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1
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Pugliese LA, De Lorenzi V, Tesi M, Marchetti P, Cardarelli F. Optical Nanoscopy of Cytokine-Induced Structural Alterations of the Endoplasmic Reticulum and Golgi Apparatus in Insulin-Secreting Cells. Int J Mol Sci 2024; 25:10391. [PMID: 39408721 PMCID: PMC11476361 DOI: 10.3390/ijms251910391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/20/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open
Abstract
Pro-inflammatory cytokines play a role in the failure of β cells in type 1 and type 2 diabetes. While existing data from 'omics' experiments allow for some understanding of the molecular mechanisms behind cytokine-induced dysfunction in β cells, no report thus far has provided information on the direct imaging of the β cell landscape with nanoscale resolution following cytokine exposure. In this study, we use Airyscan-based optical super-resolution microscopy of Insulinoma 1E (INS-1E) cells to investigate the structural properties of two subcellular membranous compartments involved in the production, maturation and secretion of insulin-containing granules, the endoplasmic reticulum (ER) and the Golgi apparatus (GA). Our findings reveal that exposure of INS-1E cells to IL-1β and IFN-γ for 24 h leads to significant structural alterations of both compartments. In more detail, both the ER and the GA fragment and give rise to vesicle-like structures with markedly reduced characteristic area and perimeter and increased circularity with respect to the original structures. These findings complement the molecular data collected thus far on these compartments and their role in β cell dysfunction and lay the groundwork for future optical microscopy-based ex vivo and in vivo investigations.
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Affiliation(s)
- Licia Anna Pugliese
- NEST Laboratory—Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy;
| | - Valentina De Lorenzi
- NEST Laboratory—Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy;
| | - Marta Tesi
- Islet Cell Laboratory, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.T.); (P.M.)
| | - Piero Marchetti
- Islet Cell Laboratory, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.T.); (P.M.)
| | - Francesco Cardarelli
- NEST Laboratory—Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy;
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2
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Singh K, Aulakh SK, Nijjar GS, Singh S, Sandhu APS, Luthra S, Tanvir F, Kaur Y, Singla A, Kaur MS. Rebalancing the Gut: Glucagon-Like Peptide-1 Agonists as a Strategy for Obesity and Metabolic Health. Cureus 2024; 16:e64738. [PMID: 39156410 PMCID: PMC11329331 DOI: 10.7759/cureus.64738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2024] [Indexed: 08/20/2024] Open
Abstract
Obesity significantly impacts gut microbial composition, exacerbating metabolic dysfunction and weight gain. Traditional treatment methods often fall short, underscoring the need for innovative approaches. Glucagon-like peptide-1 (GLP-1) agonists have emerged as promising agents in obesity management, demonstrating significant potential in modulating gut microbiota. These agents promote beneficial bacterial populations, such as Bacteroides, Lactobacillus, and Bifidobacterium, while reducing harmful species like Enterobacteriaceae. By influencing gut microbiota composition, GLP-1 agonists enhance gut barrier integrity, reducing permeability and systemic inflammation, which are hallmarks of metabolic dysfunction in obesity. Additionally, GLP-1 agonists improve metabolic functions by increasing the production of short-chain fatty acids like butyrate, propionate, and acetate, which serve as energy sources for colonocytes, modulate immune responses, and enhance the production of gut hormones that regulate appetite and glucose homeostasis. By increasing microbial diversity, GLP-1 agonists create a more resilient gut microbiome capable of resisting pathogenic invasions and maintaining metabolic balance. Thus, by shifting the gut microbiota toward a healthier profile, GLP-1 agonists help disrupt the vicious cycle of obesity-induced gut dysbiosis and inflammation. This review highlights the intricate relationship between obesity, gut microbiota, and GLP-1 agonists, providing valuable insights into their combined role in effective obesity treatment and metabolic health enhancement.
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Affiliation(s)
| | - Smriti K Aulakh
- Internal Medicine, Sri Guru Ram Das University of Health Sciences and Research, Amritsar, IND
| | | | - Sumerjit Singh
- Internal Medicine, Government Medical College, Amritsar, IND
| | - Ajay Pal Singh Sandhu
- Internal Medicine, Sri Guru Ram Das University of Health Sciences and Research, Amritsar, IND
| | - Shivansh Luthra
- Internal Medicine, Government Medical College, Amritsar, IND
| | - Fnu Tanvir
- Internal Medicine, Government Medical College, Amritsar, IND
| | - Yasmeen Kaur
- Internal Medicine, Government Medical College, Amritsar, IND
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Geng N, Gao Y, Ji Y, Niu Y, Qi C, Zhen Y, Chen J, Ren L. Geriatric nutritional risk index is correlated with islet function but not insulin resistance in elderly patients with type 2 diabetes: A retrospective study. Medicine (Baltimore) 2024; 103:e37438. [PMID: 38489692 PMCID: PMC10939577 DOI: 10.1097/md.0000000000037438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 02/05/2024] [Accepted: 02/08/2024] [Indexed: 03/17/2024] Open
Abstract
The geriatric nutritional risk index (GNRI) is a simple nutritional assessment tool that can predict poor prognosis in elderly subjects. The aim of this study was to evaluate the association between GNRI and both islet function and insulin sensitivity in patients with type 2 diabetes mellitus. This research carries significant implications for the integrated treatment and nutritional management of this patient population. A total of 173 patients with type 2 diabetes mellitus, aged 60 years or older, who were hospitalized in the Endocrinology Department at Hebei General Hospital from February 2018 to June 2021, were selected as the research subjects. These subjects were divided into 4 groups according to the quartile of their GNRI values: T1 (GNRI < 99.4, n = 43), T2 (99.4 ≤ GNRI < 103, n = 43), T3 (103 ≤ GNRI < 106.3, n = 43), and T4 (GNRI ≥ 106.3, n = 44). Glucose, insulin, and C-peptide concentrations were tested at 0, 30, 60, 120, and 180 minutes during a 75 g oral glucose tolerance test. The homeostasis model assessment for insulin resistance and the homeostasis model assessment for β cell function index were calculated. As the GNRI value increased, the levels of total protein, albumin, hemoglobin, alanine transaminase, aspartate aminotransferase, and 25-hydroxyvitamin D increased significantly. The area under the curve for blood glucose decreased significantly across the 4 groups, while the AUCs for insulin and C-peptide showed an overall increasing trend. β Cell function index increased significantly with the increase of GNRI; meanwhile, both the early-phase insulin secretion index and the late-phase insulin secretion index increased significantly. Although there was an increasing trend, homeostasis model assessment for insulin resistance did not change significantly among the 4 groups. This study indicates that elderly type 2 diabetes patients with higher nutritional risk have worse islet function, while insulin sensitivity is not associated with nutritional risk.
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Affiliation(s)
- Nan Geng
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yaxue Gao
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yuanyuan Ji
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yingchun Niu
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Cuijuan Qi
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yunfeng Zhen
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Jinhu Chen
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Luping Ren
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
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4
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Sarkar S, Deiter C, Kyle JE, Guney MA, Sarbaugh D, Yin R, Li X, Cui Y, Ramos-Rodriguez M, Nicora CD, Syed F, Juan-Mateu J, Muralidharan C, Pasquali L, Evans-Molina C, Eizirik DL, Webb-Robertson BJM, Burnum-Johnson K, Orr G, Laskin J, Metz TO, Mirmira RG, Sussel L, Ansong C, Nakayasu ES. Regulation of β-cell death by ADP-ribosylhydrolase ARH3 via lipid signaling in insulitis. Cell Commun Signal 2024; 22:141. [PMID: 38383396 PMCID: PMC10880366 DOI: 10.1186/s12964-023-01437-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 12/12/2023] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND Lipids are regulators of insulitis and β-cell death in type 1 diabetes development, but the underlying mechanisms are poorly understood. Here, we investigated how the islet lipid composition and downstream signaling regulate β-cell death. METHODS We performed lipidomics using three models of insulitis: human islets and EndoC-βH1 β cells treated with the pro-inflammatory cytokines interlukine-1β and interferon-γ, and islets from pre-diabetic non-obese mice. We also performed mass spectrometry and fluorescence imaging to determine the localization of lipids and enzyme in islets. RNAi, apoptotic assay, and qPCR were performed to determine the role of a specific factor in lipid-mediated cytokine signaling. RESULTS Across all three models, lipidomic analyses showed a consistent increase of lysophosphatidylcholine species and phosphatidylcholines with polyunsaturated fatty acids and a reduction of triacylglycerol species. Imaging assays showed that phosphatidylcholines with polyunsaturated fatty acids and their hydrolyzing enzyme phospholipase PLA2G6 are enriched in islets. In downstream signaling, omega-3 fatty acids reduce cytokine-induced β-cell death by improving the expression of ADP-ribosylhydrolase ARH3. The mechanism involves omega-3 fatty acid-mediated reduction of the histone methylation polycomb complex PRC2 component Suz12, upregulating the expression of Arh3, which in turn decreases cell apoptosis. CONCLUSIONS Our data provide insights into the change of lipidomics landscape in β cells during insulitis and identify a protective mechanism by omega-3 fatty acids. Video Abstract.
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Affiliation(s)
- Soumyadeep Sarkar
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, 99354, USA
| | - Cailin Deiter
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Center, Aurora, CO, 80045, USA
| | - Jennifer E Kyle
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, 99354, USA
| | - Michelle A Guney
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Center, Aurora, CO, 80045, USA
| | - Dylan Sarbaugh
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Center, Aurora, CO, 80045, USA
| | - Ruichuan Yin
- Department of Chemistry, Purdue University, West Lafayette, IN, 47907-2084, USA
| | - Xiangtang Li
- Department of Chemistry, Purdue University, West Lafayette, IN, 47907-2084, USA
| | - Yi Cui
- Environmental and Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, 99354, USA
- NanoString Technologies, Seattle, WA, 98109, USA
| | - Mireia Ramos-Rodriguez
- Endocrine Regulatory Genomics, Department of Experimental & Health Sciences, University Pompeu Fabra, 08003, Barcelona, Spain
| | - Carrie D Nicora
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, 99354, USA
| | - Farooq Syed
- Center for Diabetes and Metabolic Diseases and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Jonas Juan-Mateu
- ULB Center for Diabetes Research, Université Libre de Bruxelles (ULB), 1070, Brussels, Belgium
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003, Barcelona, Spain
| | - Charanya Muralidharan
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
| | - Lorenzo Pasquali
- Endocrine Regulatory Genomics, Department of Experimental & Health Sciences, University Pompeu Fabra, 08003, Barcelona, Spain
| | - Carmella Evans-Molina
- Center for Diabetes and Metabolic Diseases and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles (ULB), 1070, Brussels, Belgium
| | - Bobbie-Jo M Webb-Robertson
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, 99354, USA
- Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Center, Aurora, CO, 80045, USA
| | - Kristin Burnum-Johnson
- Environmental and Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, 99354, USA
| | - Galya Orr
- Environmental and Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, 99354, USA
| | - Julia Laskin
- Department of Chemistry, Purdue University, West Lafayette, IN, 47907-2084, USA
| | - Thomas O Metz
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, 99354, USA
| | - Raghavendra G Mirmira
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
| | - Lori Sussel
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Center, Aurora, CO, 80045, USA
| | - Charles Ansong
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, 99354, USA
| | - Ernesto S Nakayasu
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, 99354, USA.
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5
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Xu L, Cheng F, Bu D, Li X. The Effects of Prolonged Basic Amino Acid Exposures on Mitochondrial Enzyme Gene Expressions, Metabolic Profiling and Insulin Secretions and Syntheses in Rat INS-1 β-Cells. Nutrients 2023; 15:4026. [PMID: 37764809 PMCID: PMC10538135 DOI: 10.3390/nu15184026] [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: 08/13/2023] [Revised: 09/09/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
In order to investigate the chronic effects of basic amino acids (BAA) on β-cell metabolism and insulin secretion, INS-1 β-cells were randomly assigned to cultures in standard medium (Con), standard medium plus 10 mM L-Arginine (Arg), standard medium plus 10 mM L-Histidine (His) or standard medium plus 10 mM L-Lysine (Lys) for 24 h. Results showed that insulin secretion was decreased by the Arg treatment but was increased by the His treatment relative to the Con group (p < 0.05). Higher BAA concentrations reduced the high glucose-stimulated insulin secretions (p < 0.001), but only Lys treatment increased the intracellular insulin content than that in the Con group (p < 0.05). Compared with Arg and Lys, the His treatment increased the mitochondrial key enzyme gene expressions including Cs, mt-Atp6, mt-Nd4l and Ogdh, and caused a greater change in the metabolites profiling (p < 0.05). The most significant pathways affected by Arg, His and Lys were arginine and proline metabolism, aminoacyl-tRNA biosynthesis and pyrimidine metabolism, respectively. Regression analysis screened 7 genes and 9 metabolites associated with insulin releases during BAA stimulations (p < 0.05). Together, different BAAs exerted dissimilar effects on β-cell metabolism and insulin outputs.
