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Tan Q, Wang B, Ye Z, Mu G, Liu W, Nie X, Yu L, Zhou M, Chen W. Cross-sectional and longitudinal relationships between ozone exposure and glucose homeostasis: Exploring the role of systemic inflammation and oxidative stress in a general Chinese urban population. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 329:121711. [PMID: 37100372 DOI: 10.1016/j.envpol.2023.121711] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/05/2023] [Accepted: 04/22/2023] [Indexed: 05/21/2023]
Abstract
The adverse health effects of ozone pollution have been a globally concerned public health issue. Herein we aim to investigate the association between ozone exposure and glucose homeostasis, and to explore the potential role of systemic inflammation and oxidative stress in this association. A total of 6578 observations from the Wuhan-Zhuhai cohort (baseline and two follow-ups) were included in this study. Fasting plasma glucose (FPG) and insulin (FPI), plasma C-reactive protein (CRP, biomarker for systemic inflammation), urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG, biomarker for oxidative DNA damage), and urinary 8-isoprostane (biomarker for lipid peroxidation) were repeatedly measured. After adjusting for potential confounders, ozone exposure was positively associated with FPG, FPI, and homeostasis model assessment of insulin resistance (HOMA-IR), and negatively associated with HOMA of beta cell function (HOMA-β) in cross-sectional analyses. Each 10 ppb increase in cumulative 7-days moving average ozone was associated with a 13.19%, 8.31%, and 12.77% increase in FPG, FPI, and HOMA-IR, respectively, whereas a 6.63% decrease in HOMA-β (all P < 0.05). BMI modified the associations of 7-days ozone exposure with FPI and HOMA-IR, and the effects were stronger in subgroup whose BMI ≥24 kg/m2. Consistently high exposure to annual average ozone was associated with increased FPG and FPI in longitudinal analyses. Furthermore, ozone exposure was positively related to CRP, 8-OHdG, and 8-isoprostane in dose-response manner. Increased CRP, 8-OHdG, and 8-isoprostane could dose-dependently aggravate glucose homeostasis indices elevations related to ozone exposure. Increased CRP and 8-isoprostane mediated 2.11-14.96% of ozone-associated glucose homeostasis indices increment. Our findings suggested that ozone exposure could cause glucose homeostasis damage and obese people were more susceptible. Systemic inflammation and oxidative stress might be potential pathways in glucose homeostasis damage induced by ozone exposure.
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Affiliation(s)
- Qiyou Tan
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Bin Wang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Zi Ye
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Ge Mu
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Wei Liu
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Xiuquan Nie
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Linling Yu
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Min Zhou
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Weihong Chen
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
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Mastrogiacomo L, Ballagh R, Venegas-Pino DE, Kaur H, Shi P, Werstuck GH. The Effects of Hyperglycemia on Early Endothelial Activation and the Initiation of Atherosclerosis. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:121-133. [PMID: 36243046 DOI: 10.1016/j.ajpath.2022.09.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 09/01/2022] [Accepted: 09/16/2022] [Indexed: 11/11/2022]
Abstract
It is well established that patients with diabetes have an increased risk of developing atherosclerotic cardiovascular disease. The earliest detectable sign of atherosclerosis initiation is endothelial cell activation. Activated endothelial cells express adhesion proteins, P-selectin, E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, which function to recruit monocytes to the subendothelial layer. This study examines the effect of hyperglycemia on endothelial cell activation and the initiation and progression of atherosclerosis. In vitro studies revealed that exposure of human aortic endothelial cells to elevated (30 mmol/L) glucose concentrations significantly increased the expression of P-selectin, E-selectin, and vascular cell adhesion molecule-1. In vivo studies showed that, before lesion development, 5-week-old hyperglycemic ApoE-/-Ins2+/akita mice had significantly increased expression of these adhesion proteins in the aortic sinus and increased macrophage infiltration, compared with normoglycemic ApoE-/- controls. At 25 weeks of age, ApoE-/-Ins2+/akita mice had significantly larger atherosclerotic plaques than ApoE-/- controls (0.022 ± 0.004 versus 0.007± 0.001 mm3; P < 0.05). Similar endothelial activation was observed in heterozygous ApoE+/-Ins2+/akita mice; however, detectable atherosclerotic lesions did not develop in the absence of dyslipidemia. Lowering blood glucose levels (by 55%) using a sodium-glucose cotransporter 2 inhibitor reduced endothelial activation. Together, these findings support a causative role for hyperglycemia in atherogenesis and highlight the importance of blood glucose regulation in preventing atherosclerotic cardiovascular disease.
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Affiliation(s)
- Lauren Mastrogiacomo
- Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Robert Ballagh
- Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
| | | | - Hargun Kaur
- Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
| | - Peter Shi
- Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
| | - Geoff H Werstuck
- Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
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Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain-Barre Syndrome. Cells 2022; 11:cells11182897. [PMID: 36139470 PMCID: PMC9496801 DOI: 10.3390/cells11182897] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 09/06/2022] [Accepted: 09/07/2022] [Indexed: 11/30/2022] Open
Abstract
AMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolic and immune functions mainly through the inhibition of the mechanistic target of rapamycin (mTOR)-dependent anabolic pathways and the activation of catabolic processes such as autophagy. The AMPK/mTOR signaling pathway and autophagy markers were analyzed by immunoblotting in blood mononuclear cells of 20 healthy control subjects and 23 patients with an acute demyelinating form of Guillain–Barré syndrome (GBS). The activation of the liver kinase B1 (LKB1)/AMPK/Raptor signaling axis was significantly reduced in GBS compared to control subjects. In contrast, the phosphorylated forms of mTOR activator AKT and mTOR substrate 4EBP1, as well as the levels of autophagy markers LC3-II, beclin-1, ATG5, p62/sequestosome 1, and NBR1 were similar between the two groups. The downregulation of LKB1/AMPK signaling, but not the activation status of the AKT/mTOR/4EBP1 pathway or the levels of autophagy markers, correlated with higher clinical activity and worse outcomes of GBS. A retrospective study in a diabetic cohort of GBS patients demonstrated that treatment with AMPK activator metformin was associated with milder GBS compared to insulin/sulphonylurea therapy. In conclusion, the impairment of the LKB1/AMPK pathway might contribute to the development/progression of GBS, thus representing a potential therapeutic target in this immune-mediated peripheral polyneuropathy.
