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Ruan H, Li W, Chang H, Wen M, Luo S, Song F, Ye L, Mei J, Zhu X, Liu X, Jiang N. Antioxidant, Hypoglycemic, and Hypolipidemic Effects of Puerarin In Vivo. Food Sci Nutr 2025; 13:e70257. [PMID: 40336535 PMCID: PMC12056237 DOI: 10.1002/fsn3.70257] [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: 08/26/2024] [Revised: 03/12/2025] [Accepted: 04/25/2025] [Indexed: 05/09/2025] Open
Abstract
Puerarin (PUE) exhibits various pharmacological effects. This study evaluated its antioxidant, hypoglycemic, and hypolipidemic effects in vivo using models of aging, diabetes, and hyperlipidemia. D-galactose-induced aging, streptozotocin (STZ)-induced diabetic, and high-fat diet-induced hyperlipidemic mouse models were established. To evaluate the therapeutic effects, mice were administered various doses of PUE (50, 100, and 200 mg/kg). Results showed that PUE treatment improved antioxidant enzyme activities and reduced serum and liver malondialdehyde (MDA) levels in aging mice, thereby mitigating cellular oxidative stress. In diabetic mice, fasting blood glucose (FBG) levels were observed to decrease, while hepatic hexokinase (HK) activity, pyruvate kinase (PK) activity, and insulin levels increased after 7 weeks of PUE treatment. Furthermore, PUE significantly enhanced blood lipid profiles and antioxidant enzyme properties in diabetic mice. In hyperlipidemic mice, PUE administration led to decreased levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C), while increasing high-density lipoprotein cholesterol (HDL-C). These findings indicate that PUE possesses antioxidant, hypoglycemic, and hypolipidemic properties and shows potential for treating aging and related diseases like type 2 diabetes and hyperlipidemia.
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Affiliation(s)
- Hong Ruan
- Hubei Key Laboratory of Biologic Resources Protection and UtilizationHubei Minzu UniversityEnshiPeople's Republic of China
- School of Biological Science and TechnologyHubei Minzu UniversityEnshiPeople's Republic of China
| | - Wanqing Li
- School of Biological Science and TechnologyHubei Minzu UniversityEnshiPeople's Republic of China
| | - Huien Chang
- School of Biological Science and TechnologyHubei Minzu UniversityEnshiPeople's Republic of China
| | - Manlin Wen
- School of Biological Science and TechnologyHubei Minzu UniversityEnshiPeople's Republic of China
| | - Shouchun Luo
- School of Biological Science and TechnologyHubei Minzu UniversityEnshiPeople's Republic of China
| | - Fangshuai Song
- Hubei Key Laboratory of Biologic Resources Protection and UtilizationHubei Minzu UniversityEnshiPeople's Republic of China
| | - Li Ye
- School of Biological Science and TechnologyHubei Minzu UniversityEnshiPeople's Republic of China
| | - Jie Mei
- School of Biological Science and TechnologyHubei Minzu UniversityEnshiPeople's Republic of China
| | - Xiqiang Zhu
- Hubei Key Laboratory of Biologic Resources Protection and UtilizationHubei Minzu UniversityEnshiPeople's Republic of China
- School of Biological Science and TechnologyHubei Minzu UniversityEnshiPeople's Republic of China
| | - Xiaopeng Liu
- Hubei Key Laboratory of Biologic Resources Protection and UtilizationHubei Minzu UniversityEnshiPeople's Republic of China
- School of Biological Science and TechnologyHubei Minzu UniversityEnshiPeople's Republic of China
| | - Ning Jiang
- Hubei Key Laboratory of Biologic Resources Protection and UtilizationHubei Minzu UniversityEnshiPeople's Republic of China
- School of Biological Science and TechnologyHubei Minzu UniversityEnshiPeople's Republic of China
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Lan C, Li Y, Weng Z, Pan W, Lin W, Jiang Z, Yang L, Shen X. TLR4 mediates lipotoxic β-cell dysfunction by inhibiting the TMEM24/PI3K/AKT pathway. Acta Biochim Biophys Sin (Shanghai) 2025. [PMID: 40170616 DOI: 10.3724/abbs.2025045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2025] Open
Abstract
Immune imbalance is the core pathophysiological mechanism of the deterioration of β-cell function driven by lipid metabolism disorders. Toll-like receptor 4 (TLR4) inflammatory signaling is a key pathway that mediates lipotoxic injury in β-cells, but the underlying mechanism needs to be further elucidated. Transmembrane protein 24 (TMEM24) is a key transporter that regulates pulsatile insulin secretion, but its pathophysiology in lipotoxicity remains unclear. In this study, we investigate whether TLR4-mediated lipotoxicity is affected by the inhibition of TMEM24 expression. The PPI network shows that TLR4 is associated with both insulin secretion and ER stress proteins in islets from obese rats. Using in vitro lipotoxic β-cell models, we found that TMEM24 is the target signal of palmitic acid (PA)-induced insulin secretion impairment in islet β-cells, and TLR4 plays a mediating role in this process. Mechanistically, TLR4 mediates lipotoxicity by binding to TMEM24 and downregulating its protein expression to suppress PI3K/AKT signaling, leading to β-cell dysfunction. TLR4 knockout ameliorates islet function impairment through TMEM24/PI3K/AKT signaling in HFD-induced obese rats. Taken together, our results show that TLR4 mediates lipotoxicity in islet β-cells by inhibiting the TMEM24/PI3K/AKT pathway, and the mechanism of TLR4-mediated lipotoxicity is elucidated from the perspective of insulin vesicular secretion.
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Affiliation(s)
- Chao Lan
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Diabetes Research Institute of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Metabolic Diseases Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Yan Li
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Zhiyan Weng
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Wei Pan
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Wanxin Lin
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Zhen Jiang
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Diabetes Research Institute of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Metabolic Diseases Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Liyong Yang
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Diabetes Research Institute of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Metabolic Diseases Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Ximei Shen
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Diabetes Research Institute of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Metabolic Diseases Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
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Ježek P. Physiological Fatty Acid-Stimulated Insulin Secretion and Redox Signaling Versus Lipotoxicity. Antioxid Redox Signal 2025; 42:566-622. [PMID: 39834189 DOI: 10.1089/ars.2024.0799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Significance: Type 2 diabetes as a world-wide epidemic is characterized by the insulin resistance concomitant to a gradual impairment of β-cell mass and function (prominently declining insulin secretion) with dysregulated fatty acids (FAs) and lipids, all involved in multiple pathological development. Recent Advances: Recently, redox signaling was recognized to be essential for insulin secretion stimulated with glucose (GSIS), branched-chain keto-acids, and FAs. FA-stimulated insulin secretion (FASIS) is a normal physiological event upon postprandial incoming chylomicrons. This contrasts with the frequent lipotoxicity observed in rodents. Critical Issues: Overfeeding causes FASIS to overlap with GSIS providing repeating hyperinsulinemia, initiates prediabetic states by lipotoxic effects and low-grade inflammation. In contrast the protective effects of lipid droplets in human β-cells counteract excessive lipids. Insulin by FASIS allows FATP1 recruitment into adipocyte plasma membranes when postprandial chylomicrons come late at already low glycemia. Future Directions: Impaired states of pancreatic β-cells and peripheral organs at prediabetes and type 2 diabetes should be revealed, including the inter-organ crosstalk by extracellular vesicles. Details of FA/lipid molecular physiology are yet to be uncovered, such as complex phenomena of FA uptake into cells, postabsorptive inactivity of G-protein-coupled receptor 40, carnitine carrier substrate specificity, the role of carnitine-O-acetyltransferase in β-cells, and lipid droplet interactions with mitochondria. Antioxid. Redox Signal. 42, 566-622.
