis cirrhosis are aggravated by the addition of posttransplant weight gain, physical inactivity, and reversal from catabolic to anabolic state. Moreover, although immunosuppressants are vital to avoid graft rejection, long-term exposure to these medications is implicated in metabolic impairments after LT. In this review, we summarize the molecular pathogenesis of different metabolic disorders after LT, including diabetes mellitus, dyslipidemia, and nonalcoholic fatty liver disease. Furthermore, CVD, malignancies, and graft rejections were provided as significant complications of post-LT metabolic conditions threatening both the patient and graft survival. Ultimately, emerging preventive and treatment strategies for posttransplant diabetes mellitus are summarized. This review highlights the significant need for more clinical trials of antihyperglycemic agents in LT recipients. Also, translational studies will help us to better understand the molecular and genetic factors underlying these metabolic complications and could lead to more personalized management in this high-risk population.
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Affiliation(s)
- Amirhossein Azhie
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Priya Sheth
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Ahmed Hammad
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,Department of General Surgery, Mansoura University, Mansoura, Egypt
| | - Minna Woo
- Division of Endocrinology and Metabolism, Department of Medicine, University Health Network and Sinai Health System, University of Toronto, Toronto, Ontario, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Mamatha Bhat
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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24
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Rodriguez-Rodriguez AE, Porrini E, Torres A. Beta-Cell Dysfunction Induced by Tacrolimus: A Way to Explain Type 2 Diabetes? Int J Mol Sci 2021; 22:ijms221910311. [PMID: 34638652 PMCID: PMC8509035 DOI: 10.3390/ijms221910311] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 09/01/2021] [Accepted: 09/14/2021] [Indexed: 01/01/2023] Open
Abstract
The combination of insulin resistance and β-cells dysfunction leads to the onset of type-2 diabetes mellitus (T2DM). This process can last for decades, as β-cells are able to compensate the demand for insulin and maintain normoglycemia. Understanding the adaptive capacity of β-cells during this process and the causes of its failure is essential to the limit onset of diabetes. Post-transplant diabetes mellitus (PTDM) is a common and serious disease that affects 30% of renal transplant recipients. With the exception of immunosuppressive therapy, the risk factors for T2D are the same as for PTDM: obesity, dyslipidaemia, insulin resistance and metabolic syndrome. Tacrolimus (TAC) is the immunosuppressant of choice after renal transplantation but it has the highest rates of PTDM. Our group has shown that insulin resistance and glucolipotoxicity, without favouring the appearance of apoptosis, modify key nuclear factors for the maintenance of identity and functionality of β-cells. In this context, TAC accelerates or enhances these changes. Our hypothesis is that the pathways that are affected in the progression from pre-diabetes to diabetes in the general population are the same pathways that are affected by TAC. So, TAC can be considered a tool to study the pathogenesis of T2DM. Here, we review the common pathways of β-cells dysfunction on T2DM and TAC-induced diabetes.
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Affiliation(s)
- Ana Elena Rodriguez-Rodriguez
- Research Unit, Hospital Universitario de Canarias, 38320 La Laguna, Santa Cruz de Tenerife, Spain;
- Fundación General de la Universidad, Universidad de La Laguna, 38204 La Laguna, Santa Cruz de Tenerife, Spain
| | - Esteban Porrini
- Unidad Ensayos Clinicos-UCICEC, Hospital Universitario de Canarias, 38320 La Laguna, Santa Cruz de Tenerife, Spain;
- Instituto Tecnologías Biomédicas (ITB), Universidad de La Laguna, 38200 La Laguna, Santa Cruz de Tenerife, Spain
- Correspondence: ; Tel.: +34-922-678-116
| | - Armando Torres
- Unidad Ensayos Clinicos-UCICEC, Hospital Universitario de Canarias, 38320 La Laguna, Santa Cruz de Tenerife, Spain;
- Nephrology Department, Hospital Universitario de Canarias, 38320 La Laguna, Santa Cruz de Tenerife, Spain
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25
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Phillips J, Chen JHC, Ooi E, Prunster J, Lim WH. Global Epidemiology, Health Outcomes, and Treatment Options for Patients With Type 2 Diabetes and Kidney Failure. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2021; 2:731574. [PMID: 36994340 PMCID: PMC10012134 DOI: 10.3389/fcdhc.2021.731574] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 07/29/2021] [Indexed: 12/15/2022]
Abstract
The burden of type 2 diabetes and related complications has steadily increased over the last few decades and is one of the foremost global public health threats in the 21st century. Diabetes is one of the leading causes of chronic kidney disease and kidney failure and is an important contributor to the cardiovascular morbidity and mortality in this population. In addition, up to one in three patients who have received kidney transplants develop post-transplant diabetes, but the management of this common complication continues to pose a significant challenge for clinicians. In this review, we will describe the global prevalence and temporal trend of kidney failure attributed to diabetes mellitus in both developing and developed countries. We will examine the survival differences between treated kidney failure patients with and without type 2 diabetes, focusing on the survival differences in those on maintenance dialysis or have received kidney transplants. With the increased availability of novel hypoglycemic agents, we will address the potential impacts of these novel agents in patients with diabetes and kidney failure and in those who have developed post-transplant diabetes.
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Affiliation(s)
- Jessica Phillips
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
- *Correspondence: Jessica Phillips,
| | - Jenny H. C. Chen
- School of Medicine, University of Wollongong, Wollongong, NSW, Australia
- Depatment of Nephrology, Wollongong Hospital, Wollongong, NSW, Australia
| | - Esther Ooi
- School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Janelle Prunster
- Department of Renal Medicine, Cairns Hospital, Cairns, QLD, Australia
| | - Wai H. Lim
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
- Medical School, University of Western Australia, Perth, WA, Australia
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26
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Tong L, Li W, Zhang Y, Zhou F, Zhao Y, Zhao L, Liu J, Song Z, Yu M, Zhou C, Yu A. Tacrolimus inhibits insulin release and promotes apoptosis of Min6 cells through the inhibition of the PI3K/Akt/mTOR pathway. Mol Med Rep 2021; 24:658. [PMID: 34278483 DOI: 10.3892/mmr.2021.12297] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 06/06/2021] [Indexed: 11/06/2022] Open
Abstract
As a calcineurin inhibitor, tacrolimus is commonly used as a first‑line immunosuppressant in organ transplant recipients. Post‑transplantation diabetes mellitus (PTDM) is a common complication following kidney transplantation and is associated with immunosuppressant drugs, such as tacrolimus. PTDM caused by tacrolimus may be related to its influence on insulin secretion and insulin resistance. However, the specific mechanism has not been fully elucidated. The aim of the present study was to investigate whether the PI3K/Akt/mTOR signaling pathway served an important role in the pathogenesis of PTDM induced by tacrolimus. In the present study, the Cell Counting Kit‑8 assay was used to measure the effect of tacrolimus on the viability of Min6 mouse insulinoma cells. The effects of tacrolimus on the insulin secretion and the activity of caspase‑3 of Min6 cells stimulated by glucose exposure were measured by ELISA. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured using WST‑8 and thiobarbituric acid assays, respectively. The effects of tacrolimus on the mRNA expression levels of PI3K, Akt and mTOR were detected by reverse transcription‑quantitative PCR (RT‑qPCR), whereas the protein expression levels of PI3K, Akt, mTOR, phosphorylated (p)‑AKT and p‑mTOR in Min6 cells were assessed using western blotting. The present data indicated that, compared with the control group, 5, 25 and 50 ng/ml tacrolimus treatment could inhibit the insulin secretion of Min6 cells stimulated by glucose solution, and 50 ng/ml tacrolimus could notably decrease the stimulation index (P<0.05). Moreover, 50 ng/ml tacrolimus markedly increased the activity of caspase‑3 by 175.1% (P<0.05), it also decreased the SOD activity (P<0.01) and increased MDA levels (P<0.05). The RT‑qPCR results demonstrated that the mRNA expression levels of PI3K, Akt and mTOR were downregulated by 25 and 50 ng/ml tacrolimus (P<0.01). Furthermore, the western blotting results suggested that tacrolimus had no significant effects on the expression levels of total PI3K, Akt and mTOR proteins (P>0.05), but 25 and 50 ng/ml tacrolimus could significantly inhibit the expression levels of p‑Akt and p‑mTOR (P<0.01). In conclusion, tacrolimus decreased the activity and insulin secretion of pancreatic β cells and induced the apoptosis of islet β cells by inhibiting the mRNA expression levels of PI3K, Akt and mTOR and reducing the phosphorylation of Akt and mTOR proteins in the PI3K/Akt/mTOR signaling pathway, which may ultimately lead to the occurrence of diabetes mellitus, and may be considered as one of the specific mechanisms of PTDM caused by tacrolimus.