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Bolanle IO, Palmer TM. Targeting Protein O-GlcNAcylation, a Link between Type 2 Diabetes Mellitus and Inflammatory Disease. Cells 2022; 11:cells11040705. [PMID: 35203353 PMCID: PMC8870601 DOI: 10.3390/cells11040705] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/09/2022] [Accepted: 02/15/2022] [Indexed: 12/11/2022] Open
Abstract
Unresolved hyperglycaemia, a hallmark of type 2 diabetes mellitus (T2DM), is a well characterised manifestation of altered fuel homeostasis and our understanding of its role in the pathologic activation of the inflammatory system continues to grow. Metabolic disorders like T2DM trigger changes in the regulation of key cellular processes such as cell trafficking and proliferation, and manifest as chronic inflammatory disorders with severe long-term consequences. Activation of inflammatory pathways has recently emerged as a critical link between T2DM and inflammation. A substantial body of evidence has suggested that this is due in part to increased flux through the hexosamine biosynthetic pathway (HBP). The HBP, a unique nutrient-sensing metabolic pathway, produces the activated amino sugar UDP-GlcNAc which is a critical substrate for protein O-GlcNAcylation, a dynamic, reversible post-translational glycosylation of serine and threonine residues in target proteins. Protein O-GlcNAcylation impacts a range of cellular processes, including inflammation, metabolism, trafficking, and cytoskeletal organisation. As increased HBP flux culminates in increased protein O-GlcNAcylation, we propose that targeting O-GlcNAcylation may be a viable therapeutic strategy for the prevention and management of glucose-dependent pathologies with inflammatory components.
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Badal D, Sachdeva N, Maheshwari D, Basak P. Role of nucleic acid sensing in the pathogenesis of type 1 diabetes. World J Diabetes 2021; 12:1655-1673. [PMID: 34754369 PMCID: PMC8554372 DOI: 10.4239/wjd.v12.i10.1655] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/22/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
During infections, nucleic acids of pathogens are also engaged in recognition via several exogenous and cytosolic pattern recognition receptors, such as the toll-like receptors, retinoic acid inducible gene-I-like receptors, and nucleotide-binding and oligomerization domain-like receptors. The binding of the pathogen-derived nucleic acids to their corresponding sensors initiates certain downstream signaling cascades culminating in the release of type-I interferons (IFNs), especially IFN-α and other cytokines to induce proinflammatory responses towards invading pathogens leading to their clearance from the host. Although these sensors are hardwired to recognize pathogen associated molecular patterns, like viral and bacterial nucleic acids, under unusual physiological conditions, such as excessive cellular stress and increased apoptosis, endogenous self-nucleic acids like DNA, RNA, and mitochondrial DNA are also released. The presence of these self-nucleic acids in extranuclear compartments or extracellular spaces or their association with certain proteins sometimes leads to the failure of discriminating mechanisms of nucleic acid sensors leading to proinflammatory responses as seen in autoimmune disorders, like systemic lupus erythematosus, psoriasis and to some extent in type 1 diabetes (T1D). This review discusses the involvement of various nucleic acid sensors in autoimmunity and discusses how aberrant recognition of self-nucleic acids by their sensors activates the innate immune responses during the pathogenesis of T1D.
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Affiliation(s)
- Darshan Badal
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Naresh Sachdeva
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Deep Maheshwari
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Preetam Basak
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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6
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Koufakis T, Dimitriadis G, Metallidis S, Zebekakis P, Kotsa K. The role of autoimmunity in the pathophysiology of type 2 diabetes: Looking at the other side of the moon. Obes Rev 2021; 22:e13231. [PMID: 33682984 DOI: 10.1111/obr.13231] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/17/2021] [Accepted: 02/18/2021] [Indexed: 12/12/2022]
Abstract
Efforts to unravel the pathophysiological mechanisms of type 2 diabetes (T2D) have been traditionally trapped into a metabolic perspective. However, T2D is a phenotypically and pathophysiologically heterogenous disorder, and the need for a tailored approach in its management is becoming increasingly evident. There is emerging evidence that irregular immune responses contribute to the development of hyperglycemia in T2D and, inversely, that insulin resistance is a component of the pathogenesis of autoimmune diabetes. Nevertheless, it has not yet been fully elucidated to what extent the presence of conventional autoimmune markers, such as autoantibodies, in subjects with T2D might affect the natural history of the disease and particularly each response to various treatments. The challenge for future research in the field is the discovery of novel genetic, molecular, or phenotypical indicators that would enable the characterization of specific subpopulations of people with T2D who would benefit most from the addition of immunomodulatory therapies to standard glucose-lowering treatment. This narrative review aims to discuss the plausible mechanisms through which the immune system might be implicated in the development of metabolic disturbances in T2D and obesity and explore a potential role of immunotherapy in the future management of the disorder and its complications.