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Affiliation(s)
- Lianbin Xu
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Fengqi Cheng
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Dengpan Bu
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Xiuli Li
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, China
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6
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Pugliese LA, De Lorenzi V, Bernardi M, Ghignoli S, Tesi M, Marchetti P, Pesce L, Cardarelli F. Unveiling nanoscale optical signatures of cytokine-induced β-cell dysfunction. Sci Rep 2023; 13:13342. [PMID: 37587148 PMCID: PMC10432522 DOI: 10.1038/s41598-023-40272-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/08/2023] [Indexed: 08/18/2023] Open
Abstract
Pro-inflammatory cytokines contribute to β-cell failure in both Type-1 and Type-2 Diabetes. Data collected so far allowed to dissect the genomic, transcriptomic, proteomic and biochemical landscape underlying cytokine-induced β-cell progression through dysfunction. Yet, no report thus far complemented such molecular information with the direct optical nanoscopy of the β-cell subcellular environment. Here we tackle this issue in Insulinoma 1E (INS-1E) β-cells by label-free fluorescence lifetime imaging microscopy (FLIM) and fluorescence-based super resolution imaging by expansion microscopy (ExM). It is found that 24-h exposure to IL-1β and IFN-γ is associated with a neat modification of the FLIM signature of cell autofluorescence due to the increase of either enzyme-bound NAD(P)H molecules and of oxidized lipid species. At the same time, ExM-based direct imaging unveils neat alteration of mitochondrial morphology (i.e. ~ 80% increase of mitochondrial circularity), marked degranulation (i.e. ~ 40% loss of insulin granules, with mis-localization of the surviving pool), appearance of F-actin-positive membrane blebs and an hitherto unknown extensive fragmentation of the microtubules network (e.g. ~ 37% reduction in the number of branches). Reported observations provide an optical-microscopy framework to interpret the amount of molecular information collected so far on β-cell dysfunction and pave the way to future ex-vivo and in-vivo investigations.
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Affiliation(s)
- Licia Anna Pugliese
- NEST Laboratory - Scuola Normale Superiore, Piazza San Silvestro 12, Pisa, Italy.
| | - Valentina De Lorenzi
- NEST Laboratory - Scuola Normale Superiore, Piazza San Silvestro 12, Pisa, Italy
| | - Mario Bernardi
- NEST Laboratory - Scuola Normale Superiore, Piazza San Silvestro 12, Pisa, Italy
| | - Samuele Ghignoli
- NEST Laboratory - Scuola Normale Superiore, Piazza San Silvestro 12, Pisa, Italy
| | - Marta Tesi
- Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, Italy
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, Italy
| | - Luca Pesce
- NEST Laboratory - Scuola Normale Superiore, Piazza San Silvestro 12, Pisa, Italy.
| | - Francesco Cardarelli
- NEST Laboratory - Scuola Normale Superiore, Piazza San Silvestro 12, Pisa, Italy.
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7
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Prasad MK, Mohandas S, Ramkumar KM. Dysfunctions, molecular mechanisms, and therapeutic strategies of pancreatic β-cells in diabetes. Apoptosis 2023:10.1007/s10495-023-01854-0. [PMID: 37273039 DOI: 10.1007/s10495-023-01854-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/08/2023] [Indexed: 06/06/2023]
Abstract
Pancreatic beta-cell death has been established as a critical mediator in the progression of type 1 and type 2 diabetes mellitus. Beta-cell death is associated with exacerbating hyperglycemia and insulin resistance and paves the way for the progression of DM and its complications. Apoptosis has been considered the primary mechanism of beta-cell death in diabetes. However, recent pieces of evidence have implicated the substantial involvement of several other novel modes of cell death, including autophagy, pyroptosis, necroptosis, and ferroptosis. These distinct mechanisms are characterized by their unique biochemical features and often precipitate damage through the induction of cellular stressors, including endoplasmic reticulum stress, oxidative stress, and inflammation. Experimental studies were identified from PubMed literature on different modes of beta cell death during the onset of diabetes mellitus. This review summarizes current knowledge on the crucial pathways implicated in pancreatic beta cell death. The article also focuses on applying natural compounds as potential treatment strategies in inhibiting these cell death pathways.
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Affiliation(s)
- Murali Krishna Prasad
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Sundhar Mohandas
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India.
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8
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Dos Reis LFC, Cerdeira CD, Gagliano GS, de Figueiredo ABT, Ferreira JH, Castro AP, Souza RLM, Marques MJ. Alternate-day fasting, a high-sucrose/caloric diet and praziquantel treatment influence biochemical and behavioral parameters during Schistosoma mansoni infection in male BALB/c mice. Exp Parasitol 2022; 240:108316. [PMID: 35787384 DOI: 10.1016/j.exppara.2022.108316] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/12/2022] [Accepted: 06/24/2022] [Indexed: 11/17/2022]
Abstract
Schistosoma mansoni-induced granulomas result in severe damage to the host's liver, as well as neurological and metabolic disorders. We evaluated the biochemical and behavioral changes during schistosomiasis under three diet protocols: ad libitum (AL), alternate-day fasting (ADF) and a high-sucrose/caloric diet (HSD). Healthy male BALB/c mice were divided into noninfected, matched infected and infected/treated [praziquantel (PZQ)] groups. Caloric intake and energy efficiency coefficients associated with diets were measured. Behavioral (exploratory and locomotor) and biochemical (glucose, triglycerides, total cholesterol, AST, ALT, ALP, and γ-GT) tests and histological analysis were performed. Fifteen weeks postinfection, HSD and PZQ promoted weight gain, with higher caloric consumption than ADF (p < 0.05), reflecting serum glucose levels and lipid profiles. HSD and PZQ prevented liver dysfunction (AST and ALT) and significantly prevented increases in granuloma area (p < 0.05). HSD and PZQ also significantly improved mouse physical performance in exploratory and locomotor behavior (p < 0.05), reversing the impaired motivation caused by infection. These findings showed that ADF worsened the course of S. mansoni infection, while HSD and PZQ, even with synergistic effects, prevented and/or attenuated biochemical and behavioral impairment from infection.
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Affiliation(s)
- Luis F C Dos Reis
- Department of Structural Biology, Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, Minas Gerais (MG), Brazil
| | - Cláudio D Cerdeira
- Department of Biochemistry, Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, Minas Gerais (MG), Brazil.
| | - Guilherme S Gagliano
- Department of Microbiology and Immunology, Institute of Biomedical Sciences, UNIFAL-MG, Alfenas, Minas Gerais (MG), Brazil
| | - Ana B T de Figueiredo
- Department of Pathology and Parasitology, Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, Minas Gerais (MG), Brazil
| | - Juliana H Ferreira
- Department of Physiology, University of Sao Paulo, São Paulo (SP), Brazil
| | - Aline P Castro
- Department of Pathology and Parasitology, Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, Minas Gerais (MG), Brazil
| | - Raquel L M Souza
- Department of Pathology and Parasitology, Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, Minas Gerais (MG), Brazil
| | - Marcos J Marques
- Department of Pathology and Parasitology, Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, Minas Gerais (MG), Brazil
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9
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Xu L, Lin X, Li X, Hu Z, Hou Q, Wang Y, Wang Z. Integration of transcriptomics and metabolomics provides metabolic and functional insights into reduced insulin secretion in MIN6 β-cells exposed to deficient and excessive arginine. FASEB J 2022; 36:e22206. [PMID: 35199385 DOI: 10.1096/fj.202101723r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/11/2022] [Accepted: 01/31/2022] [Indexed: 01/17/2023]
Abstract
Previous work demonstrated that arginine is one of the strongest insulin secretagogues. However, knowledge of the mechanisms linking chronic arginine metabolism with β-cell function and insulin secretion is relatively limited. After preliminary selection of concentration according to the cell proliferation, the MIN6 pancreatic β-cells were randomly assigned to culture in 0.04 mM (low-arginine, LA), 0.4 mM (standard-arginine, SA), or 8 mM arginine (high-arginine, HA) for 24 h. Following the treatment, a combination of transcriptomics and metabolomics, together with a series of molecular biological tests were performed to investigate the responses of β-cells to varied arginine availability. Our results showed that HA treatment reduced the chronic insulin releases, and LA and HA treatments decreased the glucose-stimulated insulin secretions (GSIS) of β-cells relative to the SA group (p < .05). Transcriptomics analysis indicated that LA administration significantly inhibited oxidative phosphorylation and ATP metabolic process but promoted DNA repair and mRNA processing in β-cells, while HA administration affected ammonium ion metabolic process and mRNA export (p < .05). Both LA and HA regulated the expressions of genes involved in DNA replication, cell-cycle phase transition, and response to oxidative stress (p < .05). Protein-protein interaction and transcription factor analyses suggested that Trp53 and Nr4a2 genes may play key roles during arginine stimulation. On the contrary, metabolomics analysis demonstrated that the differentially expressed metabolites (DEM) of MIN6 β-cells induced by LA were mainly enriched in glycerophospholipid metabolism, linoleic acid metabolism, and purine metabolism, while most DEMs between LA vs. SA comparison belonged to amino acid metabolism. When combined the three groups, co-expression analysis suggested that insulin secretions had strong associations with L-pyroglutamic acid, L-glutamate, and creatine concentrations, while intracellular insulin contents were mainly correlated to L-arginine, argininosuccinic acid, and phosphorylcholine. At last, integrated analysis of transcriptomics and metabolomics showed that glycerophospholipid metabolism, biosynthesis of unsaturated fatty acids, and amino acid metabolism were the most relevant pathways in β-cells exposed to abnormal arginine supply. This descriptive bioinformatics analysis suggested that the disturbed carbohydrate, lipid, and amino acid metabolisms, as well as the increased apoptosis and elevated oxidative stress, contributed to the reduced insulin secretion and lower GSIS in β-cells induced by LA or HA treatments, while some underlying mechanisms need to be further explored.
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Affiliation(s)
- Lianbin Xu
- College of Animal Science and Technology, Shandong Agricultural University, Taian, P. R. China
| | - Xueyan Lin
- College of Animal Science and Technology, Shandong Agricultural University, Taian, P. R. China
| | - Xiuli Li
- Institute of Animal Immune Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing, P. R. China
| | - Zhiyong Hu
- College of Animal Science and Technology, Shandong Agricultural University, Taian, P. R. China
| | - Qiuling Hou
- College of Animal Science and Technology, Shandong Agricultural University, Taian, P. R. China
| | - Yun Wang
- College of Animal Science and Technology, Shandong Agricultural University, Taian, P. R. China
| | - Zhonghua Wang
- College of Animal Science and Technology, Shandong Agricultural University, Taian, P. R. China
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10
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Karsai M, Zuellig RA, Lehmann R, Cuozzo F, Nasteska D, Luca E, Hantel C, Hodson DJ, Spinas GA, Rutter GA, Gerber PA. Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death. J Endocrinol 2022; 253:1-11. [PMID: 35017316 PMCID: PMC8859919 DOI: 10.1530/joe-21-0271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 01/11/2022] [Indexed: 11/10/2022]
Abstract
Pancreatic β-cells depend on the well-balanced regulation of cytosolic zinc concentrations, providing sufficient zinc ions for the processing and storage of insulin, but avoiding toxic effects. The zinc transporter ZnT8, encoded by SLC30A8,is a key player regarding islet cell zinc homeostasis, and polymorphisms in this gene are associated with altered type 2 diabetes susceptibility in man. The objective of this study was to investigate the role of ZnT8 and zinc in situations of cellular stress as hypoxia or inflammation. Isolated islets of WT and global ZnT8-/- mice were exposed to hypoxia or cytokines and cell death was measured. To explore the role of changing intracellular Zn2+ concentrations, WT islets were exposed to different zinc concentrations using zinc chloride or the zinc chelator N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN). Hypoxia or cytokine (TNF-α, IFN-γ, IL1-β) treatment induced islet cell death, but to a lesser extent in islets from ZnT8-/- mice, which were shown to have a reduced zinc content. Similarly, chelation of zinc with TPEN reduced cell death in WT islets treated with hypoxia or cytokines, whereas increased zinc concentrations aggravated the effects of these stressors. This study demonstrates a reduced rate of cell death in islets from ZnT8-/- mice as compared to WT islets when exposed to two distinct cellular stressors, hypoxia or cytotoxic cytokines. This protection from cell death is, in part, mediated by a reduced zinc content in islet cells of ZnT8-/- mice. These findings may be relevant for altered diabetes burden in carriers of risk SLC30A8 alleles in man.