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Affiliation(s)
- Ling Tong
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei 430000, P.R. China
| | - Weiliang Li
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei 430000, P.R. China
| | - Ying Zhang
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei 430000, P.R. China
| | - Fan Zhou
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei 430000, P.R. China
| | - Yan Zhao
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei 430000, P.R. China
| | - Linlin Zhao
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei 430000, P.R. China
| | - Jing Liu
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei 430000, P.R. China
| | - Zhirui Song
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei 430000, P.R. China
| | - Mengchen Yu
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei 430000, P.R. China
| | - Chengrui Zhou
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei 430000, P.R. China
| | - Airong Yu
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei 430000, P.R. China
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27
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Satin LS, Soleimanpour SA, Walker EM. New Aspects of Diabetes Research and Therapeutic Development. Pharmacol Rev 2021; 73:1001-1015. [PMID: 34193595 PMCID: PMC8274312 DOI: 10.1124/pharmrev.120.000160] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Both type 1 and type 2 diabetes mellitus are advancing at exponential rates, placing significant burdens on health care networks worldwide. Although traditional pharmacologic therapies such as insulin and oral antidiabetic stalwarts like metformin and the sulfonylureas continue to be used, newer drugs are now on the market targeting novel blood glucose-lowering pathways. Furthermore, exciting new developments in the understanding of beta cell and islet biology are driving the potential for treatments targeting incretin action, islet transplantation with new methods for immunologic protection, and the generation of functional beta cells from stem cells. Here we discuss the mechanistic details underlying past, present, and future diabetes therapies and evaluate their potential to treat and possibly reverse type 1 and 2 diabetes in humans. SIGNIFICANCE STATEMENT: Diabetes mellitus has reached epidemic proportions in the developed and developing world alike. As the last several years have seen many new developments in the field, a new and up to date review of these advances and their careful evaluation will help both clinical and research diabetologists to better understand where the field is currently heading.
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Affiliation(s)
- Leslie S Satin
- Department of Pharmacology (L.S.S.), Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (L.S.S., S.A.S., E.M.W.), and Brehm Diabetes Center (L.S.S., S.A.S., E.M.W.), University of Michigan Medical School, Ann Arbor, Michigan; and VA Ann Arbor Healthcare System, Ann Arbor, Michigan (S.A.S.) ; ;
| | - Scott A Soleimanpour
- Department of Pharmacology (L.S.S.), Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (L.S.S., S.A.S., E.M.W.), and Brehm Diabetes Center (L.S.S., S.A.S., E.M.W.), University of Michigan Medical School, Ann Arbor, Michigan; and VA Ann Arbor Healthcare System, Ann Arbor, Michigan (S.A.S.)
| | - Emily M Walker
- Department of Pharmacology (L.S.S.), Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (L.S.S., S.A.S., E.M.W.), and Brehm Diabetes Center (L.S.S., S.A.S., E.M.W.), University of Michigan Medical School, Ann Arbor, Michigan; and VA Ann Arbor Healthcare System, Ann Arbor, Michigan (S.A.S.) ; ;
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28
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Ertuglu LA, Porrini E, Hornum M, Demiray A, Afsar B, Ortiz A, Covic A, Rossing P, Kanbay M. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors for diabetes after solid organ transplantation. Transpl Int 2021; 34:1341-1359. [PMID: 33880815 DOI: 10.1111/tri.13883] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/22/2021] [Accepted: 04/12/2021] [Indexed: 12/13/2022]
Abstract
Post-transplant diabetes mellitus (PTDM) is a common complication of solid organ transplantation and a major cause of increased morbidity and mortality. Additionally, solid organ transplant patients may have pre-existent type 2 diabetes mellitus (T2DM). While insulin is the treatment of choice for hyperglycemia in the first weeks after transplantation, there is no preferred first line agent for long-term management of PTDM or pre-existent T2DM. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 (SGLT2) inhibitors improve glycemic control, lower body weight, and blood pressure, are recommended after lifestyle and metformin as initial therapy for diabetic patients with cardiovascular or kidney comorbidities regarding their cardiorenal benefits. Furthermore, the mechanisms of action of GLP-1RA may counteract some of the driving forces for PTDM, as calcineurin-induced β cell toxicity as per preclinical data, and improve obesity. However, their use in the treatment of PTDM is currently limited by a paucity of data. Retrospective observational and small exploratory studies suggest that GLP-1RA effectively improve glycemic control and induce weight loss in patients with PTDM without interacting with commonly used immunosuppressive agents, although randomized-controlled clinical trials are required to confirm their safety and efficacy. In this narrative review, we evaluate the risk factors and pathogenesis of PTDM and compare the potential roles of GLP-1RA and SGLT2 inhibitors in PTDM prevention and management as well as in pre-existent T2DM, and providing a roadmap for evidence generation on newer antidiabetic drugs for solid organ transplantation.
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Affiliation(s)
- Lale A Ertuglu
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Esteban Porrini
- Red de Investigación Renal (REDINREN), Instituto Carlos III-FEDER, Tenerife, Spain.,Department of Medicine, Hospital Universitario de Canarias, Tenerife, Spain.,Instituto de Tecnologías Biomédicas, University of La Laguna, Tenerife, Spain
| | - Mads Hornum
- Department of Nephrology, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Atalay Demiray
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Baris Afsar
- Division of Nephrology, Department of Internal Medicine, Suleyman Demirel University School of Medicine, Isparta, Turkey
| | - Alberto Ortiz
- IIS-Fundacion Jimenez Diaz, Department of Medicine, School of Medicine, Universidad Autonoma de Madrid, Madrid, Spain
| | - Adrian Covic
- Department of Nephrology, Grigore T. Popa' University of Medicine, Iasi, Romania
| | - Peter Rossing
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Steno Diabetes Center Copenhagen, Copenhagen, Denmark
| | - Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
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29
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Peruhova M, Peshevska-Sekulovska M, Panayotova G, Velikova T. Foremost Concepts in Mechanisms of De Novo Post-Liver Transplantation Malignancy. GASTROENTEROLOGY INSIGHTS 2021; 12:283-292. [DOI: 10.3390/gastroent12030025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
In liver transplant patients, solid tumors and post-transplant lymphoproliferative disorders (PTLD) have emerged as significant long-term mortality causes. Additionally, it is assumed that de novo malignancy (DNM) after liver transplantation (LT) is the second-leading cause of death after cardiovascular complications. Well-established risk factors for PTLD and solid tumors are calcineurin inhibitors (CNIs), tacrolimus (TAC), and cyclosporine, the cornerstones of all immunosuppressive (IS) therapies used after LT. The loss of immunocompetence facilitated by the host immune system due to prolonged IS therapy leads to cancer development, including in LT patients. Hindering DNA repair mechanisms, promoting tumor cell invasiveness, and hampering apoptosis are critical events in tumorigenesis and tumor growth in LT patients resulting from IS administration. This paper aims to overview the refined mechanisms of IS-induced tumorigenesis after LT and the loss of immunocompetence facilitated by the host immune system due to prolonged IS therapy. In addition, we also discuss in detail the mechanisms of action in different types of IS regimen used after LT, and their putative effect on DNM.