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Affiliation(s)
- Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - George Dimitriadis
- Athens University Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Symeon Metallidis
- Infectious Diseases Division, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Pantelis Zebekakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.,Infectious Diseases Division, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
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Erendor F, Sahin EO, Sanlioglu AD, Balci MK, Griffith TS, Sanlioglu S. Lentiviral gene therapy vectors encoding VIP suppressed diabetes-related inflammation and augmented pancreatic beta-cell proliferation. Gene Ther 2021; 28:130-141. [PMID: 32733091 DOI: 10.1038/s41434-020-0183-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 07/16/2020] [Accepted: 07/22/2020] [Indexed: 02/06/2023]
Abstract
Type 1 diabetes (T1DM) is an autoimmune condition in which the immune system attacks and destroys insulin-producing beta cells in the pancreas leading to hyperglycemia. Vasoactive intestinal peptide (VIP) manifests insulinotropic and anti-inflammatory properties, which are useful for the treatment of diabetes. Because of its limited half-life due to DPP-4-mediated degradation, constant infusions or multiple injections are needed to observe any therapeutic benefit. Since gene therapy has the potential to treat genetic diseases, an HIV-based lentiviral vector carrying VIP gene (LentiVIP) was generated to provide a stable VIP gene expression in vivo. The therapeutic efficacy of LentiVIP was tested in a multiple low-dose STZ-induced animal model of T1DM. LentiVIP delivery into diabetic animals reduced hyperglycemia, improved glucose tolerance, and prevented weight loss. Also, a decrease in serum CRP levels, and serum oxidant capacity, but an increase in antioxidant capacity were observed in LentiVIP-treated animals. Restoration of islet cell mass was correlated with an increase in pancreatic beta-cell proliferation. These beneficial results suggest the therapeutic effect of LentiVIP is due to the repression of diabetes-induced inflammation, its insulinotropic properties, and VIP-induced beta-cell proliferation.
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Affiliation(s)
- Fulya Erendor
- Department of Gene and Cell Therapy, Akdeniz University, Faculty of Medicine, 07058, Antalya, Turkey
| | - Elif Ozgecan Sahin
- Department of Gene and Cell Therapy, Akdeniz University, Faculty of Medicine, 07058, Antalya, Turkey
| | - Ahter D Sanlioglu
- Department of Gene and Cell Therapy, Akdeniz University, Faculty of Medicine, 07058, Antalya, Turkey
| | - Mustafa Kemal Balci
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, 07058, Antalya, Turkey
| | - Thomas S Griffith
- Department of Urology, University of Minnesota, School of Medicine, Minneapolis, MN, 55455, USA
| | - Salih Sanlioglu
- Department of Gene and Cell Therapy, Akdeniz University, Faculty of Medicine, 07058, Antalya, Turkey.
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Behl T, Sharma E, Sehgal A, Kaur I, Kumar A, Arora R, Pal G, Kakkar M, Kumar R, Bungau S. Expatiating the molecular approaches of HMGB1 in diabetes mellitus: Highlighting signalling pathways via RAGE and TLRs. Mol Biol Rep 2021; 48:1869-1881. [PMID: 33479829 DOI: 10.1007/s11033-020-06130-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 12/24/2020] [Indexed: 12/16/2022]
Abstract
Diabetes mellitus (DM) has become one of the major healthcare challenges worldwide in the recent times and inflammation being one of its key pathogenic process/mechanism affect several body parts including the peripheral and central nervous system. High-mobility group box 1 (HMGB1) is one of the major non-histone proteins that plays a key role in triggering the inflammatory response. Upon its release into the extracellular milieu, HMGB1 acts as an "alarmin" for the immune system to initiate tissue repair as a component of the host defense system. Furthermore, HMGB1 along with its downstream receptors like Toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE) serve as the suitable target for DM. The forthcoming research in the field of diabetes would potentially focus on the development of alternative approaches to target the centre of inflammation that is primarily mediated by HMGB1 to improve diabetic-related complications. This review covers the therapeutic actions of HMGB1 protein, which acts by activating the RAGE and TLR molecules to constitute a functional tripod system, in turn activating NF-κB pathway that contributes to the production of mediators for pro-inflammatory cytokines associated with DM. The interaction between TLR2 and TLR4 with ligands present in the host and the activation of RAGE stimulates various immune and metabolic responses that contribute to diabetes. This review emphasizes to elucidate the role of HMGB1 in the initiation and progression of DM and control over the inflammatory tripod as a promising therapeutic approach in the management of DM.