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Affiliation(s)
- Petr Ježek
- Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
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Holendová B, Stokičová L, Plecitá-Hlavatá L. Lipid Dynamics in Pancreatic β-Cells: Linking Physiology to Diabetes Onset. Antioxid Redox Signal 2024; 41:865-889. [PMID: 39495600 DOI: 10.1089/ars.2024.0724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2024]
Abstract
Significance: Glucose-induced lipid metabolism is essential for preserving functional β-cells, and its disruption is linked to type 2 diabetes (T2D) development. Lipids are an integral part of the cells playing an indispensable role as structural components, energy storage molecules, and signals. Recent Advances: Glucose presence significantly impacts lipid metabolism in β-cells, where fatty acids are primarily synthesized de novo and/or are transported from the bloodstream. This process is regulated by the glycerolipid/free fatty acid cycle, which includes lipogenic and lipolytic reactions producing metabolic coupling factors crucial for insulin secretion. Disrupted lipid metabolism involving oxidative stress and inflammation is a hallmark of T2D. Critical Issues: Lipid metabolism in β-cells is complex involving multiple simultaneous processes. Exact compartmentalization and quantification of lipid metabolism and its intermediates, especially in response to glucose or chronic hyperglycemia, are essential. Current research often uses non-physiological conditions, which may not accurately reflect in vivo situations. Future Directions: Identifying and quantifying individual steps and their signaling, including redox, within the complex fatty acid and lipid metabolic pathways as well as the metabolites formed during acute versus chronic glucose stimulation, will uncover the detailed mechanisms of glucose-stimulated insulin secretion. This knowledge is crucial for understanding T2D pathogenesis and identifying pharmacological targets to prevent this disease. Antioxid. Redox Signal. 41, 865-889.
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Affiliation(s)
- Blanka Holendová
- Laboratory of Pancreatic Islet Research, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Linda Stokičová
- Laboratory of Pancreatic Islet Research, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
- Charles University, Prague, Czech Republic
| | - Lydie Plecitá-Hlavatá
- Laboratory of Pancreatic Islet Research, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
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Wang Y, Yang Z, Tang H, Sun X, Qu J, Lu S, Rao B. Faecal microbiota transplantation is better than probiotics for tissue regeneration of type 2 diabetes mellitus injuries in mice. Arch Physiol Biochem 2024; 130:333-341. [PMID: 35675471 DOI: 10.1080/13813455.2022.2080229] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 12/25/2022]
Abstract
CONTEXT Western diet and unhealthy lifestyle have contributed to the continued growth of type 2 diabetes mellitus (T2DM). T2DM is associated with dysbacteriosis, and studies have found that altering the gut microbiota has a positive effect on treatment. OBJECTIVE In addition to hyperglycaemia, T2DM often causes damage to multiple organs. However, there are few studies on organ damage from faecal microbiota transplantation (FMT). MATERIALS AND METHODS T2DM mice were divided into four groups and were given phosphate buffered saline (PBS) (T2DM group), FMT (FMT group), Lactobacillus (LAB group), and Bifidobacterium (BIO group) by gavage for six weeks, respectively. Mice on a normal diet (control group) were gavaged with PBS for six weeks. RESULTS After gavage treatment, FMT, LAB, and BIO groups were similar in lowering glucose, endotoxemia was slightly reduced, and the colonic mucus layer and liver lobules developed towards normal tissue. Surprisingly, we found that the FMT group had unique effects on islet cell regeneration, increased functional β cells, and insulin sensitivity. DISCUSSION AND CONCLUSION Lactobacillus has the best glucose-lowering effect, but FMT has obvious advantages in β-cell regeneration, which provides new treatment ideas for tissue damage caused by T2DM.
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Affiliation(s)
- Yuying Wang
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou, China
- Department of Gastrointestinal Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Zhenpeng Yang
- Department of Gastrointestinal Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Huazhen Tang
- Department of Gastrointestinal Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Xibo Sun
- Department of Gastrointestinal Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Jinxiu Qu
- Department of Gastrointestinal Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Shuai Lu
- Department of Gastrointestinal Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Benqiang Rao
- Department of Gastrointestinal Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
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Li A, Guan L, Su W, Zhao N, Song X, Wang J, Tang X, Li W, Jiao X. TXNIP inhibition in the treatment of type 2 diabetes mellitus: design, synthesis, and biological evaluation of quinazoline derivatives. J Enzyme Inhib Med Chem 2023; 38:2166937. [PMID: 36651294 PMCID: PMC9858527 DOI: 10.1080/14756366.2023.2166937] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Thioredoxin interacting protein (TXNIP) is a potential drug target for type 2 diabetes mellitus (T2DM) treatment. A series of quinazoline derivatives were designed, synthesised, and evaluated to inhibit TXNIP expression and protect from palmitate (PA)-induced β cell injury. In vitro cell viability assay showed that compounds D-2 and C-1 could effectively protect β cell from PA-induced apoptosis, and subsequent results showed that these two compounds decreased TXNIP expression by accelerating its protein degradation. Mechanistically, compounds D-2 and C-1 reduced intracellular reactive oxygen species (ROS) production and modulated TXNIP-NLRP3 inflammasome signalling, and thus alleviating oxidative stress injury and inflammatory response under PA insult. Besides, these two compounds were predicted to possess better drug-likeness properties using SwissADME. The present study showed that compounds D-2 and C-1, especially compound D-2, were potent pancreatic β cell protective agents to inhibit TXNIP expression and might serve as promising lead candidates for the treatment of T2DM.
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Affiliation(s)
- Aiyun Li
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan, PR China
| | - Li Guan
- College of Pharmacy, Xi’an Medical University, Xi’an, PR China
| | - Wanzhen Su
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan, PR China
| | - Ning Zhao
- College of Pharmacy, Xi’an Medical University, Xi’an, PR China
| | - Xuwen Song
- College of Pharmacy, Xi’an Medical University, Xi’an, PR China
| | - Jin Wang
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan, PR China
| | - Xiaoxiao Tang
- College of Pharmacy, Xi’an Medical University, Xi’an, PR China
| | - Weize Li
- College of Pharmacy, Xi’an Medical University, Xi’an, PR China,CONTACT Xiangying Jiao Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan030001, PR China
| | - Xiangying Jiao
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan, PR China,Weize Li College of Pharmacy, Xi’an Medical University, Xi’an710021, PR China
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Sui M, Li T, Lu H, Li Y, Huang J, Zhang P, Wang S, Zeng L. SOCS3 inhibits the mesenchymal stromal cell secretory factor SDF-1-mediated improvement of islet function in non-obese diabetic mice. Stem Cell Res Ther 2023; 14:172. [PMID: 37400916 DOI: 10.1186/s13287-023-03347-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/18/2023] [Indexed: 07/05/2023] Open
Abstract
BACKGROUND Islet transplantation is used therapeutically in a minority of patients with type 1 diabetes (T1D). However, successful outcomes are hampered by early islet β-cell loss caused by immune rejection and autoimmunity. Recent studies have demonstrated that mesenchymal stromal cells can enhance islet function both in vitro and in vivo by secreting ligands that activate islet G-protein coupled receptors (GPCRs). Stromal cell-derived factor 1 (SDF-1) is an MSC-secreted GPCR ligand, whereas the suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of STAT3-activating cytokines. Here, we determined whether improvement in islet function mediated by exogenous SDF-1 is impaired by SOCS3 in experimental models of T1D. METHODS Isolated islets were cultured for 48 h with SDF-1. Cytokine-induced apoptosis was measured immediately. Islets from Socs3-/- mice were pre-cultured with exogenous SDF-1 and transplanted underneath the kidney capsule of C57BL/6 mice with streptozotocin-induced diabetes. Blood glucose levels were monitored for 28 days. AMD3100, an antagonist of the SDF-1 ligand CXCR4, was administered subcutaneously to islet transplanted mice to inhibit CXCR4 before and after transplantation. RESULTS SDF-1 protected islet cells from cytokine-induced apoptosis in vitro. SOCS3-knockout (KO) islets pretreated with SDF-1 were effective in reducing blood glucose in non-obese diabetic mice in vivo. We found that SDF-1 elicits localized immunosuppression in transplanted SOCS3-KO islets. Immunomodulation was observed when SOCS-KO islets were preconditioned with SDF-1. Gene expression and flow cytometric analyses revealed significantly decreased immune cell infiltration, inflammatory cytokines, and concomitant increases in FOXP3+ regulatory T cells, alternatively activated M2 macrophages, and dendritic cell phenotypes. Administration of AMD3100 impaired the SDF-1-mediated improvement in SOCS3-KO islet function and local immune suppression. CONCLUSION SDF-1 improves the function of islet grafts in autoimmune diabetes through regulation by CXCR4; however, the presence of SOCS3 reverses the protective effect of SDF-1 on islet grafts. These data reveal a molecular pathway that can elicit localized immunosuppression and delay graft destruction in transplanted islets.