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Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital Lozenetz, 1 Kozyak str., 1407 Sofia, Bulgaria
| | | | - Gabriela Panayotova
- Department of Gastroenterology, University Hospital Lozenetz, 1 Kozyak str., 1407 Sofia, Bulgaria
| | - Tsvetelina Velikova
- Department of Clinical Immunology, Medical Faculty, University Hospital Lozenetz, Sofia University, St. Kliment Ohridski, 1407 Sofia, Bulgaria
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30
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Rysz J, Franczyk B, Radek M, Ciałkowska-Rysz A, Gluba-Brzózka A. Diabetes and Cardiovascular Risk in Renal Transplant Patients. Int J Mol Sci 2021; 22:3422. [PMID: 33810367 PMCID: PMC8036743 DOI: 10.3390/ijms22073422] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
End-stage kidney disease (ESKD) is a main public health problem, the prevalence of which is continuously increasing worldwide. Due to adverse effects of renal replacement therapies, kidney transplantation seems to be the optimal form of therapy with significantly improved survival, quality of life and diminished overall costs compared with dialysis. However, post-transplant patients frequently suffer from post-transplant diabetes mellitus (PTDM) which an important risk factor for cardiovascular and cardiovascular-related deaths after transplantation. The management of post-transplant diabetes resembles that of diabetes in the general population as it is based on strict glycemic control as well as screening and treatment of common complications. Lifestyle interventions accompanied by the tailoring of immunosuppressive regimen may be of key importance to mitigate PTDM-associated complications in kidney transplant patients. More transplant-specific approach can include the exchange of tacrolimus with an alternative immunosuppressant (cyclosporine or mammalian target of rapamycin (mTOR) inhibitor), the decrease or cessation of corticosteroid therapy and caution in the prescribing of diuretics since they are independently connected with post-transplant diabetes. Early identification of high-risk patients for cardiovascular diseases enables timely introduction of appropriate therapeutic strategy and results in higher survival rates for patients with a transplanted kidney.
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Affiliation(s)
- Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland; (J.R.); (B.F.)
| | - Beata Franczyk
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland; (J.R.); (B.F.)
| | - Maciej Radek
- Department of Neurosurgery, Surgery of Spine and Peripheral Nerves, Medical University of Lodz, 90-549 Lodz, Poland;
| | | | - Anna Gluba-Brzózka
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland; (J.R.); (B.F.)
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Abstract
Tacrolimus was discovered in 1984 and entered clinical use shortly thereafter, contributing to successful solid organ transplantation across the globe. In this review, we cover development of tacrolimus, its evolving clinical utility, and issues affecting its current usage. Since earliest use of this class of immunosuppressant, concerns for calcineurin-inhibitor toxicity have led to efforts to minimize or eliminate these agents in clinical regimens but with limited success. Current understanding of the role of tacrolimus focuses more on its efficacy in preventing graft rejection and graft loss. As we enter the fourth decade of tacrolimus use, newer studies utilizing novel combinations (as with the mammalian target of rapamycin inhibitor, everolimus, and T-cell costimulation blockade with belatacept) offer potential for enhanced benefits.
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Affiliation(s)
- Song C Ong
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL
| | - Robert S Gaston
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL
- CTI Clinical Trial and Consulting, Inc., Covington, KT
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Duque Escobar J, Kutschenko A, Schröder S, Blume R, Köster KA, Painer C, Lemcke T, Maison W, Oetjen E. Regulation of dual leucine zipper kinase activity through its interaction with calcineurin. Cell Signal 2021; 82:109953. [PMID: 33600948 DOI: 10.1016/j.cellsig.2021.109953] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 11/19/2022]
Abstract
Hyperglycemia enhancing the intracellular levels of reactive oxygen species (ROS) contributes to dysfunction and progressive loss of beta cells and thereby to diabetes mellitus. The oxidation sensitive calcium/calmodulin dependent phosphatase calcineurin promotes pancreatic beta cell function and survival whereas the dual leucine zipper kinase (DLK) induces apoptosis. Therefore, it was studied whether calcineurin interferes with DLK action. In a beta cell line similar concentrations of H2O2 decreased calcineurin activity and activated DLK. DLK interacted via its φLxVP motif (aa 362-365) with the interface of the calcineurin subunits A and B. Mutation of the Val prevented this protein protein interaction, hinting at a distinct φLxVP motif. Indeed, mutational analysis revealed an ordered structure of DLK's φLxVP motif whereby Val mediates the interaction with calcineurin and Leu maintains an enzymatically active conformation. Overexpression of DLK wild-type but not the DLK mutant unable to bind calcineurin diminished calcineurin-induced nuclear localisation of the nuclear factor of activated T-cells (NFAT), suggesting that both, DLK and NFAT compete for the substrate binding site of calcineurin. The calcineurin binding-deficient DLK mutant exhibited increased DLK activity measured as phosphorylation of the downstream c-Jun N-terminal kinase, inhibition of CRE-dependent gene transcription and induction of apoptosis. These findings show that calcineurin interacts with DLK; and inhibition of calcineurin increases DLK activity. Hence, this study demonstrates a novel mechanism regulating DLK action. These findings suggest that ROS through inhibition of calcineurin enhance DLK activity and thereby lead to beta cell dysfunction and loss and ultimately diabetes mellitus.
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Affiliation(s)
- J Duque Escobar
- Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; DZHK Standort Hamburg, Kiel, Lübeck, Germany
| | - Anna Kutschenko
- Department of Pharmacology, University of Göttingen, Robert-Koch-Str. 40, 37099 Göttingen, Germany
| | - Sabine Schröder
- Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Roland Blume
- Department of Pharmacology, University of Göttingen, Robert-Koch-Str. 40, 37099 Göttingen, Germany
| | - Kyra-Alexandra Köster
- Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; DZHK Standort Hamburg, Kiel, Lübeck, Germany
| | - Christina Painer
- Institute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146 Hamburg, Germany
| | - Thomas Lemcke
- Institute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146 Hamburg, Germany
| | - Wolfgang Maison
- Institute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146 Hamburg, Germany
| | - Elke Oetjen
- Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; DZHK Standort Hamburg, Kiel, Lübeck, Germany; Department of Pharmacology, University of Göttingen, Robert-Koch-Str. 40, 37099 Göttingen, Germany; Institute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146 Hamburg, Germany.
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Allazova SS, Novikova MS, Kotenko ON, Shilov EM. [Immunosuppressive therapy as a risk factor for new-onset diabetes after transplantation]. TERAPEVT ARKH 2020; 92:137-141. [PMID: 33720585 DOI: 10.26442/00403660.2020.12.200454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 02/07/2021] [Indexed: 11/22/2022]
Abstract
AIM To analyze the modes of immunosuppressive therapy as a risk factor for new-onset diabetes after transplantation (NODAT) in kidney recipients. MATERIALS AND METHODS The retrospective analysis included data from 1367 recipients (755 men and 612 women) who lived more than one year after NODAT and were observed at the Moscow City Nephrology Center from January 1989 to December 2018. NODAT was established for 178 (13%) patients based on criteria from the World Health Organization and the American Diabetes Association. The modes of immunosuppressive therapy using cyclosporin A (CSA), tacrolimus (Tac), mTOR inhibitors, glucocorticoids in patients with NODAT and without NODAT were evaluated. To assess the impact of risk factors, descriptive statistics methods were used, the odds ratio (OR) and the 95% confidence interval (CI) were calculated. RESULTS NODAT was diagnosed in 105 men and 73 women. The OR for men was 1.19 (95% CI 0.871.64), the OR for women was 0.84 (95% CI 0.611.15). At the time of transplantation, the average age of the kidney recipients in the NODAT group was higher than in the group without NODAT: 51 [43; 57] and 43 [32; 52] years, respectively (p=0.0001). Most patients with NODAT (82%) were older than 50 years, while in the group without NODAT, the proportion of patients of the same age was 48.5% (p=0.0001). Among patients without NODAT, transplantation of a kidney from a living donor was significantly more often compared with the group with NODAT+ (7.1% vs 1.1%;p=0.001). Among the recipients who received the regimen with CSA, diabetes developed in 75 (42.1%), those who received Tac in 102 (57.3%;p0.05). The chance (risk of development) of NODAT in patients receiving i-mTOR + Tac was 3.2 (95% CI 1.476.78;p=0.032), and for patients receiving i-mTOR + cyclosporin A, the chance of development NODAT was 1.95 (95% CI 0.884.35;p=0.044). CONCLUSION 13% of recipients developed de novo kidney diabetes after allograft. Age at the time of allotransplantation, gender, as well as the use of tacrolimus in combination with i-mTOR are the most significant risk factors for the development of NODAT.