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Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
| | - Eshita Sharma
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Ishnoor Kaur
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Arun Kumar
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Rashmi Arora
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Giridhari Pal
- Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
| | - Munish Kakkar
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Ravinder Kumar
- Cardiovascular Research Institute, Icahn School of Medicine, New York, USA
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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Timonen J, Mannerström H, Vehtari A, Lähdesmäki H. lgpr: An interpretable nonparametric method for inferring covariate effects from longitudinal Data. Bioinformatics 2021; 37:1860-1867. [PMID: 33471072 PMCID: PMC8317115 DOI: 10.1093/bioinformatics/btab021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/14/2020] [Accepted: 01/08/2021] [Indexed: 11/14/2022] Open
Abstract
MOTIVATION Longitudinal study designs are indispensable for studying disease progression. Inferring covariate effects from longitudinal data, however, requires interpretable methods that can model complicated covariance structures and detect nonlinear effects of both categorical and continuous covariates, as well as their interactions. Detecting disease effects is hindered by the fact that they often occur rapidly near the disease initiation time, and this time point cannot be exactly observed. An additional challenge is that the effect magnitude can be heterogeneous over the subjects. RESULTS We present lgpr, a widely applicable and interpretable method for nonparametric analysis of longitudinal data using additive Gaussian processes. We demonstrate that it outperforms previous approaches in identifying the relevant categorical and continuous covariates in various settings. Furthermore, it implements important novel features, including the ability to account for the heterogeneity of covariate effects, their temporal uncertainty, and appropriate observation models for different types of biomedical data. The lgpr tool is implemented as a comprehensive and user-friendly R-package. AVAILABILITY lgpr is available at jtimonen.github.io/lgpr-usage with documentation, tutorials, test data, and code for reproducing the experiments of this paper. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Juho Timonen
- Department of Computer Science, Aalto University, Espoo, 00076, Finland
| | | | - Aki Vehtari
- Department of Computer Science, Aalto University, Espoo, 00076, Finland
| | - Harri Lähdesmäki
- Department of Computer Science, Aalto University, Espoo, 00076, Finland
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Erendor F, Eksi YE, Sahin EO, Balci MK, Griffith TS, Sanlioglu S. Lentivirus Mediated Pancreatic Beta-Cell-Specific Insulin Gene Therapy for STZ-Induced Diabetes. Mol Ther 2021; 29:149-161. [PMID: 33130311 PMCID: PMC7791084 DOI: 10.1016/j.ymthe.2020.10.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/31/2020] [Accepted: 10/23/2020] [Indexed: 02/07/2023] Open
Abstract
Autoimmune destruction of pancreatic beta cells is the characteristic feature of type 1 diabetes mellitus. Consequently, both short- and intermediate-acting insulin analogs are under development to compensate for the lack of endogenous insulin gene expression. Basal insulin is continuously released at low levels in response to hepatic glucose output, while post-prandial insulin is secreted in response to hyperglycemia following a meal. As an alternative to multiple daily injections of insulin, glucose-regulated insulin gene expression by gene therapy is under development to better endure postprandial glucose excursions. Controlled transcription and translation of proinsulin, presence of glucose-sensing machinery, prohormone convertase expression, and a regulated secretory pathway are the key features unique to pancreatic beta cells. To take advantage of these hallmarks, we generated a new lentiviral vector (LentiINS) with an insulin promoter driving expression of the proinsulin encoding cDNA to sustain pancreatic beta-cell-specific insulin gene expression. Intraperitoneal delivery of HIV-based LentiINS resulted in the lowering of fasting plasma glucose, improved glucose tolerance and prevented weight loss in streptozoticin (STZ)-induced diabetic Wistar rats. However, the combinatorial use of LentiINS and anti-inflammatory lentiviral vector (LentiVIP) gene therapy was required to increase serum insulin to a level sufficient to suppress non-fasting plasma glucose and diabetes-related inflammation.
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Affiliation(s)
- Fulya Erendor
- Department of Gene and Cell Therapy, Faculty of Medicine, Akdeniz University, Antalya 07058, Turkey
| | - Yunus Emre Eksi
- Department of Gene and Cell Therapy, Faculty of Medicine, Akdeniz University, Antalya 07058, Turkey
| | - Elif Ozgecan Sahin
- Department of Gene and Cell Therapy, Faculty of Medicine, Akdeniz University, Antalya 07058, Turkey
| | - Mustafa Kemal Balci
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Akdeniz University, Antalya 07058, Turkey
| | - Thomas S Griffith
- Department of Urology, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Salih Sanlioglu
- Department of Gene and Cell Therapy, Faculty of Medicine, Akdeniz University, Antalya 07058, Turkey.
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Vitamin D(3) regulates hepatic VEGF-A and apelin expression in experimental type 1 diabetes. UKRAINIAN BIOCHEMICAL JOURNAL 2020. [DOI: 10.15407/ubj92.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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12
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LncRNA MALAT1 induces the dysfunction of β cells via reducing the histone acetylation of the PDX-1 promoter in type 1 diabetes. Exp Mol Pathol 2020; 114:104432. [DOI: 10.1016/j.yexmp.2020.104432] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 02/27/2020] [Accepted: 03/28/2020] [Indexed: 12/14/2022]
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13
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Qiao Z, Du X, Zhuang W, Yang S, Li H, Sun J, Chen J, Wang C. Schisandra Chinensis Acidic Polysaccharide Improves the Insulin Resistance in Type 2 Diabetic Rats by Inhibiting Inflammation. J Med Food 2020; 23:358-366. [PMID: 32181695 DOI: 10.1089/jmf.2019.4469] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Polysaccharide from Schisandra chinensis has the effect of lowering blood glucose and improving insulin resistance (IR). However, its underlying mechanism remains unclear. In this study, a rat model of type 2 diabetes (T2D) was created to explore whether S. chinensis acidic polysaccharide (SCAP) would improve the IR in T2D rats by inhibiting inflammation. A combination of a high-fat diet and low dose of streptozotocin (STZ, 30 mg/kg, intraperitoneally) were administered to rats for establishing the T2D model. Then, these T2D rats were orally administered with SCAP (25, 50, or 100 mg/kg) for 8 weeks. The results indicated that SCAP significantly lowered the fasting blood glucose, elevated the fasting insulin, and improved glucose tolerance. SCAP also decreased the serum interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and nuclear factor-κB (NF-κB) levels, as well as their mRNA expression in the liver tissue. Further, SCAP significantly inhibited the upregulation of phosphorylated c-Jun N-terminal kinase (p-JNK) and NF-κB protein, and it increased phosphorylated insulin receptor substrate-1 (p-IRS-1), phosphorylated phosphatidylinositol 3-kinase (p-PI3K), and phosphorylated protein kinase B (p-AKT) protein expression levels significantly. These results suggest that SCAP improves the IR in T2D rats by inhibiting inflammation.