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Affiliation(s)
- Mingxing Sui
- Department of Organ Transplantation, Shanghai Changhai Hospital, Navy Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Tuo Li
- Department of Endocrinology, Changzheng Hospital, Navy Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Hanlan Lu
- Department of Organ Transplantation, Shanghai Changhai Hospital, Navy Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Yanhua Li
- Department of Organ Transplantation, Shanghai Changhai Hospital, Navy Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Juan Huang
- Department of Organ Transplantation, Shanghai Changhai Hospital, Navy Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Pei Zhang
- Department of Organ Transplantation, Shanghai Changhai Hospital, Navy Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Shusen Wang
- Organ Transplant Center, Tianjin First Central Hospital, Tianjin, China.
| | - Li Zeng
- Department of Organ Transplantation, Shanghai Changhai Hospital, Navy Medical University, 168 Changhai Road, Shanghai, 200433, China.
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Naqvi F, Dastagir N, Jabeen A. Honey proteins regulate oxidative stress, inflammation and ameliorates hyperglycemia in streptozotocin induced diabetic rats. BMC Complement Med Ther 2023; 23:14. [PMID: 36653816 PMCID: PMC9847130 DOI: 10.1186/s12906-023-03837-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 01/06/2023] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Diabetes Mellitus (DM) poses a serious health problem worldwide and several inflammatory mediators are involved in the pathogenesis of this disease. Honey composed of various constituents which have been proven to have immunomodulatory and anti-inflammatory properties. The aim of this study is to investigate the in vitro and in vivo effects of Ziziphus honey and its isolated crude proteins in modulation of immune system and inflammation involved in the pathogenesis of diabetes. METHODOLOGY The proteins from Ziziphus honey were isolated by ammonium sulfate precipitation and estimated by Bradford method. In vitro anti-inflammatory activities were evaluated by inhibition of reactive oxygen species (ROS) from phagocytes via chemiluminescence immunoassay and nitric oxide (NO) by Griess method. Cytotoxicity was evaluated by MTT Assay. The comparative effect of oral and IP routes of honey and isolated proteins was observed in streptozotocin (STZ) induced diabetic male Wistar rats. qRT-PCR technique was utilized for gene expression studies. RESULTS The honey proteins suppressed phagocyte oxidative burst and nitric oxide (NO) at significantly lower concentrations as compared to crude honey. The isolated proteins showed promising anti-inflammatory and hypoglycemic effects along with maintenance of body weight of rodents via both oral and IP routes, with significant down-regulation of inflammatory markers TNF-α, IL-1β, IFN-γ, iNOS, caspase 1, Calgranulin A (S100A8) and NF-κB expression in diabetic rats. CONCLUSION The isolated honey proteins showed better immunomodulatory and therapeutic potential at significantly lower doses as compared to crude honey.
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Affiliation(s)
- Farwa Naqvi
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Nida Dastagir
- Dow University of Health Sciences (DUHS), Karachi, Pakistan
| | - Almas Jabeen
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
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Miyashita D, Inoue R, Tsuno T, Okuyama T, Kyohara M, Nakahashi-Oda C, Nishiyama K, Fukushima S, Inada Y, Togashi Y, Shibuya A, Terauchi Y, Shirakawa J. Protective effects of S100A8 on sepsis mortality: Links to sepsis risk in obesity and diabetes. iScience 2022; 25:105662. [PMID: 36505926 PMCID: PMC9732389 DOI: 10.1016/j.isci.2022.105662] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 10/23/2022] [Accepted: 11/21/2022] [Indexed: 11/24/2022] Open
Abstract
Obesity and diabetes are independent risk factors for death during sepsis. S100A8, an alarmin, is related to inflammation, obesity, and diabetes. Here, we examine the role of S100A8 in sepsis of obesity and diabetes models. Injection of S100A8 prolongs the survival of septic mice induced by lethal endotoxemia, Escherichia coli injection, or cecal ligation and puncture. S100A8 decrease the LPS-induced expression of proinflammatory cytokines in peritoneal macrophages by inhibiting TLR4-mediated signals in an autocrine manner. db/db, ob/ob, and western diet-fed mice demonstrate reduced upregulation of S100A8 induced by LPS treatment in both serum and peritoneal cells. These mice also show shorter survival after LPS injection, and S100A8 supplementation prolonged the survival. While myelomonocytic cells-specific S100A8-deficient mice (Lyz2 cre :S100A8 floxed/floxed ) exhibit shorter survival after LPS treatment, S100A8 supplementation prolonged the survival. Thus, myelomonocytic cell-derived S100A8 is crucial for protection from sepsis, and S100A8 supplementation improves sepsis, particularly in mice with obesity and diabetes.
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Affiliation(s)
- Daisuke Miyashita
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Ryota Inoue
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Takahiro Tsuno
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Chigusa Nakahashi-Oda
- Department of Immunology, Faculty of Medicine, and R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Japan
| | - Kuniyuki Nishiyama
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Setsuko Fukushima
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Yutaro Inada
- 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
| | - Akira Shibuya
- Department of Immunology, Faculty of Medicine, and R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Japan
- 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
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
- Corresponding author
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Jain C, Bilekova S, Lickert H. Targeting pancreatic β cells for diabetes treatment. Nat Metab 2022; 4:1097-1108. [PMID: 36131204 DOI: 10.1038/s42255-022-00618-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 07/13/2022] [Indexed: 11/09/2022]
Abstract
Insulin is a life-saving drug for patients with type 1 diabetes; however, even today, no pharmacotherapy can prevent the loss or dysfunction of pancreatic insulin-producing β cells to stop or reverse disease progression. Thus, pancreatic β cells have been a main focus for cell-replacement and regenerative therapies as a curative treatment for diabetes. In this Review, we highlight recent advances toward the development of diabetes therapies that target β cells to enhance proliferation, redifferentiation and protection from cell death and/or enable selective killing of senescent β cells. We describe currently available therapies and their mode of action, as well as insufficiencies of glucagon-like peptide 1 (GLP-1) and insulin therapies. We discuss and summarize data collected over the last decades that support the notion that pharmacological targeting of β cell insulin signalling might protect and/or regenerate β cells as an improved treatment of patients with diabetes.
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Affiliation(s)
- Chirag Jain
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Immunology Discovery, Genentech Inc., South San Francisco, CA, USA
| | - Sara Bilekova
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Heiko Lickert
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
- Chair of β-Cell Biology, Technische Universität München, School of Medicine, Klinikum Rechts der Isar, München, Germany.
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11
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Inoue R, Tsuno T, Togashi Y, Okuyama T, Sato A, Nishiyama K, Kyohara M, Li J, Fukushima S, Kin T, Miyashita D, Shiba Y, Atobe Y, Kiyonari H, Bando K, Shapiro AJ, Funakoshi K, Kulkarni RN, Terauchi Y, Shirakawa J. Uncoupling protein 2 and aldolase B impact insulin release by modulating mitochondrial function and Ca 2+ release from the ER. iScience 2022; 25:104603. [PMID: 35800776 PMCID: PMC9253497 DOI: 10.1016/j.isci.2022.104603] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 03/25/2022] [Accepted: 06/08/2022] [Indexed: 02/02/2023] Open
Abstract
Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of this increase in UCP2 expression is unclear. In this study, we highlight the molecular link between the increase in UCP2 expression in β-cells and β-cell failure by using genetically engineered mice and human islets. β-cell-specific UCP2-overexpressing transgenic mice (βUCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion. Decreased mitochondrial function and increased aldolase B (AldB) expression through oxidative-stress-mediated pathway were observed in βUCP2Tg islets. AldB, a glycolytic enzyme, was associated with reduced insulin secretion via mitochondrial dysfunction and impaired calcium release from the endoplasmic reticulum (ER). Taken together, our findings provide a new mechanism of β-cell dysfunction by UCP2 and AldB. Targeting the UCP2/AldB axis is a promising approach for the recovery of β-cell function.