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Affiliation(s)
- S S Allazova
- Sechenov First Moscow State Medical University (Sechenov University)
| | | | - O N Kotenko
- Municipal Clinical Hospital №52
- People's Friendship University of Russia
| | - E M Shilov
- Sechenov First Moscow State Medical University (Sechenov University)
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Chevallier E, Jouve T, Rostaing L, Malvezzi P, Noble J. pre-existing diabetes and PTDM in kidney transplant recipients: how to handle immunosuppression. Expert Rev Clin Pharmacol 2020; 14:55-66. [PMID: 33196346 DOI: 10.1080/17512433.2021.1851596] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Preexisting diabetes (PD) and post-transplant diabetes mellitus (PTDM) are common and severe comorbidities posttransplantation. The immunosuppressive regimens are modifiable risk factors. AREAS COVERED We reviewed Pubmed and Cochrane database and we summarize the mechanisms and impacts of available immunosuppressive treatments on the risk of PD and PTDM. We also assess the possible management of these drugs to improve glycemic parameters while considering risks inherent in transplantation. EXPERT OPINION PD i) increases the risk of sepsis, ii) is an independent risk factor for infection-related mortality, and iii) increases acute rejection risk. Regarding PTDM development i) immunosuppressive strategies without corticosteroids significantly reduce the risk but the price may be a higher incidence of rejection; ii) minimization or rapid withdrawal of steroids are two valuable approaches; iii) the diabetogenic role of calcineurin inhibitors(CNIs) is also well-described and is more important for tacrolimus than for cyclosporine. Reducing tacrolimus-exposure may improve glycemic parameters but also has a higher risk of rejection. PTDM risk is higher in patients that receive sirolimus compared to mycophenolate mofetil. Finally, conversion from CNIs to belatacept may offer the best benefits to PTDM-recipients in terms of glycemic parameters, graft and patient-outcomes.
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Affiliation(s)
- Eloi Chevallier
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
| | - Thomas Jouve
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France.,Université Grenoble Alpes , Grenoble, France
| | - Lionel Rostaing
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France.,Université Grenoble Alpes , Grenoble, France
| | - Paolo Malvezzi
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
| | - Johan Noble
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
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Bosi E, Marselli L, De Luca C, Suleiman M, Tesi M, Ibberson M, Eizirik DL, Cnop M, Marchetti P. Integration of single-cell datasets reveals novel transcriptomic signatures of β-cells in human type 2 diabetes. NAR Genom Bioinform 2020; 2:lqaa097. [PMID: 33575641 PMCID: PMC7679065 DOI: 10.1093/nargab/lqaa097] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/26/2020] [Accepted: 10/30/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic islet β-cell failure is key to the onset and progression of type 2 diabetes (T2D). The advent of single-cell RNA sequencing (scRNA-seq) has opened the possibility to determine transcriptional signatures specifically relevant for T2D at the β-cell level. Yet, applications of this technique have been underwhelming, as three independent studies failed to show shared differentially expressed genes in T2D β-cells. We performed an integrative analysis of the available datasets from these studies to overcome confounding sources of variability and better highlight common T2D β-cell transcriptomic signatures. After removing low-quality transcriptomes, we retained 3046 single cells expressing 27 931 genes. Cells were integrated to attenuate dataset-specific biases, and clustered into cell type groups. In T2D β-cells (n = 801), we found 210 upregulated and 16 downregulated genes, identifying key pathways for T2D pathogenesis, including defective insulin secretion, SREBP signaling and oxidative stress. We also compared these results with previous data of human T2D β-cells from laser capture microdissection and diabetic rat islets, revealing shared β-cell genes. Overall, the present study encourages the pursuit of single β-cell RNA-seq analysis, preventing presently identified sources of variability, to identify transcriptomic changes associated with human T2D and underscores specific traits of dysfunctional β-cells across different models and techniques.
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Affiliation(s)
- Emanuele Bosi
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Lorella Marselli
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Carmela De Luca
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Mara Suleiman
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Marta Tesi
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Mark Ibberson
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, University of Lausanne, Quartier Sorge, CH-1015 Lausanne, Switzerland
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, B-1070, Belgium
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, B-1070, Belgium
| | - Piero Marchetti
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
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36
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Kolic J, Beet L, Overby P, Cen HH, Panzhinskiy E, Ure DR, Cross JL, Huizinga RB, Johnson JD. Differential Effects of Voclosporin and Tacrolimus on Insulin Secretion From Human Islets. Endocrinology 2020; 161:5902465. [PMID: 32894758 PMCID: PMC7567406 DOI: 10.1210/endocr/bqaa162] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 09/02/2020] [Indexed: 12/16/2022]
Abstract
The incidence of new onset diabetes after transplant (NODAT) has increased over the past decade, likely due to calcineurin inhibitor-based immunosuppressants, including tacrolimus (TAC) and cyclosporin. Voclosporin (VCS), a next-generation calcineurin inhibitor, is reported to cause fewer incidences of NODAT but the reason is unclear. While calcineurin signaling plays important roles in pancreatic β-cell survival, proliferation, and function, its effects on human β-cells remain understudied. In particular, we do not understand why some calcineurin inhibitors have more profound effects on the incidence of NODAT. We compared the effects of TAC and VCS on the dynamics of insulin secretory function, programmed cell death rate, and the transcriptomic profile of human islets. We studied 2 clinically relevant doses of TAC (10 ng/mL, 30 ng/mL) and VCS (20 ng/mL, 60 ng/mL), meant to approximate the clinical trough and peak concentrations. TAC, but not VCS, caused a significant impairment of 15 mM glucose-stimulated and 30 mM KCl-stimulated insulin secretion. This points to molecular defects in the distal stages of exocytosis after voltage-gated Ca2+ entry. No significant effects on islet cell survival or total insulin content were identified. RNA sequencing showed that TAC significantly decreased the expression of 17 genes, including direct and indirect regulators of exocytosis (SYT16, TBC1D30, PCK1, SMOC1, SYT5, PDK4, and CREM), whereas VCS has less broad, and milder, effects on gene expression. Clinically relevant doses of TAC, but not VCS, directly inhibit insulin secretion from human islets, likely via transcriptional control of exocytosis machinery.
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Affiliation(s)
- Jelena Kolic
- Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada
| | - Leanne Beet
- Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada
| | - Peter Overby
- Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada
| | - Haoning Howard Cen
- Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada
| | - Evgeniy Panzhinskiy
- Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences & Department of Surgery, University of British Columbia, Vancouver, Canada
| | - Daren R Ure
- Hepion Pharmaceuticals, Edmonton, Alberta, Canada
| | | | | | - James D Johnson
- Correspondence: Professor James D. Johnson, PhD, Faculty of Medicine, Department of Cellular and Physiological Sciences & Department of Surgery, The University of British Columbia, Life Sciences Institute, 5358 – 2350 Health Sciences Mall, Vancouver, British Columbia, Canada, V6T 1Z3. E-mail: ; Twitter: @JimJohnsonSci
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37
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Nguyen LD, Fischer TT, Abreu D, Arroyo A, Urano F, Ehrlich BE. Calpain inhibitor and ibudilast rescue β cell functions in a cellular model of Wolfram syndrome. Proc Natl Acad Sci U S A 2020; 117:17389-17398. [PMID: 32632005 PMCID: PMC7382278 DOI: 10.1073/pnas.2007136117] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Wolfram syndrome is a rare multisystem disease characterized by childhood-onset diabetes mellitus and progressive neurodegeneration. Most cases are attributed to pathogenic variants in a single gene, Wolfram syndrome 1 (WFS1). There currently is no disease-modifying treatment for Wolfram syndrome, as the molecular consequences of the loss of WFS1 remain elusive. Because diabetes mellitus is the first diagnosed symptom of Wolfram syndrome, we aimed to further examine the functions of WFS1 in pancreatic β cells in the context of hyperglycemia. Knockout (KO) of WFS1 in rat insulinoma (INS1) cells impaired calcium homeostasis and protein kinase B/Akt signaling and, subsequently, decreased cell viability and glucose-stimulated insulin secretion. Targeting calcium homeostasis with reexpression of WFS1, overexpression of WFS1's interacting partner neuronal calcium sensor-1 (NCS1), or treatment with calpain inhibitor and ibudilast reversed deficits observed in WFS1-KO cells. Collectively, our findings provide insight into the disease mechanism of Wolfram syndrome and highlight new targets and drug candidates to facilitate the development of a treatment for this disorder and similar diseases.