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Affiliation(s)
- Zijing Qiao
- Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, China
| | - Xingxu Du
- Department of Endocrinology, Affiliated Hospital, Beihua University, Jilin, China
| | - Wenyue Zhuang
- Department of Molecular Biology Test Technique, College of Medical Technology, Beihua University, Jilin, China
| | - Shuo Yang
- Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, China
| | - He Li
- Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, China
| | - Jinghui Sun
- Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, China
| | - Jianguang Chen
- Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, China
| | - Chunmei Wang
- Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, China
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14
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Handelsman Y, Muskiet MHA, Meneilly GS. Combining GLP-1 Receptor Agonists and Basal Insulin in Older Adults with Type 2 Diabetes: Focus on Lixisenatide and Insulin Glargine. Adv Ther 2019; 36:3321-3339. [PMID: 31646466 PMCID: PMC6860469 DOI: 10.1007/s12325-019-01126-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Indexed: 12/14/2022]
Abstract
Estimates suggest that there are currently 122.8 million adults 65-99 years of age living with diabetes, of whom 90-95% are diagnosed with type 2 diabetes (T2D). Over the past two decades, a greater understanding of the complex and multifactorial pathogenesis of T2D has resulted in the development and introduction of new-generation classes of glucose-lowering therapies, which are now extensively endorsed by prevailing guidelines and are increasingly being used worldwide. These newer agents may further assist in the effective pharmacological management of T2D through the provision of patient-centered care that acknowledges multimorbidity and is respectful of and responsive to individual patient preferences and barriers. Given these considerations, the therapeutic approach in older patients with T2D is complex, particularly in those who have functional dependence, frailty, dementia, or who are at end-of-life. It is currently too early to draw conclusions on the long-term use of newer glucose-lowering agents in this population, as their efficacy and safety in older adults remains largely unknown. In this review, we will discuss considerations for the use of glucose-lowering treatments in older adults, with particular focus on the use of basal insulin and glucagon-like peptide-1 receptor agonists, and the rationale for the use of combination therapy comprising these agents. Finally, we will review clinical data from studies of the fixed-ratio combination of insulin glargine and lixisenatide in older patients with T2D. FUNDING: Sanofi US, Inc.
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Affiliation(s)
- Yehuda Handelsman
- Metabolic Institute of America, 18372 Clark St. Suite 212, Tarzana, CA, 91356, USA.
| | - Marcel H A Muskiet
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers (Location VUMC), 1081 HV, Amsterdam, The Netherlands
| | - Graydon S Meneilly
- Department of Medicine, The University of British Columbia, 2775 Laurel Street, Vancouver, BC, V5Z1M9, Canada
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15
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Khawandanah J. Double or hybrid diabetes: A systematic review on disease prevalence, characteristics and risk factors. Nutr Diabetes 2019; 9:33. [PMID: 31685799 PMCID: PMC6828774 DOI: 10.1038/s41387-019-0101-1] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 10/09/2019] [Accepted: 10/11/2019] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus is a worldwide epidemic affecting the health of millions of people. While type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing beta cells of the pancreas, type 2 diabetes (T2D) results from a combination of insulin resistance and beta cell insulin secretory defect. Clear definition and diagnosis of these two types of diabetes has been increasing more and more difficult, leading to the inclusion of a new category, namely double or hybrid diabetes (DD) that demonstrates symptoms of both T1D and T2D via the accelerator hypothesis. In this review, we discuss the worldwide prevalence of DD, its main physiological characteristics, including beta-cell autoimmunity, insulin resistance, and cardiovascular disease, the main risk factors of developing DD, mainly genetics, obesity and lifestyle choices, as well as potential treatments, such as insulin titration, metformin and behavioural modifications. Increasing awareness of DD among the general population and primary care practitioners is necessary for successfully treating this complex, hybrid disease in the future.
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Affiliation(s)
- Jomana Khawandanah
- Clinical Nutrition Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
- Section for Nutrition Research, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom.
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16
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Li Y, Xie M, Men L, Du J. O-GlcNAcylation in immunity and inflammation: An intricate system (Review). Int J Mol Med 2019; 44:363-374. [PMID: 31198979 PMCID: PMC6605495 DOI: 10.3892/ijmm.2019.4238] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 06/06/2019] [Indexed: 12/20/2022] Open
Abstract
Chronic, low‑grade inflammation associated with obesity and diabetes result from the infiltration of adipose and vascular tissue by immune cells and contributes to cardiovascular complications. Despite an incomplete understanding of the mechanistic underpinnings of immune cell differentiation and inflammation, O‑GlcNAcylation, the addition of O‑linked N‑acetylglucosamine (O‑GlcNAc) to cytoplasmic, nuclear and mitochondrial proteins by the two cycling enzymes, the O‑linked N‑acetylglucosamine transferase (OGT) and the O‑GlcNAcase (OGA), may contribute to fine‑tune immunity and inflammation in both physiological and pathological conditions. Early studies have indicated that O‑GlcNAcylation of proteins play a pro‑inflammatory role in diabetes and insulin resistance, whereas subsequent studies have demonstrated that this post‑translational modification could also be protective against acute injuries. These studies suggest that diverse types of insults result in dynamic changes to O‑GlcNAcylation patterns, which fluctuate with cellular metabolism to promote or inhibit inflammation. In this review, the current understanding of O‑GlcNAcylation and its adaptive modulation in immune and inflammatory responses is summarized.