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Affiliation(s)
- Maria Karsai
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
| | - Richard A Zuellig
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
| | - Roger Lehmann
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
| | - Federica Cuozzo
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
- Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - Daniela Nasteska
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
- Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - Edlira Luca
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
| | - Constanze Hantel
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
- Medizinische Klinik und Poliklinik III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
| | - David J Hodson
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
- Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - Giatgen A Spinas
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- CR-CHUM, University of Montreal, Montreal, QC, Canada
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Philipp A Gerber
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
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11
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Molecular mechanisms of hematological and biochemical alterations in malaria: A review. Mol Biochem Parasitol 2021; 247:111446. [PMID: 34953384 DOI: 10.1016/j.molbiopara.2021.111446] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/20/2021] [Accepted: 12/19/2021] [Indexed: 11/20/2022]
Abstract
Malaria is a dangerous disease that contributes to millions of hospital visits and hundreds of thousands of deaths, especially in children residing in sub-Saharan Africa. Although several interventions such as vector control, case detection, and treatment are already in place, there is no substantive reduction in the disease burden. Several studies in the past have reported the emergence of resistant strains of malaria parasites (MPs) and mosquitoes, and poor adherence and inaccessibility to effective antimalarial drugs as the major factors for this persistent menace of malaria infections. Moreover, victory against MP infections for many years has been hampered by an incomplete understanding of the complex nature of malaria pathogenesis. Very recent studies have identified different complex interactions and hematological alterations induced by malaria parasites. However, no studies have hybridized these alterations for a better understanding of Malaria pathogenesis. Hence, this review thoroughly discusses the molecular mechanisms of all reported hematological and biochemical alterations induced by MPs infections. Specifically, the mechanisms in which MP-infection induces anemia, thrombocytopenia, leukopenia, dyslipidemia, hypoglycemia, oxidative stress, and liver and kidney malfunctions were presented. The study also discussed how MPs evade the host's immune response and suggested strategies to limit evasion of the host's immune response to combat malaria and its complications.
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12
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Dietrich I, Girdlestone J, Giele H. Differential cytokine expression in direct and indirect co-culture of islets and mesenchymal stromal cells. Cytokine 2021; 150:155779. [PMID: 34923221 DOI: 10.1016/j.cyto.2021.155779] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 11/22/2021] [Accepted: 11/25/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Transplantation of allogenic Langerhans islets (ISL) has been employed as an alternative to pancreas transplantation to provide endogenous supply of insulin and treat hypoglycemia unawareness in type 1 diabetes. Nevertheless, the process of islets isolation exposes the islets to hypoxia and other aggressive conditions that results in the recover of less than half of the islets present in the pancreas. Several studies demonstrated that co-culturing islets with mesenchymal stromal cells (MSC) before implantation enhances islets survival and function and this effect is mediated by cytokines. However, it remains unclear if the profile of cytokines secreted by MSC in co-culture with islets changes upon the type of co-culture: direct and indirect. MATERIALS AND METHODS In 3 series of experiments with human islets of 3 different donors, we compared the levels of a panel of cytokines measured in the supernatant of ISL cultured alone, Wharton Jelly MSC (WJMSC) cultured alone, direct co-culture of ISL-WJMSC and indirect co-culture using a permeable transwell membrane to separate ISL and WJMSC. RESULTS Comparing the profile of cytokines secreted by islets alone with islets in direct co- culture with WJMSC, we found higher expression of IL1b, IL17, IFγ, IL4, IL10, IL13, Granulocyte-macrophage colony-stimulating factor (GMCSF) and Leptin, in the supernatant of the co-cultures. In contrast, when comparing islets cultured alone with islets in indirect co-culture with MSC, we found no significant differences in the levels of cytokines we analyzed. CONCLUSION Direct contact between human WJMSC and pancreatic islets is required for elevated expression of a range of immune cytokines, including both those considered inflammatory, and anti-inflammatory.
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Affiliation(s)
- I Dietrich
- São Paulo University Medical School, Department of Surgery, Av Jurucê 743, Suite 111., São Paulo, São Paulo, Brazil.
| | - J Girdlestone
- Head of Stem Cells and Immunotherapy Laboratory, NHS Blood and Transplant, Oxford, UK; John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9BQ, UK
| | - H Giele
- University of Oxford, Nuffield Department of Surgical Sciences, UK; Oxford University Foundation Hospitals NHS Trust, Oxford OX3 9DU, UK
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13
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Alaaraj N, Soliman A, Rogol AD. Growth of malnourished infants and children: how is inflammation involved? Expert Rev Endocrinol Metab 2021; 16:213-216. [PMID: 34289758 DOI: 10.1080/17446651.2021.1956903] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 07/13/2021] [Indexed: 10/20/2022]
Affiliation(s)
- Nada Alaaraj
- Department of Pediatrics, Hamad General Hospital, Ad Dawhah, Qatar
| | - Ashraf Soliman
- Alexandria University, Department of Pediatrics, Division of Endocrinology, Alexandria, Egypt
| | - Alan D Rogol
- University of Virginia, Department of Pediatrics, Charlottesville, VA, USA
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14
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Karbalaei M, Sahebkar A, Keikha M. Helicobacter pylori infection and susceptibility to cardiac syndrome X: A systematic review and meta-analysis. World J Meta-Anal 2021; 9:208-219. [DOI: 10.13105/wjma.v9.i2.208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/03/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
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15
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Karbalaei M, Sahebkar A, Keikha M. Helicobacter pylori infection and susceptibility to cardiac syndrome X: A systematic review and meta-analysis. World J Meta-Anal 2021; 9:207-218. [DOI: 10.13105/wjma.v9.i2.207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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16
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Losada-Barragán M. Physiological effects of nutrients on insulin release by pancreatic beta cells. Mol Cell Biochem 2021; 476:3127-3139. [PMID: 33844157 DOI: 10.1007/s11010-021-04146-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 03/31/2021] [Indexed: 10/21/2022]
Abstract
Obesity and type 2 diabetes (T2D) are growing health problems associated with a loss of insulin sensitivity. Both conditions arise from a long-term energy imbalance, and frequently, lifestyle measures can be useful in its prevention, including physical activity and a healthy diet. Pancreatic β-cells are determinant nutrient sensors that participate in energetic homeostasis needs. However, when pancreatic β-cells are incapable of secreting enough insulin to counteract the reduced sensitivity, the pathology evolves to an insulin resistance condition. The primary nutrient that stimulates insulin secretion is glucose, but also, there are multiple dietary and hormonal factors influencing that response. Many studies of the physiology of β-cells have highlighted the importance of glucose, fructose, amino acids, and free fatty acids on insulin secretion. The present review summarizes recent research on how β-cells respond to the most abundant nutrients that influence insulin secretion. Taken together, understand the subjacent mechanisms of each nutrient on β-cells can help to unravel the effects of mixed variables and complexity in the context of β-cell pathology.
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Affiliation(s)
- Monica Losada-Barragán
- Grupo de investigación en Biología celular y funcional e ingeniería de biomoléculas, Universidad Antonio Nariño-Sede Circunvalar. Cra, 3 Este # 47A - 15, Bl 5, Bogotá, Colombia.
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17
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Jutley GS, Sahota K, Sahbudin I, Filer A, Arayssi T, Young SP, Raza K. Relationship Between Inflammation and Metabolism in Patients With Newly Presenting Rheumatoid Arthritis. Front Immunol 2021; 12:676105. [PMID: 34650548 PMCID: PMC8507469 DOI: 10.3389/fimmu.2021.676105] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 08/04/2021] [Indexed: 12/29/2022] Open
Abstract
Background Systemic inflammation in rheumatoid arthritis (RA) is associated with metabolic changes. We used nuclear magnetic resonance (NMR) spectroscopy-based metabolomics to assess the relationship between an objective measure of systemic inflammation [C-reactive protein (CRP)] and both the serum and urinary metabolome in patients with newly presenting RA. Methods Serum (n=126) and urine (n=83) samples were collected at initial presentation from disease modifying anti-rheumatic drug naïve RA patients for metabolomic profile assessment using 1-dimensional 1H-NMR spectroscopy. Metabolomics data were analysed using partial least square regression (PLS-R) and orthogonal projections to latent structure discriminant analysis (OPLS-DA) with cross validation. Results Using PLS-R analysis, a relationship between the level of inflammation, as assessed by CRP, and the serum (p=0.001) and urinary (p<0.001) metabolome was detectable. Likewise, following categorisation of CRP into tertiles, patients in the lowest CRP tertile and the highest CRP tertile were statistically discriminated using OPLS-DA analysis of both serum (p=0.033) and urinary (p<0.001) metabolome. The most highly weighted metabolites for these models included glucose, amino acids, lactate, and citrate. These findings suggest increased glycolysis, perturbation in the citrate cycle, oxidative stress, protein catabolism and increased urea cycle activity are key characteristics of newly presenting RA patients with elevated CRP. Conclusions This study consolidates our understanding of a previously identified relationship between serum metabolite profile and inflammation and provides novel evidence that there is a relationship between urinary metabolite profile and inflammation as measured by CRP. Identification of these metabolic perturbations provides insights into the pathogenesis of RA and may help in the identification of therapeutic targets.
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Affiliation(s)
- Gurpreet Singh Jutley
- NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and Institute for Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Kalvin Sahota
- NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and Institute for Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Ilfita Sahbudin
- NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and Institute for Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Andrew Filer
- NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and Institute for Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom.,Research Into Inflammatory Arthritis Centre, Versus Arthritis, University of Birmingham, Birmingham, United Kingdom
| | | | - Stephen P Young
- NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and Institute for Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Karim Raza
- NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and Institute for Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom.,Research Into Inflammatory Arthritis Centre, Versus Arthritis, University of Birmingham, Birmingham, United Kingdom.,Department of Rheumatology, Sandwell and West Birmingham NHS Trust, Birmingham, United Kingdom
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18
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Drareni K, Ballaire R, Alzaid F, Goncalves A, Chollet C, Barilla S, Nguewa JL, Dias K, Lemoine S, Riveline JP, Roussel R, Dalmas E, Velho G, Treuter E, Gautier JF, Venteclef N. Adipocyte Reprogramming by the Transcriptional Coregulator GPS2 Impacts Beta Cell Insulin Secretion. Cell Rep 2020; 32:108141. [PMID: 32937117 PMCID: PMC7495095 DOI: 10.1016/j.celrep.2020.108141] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 07/03/2020] [Accepted: 08/21/2020] [Indexed: 01/10/2023] Open
Abstract
Glucose homeostasis is maintained through organ crosstalk that regulates secretion of insulin to keep blood glucose levels within a physiological range. In type 2 diabetes, this coordinated response is altered, leading to a deregulation of beta cell function and inadequate insulin secretion. Reprogramming of white adipose tissue has a central role in this deregulation, but the critical regulatory components remain unclear. Here, we demonstrate that expression of the transcriptional coregulator GPS2 in white adipose tissue is correlated with insulin secretion rate in humans. The causality of this relationship is confirmed using adipocyte-specific GPS2 knockout mice, in which inappropriate secretion of insulin promotes glucose intolerance. This phenotype is driven by adipose-tissue-secreted factors, which cause increased pancreatic islet inflammation and impaired beta cell function. Thus, our study suggests that, in mice and in humans, GPS2 controls the reprogramming of white adipocytes to influence pancreatic islet function and insulin secretion.