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Affiliation(s)
- Lien D Nguyen
- Department of Pharmacology, Yale University, New Haven, CT 06520
- Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520
| | - Tom T Fischer
- Department of Pharmacology, Yale University, New Haven, CT 06520
- Institute of Pharmacology, University of Heidelberg, 69117 Heidelberg, Germany
| | - Damien Abreu
- Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110
- Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110
| | - Alfredo Arroyo
- Department of Pharmacology, Yale University, New Haven, CT 06520
| | - Fumihiko Urano
- Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
| | - Barbara E Ehrlich
- Department of Pharmacology, Yale University, New Haven, CT 06520;
- Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520
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Abstract
Solid organ transplantation (SOT) is an established therapeutic option for chronic disease resulting from end-stage organ dysfunction. Long-term use of immunosuppression is associated with post-transplantation diabetes mellitus (PTDM), placing patients at increased risk of infections, cardiovascular disease and mortality. The incidence rates for PTDM have varied from 10 to 40% between different studies. Diagnostic criteria have evolved over the years, as a greater understating of PTDM has been reached. There are differences in pathophysiology and clinical course of type 2 diabetes and PTDM. Hence, managing this condition can be a challenge for a diabetes physician, as there are several factors to consider when tailoring therapy for post-transplant patients to achieve better glycaemic as well as long-term transplant outcomes. This article is a detailed review of PTDM, examining the pathogenesis, diagnostic criteria and management in light of the current evidence. The therapeutic options are discussed in the context of their safety and potential drug-drug interactions with immunosuppressive agents.
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Affiliation(s)
| | - Kathryn Biddle
- St George's University Hospitals NHS Foundation Trust, London, UK
| | | | - Shazli Azmi
- Manchester University NHS Foundation Trust, Manchester, UK
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Cheriyan VT, Alfaidi M, Jorgensen AN, Alam MA, Abdullah CS, Kolluru GK, Bhuiyan MS, Kevil CG, Orr AW, Nam HW. Neurogranin regulates eNOS function and endothelial activation. Redox Biol 2020; 34:101487. [PMID: 32173345 PMCID: PMC7327963 DOI: 10.1016/j.redox.2020.101487] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 02/27/2020] [Accepted: 02/29/2020] [Indexed: 02/07/2023] Open
Abstract
Endothelial nitric oxide (NO) is a critical mediator of vascular function and vascular remodeling. NO is produced by endothelial nitric oxide synthase (eNOS), which is activated by calcium (Ca2+)-dependent and Ca2+-independent pathways. Here, we report that neurogranin (Ng), which regulates Ca2+-calmodulin (CaM) signaling in the brain, is uniquely expressed in endothelial cells (EC) of human and mouse vasculature, and is also required for eNOS regulation. To test the role of Ng in eNOS activation, Ng knockdown in human aortic endothelial cells (HAEC) was performed using Ng SiRNA along with Ng knockout (Ng −/−) in mice. Depletion of Ng expression decreased eNOS activity in HAEC and NO production in mice. We show that Ng expression was decreased by short-term laminar flow and long-them oscillating flow shear stress, and that Ng siRNA with shear stress decreased eNOS expression as well as eNOS phosphorylation at S1177. We further reveled that lack of Ng expression decreases both AKT-dependent eNOS phosphorylation, NF-κB-mediated eNOS expression, and promotes endothelial activation. Our findings also indicate that Ng modulates Ca2+-dependent calcineurin (CaN) activity, which suppresses Ca2+-independent AKT-dependent eNOS signaling. Moreover, deletion of Ng in mice also reduced eNOS activity and caused endothelial dysfunction in flow-mediated dilation experiments. Our results demonstrate that Ng plays a crucial role in Ca2+-CaM-dependent eNOS regulation and contributes to vascular remodeling, which is important for the pathophysiology of cardiovascular disease.
Neurogranin is expressed in endothelial cell and is required for eNOS regulation. Short-term laminar flow and long-them oscillating flow decrease Neurogranin expression in endothelial cells. Neurogranin knockdown decreases both AKT-dependent eNOS phosphorylation and eNOS expression. Deletion of Ng in mice reduces eNOS activity and caused endothelial dysfunction in flow-mediated dilation.
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Affiliation(s)
- Vino T Cheriyan
- Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA
| | - Mabruka Alfaidi
- Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA
| | - Ashton N Jorgensen
- Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA
| | - Md Ashiqul Alam
- Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA
| | - Chowdhury S Abdullah
- Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA
| | - Gopi K Kolluru
- Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA
| | - Md Shenuarin Bhuiyan
- Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA
| | - Christopher G Kevil
- Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA
| | - A Wayne Orr
- Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA
| | - Hyung W Nam
- Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA.
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Torabi J, Konicki A, Rocca JP, Ajaimy M, Campbell A, Azzi Y, Pynadath C, Liriano-Ward L, Akalin E, Kinkhabwala M, Graham JA. The use of LCP-Tacrolimus (Envarsus XR) in simultaneous pancreas and kidney (SPK) transplant recipients. Am J Surg 2020; 219:583-586. [PMID: 32122660 DOI: 10.1016/j.amjsurg.2020.02.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 01/23/2020] [Accepted: 02/13/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Extended release LCP-tacrolimus (LCPT) allows once-daily dosing in transplant recipients. The improved bioavailability may be beneficial for simultaneous pancreas-kidney recipients (SPK). METHODS This is a study of 39 SPK recipients on standard immediate-release tacrolimus (IR-TAC, n = 21) or LCPT (n = 18). Coefficient of variability (CV = 100∗standard deviation/mean) was calculated to assess drug levels. Hemoglobin A1c (HbA1c), tacrolimus and creatinine levels were measured postoperatively. RESULTS There was no difference in tacrolimus CV in the IR-TAC and LCPT groups at 1 month or 3 months postoperatively; however, a greater difference was observed at 1 year (41.0 vs. 33.1%; p = 0.19). There were six episodes of acute rejection in the IR-TAC group compared to zero episodes in the LCPT group (p = 0.01). HbA1c was significantly higher in the IR-TAC group compared to LCPT at 3 (5.5 vs. 4.9%, p = 0.01), 6 (5.6 vs. 4.9%, p = 0.01) and 12 months (5.8 vs. 5.1%, p = 0.07). CONCLUSIONS Significantly lower rates of rejection were observed in patients receiving LCPT. The once daily dosing may facilitate medication adherence and result in improved long-term outcomes.
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Affiliation(s)
- Julia Torabi
- Albert Einstein College of Medicine, Bronx, NY, USA
| | | | - Juan P Rocca
- Albert Einstein College of Medicine, Bronx, NY, USA; Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, Bronx, NY, USA
| | - Maria Ajaimy
- Albert Einstein College of Medicine, Bronx, NY, USA; Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, Bronx, NY, USA
| | - Alesa Campbell
- Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, Bronx, NY, USA
| | - Yorg Azzi
- Albert Einstein College of Medicine, Bronx, NY, USA; Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, Bronx, NY, USA
| | - Cindy Pynadath
- Albert Einstein College of Medicine, Bronx, NY, USA; Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, Bronx, NY, USA
| | - Luz Liriano-Ward
- Albert Einstein College of Medicine, Bronx, NY, USA; Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, Bronx, NY, USA
| | - Enver Akalin
- Albert Einstein College of Medicine, Bronx, NY, USA; Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, Bronx, NY, USA
| | - Milan Kinkhabwala
- Albert Einstein College of Medicine, Bronx, NY, USA; Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, Bronx, NY, USA
| | - Jay A Graham
- Albert Einstein College of Medicine, Bronx, NY, USA; Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, Bronx, NY, USA.