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Affiliation(s)
- Ryota Inoue
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Takahiro Tsuno
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Aoi Sato
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
| | - Kuniyuki Nishiyama
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Jinghe Li
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Setsuko Fukushima
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
| | - Tatsuya Kin
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB T6G2C8, Canada
| | - Daisuke Miyashita
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Yusuke Shiba
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Yoshitoshi Atobe
- Department of Neuroanatomy, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
| | - Hiroshi Kiyonari
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
| | - Kana Bando
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
| | - A.M. James Shapiro
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB T6G2C8, Canada
| | - Kengo Funakoshi
- Department of Neuroanatomy, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
| | - Rohit N. Kulkarni
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Jun Shirakawa
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
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12
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Jonas W, Kluth O, Helms A, Voß S, Jähnert M, Gottmann P, Speckmann T, Knebel B, Chadt A, Al-Hasani H, Schürmann A, Vogel H. Identification of Novel Genes Involved in Hyperglycemia in Mice. Int J Mol Sci 2022; 23:3205. [PMID: 35328627 PMCID: PMC8949927 DOI: 10.3390/ijms23063205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/09/2022] [Accepted: 03/14/2022] [Indexed: 11/16/2022] Open
Abstract
Current attempts to prevent and manage type 2 diabetes have been moderately effective, and a better understanding of the molecular roots of this complex disease is important to develop more successful and precise treatment options. Recently, we initiated the collective diabetes cross, where four mouse inbred strains differing in their diabetes susceptibility were crossed with the obese and diabetes-prone NZO strain and identified the quantitative trait loci (QTL) Nidd13/NZO, a genomic region on chromosome 13 that correlates with hyperglycemia in NZO allele carriers compared to B6 controls. Subsequent analysis of the critical region, harboring 644 genes, included expression studies in pancreatic islets of congenic Nidd13/NZO mice, integration of single-cell data from parental NZO and B6 islets as well as haplotype analysis. Finally, of the five genes (Acot12, S100z, Ankrd55, Rnf180, and Iqgap2) within the polymorphic haplotype block that are differently expressed in islets of B6 compared to NZO mice, we identified the calcium-binding protein S100z gene to affect islet cell proliferation as well as apoptosis when overexpressed in MIN6 cells. In summary, we define S100z as the most striking gene to be causal for the diabetes QTL Nidd13/NZO by affecting β-cell proliferation and apoptosis. Thus, S100z is an entirely novel diabetes gene regulating islet cell function.
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Affiliation(s)
- Wenke Jonas
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (W.J.); (O.K.); (A.H.); (S.V.); (M.J.); (P.G.); (T.S.); (A.S.)
- German Center for Diabetes Research (DZD), München-Neuherberg, 85764 München, Germany; (B.K.); (A.C.); (H.A.-H.)
| | - Oliver Kluth
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (W.J.); (O.K.); (A.H.); (S.V.); (M.J.); (P.G.); (T.S.); (A.S.)
- German Center for Diabetes Research (DZD), München-Neuherberg, 85764 München, Germany; (B.K.); (A.C.); (H.A.-H.)
| | - Anett Helms
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (W.J.); (O.K.); (A.H.); (S.V.); (M.J.); (P.G.); (T.S.); (A.S.)
- German Center for Diabetes Research (DZD), München-Neuherberg, 85764 München, Germany; (B.K.); (A.C.); (H.A.-H.)
| | - Sarah Voß
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (W.J.); (O.K.); (A.H.); (S.V.); (M.J.); (P.G.); (T.S.); (A.S.)
- German Center for Diabetes Research (DZD), München-Neuherberg, 85764 München, Germany; (B.K.); (A.C.); (H.A.-H.)
| | - Markus Jähnert
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (W.J.); (O.K.); (A.H.); (S.V.); (M.J.); (P.G.); (T.S.); (A.S.)
- German Center for Diabetes Research (DZD), München-Neuherberg, 85764 München, Germany; (B.K.); (A.C.); (H.A.-H.)
| | - Pascal Gottmann
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (W.J.); (O.K.); (A.H.); (S.V.); (M.J.); (P.G.); (T.S.); (A.S.)
- German Center for Diabetes Research (DZD), München-Neuherberg, 85764 München, Germany; (B.K.); (A.C.); (H.A.-H.)
| | - Thilo Speckmann
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (W.J.); (O.K.); (A.H.); (S.V.); (M.J.); (P.G.); (T.S.); (A.S.)
- German Center for Diabetes Research (DZD), München-Neuherberg, 85764 München, Germany; (B.K.); (A.C.); (H.A.-H.)
| | - Birgit Knebel
- German Center for Diabetes Research (DZD), München-Neuherberg, 85764 München, Germany; (B.K.); (A.C.); (H.A.-H.)
- German Diabetes Center (DDZ), Medical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, Heinrich Heine University, 40225 Duesseldorf, Germany
| | - Alexandra Chadt
- German Center for Diabetes Research (DZD), München-Neuherberg, 85764 München, Germany; (B.K.); (A.C.); (H.A.-H.)
- German Diabetes Center (DDZ), Medical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, Heinrich Heine University, 40225 Duesseldorf, Germany
| | - Hadi Al-Hasani
- German Center for Diabetes Research (DZD), München-Neuherberg, 85764 München, Germany; (B.K.); (A.C.); (H.A.-H.)
- German Diabetes Center (DDZ), Medical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, Heinrich Heine University, 40225 Duesseldorf, Germany
| | - Annette Schürmann
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (W.J.); (O.K.); (A.H.); (S.V.); (M.J.); (P.G.); (T.S.); (A.S.)
- German Center for Diabetes Research (DZD), München-Neuherberg, 85764 München, Germany; (B.K.); (A.C.); (H.A.-H.)
- Institute of Nutritional Sciences, University of Potsdam, 14558 Nuthetal, Germany
| | - Heike Vogel
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany; (W.J.); (O.K.); (A.H.); (S.V.); (M.J.); (P.G.); (T.S.); (A.S.)
- German Center for Diabetes Research (DZD), München-Neuherberg, 85764 München, Germany; (B.K.); (A.C.); (H.A.-H.)
- Research Group Genetics of Obesity, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany
- Research Group Molecular and Clinical Life Science of Metabolic Diseases, Faculty of Health Sciences Brandenburg, University of Potsdam, 14469 Potsdam, Germany
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13
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Fuh KF, Withell J, Shepherd RD, Rinker KD. Fluid Flow Stimulation Modulates Expression of S100 Genes in Normal Breast Epithelium and Breast Cancer. Cell Mol Bioeng 2022; 15:115-127. [PMID: 35087607 PMCID: PMC8761192 DOI: 10.1007/s12195-021-00704-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 09/07/2021] [Indexed: 12/05/2022] Open
Abstract
INTRODUCTION S100 proteins are intracellular calcium ion sensors that participate in cellular processes, some of which are involved in normal breast functioning and breast cancer development. Despite several S100 genes being overexpressed in breast cancer, their roles during disease development remain elusive. Human mammary epithelial cells (HMECs) can be exposed to fluid shear stresses and implications of such interactions have not been previously studied. The goal of this study was to analyze expression profiles of S100 genes upon exposing HMECs to fluid flow. METHODS HMECs and breast cancer cell lines were exposed to fluid flow in a parallel-plate bioreactor system. Changes in gene expression were quantified using microarrays and qPCR, gene-gene interactions were elucidated using network analysis, and key modified genes were examined in three independent clinical datasets. RESULTS S100 genes were among the most upregulated genes upon flow stimulation. Network analysis revealed interactions between upregulated transcripts, including interactions between S100P, S100PBP, S100A4, S100A7, S100A8 and S100A9. Overexpression of S100s was also observed in patients with early stage breast cancer compared to normal breast tissue, and in most breast cancer patients. Finally, survival analysis revealed reduced survival times for patients with elevated expression of S100A7 and S100P. CONCLUSION This study shows that exposing HMECs to fluid flow upregulates genes identified clinically to be overexpressed during breast cancer development, including S100A7 and S100P. These findings are the first to show that S100 genes are flow-responsive and might be participating in a fundamental adaptation pathway in normal tissue that is also active in breast cancer.
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Affiliation(s)
- Kenneth F. Fuh
- Biomedical Engineering Graduate Program, University of Calgary, Calgary, AB T2N 1N4 Canada
- Cellular and Molecular Bioengineering Research Lab, University of Calgary, Calgary, AB T2N 1N4 Canada
| | - Jessica Withell
- Cellular and Molecular Bioengineering Research Lab, University of Calgary, Calgary, AB T2N 1N4 Canada
| | - Robert D. Shepherd
- Cellular and Molecular Bioengineering Research Lab, University of Calgary, Calgary, AB T2N 1N4 Canada
- Department of Chemical and Petroleum Engineering, University of Calgary, Calgary, AB T2N 1N4 Canada
| | - Kristina D. Rinker
- Cellular and Molecular Bioengineering Research Lab, University of Calgary, Calgary, AB T2N 1N4 Canada
- Department of Chemical and Petroleum Engineering, University of Calgary, Calgary, AB T2N 1N4 Canada
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 1N4 Canada
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB T2N 1N4 Canada
- Libin Cardiovascular Institute of Canada, University of Calgary, Calgary, AB T2N 1N4 Canada
- Centre for Bioengineering Research & Education, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4 Canada
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14
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You S, Zheng J, Chen Y, Huang H. Research progress on the mechanism of beta-cell apoptosis in type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2022; 13:976465. [PMID: 36060972 PMCID: PMC9434279 DOI: 10.3389/fendo.2022.976465] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022] Open
Abstract
Type 2 diabetes mellitus(T2DM) is regarded as one of the most severe chronic metabolic diseases worldwide, which poses a great threat to human safety and health. The main feature of T2DM is the deterioration of pancreatic beta-cell function. More and more studies have shown that the decline of pancreatic beta-cell function in T2DM can be attributable to beta-cell apoptosis, but the exact mechanisms of beta-cell apoptosis in T2DM are not yet fully clarified. Therefore, in this review, we will focus on the current status and progress of research on the mechanism of pancreatic beta-cell apoptosis in T2DM, to provide new ideas for T2DM treatment strategies.