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Affiliation(s)
- Yu Li
- Department of Endocrinology
| | - Mingzheng Xie
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | | | - Jianling Du
- Department of Endocrinology
- Correspondence to: Dr Jianling Du, Department of Endocrinology, The First Affiliated Hospital of Dalian Medical University, 193 Lianhe Road, Dalian, Liaoning 116011, P.R. China, E-mail:
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17
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Possible protective effect of procainamide as an epigenetic modifying agent in experimentally induced type 2 diabetes mellitus in rats. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2014.02.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
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18
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Tasyurek HM, Altunbas HA, Balci MK, Griffith TS, Sanlioglu S. Therapeutic Potential of Lentivirus-Mediated Glucagon-Like Peptide-1 Gene Therapy for Diabetes. Hum Gene Ther 2018; 29:802-815. [PMID: 29409356 DOI: 10.1089/hum.2017.180] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Postprandial glucose-induced insulin secretion from the islets of Langerhans is facilitated by glucagon-like peptide-1 (GLP-1)-a metabolic hormone with insulinotropic properties. Among the variety of effects it mediates, GLP-1 induces delta cell secretion of somatostatin, inhibits alpha cell release of glucagon, reduces gastric emptying, and slows food intake. These events collectively contribute to weight loss over time. During type 2 diabetes (T2DM), however, the incretin response to glucose is reduced and accompanied by a moderate reduction in GLP-1 secretion. To compensate for the reduced incretin effect, a human immunodeficiency virus-based lentiviral vector was generated to deliver DNA encoding human GLP-1 (LentiGLP-1), and the anti-diabetic efficacy of LentiGLP-1 was tested in a high-fat diet/streptozotocin-induced model of T2DM. Therapeutic administration of LentiGLP-1 reduced blood glucose levels in obese diabetic Sprague Dawley rats, along with improving insulin sensitivity and glucose tolerance. Normoglycemia was correlated with increased blood GLP-1 and pancreatic beta cell regeneration in LentiGLP-1-treated rats. Plasma triglyceride levels were also normalized after LentiGLP-1 injection. Collectively, these data suggest the clinical potential of GLP-1 gene transfer therapy for the treatment of T2DM.
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Affiliation(s)
- Hale M Tasyurek
- 1 Human Gene and Cell Therapy Center of Akdeniz University Hospitals , Antalya, Turkey
| | - Hasan Ali Altunbas
- 2 Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Mustafa Kemal Balci
- 2 Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Thomas S Griffith
- 3 Department of Urology, University of Minnesota , School of Medicine, Minneapolis, Minnesota
| | - Salih Sanlioglu
- 1 Human Gene and Cell Therapy Center of Akdeniz University Hospitals , Antalya, Turkey
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19
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O'Day E, Hosta-Rigau L, Oyarzún DA, Okano H, de Lorenzo V, von Kameke C, Alsafar H, Cao C, Chen GQ, Ji W, Roberts RJ, Ronaghi M, Yeung K, Zhang F, Lee SY. Are We There Yet? How and When Specific Biotechnologies Will Improve Human Health. Biotechnol J 2018; 14:e1800195. [PMID: 29799175 DOI: 10.1002/biot.201800195] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 05/11/2018] [Indexed: 12/11/2022]
Abstract
Patient X: A 67-year-old Caucasian man slips on a patch of ice. He has abrasions to his hands and has sustained significant damage to his hip. At the emergency room, he informs clinicians he takes atorvastatin, metformin, and glimepiride to treat hypertension and Type 2 Diabetes Mellitus (T2DM). X-rays reveal a fractured hip, which will require total hip replacement surgery.
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Affiliation(s)
- Elizabeth O'Day
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,Olaris Therapeutics, Inc., 45 Moulton St., Cambridge, MA, 02138, USA
| | - Leticia Hosta-Rigau
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,Department of Micro- and Nanotechnology, Center for Nanomedicine and Theranostics, Technical University of Denmark, 2800, Kongens Lyngby, Denmark
| | - Diego A Oyarzún
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,Department of Mathematics, Imperial College London, London, SW7 2AZ, UK.,EPSRC Centre for Mathematics of Precision Healthcare, Imperial College London, London, SW7 2AZ, UK
| | - Hideyuki Okano
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Víctor de Lorenzo
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,National Center of Biotechnology CSIC, Systems Biology Program, Campus de Cantoblanco, E-28049, Madrid, Spain
| | - Conrad von Kameke
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,BioInnovators Europe, Berlin, Germany
| | - Habiba Alsafar
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,Khalifa University Center for Biotechnology, Khalifa University, PO Box 127788, Abu Dhabi, United Arab Emirates
| | - Cong Cao
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,University of Nottingham, 199 East Taikang Road, Ningbo, 315100, China
| | - Guo-Qiang Chen
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,Center for Synthetic and Systems Biology, MOE Lab for Industrial Biocatalysis, Tsinghua-Peking University Center of Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Weizhi Ji
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,Kunming University of Science and Technology, 727 Jingming South Rd. Chenh Gong, Kunming, 650500, Yunnan, China
| | - Richard J Roberts
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,New England Biolabs, 240 County Road, Ipswich, MA, 01938, USA
| | - Mostafa Ronaghi
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,Illumina Inc., 5200 Illumina Way, San Diego, CA, 92121, USA
| | - Karen Yeung
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,Law School and School of Computer Science University of Birmingham, Birmingham, UK, B15 2TT
| | - Feng Zhang
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.,McGovern Institute for Brain Research at MIT, Cambridge, MA, 02139, USA.,Department of Brain and Cognitive Sciences and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Sang Yup Lee
- Global Future Council on the Future of Biotechnologies, World Economic Forum, Cologny, CH-1223, Geneva, Switzerland.,Department of Chemical and Biomolecular Engineering (BK21 Plus program), Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-Ro, Daejeon, 34141, Republic of Korea.,The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet Bygning 220, 2800, Kongens Lyngby, Denmark