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41
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Zhang IX, Raghavan M, Satin LS. The Endoplasmic Reticulum and Calcium Homeostasis in Pancreatic Beta Cells. Endocrinology 2020; 161:bqz028. [PMID: 31796960 PMCID: PMC7028010 DOI: 10.1210/endocr/bqz028] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Accepted: 12/01/2019] [Indexed: 12/14/2022]
Abstract
The endoplasmic reticulum (ER) mediates the first steps of protein assembly within the secretory pathway and is the site where protein folding and quality control are initiated. The storage and release of Ca2+ are critical physiological functions of the ER. Disrupted ER homeostasis activates the unfolded protein response (UPR), a pathway which attempts to restore cellular equilibrium in the face of ER stress. Unremitting ER stress, and insufficient compensation for it results in beta-cell apoptosis, a process that has been linked to both type 1 diabetes (T1D) and type 2 diabetes (T2D). Both types are characterized by progressive beta-cell failure and a loss of beta-cell mass, although the underlying causes are different. The reduction of mass occurs secondary to apoptosis in the case of T2D, while beta cells undergo autoimmune destruction in T1D. In this review, we examine recent findings that link the UPR pathway and ER Ca2+ to beta cell dysfunction. We also discuss how UPR activation in beta cells favors cell survival versus apoptosis and death, and how ER protein chaperones are involved in regulating ER Ca2+ levels. Abbreviations: BiP, Binding immunoglobulin Protein ER; endoplasmic reticulum; ERAD, ER-associated protein degradation; IFN, interferon; IL, interleukin; JNK, c-Jun N-terminal kinase; KHE, proton-K+ exchanger; MODY, maturity-onset diabetes of young; PERK, PRKR-like ER kinase; SERCA, Sarco/Endoplasmic Reticulum Ca2+-ATPases; T1D, type 1 diabetes; T2D, type 2 diabetes; TNF, tumor necrosis factor; UPR, unfolded protein response; WRS, Wolcott-Rallison syndrome.
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Affiliation(s)
- Irina X Zhang
- Department of Pharmacology and Brehm Diabetes Research Center, University of Michigan, Ann Arbor, MI
| | - Malini Raghavan
- Department of Microbiology and Immunology Michigan Medicine, University of Michigan, Ann Arbor, MI
| | - Leslie S Satin
- Department of Pharmacology and Brehm Diabetes Research Center, University of Michigan, Ann Arbor, MI
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Dai C, Walker JT, Shostak A, Padgett A, Spears E, Wisniewski S, Poffenberger G, Aramandla R, Dean ED, Prasad N, Levy SE, Greiner DL, Shultz LD, Bottino R, Powers AC. Tacrolimus- and sirolimus-induced human β cell dysfunction is reversible and preventable. JCI Insight 2020; 5:130770. [PMID: 31941840 PMCID: PMC7030815 DOI: 10.1172/jci.insight.130770] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 11/20/2019] [Indexed: 12/20/2022] Open
Abstract
Posttransplantation diabetes mellitus (PTDM) is a common and significant complication related to immunosuppressive agents required to prevent organ or cell transplant rejection. To elucidate the effects of 2 commonly used agents, the calcineurin inhibitor tacrolimus (TAC) and the mTOR inhibitor sirolimus (SIR), on islet function and test whether these effects could be reversed or prevented, we investigated human islets transplanted into immunodeficient mice treated with TAC or SIR at clinically relevant levels. Both TAC and SIR impaired insulin secretion in fasted and/or stimulated conditions. Treatment with TAC or SIR increased amyloid deposition and islet macrophages, disrupted insulin granule formation, and induced broad transcriptional dysregulation related to peptide processing, ion/calcium flux, and the extracellular matrix; however, it did not affect regulation of β cell mass. Interestingly, these β cell abnormalities reversed after withdrawal of drug treatment. Furthermore, cotreatment with a GLP-1 receptor agonist completely prevented TAC-induced β cell dysfunction and partially prevented SIR-induced β cell dysfunction. These results highlight the importance of both calcineurin and mTOR signaling in normal human β cell function in vivo and suggest that modulation of these pathways may prevent or ameliorate PTDM.
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Affiliation(s)
- Chunhua Dai
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and
| | - John T. Walker
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Alena Shostak
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and
| | - Ana Padgett
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and
| | - Erick Spears
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and
| | - Scott Wisniewski
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and
| | - Greg Poffenberger
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and
| | - Radhika Aramandla
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and
| | - E. Danielle Dean
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and
| | - Nripesh Prasad
- HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA
| | - Shawn E. Levy
- HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA
| | - Dale L. Greiner
- Department of Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | | | - Rita Bottino
- Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
| | - Alvin C. Powers
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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43
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Wang L, Chang JH, Buckley AF, Spurney RF. Knockout of TRPC6 promotes insulin resistance and exacerbates glomerular injury in Akita mice. Kidney Int 2020; 95:321-332. [PMID: 30665571 DOI: 10.1016/j.kint.2018.09.026] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 09/22/2018] [Accepted: 09/27/2018] [Indexed: 12/17/2022]
Abstract
Gain-of-function mutations in TRPC6 cause familial focal segmental glomerulosclerosis, and TRPC6 is upregulated in glomerular diseases including diabetic kidney disease. We studied the effect of systemic TRPC6 knockout in the Akita model of type 1 diabetes. Knockout of TRPC6 inhibited albuminuria in Akita mice at 12 and 16 weeks of age, but this difference disappeared by 20 weeks. Knockout of TRPC6 also reduced tubular injury in Akita mice; however, mesangial expansion was significantly increased. Hyperglycemia and blood pressure were similar between TRPC6 knockout and wild-type Akita mice, but knockout mice were more insulin resistant. In cultured podocytes, knockout of TRPC6 inhibited expression of the calcium/calcineurin responsive gene insulin receptor substrate 2 and decreased insulin responsiveness. Insulin resistance is reported to promote diabetic kidney disease independent of blood glucose levels. While the mechanisms are not fully understood, insulin activates both Akt2 and ERK, which inhibits apoptosis signal regulated kinase 1 (ASK1)-p38-induced apoptosis. In cultured podocytes, hyperglycemia stimulated p38 signaling and induced apoptosis, which was reduced by insulin and ASK1 inhibition and enhanced by Akt or ERK inhibition. Glomerular p38 signaling was increased in TRPC6 knockout Akita mice and was associated with enhanced expression of the p38 gene target cyclooxygenase 2. These data suggest that knockout of TRPC6 in Akita mice promotes insulin resistance and exacerbates glomerular disease independent of hyperglycemia.
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Affiliation(s)
- Liming Wang
- Division of Nephrology, Department of Medicine, Duke University Health System, Durham, North Carolina, USA
| | - Jae-Hyung Chang
- Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Anne F Buckley
- Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA
| | - Robert F Spurney
- Division of Nephrology, Department of Medicine, Duke University Health System, Durham, North Carolina, USA; Durham VA Medical Center, Durham, North Carolina, USA.