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Affiliation(s)
- SuFang You
- The Second Clinical Medical College of Fujian Medical University, Quanzhou, China
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - JingYi Zheng
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - YuPing Chen
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - HuiBin Huang
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
- *Correspondence: HuiBin Huang,
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15
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Shirakawa J. Translational research on human pancreatic β-cell mass expansion for the treatment of diabetes. Diabetol Int 2021; 12:349-355. [PMID: 34567917 DOI: 10.1007/s13340-021-00531-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 08/15/2021] [Indexed: 11/27/2022]
Abstract
The structural, functional, and pathological differences between human islets and rodent islets, such as mouse or rat islets, have been clarified, and research using human islets is becoming more important for elucidating the pathophysiology of diabetes and developing therapeutic strategies for diabetes. Increasing the functional human β-cell mass is a feasible method for the treatment of both type 1 and type 2 diabetes. The glucokinase-mediated glucose signaling pathway is known to promote β-cell proliferation not only in rodent models but also in humans. However, little is known about the signaling components of glucose- or glucokinase-mediated signaling pathways. Studies have gradually revealed the involvement of ER stress-related molecules, cell cycle regulators, inflammatory proteins, extracellular matrix proteins, and neurotransmitters in the glucokinase-mediated signaling pathway in β-cells. Unraveling the mechanisms of those molecules in the regulation of human β-cell mass will provide new insights into how the functional β-cell mass can be increased. The human islet distribution program is essential for human islet research. However, human islets for research are only available by import from Europe and America into Japan or Asia. Since Japanese or Asian diabetes patients possibly show different features compared with European or American diabetes patients, studies using human islets from Japanese or Asian populations have become important for the elucidation of pathophysiology in these specific population groups. This review outlines new pathways important for the regulation of human pancreatic β-cell mass and expectations regarding the establishment of a human islet distribution program in Japan.
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Affiliation(s)
- Jun Shirakawa
- Laboratory and Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, 371-8510 Japan
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16
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Viurcos-Sanabria R, Escobedo G. Immunometabolic bases of type 2 diabetes in the severity of COVID-19. World J Diabetes 2021; 12:1026-1041. [PMID: 34326952 PMCID: PMC8311488 DOI: 10.4239/wjd.v12.i7.1026] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/16/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 and type 2 diabetes (T2D) have now merged into an ongoing global syndemic that is threatening the lives of millions of people around the globe. For this reason, there is a deep need to understand the immunometabolic bases of the main etiological factors of T2D that affect the severity of COVID-19. Here, we discuss how hyperglycemia contributes to the cytokine storm commonly associated with COVID-19 by stimulating monocytes and macrophages to produce interleukin IL-1β, IL-6, and TNF-α in the airway epithelium. The main mechanisms through which hyperglycemia promotes reactive oxygen species release, inhibition of T cell activation, and neutrophil extracellular traps in the lungs of patients with severe SARS-CoV-2 infection are also studied. We further examine the molecular mechanisms by which proinflammatory cytokines induce insulin resistance, and their deleterious effects on pancreatic β-cell exhaustion in T2D patients critically ill with COVID-19. We address the effect of excess glucose on advanced glycation end product (AGE) formation and the role of AGEs in perpetuating pneumonia and acute respiratory distress syndrome. Finally, we discuss the contribution of preexisting endothelial dysfunction secondary to diabetes in the development of neutrophil trafficking, vascular leaking, and thrombotic events in patients with severe SARS-CoV-2 infection. As we outline here, T2D acts in synergy with SARS-CoV-2 infection to increase the progression, severity, and mortality of COVID-19. We think a better understanding of the T2D-related immunometabolic factors that contribute to exacerbate the severity of COVID-19 will improve our ability to identify patients with high mortality risk and prevent adverse outcomes.
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Affiliation(s)
| | - Galileo Escobedo
- Laboratorio de Proteómica, Dirección de Investigación, Hospital General de Mexico “Dr. Eduardo Liceaga”, Mexico City 06720, Mexico
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17
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Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies. Int J Mol Sci 2021; 22:ijms22105303. [PMID: 34069914 PMCID: PMC8157542 DOI: 10.3390/ijms22105303] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/07/2021] [Accepted: 05/13/2021] [Indexed: 12/22/2022] Open
Abstract
Type 2 diabetes (T2D) is characterized by chronic hyperglycemia secondary to the decline of functional beta-cells and is usually accompanied by a reduced sensitivity to insulin. Whereas altered beta-cell function plays a key role in T2D onset, a decreased beta-cell mass was also reported to contribute to the pathophysiology of this metabolic disease. The decreased beta-cell mass in T2D is, at least in part, attributed to beta-cell apoptosis that is triggered by diabetogenic situations such as amyloid deposits, lipotoxicity and glucotoxicity. In this review, we discussed the molecular mechanisms involved in pancreatic beta-cell apoptosis under such diabetes-prone situations. Finally, we considered the molecular signaling pathways recruited by glucagon-like peptide-1-based therapies to potentially protect beta-cells from death under diabetogenic situations.
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18
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Benito-Vicente A, Jebari-Benslaiman S, Galicia-Garcia U, Larrea-Sebal A, Uribe KB, Martin C. Molecular mechanisms of lipotoxicity-induced pancreatic β-cell dysfunction. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 359:357-402. [PMID: 33832653 DOI: 10.1016/bs.ircmb.2021.02.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes (T2D), a heterogeneous disorder derived from metabolic dysfunctions, leads to a glucose overflow in the circulation due to both defective insulin secretion and peripheral insulin resistance. One of the critical risk factor for T2D is obesity, which represents a global epidemic that has nearly tripled since 1975. Obesity is characterized by chronically elevated free fatty acid (FFA) levels, which cause deleterious effects on glucose homeostasis referred to as lipotoxicity. Here, we review the physiological FFA roles onto glucose-stimulated insulin secretion (GSIS) and the pathological ones affecting many steps of the mechanisms and modulation of GSIS. We also describe in vitro and in vivo experimental evidences addressing lipotoxicity in β-cells and the role of saturation and chain length of FFA on the potency of GSIS stimulation. The molecular mechanisms underpinning lipotoxic-β-cell dysfunction are also reviewed. Among them, endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, inflammation, impaired autophagy and β-cell dedifferentiation. Finally therapeutic strategies for the β-cells dysfunctions such as the use of metformin, glucagon-like peptide 1, thiazolidinediones, anti-inflammatory drugs, chemical chaperones and weight are discussed.
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Affiliation(s)
- Asier Benito-Vicente
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Shifa Jebari-Benslaiman
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Unai Galicia-Garcia
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Molecular Biophysics, Fundación Biofísica Bizkaia, Leioa, Spain
| | - Asier Larrea-Sebal
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Molecular Biophysics, Fundación Biofísica Bizkaia, Leioa, Spain
| | - Kepa B Uribe
- Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Donostia San Sebastián, Spain
| | - Cesar Martin
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain.
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19
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Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System. Front Immunol 2020; 11:1582. [PMID: 32793223 PMCID: PMC7387426 DOI: 10.3389/fimmu.2020.01582] [Citation(s) in RCA: 275] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 06/15/2020] [Indexed: 12/14/2022] Open
Abstract
Metabolic abnormalities such as dyslipidemia, hyperinsulinemia, or insulin resistance and obesity play key roles in the induction and progression of type 2 diabetes mellitus (T2DM). The field of immunometabolism implies a bidirectional link between the immune system and metabolism, in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and T2DM), and metabolic factors, in turn, regulate immune cell functions. Obesity as the main inducer of a systemic low-level inflammation is a main susceptibility factor for T2DM. Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. Hyperglycemia and the subsequent inflammation are the main causes of micro- and macroangiopathies in the circulatory system. They also promote the gut microbiota dysbiosis, increased intestinal permeability, and fatty liver disease. The impaired immune system together with metabolic imbalance also increases the susceptibility of patients to several pathogenic agents such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, the need for a proper immunization protocol among such patients is granted. The focus of the current review is to explore metabolic and immunological abnormalities affecting several organs of T2DM patients and explain the mechanisms, whereby diabetic patients become more susceptible to infectious diseases.