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Affiliation(s)
- Karima Drareni
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France.
| | | | - Fawaz Alzaid
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France
| | - Andreia Goncalves
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France
| | - Catherine Chollet
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France
| | - Serena Barilla
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge 14157, Sweden
| | - Jean-Louis Nguewa
- Department of Diabetes, Clinical Investigation Centre (CIC-9504), Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Karine Dias
- École Normale Supérieure, PSL Research University, Centre National de la Recherche Scientifique (CNRS), INSERM, Institut de Biologie de l'École Normale Supérieure (IBENS), Plateforme Génomique, Paris, France
| | - Sophie Lemoine
- École Normale Supérieure, PSL Research University, Centre National de la Recherche Scientifique (CNRS), INSERM, Institut de Biologie de l'École Normale Supérieure (IBENS), Plateforme Génomique, Paris, France
| | - Jean-Pierre Riveline
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France; Department of Diabetes, Clinical Investigation Centre (CIC-9504), Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Ronan Roussel
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France; Department of Diabetology, Endocrinology and Nutrition, DHU FIRE, Bichat Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Elise Dalmas
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France
| | - Gilberto Velho
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France
| | - Eckardt Treuter
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge 14157, Sweden
| | - Jean-François Gautier
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France; Department of Diabetes, Clinical Investigation Centre (CIC-9504), Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Nicolas Venteclef
- Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France.
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19
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Rattanaporn P, Tongsima S, Mandrup-Poulsen T, Svasti S, Tanyong D. Combination of ferric ammonium citrate with cytokines involved in apoptosis and insulin secretion of human pancreatic beta cells related to diabetes in thalassemia. PeerJ 2020; 8:e9298. [PMID: 32587797 PMCID: PMC7304432 DOI: 10.7717/peerj.9298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 05/14/2020] [Indexed: 01/09/2023] Open
Abstract
Background Diabetes mellitus (DM) is a common complication found in β-thalassemia patients. The mechanism of DM in β-thalassemia patients is still unclear, but it could be from an iron overload and increase of some cytokines, such as interleukin1-β (IL-1β) and tumor necrosis factor-α (TNF-α). The objective of this study was to study the effect of interaction between ferric ammonium citrate (FAC) and cytokines, IL-1β and TNF-α, on 1.1B4 human pancreatic β-cell line. Methods The effect of the combination of FAC and cytokines on cell viability was studied by MTT assay. Insulin secretion was assessed by the enzyme-linked immunosorbent assay (ELISA). The reactive oxygen species (ROS) and cell apoptosis in normal and high glucose condition were determined by flow cytometer. In addition, gene expression of apoptosis, antioxidant; glutathione peroxidase 1 (GPX1) and superoxide dismutase 2 (SOD2), and insulin secretory function were studied by real-time polymerase chain reaction (Real-time PCR). Results The findings revealed that FAC exposure resulted in the decrease of cell viability and insulin-release, and the induction of ROS and apoptosis in pancreatic cells. Interestingly, a combination of FAC and cytokines had an additive effect on SOD2 antioxidants' genes expression and endoplasmic reticulum (ER) stress. In addition, it reduced the insulin secretion genes expression; insulin (INS), glucose kinase (GCK), protein convertase 1 (PSCK1), and protein convertase 2 (PSCK2). Moreover, the highest ROS and the lowest insulin secretion were found in FAC combined with IL-1β and TNF-α in the high-glucose condition of human pancreatic beta cell, which could be involved in the mechanism of DM development in β-thalassemia patients.
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Affiliation(s)
- Patchara Rattanaporn
- Department of Clinical Microscopic, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand.,Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Sissades Tongsima
- National Biobank of Thailand, National Science and Technology Development Agency, Pathum Thani, Thailand.,National Center for Genetics Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Thomas Mandrup-Poulsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Saovaros Svasti
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand.,Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Dalina Tanyong
- Department of Clinical Microscopic, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand
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20
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Menon K, Marquina C, Liew D, Mousa A, de Courten B. Histidine-containing dipeptides reduce central obesity and improve glycaemic outcomes: A systematic review and meta-analysis of randomized controlled trials. Obes Rev 2020; 21:e12975. [PMID: 31828942 DOI: 10.1111/obr.12975] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/06/2019] [Accepted: 10/15/2019] [Indexed: 12/21/2022]
Abstract
Supplementation with histidine-containing dipeptides has been shown to improve obesity and glycaemic outcomes in animal and human studies. We conducted a systematic review and meta-analysis of randomized controlled trials to examine these effects. Electronic databases were searched investigating the effects of histidine-containing dipeptides supplementation on anthropometric and glycaemic outcomes. Meta-analyses were performed using random-effects models to calculate the weighted mean difference and 95% confidence interval. There were 30 studies for the systematic review and 23 studies pooled for meta-analysis. Histidine-containing dipeptide groups had a lower waist circumference (WMD [95% CI] = -3.53 cm [-5.65, -1.41], p = 0.001) and HbA1c level (WMD [95% CI] = -0.76% (8.5 mmol/mol) [-1.29% (14.3 mmol/mol), -0.24% (2.8 mmol/mol)], p = 0.004) at follow-up compared with controls. In sensitivity analyses of studies with low risk of bias, waist circumference, HbA1c, and fasting glucose levels (WMD [95% CI] = -0.63 mmol/L [-1.09, -0.18], p = 0.006) were significantly lower in intervention groups versus controls. There was also a trend toward lower fat mass (p = 0.09), insulin resistance (p = 0.07), and higher insulin secretion (p = 0.06) in intervention versus control groups. Supplementation with histidine-containing dipeptides may reduce central obesity and improve glycaemic outcomes. Further studies exploring histidine-containing dipeptide use in obesity and diabetes prevention and treatment are warranted.
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Affiliation(s)
- Kirthi Menon
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Clara Marquina
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Danny Liew
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Aya Mousa
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Barbora de Courten
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
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21
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Bittencourt A, Schroeder HT, Porto RR, de Lemos Muller CH, Krause M, Homem de Bittencourt PI. Heat shock response to exercise in pancreatic islets of obese mice. Biochimie 2019; 168:28-40. [PMID: 31678111 DOI: 10.1016/j.biochi.2019.10.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 10/27/2019] [Indexed: 12/18/2022]
Abstract
Chronic obesity imposes an organismal state of low-grade inflammation because the physiological resolution of inflammation is progressively repressed giving rise to cellular senescence and its accompanying Senescence-Associated Secretory Phenotype (SASP), which avoids apoptosis but perpetuates the relay of inflammatory signals from adipose tissue toward the rest of the body. Conversely, resolution of inflammation depends on the integrity of heat shock response (HSR) pathway that leads to the expression of cytoprotective and anti-inflammatory protein chaperones of the 70 kDa family (HSP70). However, chronic exposure to the aforementioned injuring factors leads to SASP, which, in turn, suppresses the HSR. A main metabolic tissue severely jeopardized by obesity-related dysfunctions is the endocrine pancreas, particularly β-cells of the islets of Langerhans. Because exercise is a powerful inducer of HSR and predicted to alleviate negative health outcomes of obesity, we sought whether obesity influence HSP70 expression in pancreatic islets and other metabolic tissues (adipose tissue and skeletal muscle) of adult B6.129SF2/J mice fed on a high-fat diet (HFD) for 13 weeks since the weaning and whether acute exercise as well as moderate-intensity exercise training (8 weeks) could interfere with this scenario. We showed that acute exercise of moderate intensity protects pancreatic islets against cytokine-induced cell death. In addition, acute exercise challenge time-dependently increased islet HSP70 that peaked at 12 h post-exercise in both trained and untrained mice fed on a control diet, suggesting an adequate HSR to exercise training. Unexpectedly, however, neither exercise training nor acute exercise challenges were able to increase islet HSP70 contents in trained mice submitted to HFD, but only in untrained HFD animals. In parallel, HFD disrupted glycemic status which is accompanied by loss of muscular mass resembling sarcopenic obesity that could not be rescued by exercise training. These results suggest that exercise influences HSR in pancreatic islets but obesity undermines islet, muscle and adipose tissue HSR, which is associated with metabolic abnormalities observed in such tissues.
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Affiliation(s)
- Aline Bittencourt
- Laboratory of Cellular Physiology (FisCel) and Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX), Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Helena Trevisan Schroeder
- Laboratory of Cellular Physiology (FisCel) and Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX), Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Rossana Rosa Porto
- Laboratory of Cellular Physiology (FisCel) and Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX), Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Carlos Henrique de Lemos Muller
- Laboratory of Cellular Physiology (FisCel) and Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX), Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Mauricio Krause
- Laboratory of Cellular Physiology (FisCel) and Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX), Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Paulo Ivo Homem de Bittencourt
- Laboratory of Cellular Physiology (FisCel) and Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX), Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
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22
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The cytokine alterations/abnormalities and oxidative damage in the pancreas during hypertension development. Pflugers Arch 2019; 471:1331-1340. [PMID: 31624954 PMCID: PMC6814849 DOI: 10.1007/s00424-019-02312-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 08/30/2019] [Accepted: 09/20/2019] [Indexed: 02/04/2023]
Abstract
The aim of the present study was to compare the content of cytokines, chemokines, and oxidative stress markers in the pancreas of spontaneously hypertensive rats (SHRs) and Wistar Kyoto Rats (WKYs) serving as controls. Enzyme-like immunosorbent assay (ELISA) and biochemical methods were used to measure pancreatic levels of interleukin-1ß, interleukin-6, tumor necrosis factor α, transforming growth factor β, RANES, monocyte chemoattractant protein 1, interferon gamma-induced protein 10, malondialdehyde, and sulfhydryl groups. The results showed that the pancreatic concentrations of all studied cytokines and chemokines did not differ between 5-week-old SHRs and WKYs, except RANTES which was significantly reduced in juvenile SHRs. In 10-week-old animals, except interleukin-1ß, the levels of all these proteins were significantly reduced in SHRs. The pancreatic levels of malondialdehyde were significantly reduced in 5-week-old SHRs and significantly elevated in 10-week-old SHRs while the contents of sulfhydryl groups were similar in both rat strains at any age studied. In conclusion, these data provide evidence that in maturating SHRs, the pancreatic levels of cytokines and chemokines are significantly reduced, while malondialdehyde significantly elevated. This suggests that in the pancreas of mature SHRs, the inflammation process is suppressed but there is ongoing oxidative damage.
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Abstract
PURPOSE OF REVIEW Proper cartilage development is critical to bone formation during endochondral ossification. This review highlights the current understanding of various aspects of glucose metabolism in chondrocytes during cartilage development. RECENT FINDINGS Recent studies indicate that chondrocytes transdifferentiate into osteoblasts and bone marrow stromal cells during endochondral ossification. In cartilage development, signaling molecules, including IGF2 and BMP2, tightly control glucose uptake and utilization in a stage-specific manner. Perturbation of glucose metabolism alters the course of chondrocyte maturation, suggesting a key role for glucose metabolism during endochondral ossification. During prenatal and postnatal growth, chondrocytes experience bursts of nutrient availability and energy expenditure, which demand sophisticated control of the glucose-dependent processes of cartilage matrix production, cell proliferation, and hypertrophy. Investigating the regulation of glucose metabolism may therefore lead to a unifying mechanism for signaling events in cartilage development and provide insight into causes of skeletal growth abnormalities.
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Affiliation(s)
- Judith M Hollander
- Program in Cell, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, 02111, USA
| | - Li Zeng
- Program in Cell, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, 02111, USA.
- Program of Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, 02111, USA.
- Program of Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, 02111, USA.
- Department of Immunology, Tufts University School of Medicine, Boston, MA, 02111, USA.
- Department of Orthopaedics, Tufts Medical Center, Boston, MA, 02111, USA.