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Fan L, Shan A, Su Y, Cheng Y, Ji H, Yang Q, Lei Y, Liu B, Wang W, Ning G, Cao Y, Jiang X. MiR-221/222 Inhibit Insulin Production of Pancreatic β-Cells in Mice. Endocrinology 2020; 161:5639771. [PMID: 31761936 DOI: 10.1210/endocr/bqz027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 11/23/2019] [Indexed: 11/19/2022]
Abstract
Microribonucleic acids (miRNAs) are essential for the regulation of development, proliferation, and functions of pancreatic β-cells. The conserved miR-221/222 cluster is an important regulator in multiple cellular processes. Here we investigated the functional role of miR-221/222 in the regulation of β-cell proliferation and functions in transgenic mouse models. We generated 2 pancreatic β-cell-specific-miR-221/222 transgenic mouse models on a C57BL/6J background. The glucose metabolic phenotypes, β-cell mass, and β-cell functions were analyzed in the mouse models. Adenovirus-mediated overexpression of miR-221/222 was performed on β-cells and mouse insulinoma 6 (MIN6) cells to explore the effect and mechanisms of miR-221/222 on β-cell proliferation and functions. Luciferase reporter assay, histological analysis, and quantitative polymerase chain reaction (PCR) were carried out to study the direct target genes of miR-221/222 in β-cells. The expression of miR-221/222 was significantly upregulated in β-cells from the high-fat diet (HFD)-fed mice and db/db mice. Overexpression of miR-221/222 impaired the insulin production and secretion of β-cells and resulted in glucose intolerance in vivo. The β-cell mass and proliferation were increased by miR-221/222 expression via Cdkn1b and Cdkn1c. MiR-221/222 repressed insulin transcription activity through targeting Nfatc3 and lead to reduction of insulin in β-cells. Our findings demonstrate that miR-221/222 are important regulators of β-cell proliferation and insulin production. The expression of miR-221/222 in β-cells could regulate glucose metabolism in physiological and pathological processes.
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Affiliation(s)
- Liwen Fan
- National Clinical Research Centre for Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Aijing Shan
- National Clinical Research Centre for Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Yutong Su
- National Clinical Research Centre for Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Yulong Cheng
- National Clinical Research Centre for Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - He Ji
- National Clinical Research Centre for Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Qi Yang
- National Clinical Research Centre for Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Ying Lei
- National Clinical Research Centre for Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Bei Liu
- National Clinical Research Centre for Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Weiqing Wang
- National Clinical Research Centre for Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Guang Ning
- National Clinical Research Centre for Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Yanan Cao
- National Clinical Research Centre for Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Xiuli Jiang
- National Clinical Research Centre for Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
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45
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Calcium Signaling in ß-cell Physiology and Pathology: A Revisit. Int J Mol Sci 2019; 20:ijms20246110. [PMID: 31817135 PMCID: PMC6940736 DOI: 10.3390/ijms20246110] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 11/28/2019] [Accepted: 12/02/2019] [Indexed: 12/12/2022] Open
Abstract
Pancreatic beta (β) cell dysfunction results in compromised insulin release and, thus, failed regulation of blood glucose levels. This forms the backbone of the development of diabetes mellitus (DM), a disease that affects a significant portion of the global adult population. Physiological calcium (Ca2+) signaling has been found to be vital for the proper insulin-releasing function of β-cells. Calcium dysregulation events can have a dramatic effect on the proper functioning of the pancreatic β-cells. The current review discusses the role of calcium signaling in health and disease in pancreatic β-cells and provides an in-depth look into the potential role of alterations in β-cell Ca2+ homeostasis and signaling in the development of diabetes and highlights recent work that introduced the current theories on the connection between calcium and the onset of diabetes.
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Ferreira DMS, Cheng AJ, Agudelo LZ, Cervenka I, Chaillou T, Correia JC, Porsmyr-Palmertz M, Izadi M, Hansson A, Martínez-Redondo V, Valente-Silva P, Pettersson-Klein AT, Estall JL, Robinson MM, Nair KS, Lanner JT, Ruas JL. LIM and cysteine-rich domains 1 (LMCD1) regulates skeletal muscle hypertrophy, calcium handling, and force. Skelet Muscle 2019; 9:26. [PMID: 31666122 PMCID: PMC6822430 DOI: 10.1186/s13395-019-0214-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 09/30/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Skeletal muscle mass and strength are crucial determinants of health. Muscle mass loss is associated with weakness, fatigue, and insulin resistance. In fact, it is predicted that controlling muscle atrophy can reduce morbidity and mortality associated with diseases such as cancer cachexia and sarcopenia. METHODS We analyzed gene expression data from muscle of mice or human patients with diverse muscle pathologies and identified LMCD1 as a gene strongly associated with skeletal muscle function. We transiently expressed or silenced LMCD1 in mouse gastrocnemius muscle or in mouse primary muscle cells and determined muscle/cell size, targeted gene expression, kinase activity with kinase arrays, protein immunoblotting, and protein synthesis levels. To evaluate force, calcium handling, and fatigue, we transduced the flexor digitorum brevis muscle with a LMCD1-expressing adenovirus and measured specific force and sarcoplasmic reticulum Ca2+ release in individual fibers. Finally, to explore the relationship between LMCD1 and calcineurin, we ectopically expressed Lmcd1 in the gastrocnemius muscle and treated those mice with cyclosporine A (calcineurin inhibitor). In addition, we used a luciferase reporter construct containing the myoregulin gene promoter to confirm the role of a LMCD1-calcineurin-myoregulin axis in skeletal muscle mass control and calcium handling. RESULTS Here, we identify LIM and cysteine-rich domains 1 (LMCD1) as a positive regulator of muscle mass, that increases muscle protein synthesis and fiber size. LMCD1 expression in vivo was sufficient to increase specific force with lower requirement for calcium handling and to reduce muscle fatigue. Conversely, silencing LMCD1 expression impairs calcium handling and force, and induces muscle fatigue without overt atrophy. The actions of LMCD1 were dependent on calcineurin, as its inhibition using cyclosporine A reverted the observed hypertrophic phenotype. Finally, we determined that LMCD1 represses the expression of myoregulin, a known negative regulator of muscle performance. Interestingly, we observed that skeletal muscle LMCD1 expression is reduced in patients with skeletal muscle disease. CONCLUSIONS Our gain- and loss-of-function studies show that LMCD1 controls protein synthesis, muscle fiber size, specific force, Ca2+ handling, and fatigue resistance. This work uncovers a novel role for LMCD1 in the regulation of skeletal muscle mass and function with potential therapeutic implications.
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Affiliation(s)
- Duarte M S Ferreira
- Molecular & Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden
| | - Arthur J Cheng
- Molecular Muscle Physiology and Pathophysiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden.,Present Address: Faculty of Health, York University, School of Kinesiology and Health Science, Toronto, Ontario, Canada
| | - Leandro Z Agudelo
- Molecular & Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden.,Present Address: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Igor Cervenka
- Molecular & Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden
| | - Thomas Chaillou
- Molecular Muscle Physiology and Pathophysiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden.,School of Health Sciences, Örebro University, Örebro, Sweden
| | - Jorge C Correia
- Molecular & Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden
| | - Margareta Porsmyr-Palmertz
- Molecular & Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden
| | - Manizheh Izadi
- Molecular & Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden.,Present Address: Karp Research Building, Boston, MA, 02115, USA
| | - Alicia Hansson
- Molecular & Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden
| | - Vicente Martínez-Redondo
- Molecular & Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden
| | - Paula Valente-Silva
- Molecular & Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden
| | - Amanda T Pettersson-Klein
- Molecular & Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden
| | - Jennifer L Estall
- Division of Cardiovascular and Metabolic Disease, Institut de recherches cliniques de Montreal (IRCM), Montreal, QC, Canada
| | - Matthew M Robinson
- Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester, MN, 55905, USA
| | - K Sreekumaran Nair
- Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester, MN, 55905, USA
| | - Johanna T Lanner
- Molecular Muscle Physiology and Pathophysiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden
| | - Jorge L Ruas
- Molecular & Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum, SE-171 77, Stockholm, Sweden.