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Affiliation(s)
- Gholamreza Daryabor
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohamad Reza Atashzar
- Department of Immunology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | | | - Seppo Meri
- Department of Bacteriology and Immunology and the Translational Immunology Research Program (TRIMM), The University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland
| | - Kurosh Kalantar
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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20
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Chessa C, Bodet C, Jousselin C, Wehbe M, Lévêque N, Garcia M. Antiviral and Immunomodulatory Properties of Antimicrobial Peptides Produced by Human Keratinocytes. Front Microbiol 2020; 11:1155. [PMID: 32582097 PMCID: PMC7283518 DOI: 10.3389/fmicb.2020.01155] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 05/06/2020] [Indexed: 12/15/2022] Open
Abstract
Keratinocytes, the main cells of the epidermis, are the first site of replication as well as the first line of defense against many viruses such as arboviruses, enteroviruses, herpes viruses, human papillomaviruses, or vaccinia virus. During viral replication, these cells can sense virus associated molecular patterns leading to the initiation of an innate immune response composed of pro-inflammatory cytokines, chemokines, and antimicrobial peptides. Human keratinocytes produce and secrete at least nine antimicrobial peptides: human cathelicidin LL-37, types 1–4 human β-defensins, S100 peptides such as psoriasin (S100A7), calprotectin (S100A8/9) and koebnerisin (S100A15), and RNase 7. These peptides can exert direct antiviral effects on the viral particle or its replication cycle, and indirect antiviral activity, by modulating the host immune response. The purpose of this review is to summarize current knowledge of antiviral and immunomodulatory properties of human keratinocyte antimicrobial peptides.
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Affiliation(s)
- Céline Chessa
- Laboratoire de Virologie et Mycobactériologie, CHU de Poitiers, Poitiers, France.,Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, LITEC EA 4331, Université de Poitiers, Poitiers, France
| | - Charles Bodet
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, LITEC EA 4331, Université de Poitiers, Poitiers, France
| | - Clément Jousselin
- Laboratoire de Virologie et Mycobactériologie, CHU de Poitiers, Poitiers, France.,Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, LITEC EA 4331, Université de Poitiers, Poitiers, France
| | - Michel Wehbe
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, LITEC EA 4331, Université de Poitiers, Poitiers, France
| | - Nicolas Lévêque
- Laboratoire de Virologie et Mycobactériologie, CHU de Poitiers, Poitiers, France.,Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, LITEC EA 4331, Université de Poitiers, Poitiers, France
| | - Magali Garcia
- Laboratoire de Virologie et Mycobactériologie, CHU de Poitiers, Poitiers, France.,Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, LITEC EA 4331, Université de Poitiers, Poitiers, France
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21
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Ebrahimi AG, Hollister-Lock J, Sullivan BA, Tsuchida R, Bonner-Weir S, Weir GC. Beta cell identity changes with mild hyperglycemia: Implications for function, growth, and vulnerability. Mol Metab 2020; 35:100959. [PMID: 32244186 PMCID: PMC7082551 DOI: 10.1016/j.molmet.2020.02.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 02/03/2020] [Accepted: 02/04/2020] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE As diabetes develops, marked reductions of insulin secretion are associated with very modest elevations of glucose. We wondered if these glucose changes disrupt beta cell differentiation enough to account for the altered function. METHODS Rats were subjected to 90% partial pancreatectomies and those with only mild glucose elevations 4 weeks or 10 weeks after surgery had major alterations of gene expression in their islets as determined by RNAseq. RESULTS Changes associated with glucose toxicity demonstrated that many of the critical genes responsible for insulin secretion were downregulated while the expression of normally suppressed genes increased. Also, there were marked changes in genes associated with replication, aging, senescence, stress, inflammation, and increased expression of genes controlling both class I and II MHC antigens. CONCLUSIONS These findings suggest that mild glucose elevations in the early stages of diabetes lead to phenotypic changes that adversely affect beta cell function, growth, and vulnerability.
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Affiliation(s)
- Aref G Ebrahimi
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, One Joslin Place, Harvard Medical School, Boston, MA 02215, USA
| | - Jennifer Hollister-Lock
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, One Joslin Place, Harvard Medical School, Boston, MA 02215, USA
| | - Brooke A Sullivan
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, One Joslin Place, Harvard Medical School, Boston, MA 02215, USA
| | - Ryohei Tsuchida
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, One Joslin Place, Harvard Medical School, Boston, MA 02215, USA
| | - Susan Bonner-Weir
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, One Joslin Place, Harvard Medical School, Boston, MA 02215, USA
| | - Gordon C Weir
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, One Joslin Place, Harvard Medical School, Boston, MA 02215, USA.
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22
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Abstract
Insulin secretion by the pancreatic β-cells is elicited in response to elevated extracellular glucose concentration. In addition to triggering insulin secretion, glucose-induced signal regulates β-cell proliferation and survival. However, the molecular mechanism underlying the effects of glucose on the β-cell functionality still remains unclear. Glucokinase, a hexokinase isozyme that catalyzes the phosphorylation of glucose, acts as the glucose sensor in the β-cells. To investigate the mechanisms of glucose signaling in the regulation of β-cell functions, we analyzed the role of glucokinase in insulin secretion, β-cell proliferation and β-cell apoptosis, using β-cell-specific glucokinase-haploinsufficient (Gck+/-) mice and allosteric glucokinase activators (GKAs). Glucokinase-mediated glucose metabolism (1) suppresses endoplasmic reticulum (ER) stress-induced β-cell apoptosis via inducing insulin receptor substrate-2 (IRS-2) expression and expression of ER stress-related molecules, (2) promotes adaptive β-cell proliferation through activation of the Forkhead Box M1 (FoxM1)/polo-like kinase-1 (PLK1)/centromere protein-A (CENP-A) pathway, (3) induces islet inflammation by promoting interaction of islet-derived S100 calcium-binding protein A8 (S100A8) with macrophages, (4) induces the expression of Fibulin-5 (Fbln5), an extracellular matrix protein to regulate β-cell functions, and (5) activates other unknown pathways. Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors have been found to possibly compensate for dysregulation of glucose metabolism in the β-cells. This review provides an update and overview of the recent advances in the study of β-cell pathophysiology and some therapeutic possibilities focusing on glucose-/glucokinase-mediated signaling.
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Affiliation(s)
- Jun Shirakawa
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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23
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Yan S, Jiang Z, Cheng L, Lin Y, Fan B, Luo L, Yan Y, Yang L, Shen X. TLR4 knockout can improve dysfunction of β-cell by rebalancing proteomics disorders in pancreas of obese rats. Endocrine 2020; 67:67-79. [PMID: 31598849 DOI: 10.1007/s12020-019-02106-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 09/26/2019] [Indexed: 02/06/2023]
Abstract
PURPOSE Studies showed that TLR4 knockout (TLR4KO) could mitigate obesity and insulin resistance induced by high-fat diet in rats. In this study, we further investigated the effects of TLR4KO on islet function and pancreatic proteomics in obese rats by high-fat diet. METHODS PA-induced lipotoxicity β-cells, SD and TLR4KO rats were used in this study. iTRAQ was used to screen out meaningful differential proteins.The protein expression level was evaluated by Western blotting; the cell apoptosis was detected by TUNEL assay. RESULTS TLR4KO could reduce inflammatory and regulate body composition in obese rats, and improve β-cells function. The quantitative analysis of protein revealed that TLR4KO rebalanced proteomics disorders in pancreas of obese rats. In addition, the pathways involved in differential proteins were mainly metabolic pathways, arachidonic acid metabolism, ECM-receptor interaction, pancreatic secretion, PI3K-Akt signaling pathway, and FoxO signaling pathway. Further analysis of protein-protein interaction (PPI) revealed that Stk39 and Ass1 interacting through Mapk14-Ywhae were node proteins and participated in inflammatory response, carboxylic acid metabolic process, and small molecule metabolic process. In vitro experiments we confirmed that silencing TLR4 can inhibit PA-induced β-cell apoptosis, insulin secretion disorders, and increase Ass1 expression. While, overexpression of Ass1 in β-cell inhibited PA or LPS-induced β-cell damage. CONCLUSIONS Our study confirmed that TLR4KO could improve dysfunction of β-cell, and the underlying mechanism might be involved in ebalancing proteomics disorders in pancreas, affecting the expression of Ass1.