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24
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Ahmed S, Dubey D, Chowdhury A, Chaurasia S, Guleria A, Kumar S, Singh R, Kumar D, Misra R. Nuclear magnetic resonance‐based metabolomics reveals similar metabolomics profiles in undifferentiated peripheral spondyloarthritis and reactive arthritis. Int J Rheum Dis 2019; 22:725-733. [DOI: 10.1111/1756-185x.13490] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 12/30/2018] [Accepted: 01/01/2019] [Indexed: 11/29/2022]
Affiliation(s)
- Sakir Ahmed
- Department of Clinical Immunology Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow India
| | - Durgesh Dubey
- Centre of Biomedical Research Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow India
| | - Abhra Chowdhury
- Department of Clinical Immunology Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow India
| | - Smriti Chaurasia
- Department of Clinical Immunology Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow India
| | - Anupam Guleria
- Centre of Biomedical Research Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow India
| | - Sandeep Kumar
- Department of Clinical Immunology Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow India
| | - Rajeev Singh
- Department of Clinical Immunology Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow India
| | - Dinesh Kumar
- Centre of Biomedical Research Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow India
| | - Ramnath Misra
- Department of Clinical Immunology Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow India
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25
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Lontchi-Yimagou E, Boudou P, Nguewa JL, Noubiap JJ, Kamwa V, Djahmeni EN, Atogho-Tiedeu B, Azabji-Kenfack M, Etoa M, Lemdjo G, Dehayem MY, Mbanya JC, Gautier JF, Sobngwi E. Acute phase ketosis-prone atypical diabetes is associated with a pro-inflammatory profile: a case-control study in a sub-Saharan African population. J Diabetes Metab Disord 2018; 17:37-43. [PMID: 30288384 PMCID: PMC6154517 DOI: 10.1007/s40200-018-0336-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 01/01/2018] [Indexed: 12/01/2022]
Affiliation(s)
- Eric Lontchi-Yimagou
- 1Laboratory for Molecular Medicine and Metabolism, Biotechnology Center, University of Yaoundé 1, PO Box 87, Yaoundé, Cameroon
| | - Philippe Boudou
- 2Unit of Hormonal Biology, Department of Biochemistry, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris (APHP), 1 avenue Claude Vellefaux, 75010 Paris, France
| | - Jean Louis Nguewa
- 3Inserm UMRS 1138, Cordeliers Research Centre, University Paris-6, 75006 Paris, France
| | - Jean Jacques Noubiap
- 4Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
| | - Vicky Kamwa
- University hospital of Birmingham, Birmingham, UK
| | | | - Babara Atogho-Tiedeu
- 1Laboratory for Molecular Medicine and Metabolism, Biotechnology Center, University of Yaoundé 1, PO Box 87, Yaoundé, Cameroon
| | - Marcel Azabji-Kenfack
- 7Department of Physiological Sciences and Biochemistry, Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé, Cameroon
| | - Martine Etoa
- National Obesity Centre, Yaoundé Central Hospital, Yaoundé, Cameroon
| | - Gaelle Lemdjo
- National Obesity Centre, Yaoundé Central Hospital, Yaoundé, Cameroon
| | | | - Jean Claude Mbanya
- 1Laboratory for Molecular Medicine and Metabolism, Biotechnology Center, University of Yaoundé 1, PO Box 87, Yaoundé, Cameroon.,National Obesity Centre, Yaoundé Central Hospital, Yaoundé, Cameroon.,8Department of Internal Medicine, Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé, Cameroon
| | - Jean-Francois Gautier
- 2Unit of Hormonal Biology, Department of Biochemistry, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris (APHP), 1 avenue Claude Vellefaux, 75010 Paris, France.,3Inserm UMRS 1138, Cordeliers Research Centre, University Paris-6, 75006 Paris, France
| | - Eugène Sobngwi
- 1Laboratory for Molecular Medicine and Metabolism, Biotechnology Center, University of Yaoundé 1, PO Box 87, Yaoundé, Cameroon.,National Obesity Centre, Yaoundé Central Hospital, Yaoundé, Cameroon.,8Department of Internal Medicine, Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé, Cameroon
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26
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Exploring pancreatic pathology in Plasmodium falciparum malaria patients. Sci Rep 2018; 8:10456. [PMID: 29993021 PMCID: PMC6041343 DOI: 10.1038/s41598-018-28797-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 06/28/2018] [Indexed: 01/11/2023] Open
Abstract
Hypoglycaemia is an important complication of Plasmodium falciparum malaria infection, which can be lethal if not treated. A decrease in blood sugar (BS) level has been correlated with disease severity, parasitaemia and the use of certain antimalarial drugs. This study explored the relationship between pancreatic pathology, including the expressions of insulin and glucagon in the islets of Langerhans, and the BS levels in P. falciparum malaria patients. Pancreatic tissues from malaria patients were divided into three groups, namely those with BS < 40 mg/dl, BS = 40–120 mg/dl, and BS > 120 mg/dl. In P. falciparum malaria, pancreatic tissues showed numerous parasitised red blood cells (PRBCs) in the capillaries, oedema, acinar necrosis and the presence of inflammatory cells. The islet size and the expression of insulin were significantly increased in P. falciparum malaria patients with hypoglycaemia. In addition, insulin expression was positively correlated with islet size and negatively correlated with BS levels. This pioneer study documents an increase in insulin expression and an increase in islet size in hypoglycaemic patients with P. falciparum malaria. This could contribute to the pathogenesis of hypoglycaemia and provides evidence for the potential need to effectively manage the hypoglycaemia seen in malaria infection.
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27
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Cardiovascular Safety of Biologics and JAK Inhibitors in Patients with Rheumatoid Arthritis. Curr Rheumatol Rep 2018; 20:42. [DOI: 10.1007/s11926-018-0752-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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28
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Zhang G, Dervishi E, Ametaj BN. Milk fever in dairy cows is preceded by activation of innate immunity and alterations in carbohydrate metabolism prior to disease occurrence. Res Vet Sci 2018; 117:167-177. [PMID: 29277015 DOI: 10.1016/j.rvsc.2017.12.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 12/11/2017] [Accepted: 12/14/2017] [Indexed: 01/12/2023]
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29
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Zhang G, Dervishi E, Ametaj BN. Reprint of Milk fever in dairy cows is preceded by activation of innate immunity and alterations in carbohydrate metabolism prior to disease occurrence. Res Vet Sci 2018. [PMID: 29519703 DOI: 10.1016/j.rvsc.2018.02.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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30
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Abnormal Glucose Metabolism in Rheumatoid Arthritis. BIOMED RESEARCH INTERNATIONAL 2017; 2017:9670434. [PMID: 28529957 PMCID: PMC5424188 DOI: 10.1155/2017/9670434] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 04/09/2017] [Indexed: 11/24/2022]
Abstract
The incidence of abnormal glucose metabolism in patients with rheumatoid arthritis was considerably higher than the general population. The persistent systemic inflammatory state in rheumatoid arthritis might be associated with the glucose metabolism dysfunction. In this context, insulin resistance, islet β cell apoptosis, inflammatory cytokines, and other aspects which were linked with abnormal glucose metabolism in rheumatoid arthritis were reviewed. This review will be helpful in understanding the abnormal glucose metabolism mechanism in patients with rheumatoid arthritis and might be conducive to finding an effective treatment.
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31
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Frikke-Schmidt H, Zamarron BF, O'Rourke RW, Sandoval DA, Lumeng CN, Seeley RJ. Weight loss independent changes in adipose tissue macrophage and T cell populations after sleeve gastrectomy in mice. Mol Metab 2017; 6:317-326. [PMID: 28377871 PMCID: PMC5369283 DOI: 10.1016/j.molmet.2017.02.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 02/02/2017] [Accepted: 02/11/2017] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE In addition to adipocytes, adipose tissue contains large numbers of immune cells. A wide range of evidence links the activity of these cells to regulation of adipocyte and systemic metabolic function. Bariatric surgery improves several aspects of metabolic derangements and at least some of these effects occur in a weight-loss independent manner. We sought to investigate the impact of vertical sleeve gastrectomy (VSG) on adipose immune cell frequencies. METHODS We analyzed the frequencies of immune cells within distinct adipose tissue depots in obese mice that had VSG or sham surgery with a portion of the latter group pair-fed such that their body mass was matched to the VSG animals. RESULTS We demonstrate that VSG induced a shift in the epididymal adipose tissue leukocyte profile including increased frequencies of CD11c- macrophages, increased frequencies of T cells (CD4+, CD8+, and CD4-/CD8- T cells all increased), but a significantly decreased frequency of adipose tissue dendritic cells (ATDC) that, despite the continued high fat feeding of the VSG group, dropped below control diet levels. CONCLUSIONS These results indicate that VSG induces substantial changes in the immune populations residing in the adipose depots independent of weight loss.
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Affiliation(s)
| | - Brian F Zamarron
- Department Pediatrics and Communicable Diseases, University of Michigan Health System, Ann Arbor, MI, USA
| | - Robert W O'Rourke
- Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA; Ann Arbor Veteran's Administration Hospital, Ann Arbor, MI, USA
| | - Darleen A Sandoval
- Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA
| | - Carey N Lumeng
- Department Pediatrics and Communicable Diseases, University of Michigan Health System, Ann Arbor, MI, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA.
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32
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Kelly RS, Croteau-Chonka DC, Dahlin A, Mirzakhani H, Wu AC, Wan ES, McGeachie MJ, Qiu W, Sordillo JE, Al-Garawi A, Gray KJ, McElrath TF, Carey VJ, Clish CB, Litonjua AA, Weiss ST, Lasky-Su JA. Integration of metabolomic and transcriptomic networks in pregnant women reveals biological pathways and predictive signatures associated with preeclampsia. Metabolomics 2017; 13:7. [PMID: 28596717 PMCID: PMC5458629 DOI: 10.1007/s11306-016-1149-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Preeclampsia is a leading cause of maternal and fetal mortality worldwide, yet its exact pathogenesis remains elusive. OBJECTIVES This study, nested within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), aimed to develop integrated omics models of preeclampsia that have utility in both prediction and in the elucidation of underlying biological mechanisms. METHODS Metabolomic profiling was performed on first trimester plasma samples of 47 pregnant women from VDAART who subsequently developed preeclampsia and 62 controls with healthy pregnancies, using liquid-chromatography tandem mass-spectrometry. Metabolomic profiles were generated based on logistic regression models and assessed using Received Operator Characteristic Curve analysis. These profiles were compared to profiles from generated using third trimester samples. The first trimester metabolite profile was then integrated with a pre-existing transcriptomic profile using network methods. RESULTS In total, 72 (0.9%) metabolite features were associated (p<0.01) with preeclampsia after adjustment for maternal age, race, and gestational age. These features had moderate to good discriminatory ability; in ROC curve analyses a summary score based on these features displayed an area under the curve (AUC) of 0.794 (95%CI 0.700, 0.888). This profile retained the ability to distinguish preeclamptic from healthy pregnancies in the third trimester (AUC:0.762 (95% CI 0.663, 0.860)). Additionally, metabolite set enrichment analysis identified common pathways, including glycerophospholipid metabolism, at the two time-points. Integration with the transcriptomic signature refined these results suggesting a particular role for lipid imbalance, immune function and the circulatory system. CONCLUSIONS These findings suggest it is possible to develop a predictive metabolomic profile of preeclampsia. This profile is characterized by changes in lipid and amino acid metabolism and dysregulation of immune response and can be refined through interaction with transcriptomic data. However validation in larger and more diverse populations is required.