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20
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Diethylnitrosamine Increases Proliferation in Early Stages of Hepatic Carcinogenesis in Insulin-Treated Type 1 Diabetic Mice. BIOMED RESEARCH INTERNATIONAL 2018; 2018:9472939. [PMID: 29850590 PMCID: PMC5937583 DOI: 10.1155/2018/9472939] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 03/01/2018] [Accepted: 03/14/2018] [Indexed: 12/13/2022]
Abstract
Diethylnitrosamine (DEN) induces hepatocarcinogenesis, increasing mitotic hepatocytes and leading to chronic inflammation. In addition, type 1 diabetes mellitus (T1DM) is also characterized by a proinflammatory state and by requiring insulin exogenous treatment. Given the association of diabetes, insulin treatment, and cell proliferation, our specific goal was to determine whether the liver in the diabetic state presents a greater response to DEN-induced cell cycle alteration, which is essential for the malignant transformation. Male C57BL/6 mice (four-week-old) were divided into 4 groups: C, C + DEN, T1DM, and T1DM + DEN. Mice were euthanized ten weeks after DEN injection. DEN per se produced an increase in liver lipid peroxidation levels. Besides, in T1DM + DEN, we found a greater increase in the proliferation index, in comparison with C + DEN. These results are in agreement with the increased expression observed in cell cycle progression markers: cyclin D1 and E1. In addition, a proapoptotic factor, such as activated caspase-3, evidenced a decrease in T1DM + DEN, while the Vascular Endothelial Growth Factor (VEGF) and the protooncogene p53 showed a higher increase with respect to C + DEN. Overall, the results allow us to highlight a major DEN response in T1DM, which may explain in part the greater predisposition to the development of hepatocarcinoma (HCC) during the diabetic state.
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21
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Li R, Huang J, Yu Y, Yang Y. Islet Autoantibody Patterns in Patients With Type 2 Diabetes Aged 60 and Higher: A Cross-Sectional Study in a Chinese Hospital. Front Endocrinol (Lausanne) 2018; 9:260. [PMID: 29887833 PMCID: PMC5980972 DOI: 10.3389/fendo.2018.00260] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 05/07/2018] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Some elderly citizens with a clinical diagnosis of type 2 diabetes had evidence of positive islet autoantibodies. We aimed to discover their islet autoantibody patterns and independent correlative factors that might lead to a better understanding of significance of islet autoimmunity in the progression of elderly diabetes. METHODS A total of 541 inpatients of clinically diagnosed type 2 diabetes aged 60 and over were recruited. Three islet autoantibodies including insulin autoantibody (IAA), islet cell antibody (ICA), and glutamic acid decarboxylase antibody (GADA) as well as clinical and biochemical characteristics were tested and collected in Huashan Hospital. Associations between these antibodies and clinical features were analyzed by Spearman correlation and binary logistic analyses. RESULTS In our current study, total positive rate of islet autoantibodies (IAA, ICA, and GADA) was 35.67% with 26.62% for individual IAA, 5.55% for ICA, and 5.91% for GADA, in elderly with type 2 diabetes. None of combinations of such autoantibodies were observed, with the exception of IAA + ICA (0.74%, n = 4), IAA + GADA (1.48%, n = 8), and ICA + GADA (0.18%, n = 1). Compared with GADA negative group, patients in positive group tended to have lower level of fasting and postprandial C peptide, fasting blood glucose (FBG), and body mass index (BMI). After adjusted for the BMI, FBG, and postprandial C peptide, fasting C peptide seemed to be an independent factor related to GADA positivity (OR = 0.52, p = 0.02). As for patients with positive IAA, they were more likely to have insulin treatment with longer duration of diabetes, higher level of BMI, and lower level of postprandial C peptide. After adjusted for the duration of diabetes, BMI, and postprandial C peptide, insulin treatment was a significant predictor for IAA positivity (OR = 5.20, p < 0.0001). Furthermore, hs-CRP was positively related to ICA positivity, and hs-CRP appeared to be an independent indicator for ICA (OR = 3.43, p = 0.008). CONCLUSION In elderly with type 2 diabetes, high prevalence rate of IAA was frequently accompanied with insulin treatment, while ICA and GADA were more closely associated with the systemic inflammation and beta-cell failure, respectively.
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22
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Increased inflammation is associated with islet autoimmunity and type 1 diabetes in the Diabetes Autoimmunity Study in the Young (DAISY). PLoS One 2017; 12:e0174840. [PMID: 28380011 PMCID: PMC5381877 DOI: 10.1371/journal.pone.0174840] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 03/09/2017] [Indexed: 12/13/2022] Open
Abstract
Background Type 1 diabetes (TID) is characterized by a loss of pancreatic islet beta cell function resulting in loss of insulin production. Genetic and environmental factors may trigger immune responses targeting beta cells thus generating islet antibodies (IA). Immune response pathways involve a cascade of events, initiated by cytokines and chemokines, producing inflammation which can result in tissue damage. Methods A nested case-control study was performed to identify temporal changes in cytokine levels in 75 DAISY subjects: 25 diagnosed T1D, 25 persistent IA, and 25 controls. Serum samples were selected at four time points: (T1) earliest, (T2) just prior to IA, (T3) just after IA, and (T4) prior to T1D diagnosis or most recent. Cytokines (IFN-α2a, IL-6, IL-17, IL-1β, IP-10, MCP-1, IFN-γ, IL-1α, and IL-1ra) were measured using the Meso Scale Discovery system Human Custom Cytokine 9-Plex assay. Results Multivariate mixed models adjusting for HLA risk, first-degree relative status, age, and gender, showed MCP-1 and IFN-үto be significantly higher at T3 in T1D compared to IA subjects. At T4, IP-10 was significantly higher in IA subjects than controls. Conclusions This repeated measures nested case-control study identified increased inflammatory markers in IA children who developed T1D compared to IA children who had not progressed to clinical disease. It also showed increased inflammation in both T1D and IA children when compared to controls. Results suggest inflammation may be related to both the development of IA and progression to T1D.