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Affiliation(s)
- Sunjie Yan
- From Endocrinology Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
- Diabetes Research Institute of Fujian Province, Fuzhou, 350005, Fujian, China
| | - Zhen Jiang
- From Endocrinology Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Ling Cheng
- From Endocrinology Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Youfen Lin
- From Endocrinology Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Beibei Fan
- From Endocrinology Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Liufen Luo
- From Endocrinology Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Yuanli Yan
- From Endocrinology Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Liyong Yang
- From Endocrinology Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
- Diabetes Research Institute of Fujian Province, Fuzhou, 350005, Fujian, China
| | - Ximei Shen
- From Endocrinology Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China.
- Diabetes Research Institute of Fujian Province, Fuzhou, 350005, Fujian, China.
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24
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Lytrivi M, Castell AL, Poitout V, Cnop M. Recent Insights Into Mechanisms of β-Cell Lipo- and Glucolipotoxicity in Type 2 Diabetes. J Mol Biol 2019; 432:1514-1534. [PMID: 31628942 DOI: 10.1016/j.jmb.2019.09.016] [Citation(s) in RCA: 267] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 09/15/2019] [Accepted: 09/16/2019] [Indexed: 12/24/2022]
Abstract
The deleterious effects of chronically elevated free fatty acid (FFA) levels on glucose homeostasis are referred to as lipotoxicity, and the concurrent exposure to high glucose may cause synergistic glucolipotoxicity. Lipo- and glucolipotoxicity have been studied for over 25 years. Here, we review the current evidence supporting the role of pancreatic β-cell lipo- and glucolipotoxicity in type 2 diabetes (T2D), including lipid-based interventions in humans, prospective epidemiological studies, and human genetic findings. In addition to total FFA quantity, the quality of FFAs (saturation and chain length) is a key determinant of lipotoxicity. We discuss in vitro and in vivo experimental models to investigate lipo- and glucolipotoxicity in β-cells and describe experimental pitfalls. Lipo- and glucolipotoxicity adversely affect many steps of the insulin production and secretion process. The molecular mechanisms underpinning lipo- and glucolipotoxic β-cell dysfunction and death comprise endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, impaired autophagy, and inflammation. Crosstalk between these stress pathways exists at multiple levels and may aggravate β-cell lipo- and glucolipotoxicity. Lipo- and glucolipotoxicity are therapeutic targets as several drugs impact the underlying stress responses in β-cells, potentially contributing to their glucose-lowering effects in T2D.
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Affiliation(s)
- Maria Lytrivi
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium; Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Anne-Laure Castell
- CRCHUM, Montréal, QC, Canada; Department of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Vincent Poitout
- CRCHUM, Montréal, QC, Canada; Department of Medicine, Université de Montréal, Montréal, QC, Canada.
| | - Miriam Cnop
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium; Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium.
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25
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Ježek P, Jabůrek M, Plecitá-Hlavatá L. Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes. Antioxid Redox Signal 2019; 31:722-751. [PMID: 30450940 PMCID: PMC6708273 DOI: 10.1089/ars.2018.7656] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 11/05/2018] [Indexed: 12/14/2022]
Abstract
Significance: Type 2 diabetes development involves multiple changes in β-cells, related to the oxidative stress and impaired redox signaling, beginning frequently by sustained overfeeding due to the resulting lipotoxicity and glucotoxicity. Uncovering relationships among the dysregulated metabolism, impaired β-cell "well-being," biogenesis, or cross talk with peripheral insulin resistance is required for elucidation of type 2 diabetes etiology. Recent Advances: It has been recognized that the oxidative stress, lipotoxicity, and glucotoxicity cannot be separated from numerous other cell pathology events, such as the attempted compensation of β-cell for the increased insulin demand and dynamics of β-cell biogenesis and its "reversal" at dedifferentiation, that is, from the concomitantly decreasing islet β-cell mass (also due to transdifferentiation) and low-grade islet or systemic inflammation. Critical Issues: At prediabetes, the compensation responses of β-cells, attempting to delay the pathology progression-when exaggerated-set a new state, in which a self-checking redox signaling related to the expression of Ins gene expression is impaired. The resulting altered redox signaling, diminished insulin secretion responses to various secretagogues including glucose, may lead to excretion of cytokines or chemokines by β-cells or excretion of endosomes. They could substantiate putative stress signals to the periphery. Subsequent changes and lasting glucolipotoxicity promote islet inflammatory responses and further pathology spiral. Future Directions: Should bring an understanding of the β-cell self-checking and related redox signaling, including the putative stress signal to periphery. Strategies to cure or prevent type 2 diabetes could be based on the substitution of the "wrong" signal by the "correct" self-checking signal.
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Affiliation(s)
- Petr Ježek
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Martin Jabůrek
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Lydie Plecitá-Hlavatá
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
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26
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Silveira AAA, Mahon OR, Cunningham CC, Corr EM, Mendonça R, Saad STO, Costa FF, Dunne A, Conran N. S100A8 acts as an autocrine priming signal for heme-induced human Mϕ pro-inflammatory responses in hemolytic inflammation. J Leukoc Biol 2019; 106:35-43. [PMID: 31091351 DOI: 10.1002/jlb.3mia1118-418rr] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 04/10/2019] [Accepted: 05/02/2019] [Indexed: 12/28/2022] Open
Abstract
Intravascular hemolysis, in addition to reducing red cell counts, incurs extensive vascular inflammation and oxidative stress. One product of hemolysis, heme, is a potent danger associated molecular pattern (DAMP), activating leukocytes and inducing cytokine expression and processing, among other pro-inflammatory effects. We explored pathways by which heme-induced inflammation may be amplified under sterile conditions. Incubation of human Mϕs, differentiated from CD14+ cells, with heme induced time- and concentration-dependent gene and protein expression of S100A8, a myeloid cell-derived alarmin. Human Mϕ stimulation with recombinant S100A8, in turn, induced robust pro-IL-1β expression that was dependent upon NF-κB activation, gene transcription, and partially dependent upon TLR4-mediated signaling. Moreover, heme itself stimulated significant Mϕ pro-IL-1β gene and protein expression via an S100A8-mediated mechanism and greatly amplified S100A8-driven NLRP3 inflammasome-mediated IL-1β secretion. In vivo, induction of acute intravascular hemolysis in mice induced a rapid elevation of plasma S100A8 that could be abolished by hemopexin, a heme scavenger. Finally, plasma S100A8 levels were found to be significantly elevated in patients with the inherited hemolytic anemia, sickle cell anemia, when compared with levels in healthy individuals. In conclusion, we demonstrate that hemolytic processes are associated with S100A8 generation and that some of the inflammatory effects of heme may be amplified by autocrine S100A8 production. Findings suggest a mechanism by which hemolytic inflammation could be propagated via leukocyte priming by endogenous proteins, even in sterile inflammatory environments such as those that occur in the hemolytic diseases. S100A8 may represent a therapeutic target for reducing inflammation in hemolytic disorders.