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Affiliation(s)
- Rachel S. Kelly
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Damien C. Croteau-Chonka
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Amber Dahlin
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Hooman Mirzakhani
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Ann C. Wu
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
- Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
- Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA
| | - Emily S. Wan
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Michael J. McGeachie
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Weiliang Qiu
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Joanne E. Sordillo
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Amal Al-Garawi
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Kathryn J. Gray
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Thomas F. McElrath
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Vincent J. Carey
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Clary B. Clish
- Metabolomics Platform, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02141, USA
| | - Augusto A. Litonjua
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Scott T. Weiss
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Jessica A. Lasky-Su
- Channing Department of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
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Hyperglycemia in Acutely Ill Non-diabetic Children in the Emergency Rooms of 2 Tertiary Hospitals in Lagos, Nigeria. Pediatr Emerg Care 2016; 32:608-13. [PMID: 27589386 DOI: 10.1097/pec.0000000000000440] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES The study aimed to determine the prevalence of hyperglycemia in sick children admitted into the emergency rooms and to investigate its relationship with adverse outcomes. METHODS A prospective study involving 2 tertiary hospitals in Lagos. Study subjects included all children aged beyond 1 month. An Accu-Chek Active glucometer was used for the bedside blood glucose determination. Hyperglycemia was defined as blood glucose greater than 7.8 mmol/L. RESULTS A total of 1045 patients were recruited with hyperglycemia being recorded in 135 patients (prevalence rate of 12.9%). Mean age of the hyperglycemic patients was 29.0 ± 31.23 months. Prevalence rates of hyperglycemia among the leading diagnoses were 17.4% in acute respiratory tract infections, 11% in malaria, 15.3% in septicemia, 14.9% in gastroenteritis, and 18.2% in burns. Other conditions include sickle cell anemia, meningitis, and malnutrition. Mortality rate was significantly higher overall in hyperglycemic compared with the normoglycemic patients (15.4% vs 8.0%, P = 0.011). With regard to specific diagnoses, significantly higher mortality rates were recorded in hyperglycemic patients with acute respiratory tract infections (28% vs 8%, P = 0.011) and malaria (21.4% vs 5.0%, P = 0.006) than in their normoglycemic counterparts. CONCLUSIONS Hyperglycemia is common in ill children admitted to the emergency rooms and is associated with 2 to 4 times higher mortality in common childhood diseases encountered. Blood glucose determination is important in all acutely ill children at presentation. The practice of empirical administration of intravenous glucose in some resource-constrained facilities where blood glucose testing facilities are not readily available should be discouraged.
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Meyerovich K, Ortis F, Allagnat F, Cardozo AK. Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. J Mol Endocrinol 2016; 57:R1-R17. [PMID: 27067637 DOI: 10.1530/jme-15-0306] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 04/11/2016] [Indexed: 12/13/2022]
Abstract
Insulin-secreting pancreatic β-cells are extremely dependent on their endoplasmic reticulum (ER) to cope with the oscillatory requirement of secreted insulin to maintain normoglycemia. Insulin translation and folding rely greatly on the unfolded protein response (UPR), an array of three main signaling pathways designed to maintain ER homeostasis and limit ER stress. However, prolonged or excessive UPR activation triggers alternative molecular pathways that can lead to β-cell dysfunction and apoptosis. An increasing number of studies suggest a role of these pro-apoptotic UPR pathways in the downfall of β-cells observed in diabetic patients. Particularly, the past few years highlighted a cross talk between the UPR and inflammation in the context of both type 1 (T1D) and type 2 diabetes (T2D). In this article, we describe the recent advances in research regarding the interplay between ER stress, the UPR, and inflammation in the context of β-cell apoptosis leading to diabetes.
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Affiliation(s)
- Kira Meyerovich
- ULB Center for Diabetes ResearchUniversité Libre de Bruxelles (ULB), Brussels, Belgium
| | - Fernanda Ortis
- Department of Cell and Developmental BiologyUniversidade de São Paulo, São Paulo, Brazil
| | - Florent Allagnat
- Department of Vascular SurgeryCentre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Alessandra K Cardozo
- ULB Center for Diabetes ResearchUniversité Libre de Bruxelles (ULB), Brussels, Belgium
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Zaitseva II, Zaitsev SV, Berggren PO. The imidazoline compound RX871024 promotes insulinoma cell death independent of AMP-activated protein kinase inhibition. Invest New Drugs 2016; 34:522-9. [DOI: 10.1007/s10637-016-0362-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 05/18/2016] [Indexed: 11/29/2022]
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36
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Baye E, Ukropcova B, Ukropec J, Hipkiss A, Aldini G, de Courten B. Physiological and therapeutic effects of carnosine on cardiometabolic risk and disease. Amino Acids 2016; 48:1131-49. [PMID: 26984320 DOI: 10.1007/s00726-016-2208-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 02/25/2016] [Indexed: 12/12/2022]
Abstract
Obesity, type 2 diabetes (T2DM) and cardiovascular disease (CVD) are the most common preventable causes of morbidity and mortality worldwide. They represent major public health threat to our society. Increasing prevalence of obesity and T2DM contributes to escalating morbidity and mortality from CVD and stroke. Carnosine (β-alanyl-L-histidine) is a dipeptide with anti-inflammatory, antioxidant, anti-glycation, anti-ischaemic and chelating roles and is available as an over-the-counter food supplement. Animal evidence suggests that carnosine may offer many promising therapeutic benefits for multiple chronic diseases due to these properties. Carnosine, traditionally used in exercise physiology to increase exercise performance, has potential preventative and therapeutic benefits in obesity, insulin resistance, T2DM and diabetic microvascular and macrovascular complications (CVD and stroke) as well as number of neurological and mental health conditions. However, relatively little evidence is available in humans. Thus, future studies should focus on well-designed clinical trials to confirm or refute a potential role of carnosine in the prevention and treatment of chronic diseases in humans, in addition to advancing knowledge from the basic science and animal studies.
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Affiliation(s)
- Estifanos Baye
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, 43-51 Kanooka Grove, Clayton, Melbourne, VIC, 3168, Australia.,Department of Public Health, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia
| | - Barbara Ukropcova
- Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia.,Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Jozef Ukropec
- Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Alan Hipkiss
- School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Giancarlo Aldini
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Barbora de Courten
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, 43-51 Kanooka Grove, Clayton, Melbourne, VIC, 3168, Australia. .,Diabetes and Vascular Medicine Unit, Monash Health, Clayton, VIC, 3168, Australia.
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37
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van der Torren CR, Verrijn Stuart AA, Lee D, Meerding J, van de Velde U, Pipeleers D, Gillard P, Keymeulen B, de Jager W, Roep BO. Serum Cytokines as Biomarkers in Islet Cell Transplantation for Type 1 Diabetes. PLoS One 2016; 11:e0146649. [PMID: 26751709 PMCID: PMC4713434 DOI: 10.1371/journal.pone.0146649] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 12/21/2015] [Indexed: 11/19/2022] Open
Abstract
Background Islet cell transplantation holds a potential cure for type 1 diabetes, but many islet recipients do not reach long-lasting insulin independence. In this exploratory study, we investigated whether serum cytokines, chemokines and adipokines are associated with the clinical outcome of islet transplantation. Methods Thirteen islet transplant patients were selected on basis of good graft function (reaching insulin independence) or insufficient engraftment (insulin requiring) from our cohort receiving standardized grafts and immune suppressive therapy. Patients reaching insulin independence were divided in those with continued (>12 months) versus transient (<6 months) insulin independence. A panel of 94 proteins including cytokines and adipokines was measured in sera taken before and at one year after transplantation using a validated multiplex immunoassay platform. Results Ninety serum proteins were detectable in concentrations varying markedly among patients at either time point. Thirteen markers changed after transplantation, while another seven markers changed in a clinical subpopulation. All other markers remained unaffected after transplantation under generalized immunosuppression. Patterns of cytokines could distinguish good graft function from insufficient function including IFN-α, LIF, SCF and IL-1RII before and after transplantation, by IL-16, CCL3, BDNF and M-CSF only before and by IL-22, IL-33, KIM-1, S100A12 and sCD14 after transplantation. Three other proteins (Leptin, Cathepsin L and S100A12) associated with loss of temporary graft function before or after transplantation. Conclusions Distinct cytokine signatures could be identified in serum that predict or associate with clinical outcome. These serum markers may help guiding patient selection and choice of immunotherapy, or act as novel drug targets in islet transplantation.
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Affiliation(s)
- Cornelis R. van der Torren
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
- Juvenile Diabetes Research Foundation Center for Beta Cell Therapy in Diabetes
| | - Annemarie A. Verrijn Stuart
- Department of Pediatric Immunology, Department of Pediatric Endocrinology and Laboratory of Translational Immunology and Multiplex Core Facility, Wilhelmina Children’s Hospital, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
| | - DaHae Lee
- Dept. of Endocrinology, University Hospital, Katholieke Universiteit Leuven, 3000, Leuven, Belgium
- Juvenile Diabetes Research Foundation Center for Beta Cell Therapy in Diabetes
| | - Jenny Meerding
- Department of Pediatric Immunology, Department of Pediatric Endocrinology and Laboratory of Translational Immunology and Multiplex Core Facility, Wilhelmina Children’s Hospital, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
| | - Ursule van de Velde
- Diabetes Research Center and Academic Hospital, Free University-Vrije Universiteit Brussel (VUB), 1090, Brussels, Belgium
- Juvenile Diabetes Research Foundation Center for Beta Cell Therapy in Diabetes
| | - Daniel Pipeleers
- Diabetes Research Center and Academic Hospital, Free University-Vrije Universiteit Brussel (VUB), 1090, Brussels, Belgium
| | - Pieter Gillard
- Dept. of Endocrinology, University Hospital, Katholieke Universiteit Leuven, 3000, Leuven, Belgium
- Juvenile Diabetes Research Foundation Center for Beta Cell Therapy in Diabetes
| | - Bart Keymeulen
- Diabetes Research Center and Academic Hospital, Free University-Vrije Universiteit Brussel (VUB), 1090, Brussels, Belgium
- Juvenile Diabetes Research Foundation Center for Beta Cell Therapy in Diabetes
| | - Wilco de Jager
- Department of Pediatric Immunology, Department of Pediatric Endocrinology and Laboratory of Translational Immunology and Multiplex Core Facility, Wilhelmina Children’s Hospital, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
| | - Bart O. Roep
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
- Juvenile Diabetes Research Foundation Center for Beta Cell Therapy in Diabetes
- * E-mail:
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McEvoy B, Sumayao R, Slattery C, McMorrow T, Newsholme P. Cystine accumulation attenuates insulin release from the pancreatic β-cell due to elevated oxidative stress and decreased ATP levels. J Physiol 2015; 593:5167-82. [PMID: 26482480 DOI: 10.1113/jp271237] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 10/13/2015] [Indexed: 12/26/2022] Open
Abstract
The pancreatic β-cell has reduced antioxidant defences making it more susceptible to oxidative stress. In cystinosis, a lysosomal storage disorder, an altered redox state may contribute to cellular dysfunction. This rare disease is caused by an abnormal lysosomal cystine transporter, cystinosin, which causes excessive accumulation of cystine in the lysosome. Cystinosis associated kidney damage and dysfunction leads to the Fanconi syndrome and ultimately end-stage renal disease. Following kidney transplant, cystine accumulation in other organs including the pancreas leads to multi-organ dysfunction. In this study, a Ctns gene knockdown model of cystinosis was developed in the BRIN-BD11 rat clonal pancreatic β-cell line using Ctns-targeting siRNA. Additionally there was reduced cystinosin expression, while cell cystine levels were similarly elevated to the cystinotic state. Decreased levels of chronic (24 h) and acute (20 min) nutrient-stimulated insulin secretion were observed. This decrease may be due to depressed ATP generation particularly from glycolysis. Increased ATP production and the ATP/ADP ratio are essential for insulin secretion. Oxidised glutathione levels were augmented, resulting in a lower [glutathione/oxidised glutathione] redox potential. Additionally, the mitochondrial membrane potential was reduced, apoptosis levels were elevated, as were markers of oxidative stress, including reactive oxygen species, superoxide and hydrogen peroxide. Furthermore, the basal and activated phosphorylated forms of the redox-sensitive transcription factor NF-κB were increased in cells with silenced Ctns. From this study, the cystinotic-like pancreatic β-cell model demonstrated that the altered oxidative status of the cell, resulted in depressed mitochondrial function and pathways of ATP production, causing reduced nutrient-stimulated insulin secretion.