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Luo K, Yu JH, Quan Y, Shin YJ, Lee KE, Kim HL, Ko EJ, Chung BH, Lim SW, Yang CW. Therapeutic potential of coenzyme Q 10 in mitochondrial dysfunction during tacrolimus-induced beta cell injury. Sci Rep 2019; 9:7995. [PMID: 31142763 PMCID: PMC6541596 DOI: 10.1038/s41598-019-44475-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 05/17/2019] [Indexed: 02/06/2023] Open
Abstract
We previously reported that oxidative stress induced by long-term tacrolimus treatment impairs mitochondrial function in pancreatic beta cells. In this study, we aimed to investigate the therapeutic potential of coenzyme Q10, which is known to be a powerful antioxidant, in mitochondrial dysfunction in tacrolimus-induced diabetic rats. In a rat model of tacrolimus-induced diabetes mellitus, coenzyme Q10 treatment improved pancreatic beta cell function. The administration of coenzyme Q10 improved insulin immunoreactivity within islets, which was accompanied by reductions in oxidative stress and apoptosis. Assessment of the mitochondrial ultrastructure by electron microscopy revealed that coenzyme Q10 treatment increased the size, number, and volume of mitochondria, as well as the number of insulin granules compared with that induced by tacrolimus treatment alone. An in vitro study using a pancreatic beta cell line showed that tacrolimus treatment increased apoptosis and the production of mitochondrial reactive oxygen species, while cotreatment with coenzyme Q10 effectively attenuated these alterations. At the subcellular level, tacrolimus-induced impairment of mitochondrial respiration was significantly improved by coenzyme Q10, as evidenced by the increased mitochondrial oxygen consumption and ATP production. Our data indicate that coenzyme Q10 plays an important role in reducing tacrolimus-induced oxidative stress and protects the mitochondria in pancreatic beta cells. These findings suggest that supplementation with coenzyme Q10 has beneficial effects in tacrolimus-induced diabetes mellitus.
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Affiliation(s)
- Kang Luo
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea.,Transplant Research Center, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea
| | - Ji Hyun Yu
- Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Korea
| | - Yi Quan
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea.,Transplant Research Center, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea
| | - Yoo Jin Shin
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea.,Transplant Research Center, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea
| | - Kyung Eun Lee
- Advanced Analysis Center, Korea Institute of Science and Technology, Seoul, Korea
| | - Hong Lim Kim
- Integrative Research Support Center, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea
| | - Eun Jeong Ko
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea.,Transplant Research Center, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea.,Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Korea
| | - Byung Ha Chung
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea.,Transplant Research Center, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea.,Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Korea
| | - Sun Woo Lim
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea. .,Transplant Research Center, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea.
| | - Chul Woo Yang
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea.,Transplant Research Center, The Catholic University of Korea School of Medicine, Seoul, Republic of Korea.,Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Korea
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48
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Choudhury PS, Mukhopadhyay P, Roychowdhary A, Chowdhury S, Ghosh S. Prevalence and Predictors of "New-onset Diabetes after Transplantation" (NODAT) in Renal Transplant Recipients: An Observational Study. Indian J Endocrinol Metab 2019; 23:273-277. [PMID: 31641626 PMCID: PMC6683686 DOI: 10.4103/ijem.ijem_178_19] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVE New-onset diabetes after transplantation (NODAT) develops frequently after renal transplant. The study aims at the prevalence of NODAT, predictors for developing it and therapeutic glycemic responses in NODAT. MATERIALS AND METHODS Consecutive renal transplant recipients excluding Diabetic Kidney Disease (DKD) or pretransplant diabetes were evaluated. Forty-three out of 250 persons were found to have NODAT. Ninety age-matched transplant recipients from the rest were recruited as control. Fasting blood sugar (FBS), HbA1c, lipid profile, and trough tacrolimus level (T0) were examined in all. HOMA IR C-peptide and HOMA-beta C-peptide were calculated. RESULTS Prevalence of NODAT in renal transplant recipients was 17.2% (43/250). Twenty-four (55.8%) developed early NODAT (<1 year) and 19 (44.2%) developed late NODAT (>1 year). Significantly higher pretransplant body mass index (BMI) (kg/m2) (P < 0.001), waist circumference (WC) (cm) (P < 0.001), pretransplant cholesterol (mg%) (P = 0.04), triglyceride (mg%) (P < 0.001), and FBS (mg%) (P < 0.001) were found in NODAT compared with non-NODAT. Trough tacrolimus (ng/mL) was found to be higher in NODAT (10.2 vs. 5.37, P < 0.001). Though HOMA IR was not found to be different between groups, HOMA-beta C-peptide was low in NODAT compared with non-NODAT (P = 0.03). Predictors of NODAT were WC [odds ratio (OR) = 01.15] and trough tacrolimus level (OR = 1.316). Best cut-off of WC for predicting NODAT was 87.5 cm for male and 83.5 cm for female. Best cut-off of T0 was 8.5 ng/mL. In NODAT, 9.3% were treated by lifestyle modification, 67.4% by oral hypoglycemic agents, 11.6% by insulin, and 11.6% by combined insulin and oral antidiabetic agents with HbA1c <7%. CONCLUSION NODAT in renal transplant recipients is more common in those with higher pretransplant BMI, WC, pretransplant total cholesterol, triglyceride, and FBS. Beta-cell secretory defect is more relevant as etiological factor rather than insulin resistance. Higher WC and trough tacrolimus level above 8.5 ng/mL may be important factors for predicting NODAT.
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Affiliation(s)
| | | | | | | | - Sujoy Ghosh
- Department of Endocrinology, IPGME&R, Kolkata, West Bengal, India
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Sabatini PV, Speckmann T, Lynn FC. Friend and foe: β-cell Ca 2+ signaling and the development of diabetes. Mol Metab 2019; 21:1-12. [PMID: 30630689 PMCID: PMC6407368 DOI: 10.1016/j.molmet.2018.12.007] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 12/03/2018] [Accepted: 12/19/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The divalent cation Calcium (Ca2+) regulates a wide range of processes in disparate cell types. Within insulin-producing β-cells, increases in cytosolic Ca2+ directly stimulate insulin vesicle exocytosis, but also initiate multiple signaling pathways. Mediated through activation of downstream kinases and transcription factors, Ca2+-regulated signaling pathways leverage substantial influence on a number of critical cellular processes within the β-cell. Additionally, there is evidence that prolonged activation of these same pathways is detrimental to β-cell health and may contribute to Type 2 Diabetes pathogenesis. SCOPE OF REVIEW This review aims to briefly highlight canonical Ca2+ signaling pathways in β-cells and how β-cells regulate the movement of Ca2+ across numerous organelles and microdomains. As a main focus, this review synthesizes experimental data from in vitro and in vivo models on both the beneficial and detrimental effects of Ca2+ signaling pathways for β-cell function and health. MAJOR CONCLUSIONS Acute increases in intracellular Ca2+ stimulate a number of signaling cascades, resulting in (de-)phosphorylation events and activation of downstream transcription factors. The short-term stimulation of these Ca2+ signaling pathways promotes numerous cellular processes critical to β-cell function, including increased viability, replication, and insulin production and secretion. Conversely, chronic stimulation of Ca2+ signaling pathways increases β-cell ER stress and results in the loss of β-cell differentiation status. Together, decades of study demonstrate that Ca2+ movement is tightly regulated within the β-cell, which is at least partially due to its dual roles as a potent signaling molecule.
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Affiliation(s)
- Paul V Sabatini
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Thilo Speckmann
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Francis C Lynn
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
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Grancini V, Resi V, Palmieri E, Pugliese G, Orsi E. Management of diabetes mellitus in patients undergoing liver transplantation. Pharmacol Res 2019; 141:556-573. [PMID: 30690071 DOI: 10.1016/j.phrs.2019.01.042] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 01/24/2019] [Accepted: 01/24/2019] [Indexed: 02/07/2023]
Abstract
Diabetes is a common feature in cirrhotic individuals both before and after liver transplantation and negatively affects prognosis. Certain aetiological agents of chronic liver disease and loss of liver function per se favour the occurrence of pre-transplant diabetes in susceptible individuals, whereas immunosuppressant treatment, changes in lifestyle habits, and donor- and procedure-related factors contribute to diabetes development/persistence after transplantation. Challenges in the management of pre-transplant diabetes include the profound nutritional alterations characterizing cirrhotic individuals and the limitations to the use of drugs with liver metabolism. Special issues in the management of post-transplant diabetes include the diabetogenic potential of immunosuppressant drugs and the increased cardiovascular risk characterizing solid organ transplant survivors. Overall, the pharmacological management of cirrhotic patients undergoing liver transplantation is complicated by the lack of specific guidelines reflecting the paucity of data on the impact of glycaemic control and the safety and efficacy of anti-hyperglycaemic agents in these individuals.
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Affiliation(s)
- Valeria Grancini
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Veronica Resi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Eva Palmieri
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Diabetes Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Emanuela Orsi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
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