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Affiliation(s)
| | - Olwyn R Mahon
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Clare C Cunningham
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Emma M Corr
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Rafaela Mendonça
- Hematology Center, University of Campinas-UNICAMP, Campinas, São Paulo, Brazil
| | - Sara T O Saad
- Hematology Center, University of Campinas-UNICAMP, Campinas, São Paulo, Brazil
| | - Fernando F Costa
- Hematology Center, University of Campinas-UNICAMP, Campinas, São Paulo, Brazil
| | - Aisling Dunne
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Nicola Conran
- Hematology Center, University of Campinas-UNICAMP, Campinas, São Paulo, Brazil
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27
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Martinez-Rios MA, Vargas-Alarcon G, Peña-Duque MA, Perez-Mendez O, Rodriguez-Perez JM, Perez-Hernandez N, Herrera-Maya G, Posadas-Sanchez R, Posadas-Romero C, Fragoso JM. The -44 C/G (rs1800972) polymorphism of the β-defensin 1 is associated with increased risk of developing type 2 diabetes mellitus. Mol Genet Genomic Med 2018; 7:e00509. [PMID: 30549243 PMCID: PMC6382445 DOI: 10.1002/mgg3.509] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 10/03/2018] [Accepted: 10/15/2018] [Indexed: 12/25/2022] Open
Abstract
Background The aim of this study was to establish the association of two polymorphisms of the β‐defensin 1 gene (DEFB1, OMIM#602056) with the risk of developing type 2 diabetes mellitus (T2DM) in a group of Mexican patients. Methods The 5′UTR −20 G/A, and −44 C/G polymorphisms of DEFB1 gene were genotyped by 5′ exonuclease TaqMan assays in a group of 252 patients with T2DM and 522 healthy control. Results Under dominant and additive models adjusted for the risk factors, the C allele of the −44 C/G polymorphism was associated with increased risk of T2DM (OR = 1.63, 95% CI = 1.07–2.48, pCdom = 0.021 and OR = 1.42, 95% CI = 1.05–1.91, pCadd = 0.023, respectively). In addition, the linkage disequilibrium analysis showed that AC haplotype was associated with an increased risk of developing T2DM (OR = 4.39, p = 0.04). The in‐silico analysis showed that the −44 C allele produces a binding site for the transcription factor Ikaros (IK). Conclusion This study demonstrates that the C allele of −44 C/G polymorphism, as well as haplotype AC are associated with the presence of T2DM in the Mexican population. The variation in this polymorphism of the DEFB1 gene could increase the migration of the macrophages to pancreatic islets accelerate the β‐cell dysfunction in T2DM.
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Affiliation(s)
| | - Gilberto Vargas-Alarcon
- Department of Molecular Biology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Marco Antonio Peña-Duque
- Interventional Cardiology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Oscar Perez-Mendez
- Department of Molecular Biology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | | | - Nonanzit Perez-Hernandez
- Department of Molecular Biology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Gabriel Herrera-Maya
- Department of Molecular Biology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | | | - Carlos Posadas-Romero
- Department of Endocrinology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Jose Manuel Fragoso
- Department of Molecular Biology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
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28
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Fan J, Campioli E, Papadopoulos V. Nr5a1-Cre-mediated Tspo conditional knockout mice with low growth rate and prediabetes symptoms - A mouse model of stress diabetes. Biochim Biophys Acta Mol Basis Dis 2018; 1865:56-62. [PMID: 30343141 DOI: 10.1016/j.bbadis.2018.10.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 10/10/2018] [Accepted: 10/16/2018] [Indexed: 12/16/2022]
Abstract
Translocator protein (TSPO) is a high-affinity cholesterol- and drug-binding mitochondrial protein. Nuclear receptor subfamily 5 group A member 1 or steroidogenic factor 1 (Nr5a1)-Cre mice were previously used to generate steroidogenic cell-specific Tspo gene conditional knockout (cKO) mice. TSPO-depleted homozygotes showed no response to adrenocorticotropic hormone (ACTH) in stimulating adrenal cortex corticosterone production but showed increased epinephrine synthesis in the medulla. No other phenotype was observed under normal growth conditions. During these studies, we noted that pairing two cKO mice resulted in the generation of small pups. These pups showed low growth rate at weaning, which has been linked to the development of type 2 diabetes (T2D) in adulthood. Experimental verification of T2D symptoms via blood testing of the adult mice, including glycated hemoglobin and insulin C-peptide measurements, showed that these Tspo cKO mice exhibited sustained hyperglycemia, a sign of prediabetes, likely due to the augmentation of hepatic glucose production mediated by the increased epinephrine. We also observed increased expression of the S100a8 gene, which is upregulated after chronic glucose stimulation. Taken together, the observed prediabetes phenotype and lack of response to ACTH indicate that Tspo cKO mice (Nr5a1-Cre+/-, Tspofl/fl) could provide a useful model to study the link between diabetes and stress.
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Affiliation(s)
- Jinjiang Fan
- The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Enrico Campioli
- The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Vassilios Papadopoulos
- The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States.
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29
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Gonzalez LL, Garrie K, Turner MD. Type 2 diabetes - An autoinflammatory disease driven by metabolic stress. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3805-3823. [PMID: 30251697 DOI: 10.1016/j.bbadis.2018.08.034] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 08/27/2018] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes has traditionally been viewed as a metabolic disorder characterised by chronic high glucose levels, insulin resistance, and declining insulin secretion from the pancreas. Modern lifestyle, with abundant nutrient supply and reduced physical activity, has resulted in dramatic increases in the rates of obesity-associated disease conditions, including diabetes. The associated excess of nutrients induces a state of systemic low-grade chronic inflammation that results from production and secretion of inflammatory mediators from the expanded pool of activated adipocytes. Here, we review the mechanisms by which obesity induces adipose tissue dysregulation, detailing the roles of adipose tissue secreted factors and their action upon other cells and tissues central to glucose homeostasis and type 2 diabetes. Furthermore, given the emerging importance of adipokines, cytokines and chemokines in disease progression, we suggest that type 2 diabetes should now be viewed as an autoinflammatory disease, albeit one that is driven by metabolic dysregulation.
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Affiliation(s)
- Laura L Gonzalez
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom
| | - Karin Garrie
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom
| | - Mark D Turner
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom.
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Lytrivi M, Igoillo-Esteve M, Cnop M. Inflammatory stress in islet β-cells: therapeutic implications for type 2 diabetes? Curr Opin Pharmacol 2018; 43:40-45. [PMID: 30142486 DOI: 10.1016/j.coph.2018.08.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 07/25/2018] [Accepted: 08/02/2018] [Indexed: 01/05/2023]
Abstract
Type 2 diabetes is a common complex disease. Relatively little is known about the underlying pathophysiology. Mild islet inflammation has been suggested to play a pathogenic role; here we review the available evidence. Mild islet inflammation is histologically detected in pancreas sections of type 2 diabetic patients. In experimental models, it can be triggered by excess nutrients, amyloid, lipopolysaccharide, and endoplasmic reticulum and oxidative stress. Transcriptome studies do not consistently identify pro-inflammatory gene expression signatures in type 2 diabetic islets, and genetic evidence calls into question the causality of inflammation. Several anti-inflammatory medications confer a modest glucose-lowering effect, supporting the role for inflammation in type 2 diabetes. Whether these anti-inflammatory therapies target inflammation in islets or in other metabolically relevant tissues remains unknown.
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Affiliation(s)
- Maria Lytrivi
- ULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium; Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium.
| | - Mariana Igoillo-Esteve
- ULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - Miriam Cnop
- ULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium; Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium.
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Fatty Acid-Stimulated Insulin Secretion vs. Lipotoxicity. Molecules 2018; 23:molecules23061483. [PMID: 29921789 PMCID: PMC6100479 DOI: 10.3390/molecules23061483] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 06/13/2018] [Accepted: 06/15/2018] [Indexed: 12/29/2022] Open
Abstract
Fatty acid (FA)-stimulated insulin secretion (FASIS) is reviewed here in contrast to type 2 diabetes etiology, resulting from FA overload, oxidative stress, intermediate hyperinsulinemia, and inflammation, all converging into insulin resistance. Focusing on pancreatic islet β-cells, we compare the physiological FA roles with the pathological ones. Considering FAs not as mere amplifiers of glucose-stimulated insulin secretion (GSIS), but as parallel insulin granule exocytosis inductors, partly independent of the KATP channel closure, we describe the FA initiating roles in the prediabetic state that is induced by retardations in the glycerol-3-phosphate (glucose)-promoted glycerol/FA cycle and by the impaired GPR40/FFA1 (free FA1) receptor pathway, specifically in its amplification by the redox-activated mitochondrial phospholipase, iPLA2γ. Also, excessive dietary FAs stimulate intestine enterocyte incretin secretion, further elevating GSIS, even at low glucose levels, thus contributing to diabetic hyperinsulinemia. With overnutrition and obesity, the FA overload causes impaired GSIS by metabolic dysbalance, paralleled by oxidative and metabolic stress, endoplasmic reticulum stress and numerous pro-apoptotic signaling, all leading to decreased β-cell survival. Lipotoxicity is exerted by saturated FAs, whereas ω-3 polyunsaturated FAs frequently exert antilipotoxic effects. FA-facilitated inflammation upon the recruitment of excess M1 macrophages into islets (over resolving M2 type), amplified by cytokine and chemokine secretion by β-cells, leads to an inevitable failure of pancreatic β-cells.
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