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Affiliation(s)
- Bernadette McEvoy
- Conway Institute, School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Rodolfo Sumayao
- Conway Institute, School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Craig Slattery
- Conway Institute, School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Tara McMorrow
- Conway Institute, School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Philip Newsholme
- School of Biomedical Sciences, CHIRI Biosciences Research Precinct and Faculty of Health Sciences, Curtin University, Perth, Australia
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Krause M, Bock PM, Takahashi HK, Homem De Bittencourt PI, Newsholme P. The regulatory roles of NADPH oxidase, intra- and extra-cellular HSP70 in pancreatic islet function, dysfunction and diabetes. Clin Sci (Lond) 2015; 128:789-803. [PMID: 25881670 DOI: 10.1042/cs20140695] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
The 70 kDa heat-shock protein (HSP70) family is important for a dynamic range of cellular processes that include protection against cell stress, modulation of cell signalling, gene expression, protein synthesis, protein folding and inflammation. Within this family, the inducible 72 kDa and the cognate 73 kDa forms are found at the highest level. HSP70 has dual functions depending on location. For example, intracellular HSP70 (iHSP70) is anti-inflammatory whereas extracellular HSP70 (eHSP70) has a pro-inflammatory function, resulting in local and systemic inflammation. We have recently identified a divergence in the levels of eHSP70 and iHSP70 in subjects with diabetes compared with healthy subjects and also reported that eHSP70 was correlated with insulin resistance and pancreatic β-cell dysfunction/death. In the present review, we describe possible mechanisms by which HSP70 participates in cell function/dysfunction, including the activation of NADPH oxidase isoforms leading to oxidative stress, focusing on the possible role of HSPs and signalling in pancreatic islet α- and β-cell physiological function in health and Type 2 diabetes mellitus.
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Affiliation(s)
- Mauricio Krause
- *Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Patricia Martins Bock
- *Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Hilton Kenji Takahashi
- *Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Paulo Ivo Homem De Bittencourt
- *Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Philip Newsholme
- ‡School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, Western Australia
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Cruzat VF, Keane KN, Scheinpflug AL, Cordeiro R, Soares MJ, Newsholme P. Alanyl-glutamine improves pancreatic β-cell function following ex vivo inflammatory challenge. J Endocrinol 2015; 224:261-71. [PMID: 25550445 DOI: 10.1530/joe-14-0677] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Obesity-associated diabetes and concomitant inflammation may compromise pancreatic β-cell integrity and function. l-glutamine and l-alanine are potent insulin secretagogues, with antioxidant and cytoprotective properties. Herein, we studied whether the dipeptide l-alanyl-l-glutamine (Ala-Gln) could exert protective effects via sirtuin 1/HUR (SIRT1/HUR) signalling in β-cells, against detrimental responses following ex vivo stimulation with inflammatory mediators derived from macrophages (IMMs). The macrophages were derived from blood obtained from obese subjects. Macrophages were exposed (or not) to lipopolysaccharide (LPS) to generate a pro-inflammatory cytokine cocktail. The cytokine profile was determined following analysis by flow cytometry. Insulin-secreting BRIN-BD11 β-cells were exposed to IMMs and then cultured with or without Ala-Gln for 24 h. Chronic insulin secretion, the l-glutamine-glutathione (GSH) axis, and the level of insulin receptor β (IR-β), heat shock protein 70 (HSP70), SIRT1/HUR, CCAAT-enhancer-binding protein homologous protein (CHOP) and cytochrome c oxidase IV (COX IV) were evaluated. Concentrations of cytokines, including interleukin 1β (IL1β), IL6, IL10 and tumour necrosis factor alpha (TNFα) in the IMMs, were higher following exposure to LPS. Subsequently, when β-cells were exposed to IMMs, chronic insulin secretion, and IR-β and COX IV levels were decreased, but these effects were partially or fully attenuated by the addition of Ala-Gln. The glutamine-GSH axis and HSP70 levels, which were compromised by IMMs, were also restored by Ala-Gln, possibly due to protection of SIRT1/HUR levels, and a reduction of CHOP expression. Using an ex vivo inflammatory approach, we have demonstrated Ala-Gln-dependent β-cell protection mediated by coordinated effects on the glutamine-GSH axis, and the HSP pathway, maintenance of mitochondrial metabolism and stimulus-secretion coupling essential for insulin release.
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Affiliation(s)
- Vinicius Fernandes Cruzat
- School of Biomedical SciencesDirectorate of NutritionDietetics and Food Technology, School of Public Health, Curtin Health Innovation Research Institute of Ageing and Chronic Disease - Curtin University, GPO Box U1987, Perth, Western Australia, Australia 6845
| | - Kevin Noel Keane
- School of Biomedical SciencesDirectorate of NutritionDietetics and Food Technology, School of Public Health, Curtin Health Innovation Research Institute of Ageing and Chronic Disease - Curtin University, GPO Box U1987, Perth, Western Australia, Australia 6845
| | - Anita Lavarda Scheinpflug
- School of Biomedical SciencesDirectorate of NutritionDietetics and Food Technology, School of Public Health, Curtin Health Innovation Research Institute of Ageing and Chronic Disease - Curtin University, GPO Box U1987, Perth, Western Australia, Australia 6845
| | - Robson Cordeiro
- School of Biomedical SciencesDirectorate of NutritionDietetics and Food Technology, School of Public Health, Curtin Health Innovation Research Institute of Ageing and Chronic Disease - Curtin University, GPO Box U1987, Perth, Western Australia, Australia 6845
| | - Mario J Soares
- School of Biomedical SciencesDirectorate of NutritionDietetics and Food Technology, School of Public Health, Curtin Health Innovation Research Institute of Ageing and Chronic Disease - Curtin University, GPO Box U1987, Perth, Western Australia, Australia 6845
| | - Philip Newsholme
- School of Biomedical SciencesDirectorate of NutritionDietetics and Food Technology, School of Public Health, Curtin Health Innovation Research Institute of Ageing and Chronic Disease - Curtin University, GPO Box U1987, Perth, Western Australia, Australia 6845
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Anuradha R, Saraswati M, Kumar KG, Rani SH. Apoptosis of beta cells in diabetes mellitus. DNA Cell Biol 2014; 33:743-8. [PMID: 25093391 DOI: 10.1089/dna.2014.2352] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Diabetes mellitus is a multifactorial metabolic disorder characterized by hyperglycemia. Apoptosis in beta cells has been observed in response to diverse stimuli, such as glucose, cytokines, free fatty acids, leptin, and sulfonylureas, leading to the activation of polyol, hexosamine, and diacylglycerol/protein kinase-C (DAG/PKC) pathways that mediate oxidative and nitrosative stress causing the release of different cytokines. Cytokines induce the expression of Fas and tumor necrosis factor-alpha (TNF-α) by activating the transcription factor, nuclear factor-κb, and signal transducer and activator of transcription 1 (STAT-1) in the β cells in the extrinsic pathway of apoptosis. Cytokines produced in beta cells also induce proapoptotic members of the intrinsic pathway of apoptosis. The genetic alterations in apoptosis signaling machinery and the pathogenesis of diabetes include Fas, FasL, Akt, caspases, calpain-10, and phosphatase and tensin homolog (Pten). The other gene products that are involved in diabetes are nitric oxide synthase-2 (NOS2), small ubiquitin-like modifier (SUMO), apolipoprotein CIII (ApoCIII), forkhead box protein O1 (FOXO1), and Kruppel-like zinc finger protein Gli-similar 3 (GLIS3). The gene products having antiapoptotic nature are Bcl-2 and Bcl-XL. Epigenetic mechanisms play an important role in type I and type II diabetes. Further studies on the apoptotic genes and gene products in diabetics may be helpful in pharmacogenomics and individualized treatment along with antioxidants targeting apoptosis in diabetes.
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Elevated levels of extracellular heat-shock protein 72 (eHSP72) are positively correlated with insulin resistance in vivo and cause pancreatic β-cell dysfunction and death in vitro. Clin Sci (Lond) 2014; 126:739-52. [PMID: 24325467 DOI: 10.1042/cs20130678] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
eHSP72 (extracellular heat-shock protein 72) is increased in the plasma of both types of diabetes and is positively correlated with inflammatory markers. Since aging is associated with a low-grade inflammation and IR (insulin resistance), we aimed to: (i) analyse the concentration of eHSP72 in elderly people and determine correlation with insulin resistance, and (ii) determine the effects of eHSP72 on β-cell function and viability in human and rodent pancreatic β-cells. Fasting blood samples were collected from 50 older people [27 females and 23 males; 63.4±4.4 years of age; BMI (body mass index)=25.5±2.7 kg/m2]. Plasma samples were analysed for eHSP72, insulin, TNF (tumour necrosis factor)-α, leptin, adiponectin and cortisol, and glycaemic and lipid profile. In vitro studies were conducted using rodent islets and clonal rat and human pancreatic β-cell lines (BRIN-BD11 and 1.1B4 respectively). Cells/islets were incubated for 24 h with eHSP72 (0, 0.2, 4, 8 and 40 ng/ml). Cell viability was measured using three different methods. The impact of HSP72 on β-cell metabolic status was determined using Seahorse Bioscience XFe96 technology. To assess whether the effects of eHSP72 were mediated by Toll-like receptors (TLR2/TLR4), we co-incubated rodent islets with eHSP72 and the TLR2/TLR4 inhibitor OxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine; 30 μg/ml). We found a positive correlation between plasma eHSP72 and HOMA-IR (homoeostasis model assessment of IR) (r=0.528, P<0.001), TNF-α (r=0.389, P<0.014), cortisol (r=0.348, P<0.03) and leptin/adiponectin (r=0.334, P<0.03). In the in vitro studies, insulin secretion was decreased in an eHSP72 dose-dependent manner in BRIN-BD11 cells (from 257.7±33 to 84.1±10.2 μg/mg of protein per 24 h with 40 ng/ml eHSP72), and in islets in the presence of 40 ng/ml eHSP72 (from 0.48±0.07 to 0.33±0.009 μg/20 islets per 24 h). Similarly, eHSP72 reduced β-cell viability (at least 30% for BRIN-BD11 and 10% for 1.1B4 cells). Bioenergetic studies revealed that eHSP72 altered pancreatic β-cell metabolism. OxPAPC restored insulin secretion in islets incubated with 40 ng/ml eHSP72. In conclusion, we have demonstrated a positive correlation between eHSP72 and IR. In addition, we suggest that chronic eHSP72 exposure may mediate β-cell failure.
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Wang C, Geng B, Cui Q, Guan Y, Yang J. Intracellular and extracellular adenosine triphosphate in regulation of insulin secretion from pancreatic β cells (β). J Diabetes 2014; 6:113-9. [PMID: 24134160 DOI: 10.1111/1753-0407.12098] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Revised: 09/27/2013] [Accepted: 10/11/2013] [Indexed: 01/09/2023] Open
Abstract
Adenosine triphosphate (ATP) synthesis and release in mitochondria play critical roles in regulating insulin secretion in pancreatic β cells. Mitochondrial dysfunction is mainly characterized by a decrease in ATP production, which is a central event in the progression of pancreatic β cell dysfunction and diabetes. ATP has been demonstrated to regulate insulin secretion via several pathways: (i) Intracellular ATP directly closes ATP-sensitive potassium channel to open L-type calcium channel, leading to an increase in free cytosolic calcium levels and exocytosis of insulin granules; (ii) A decrease in ATP production is always associated with an increase in production of reactive oxygen species, which exerts deleterious effects on pancreatic β cell survival and insulin secretion; and (iii) ATP can be co-secreted with insulin from pancreatic β cells, and the released ATP functions as an autocrine signal to modulate insulin secretory process via P2 receptors on the cell membrane. In this review, the recent findings regarding the role and mechanism of ATP synthesis and release in regulation of insulin secretion from pancreatic β cells will be summarized and discussed.
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Affiliation(s)
- Chunjiong Wang
- Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
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Mullooly N, Vernon W, Smith DM, Newsholme P. Elevated levels of branched-chain amino acids have little effect on pancreatic islet cells, but L-arginine impairs function through activation of the endoplasmic reticulum stress response. Exp Physiol 2013; 99:538-51. [PMID: 24334335 DOI: 10.1113/expphysiol.2013.077495] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Recent metabolic profiling studies have identified a correlation between branched-chain amino acid levels, insulin resistance associated with prediabetes and susceptibility to type 2 diabetes. Glucose and lipids in chronic excess have been reported to induce toxic effects in pancreatic β-cells, but the effect of elevated amino acid concentrations on primary islet cell function has not been investigated to date. The aim of this study was to investigate the effect of chronic exposure to various amino acids on islet cell function in vitro. Isolated rat islets were incubated over periods of 48 h with a range of concentrations of individual amino acids (0.1 μm to 10 mm). After 48 h, islets were assessed for glucose-dependent insulin secretion capacity, proliferation or islet cell apoptosis. We report that elevated levels of branched-chain amino acids have little effect on pancreatic islet cell function or viability; however, increased levels of the amino acid l-arginine were found to be β-cell toxic, causing a dose-dependent decrease in insulin secretion accompanied by a decrease in islet cell proliferation and an increase in islet cell apoptosis. These effects were not due to l-arginine-dependent increases in production of nitric oxide but arose through elicitation of the islet cell endoplasmic reticulum stress response. This novel finding indicates, for the first time, that the l-arginine concentration in vitro may impact negatively on islet cell function, thus indicating further complexity in relationship to in vivo susceptibility of β-cells to nutrient-induced dysfunction.
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Affiliation(s)
- Niamh Mullooly
- * Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, GPO Box U1987, Perth, WA 6845, Australia.
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Morris G, Maes M. A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome. Metab Brain Dis 2013; 28:523-40. [PMID: 22718491 DOI: 10.1007/s11011-012-9324-8] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Accepted: 06/07/2012] [Indexed: 12/15/2022]
Abstract
This paper proposes a neuro-immune model for Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). A wide range of immunological and neurological abnormalities have been reported in people suffering from ME/CFS. They include abnormalities in proinflammatory cytokines, raised production of nuclear factor-κB, mitochondrial dysfunctions, autoimmune responses, autonomic disturbances and brain pathology. Raised levels of oxidative and nitrosative stress (O&NS), together with reduced levels of antioxidants are indicative of an immuno-inflammatory pathology. A number of different pathogens have been reported either as triggering or maintaining factors. Our model proposes that initial infection and immune activation caused by a number of possible pathogens leads to a state of chronic peripheral immune activation driven by activated O&NS pathways that lead to progressive damage of self epitopes even when the initial infection has been cleared. Subsequent activation of autoreactive T cells conspiring with O&NS pathways cause further damage and provoke chronic activation of immuno-inflammatory pathways. The subsequent upregulation of proinflammatory compounds may activate microglia via the vagus nerve. Elevated proinflammatory cytokines together with raised O&NS conspire to produce mitochondrial damage. The subsequent ATP deficit together with inflammation and O&NS are responsible for the landmark symptoms of ME/CFS, including post-exertional malaise. Raised levels of O&NS subsequently cause progressive elevation of autoimmune activity facilitated by molecular mimicry, bystander activation or epitope spreading. These processes provoke central nervous system (CNS) activation in an attempt to restore immune homeostatsis. This model proposes that the antagonistic activities of the CNS response to peripheral inflammation, O&NS and chronic immune activation are responsible for the remitting-relapsing nature of ME/CFS. Leads for future research are suggested based on this neuro-immune model.
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Gaudel C, Nongonierma AB, Maher S, Flynn S, Krause M, Murray BA, Kelly PM, Baird AW, FitzGerald RJ, Newsholme P. A whey protein hydrolysate promotes insulinotropic activity in a clonal pancreatic β-cell line and enhances glycemic function in ob/ob mice. J Nutr 2013; 143:1109-14. [PMID: 23658425 DOI: 10.3945/jn.113.174912] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Whey protein hydrolysates (WPHs) represent novel antidiabetic agents that affect glycemia in animals and humans, but little is known about their insulinotropic effects. The effects of a WPH were analyzed in vitro on acute glucose-induced insulin secretion in pancreatic BRIN-BD11 β cells. WPH permeability across Caco-2 cell monolayers was determined in a 2-tiered intestinal model. WPH effects on insulin resistance were studied in vivo following an 8-wk oral ingestion (100 mg/kg body weight) by ob/ob (OB-WPH) and wild-type mice (WT-WPH) compared with vehicle control (OB and WT groups) using a 2 × 2 factorial design, genotype × treatment. BRIN-BD11 cells showed a robust and reproducible dose-dependent insulinotropic effect of WPH (from 0.01 to 5.00 g/L). WPH bioactive constituents were permeable across Caco-2 cell monolayers. In the OB-WPH and WT-WPH groups, WPH administration improved glucose clearance after a glucose challenge (2 g/kg body weight), as indicated by differences in the area under curves (AUCs) (P ≤ 0.05). The basal plasma glucose concentration was not affected by WPH treatment in either genotype. The plasma insulin concentration was lower in the OB-WPH than in the OB group (P ≤ 0.005) but was similar between the WT and WT-WPH groups; the interaction genotype × treatment was significant (P ≤ 0.005). Insulin release from pancreatic islets isolated from the OB-WPH group was greater (P ≤ 0.005) than that from the OB group but did not differ between the WT-WPH and WT groups; the interaction genotype × treatment was not significant. In conclusion, an 8-wk oral administration of WPH improved blood glucose clearance, reduced hyperinsulinemia, and restored the pancreatic islet capacity to secrete insulin in response to glucose in ob/ob mice. Hence, it may be useful in diabetes management.
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Affiliation(s)
- Celine Gaudel
- School of Biomolecular and Biomedical Sciences, Health Sciences Centre, University College Dublin, Belfield, Dublin, Ireland
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Salvucci M, Neufeld Z, Newsholme P. Mathematical model of metabolism and electrophysiology of amino acid and glucose stimulated insulin secretion: in vitro validation using a β-cell line. PLoS One 2013; 8:e52611. [PMID: 23520444 PMCID: PMC3592881 DOI: 10.1371/journal.pone.0052611] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Accepted: 11/20/2012] [Indexed: 12/29/2022] Open
Abstract
We integrated biological experimental data with mathematical modelling to gain insights into the role played by L-alanine in amino acid-stimulated insulin secretion (AASIS) and in D-glucose-stimulated insulin secretion (GSIS), details important to the understanding of complex β-cell metabolic coupling relationships. We present an ordinary differential equations (ODEs) based simplified kinetic model of core metabolic processes leading to ATP production (glycolysis, TCA cycle, L-alanine-specific reactions, respiratory chain, ATPase and proton leak) and Ca(2+) handling (essential channels and pumps in the plasma membrane) in pancreatic β-cells and relate these to insulin secretion. Experimental work was performed using a clonal rat insulin-secreting cell line (BRIN-BD11) to measure the consumption or production of a range of important biochemical parameters (D-glucose, L-alanine, ATP, insulin secretion) and Ca(2+) levels. These measurements were then used to validate the theoretical model and fine-tune the parameters. Mathematical modelling was used to predict L-lactate and L-glutamate concentrations following D-glucose and/or L-alanine challenge and Ca(2+) levels upon stimulation with a non metabolizable L-alanine analogue. Experimental data and mathematical model simulations combined suggest that L-alanine produces a potent insulinotropic effect via both a stimulatory impact on β-cell metabolism and as a direct result of the membrane depolarization due to Ca(2+) influx triggered by L-alanine/Na(+) co-transport. Our simulations indicate that both high intracellular ATP and Ca(2+) concentrations are required in order to develop full insulin secretory responses. The model confirmed that K(+) ATP channel independent mechanisms of stimulation of intracellular Ca(2+) levels, via generation of mitochondrial coupling messengers, are essential for promotion of the full and sustained insulin secretion response in β-cells.
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Affiliation(s)
- Manuela Salvucci
- School of Biomolecular and Biomedical Sciences, University College Dublin, Dublin, Ireland.
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da Silva Krause M, Bittencourt A, Homem de Bittencourt PI, McClenaghan NH, Flatt PR, Murphy C, Newsholme P. Physiological concentrations of interleukin-6 directly promote insulin secretion, signal transduction, nitric oxide release, and redox status in a clonal pancreatic β-cell line and mouse islets. J Endocrinol 2012; 214:301-11. [PMID: 22761278 DOI: 10.1530/joe-12-0223] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Interleukin-6 (IL6) has recently been reported to promote insulin secretion in a glucagon-like peptide-1-dependent manner. Herein, the direct effects of IL6 (at various concentrations from 0 to 1000 pg/ml) on pancreatic β-cell metabolism, AMP-activated protein kinase (AMPK) signaling, insulin secretion, nitrite release, and redox status in a rat clonal β-cell line and mouse islets are reported. Chronic insulin secretion (in μg/mg protein per 24 h) was increased from 128·7±7·3 (no IL6) to 178·4±7·7 (at 100 pg/ml IL6) in clonal β-cells and increased significantly in islets incubated in the presence of 5·5 mM glucose for 2 h, from 0·148 to 0·167±0·003 ng/islet. Pretreatment with IL6 also induced a twofold increase in basal and nutrient-stimulated insulin secretion in subsequent 20 min static incubations. IL6 enhanced both glutathione (GSH) and glutathione disulphide (GSSG) by nearly 20% without changing intracellular redox status (GSSG/GSH). IL6 dramatically increased iNOS expression (by ca. 100-fold) with an accompanying tenfold rise in nitrite release in clonal β-cells. Phosphorylated AMPK levels were elevated approximately twofold in clonal β-cells and mouse islet cells. Calmodulin-dependent protein kinase kinase levels (CaMKK), an upstream kinase activator of AMPK, were also increased by 50% after IL6 exposure (in β-cells and islets). Our data have demonstrated that IL6 can stimulate β-cell-dependent insulin secretion via direct cell-based mechanisms. AMPK, CaMKK (an upstream kinase activator of AMPK), and the synthesis of nitric oxide appear to alter cell metabolism to benefit insulin secretion. In summary, IL6 exerts positive effects on β-cell signaling, metabolism, antioxidant status, and insulin secretion.
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Newsholme P, Rebelato E, Abdulkader F, Krause M, Carpinelli A, Curi R. Reactive oxygen and nitrogen species generation, antioxidant defenses, and β-cell function: a critical role for amino acids. J Endocrinol 2012; 214:11-20. [PMID: 22547566 DOI: 10.1530/joe-12-0072] [Citation(s) in RCA: 108] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Growing evidence indicates that the regulation of intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels is essential for maintaining normal β-cell glucose responsiveness. While long-term exposure to high glucose induces oxidative stress in β cells, conflicting results have been published regarding the impact of ROS on acute glucose exposure and their role in glucose stimulated insulin secretion (GSIS). Although β cells are considered to be particularly vulnerable to oxidative damage, as they express relatively low levels of some peroxide-metabolizing enzymes such as catalase and glutathione (GSH) peroxidase, other less known GSH-based antioxidant systems are expressed in β cells at higher levels. Herein, we discuss the key mechanisms of ROS/RNS production and their physiological function in pancreatic β cells. We also hypothesize that specific interactions between RNS and ROS may be the cause of the vulnerability of pancreatic β cells to oxidative damage. In addition, using a hypothetical metabolic model based on the data available in the literature, we emphasize the importance of amino acid availability for GSH synthesis and for the maintenance of β-cell function and viability during periods of metabolic disturbance before the clinical onset of diabetes.
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Affiliation(s)
- P Newsholme
- School of Biomedical Sciences, Curtin University, PO Box U1987, Perth, Western Australia 6845, Australia.
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Felipe ET, Maestri JS, Kanunfre CC, Curi R, Newsholme P, Carpinelli AR, Oliveira-Emilio HR. Cytotoxicity and cytoprotective effects of citrus flavonoids on insulin-secreting cells BRIN-BD11: beneficial synergic effects. Nat Prod Res 2012; 27:925-8. [PMID: 22443082 DOI: 10.1080/14786419.2012.671315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Flavonoids, in general, have potent antioxidant activity and they can be used in treating chronic diseases involving oxidative stress, such as diabetes mellitus. The purpose of this study was to evaluate the cytotoxicity and cytoprotective effects of citrus flavonoids on the functionality of BRIN-BD11 cells. The assessment of cytotoxic and cytoprotective flavonoid tested was performed using the MTT reduction assay. The flavonoids did not show cytotoxic effects in any of the tested concentrations (5-20 µM) and also negative insulinotropic effects were not observed. To cytoprotective assay, the IC50 of H2O2 in treatment of 2 h (acute oxidative stress) was measured (350 µM). Moreover, under acute oxidative stress, the isolated flavonoids (10 µM) had no cytoprotective effects. Besides an antioxidant role of the flavonoids was only observed when using in association. Thus future experiments are needed, varying the experimental condition, to better evaluate the possible mechanisms of action of these flavonoids.
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Affiliation(s)
- E T Felipe
- Evolutive Biology Post-Graduate Course, Ponta Grossa State University, Ponta Grossa, Parana, Brazil
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