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23
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Acevedo-Calado M, James EA, Morran MP, Pietropaolo SL, Ouyang Q, Arribas-Layton D, Songini M, Liguori M, Casu A, Auchus RJ, Huang S, Yu L, Michels A, Gianani R, Pietropaolo M. Identification of Unique Antigenic Determinants in the Amino Terminus of IA-2 (ICA512) in Childhood and Adult Autoimmune Diabetes: New Biomarker Development. Diabetes Care 2017; 40:561-568. [PMID: 28174261 PMCID: PMC5360285 DOI: 10.2337/dc16-1527] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 01/11/2017] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The characterization of diverse subtypes of diabetes is a dynamic field of clinical research and an active area of discussion. The objective of this study was to identify new antigenic determinants in the neuroendocrine autoantigen IA-2 (ICA512) and assess whether circulating autoantibodies directed to new IA-2 epitopes identify autoimmune diabetes in young and adult populations with diabetes. RESEARCH DESIGN AND METHODS Clinically diagnosed patients with type 2 diabetes (n = 258; diabetes duration: 0.01-31 years) were evaluated using a new biomarker detecting autoantibodies directed to the extracellular domain of the neuroendocrine autoantigen IA-2 (IA-2ec). The proportion of IA-2ec autoantibodies was also evaluated in newly diagnosed patients with type 1 diabetes (n = 150; diabetes duration: 0.04-0.49 years). In addition, IA-2 (intracellular domain), GAD65, and zinc transporter 8 autoantibodies were assayed. RESULTS IA-2ec autoantibodies were detected in patients with type 1 diabetes and, surprisingly, in 5% of patients with type 2 diabetes without serologic responses to other IA-2 antigenic epitopes or other islet autoantigens. We also assessed the ability of IA-2ec-derived peptides to elicit CD4+ T-cell responses by stimulating peripheral blood mononuclear cells from patients with type 1 diabetes (n = 18) and HLA-matched healthy subjects (n = 13) with peptides and staining with the peptide/DQ8-specific tetramers, observing disease-associated responses to previously unreported epitopes within IA-2ec. CONCLUSIONS We developed a new antibody biomarker identifying novel antigenic determinants within the N terminus of IA-2. IA-2ec autoantibodies can be detected in patients with type 1 diabetes and in a subgroup of adult autoimmune patients with type 2 diabetes phenotype negative for conventional islet autoantibody testing. These observations suggest that islet autoimmunity may be more common in clinically diagnosed type 2 diabetes than previously observed.
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Affiliation(s)
- Maria Acevedo-Calado
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Eddie A James
- Benaroya Research Institute, University of Washington, Seattle, WA
| | - Michael P Morran
- Department of Medicinal Chemistry, College of Pharmacy, University of Toledo, Toledo, OH
| | - Susan L Pietropaolo
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Qin Ouyang
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX
| | | | - Marco Songini
- Diabetes Clinic, Department of Internal Medicine, and Laboratory of Microbiology & Immunology, Azienda Ospedaliera G. Brotzu, Cagliari, Italy
| | - Marco Liguori
- Diabetes Clinic, Department of Internal Medicine, and Laboratory of Microbiology & Immunology, Azienda Ospedaliera G. Brotzu, Cagliari, Italy
| | - Anna Casu
- Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, Palermo, Italy
| | - Richard J Auchus
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - Shuai Huang
- Department of Industrial and Systems Engineering, University of Washington, Seattle, WA
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Aaron Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Roberto Gianani
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX.,Rocky Vista University College of Osteopathic Medicine, Parker, CO
| | - Massimo Pietropaolo
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX
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Hwang YH, Kim MJ, Lee YK, Lee M, Lee DY. HMGB1 modulation in pancreatic islets using a cell-permeable A-box fragment. J Control Release 2017; 246:155-163. [DOI: 10.1016/j.jconrel.2016.12.028] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 11/19/2016] [Accepted: 12/25/2016] [Indexed: 12/11/2022]
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25
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Qin W, Liang YZ, Qin BY, Zhang JL, Xia N. The Clinical Significance of Glycoprotein Phospholipase D Levels in Distinguishing Early Stage Latent Autoimmune Diabetes in Adults and Type 2 Diabetes. PLoS One 2016; 11:e0156959. [PMID: 27351175 PMCID: PMC4925120 DOI: 10.1371/journal.pone.0156959] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 05/22/2016] [Indexed: 01/15/2023] Open
Abstract
Autoantibodies have been widely used as markers of latent autoimmune diabetes in adults (LADA); however, the specificity and sensitivity of autoantibodies as markers of LADA are weak compared with those found in type 1 diabetes (T1DM). In this study, we aimed to identify other plasma proteins as potential candidates that can be used effectively to determine early stage LADA and type 2 diabetes (T2DM) to facilitate early diagnosis and treatment. These issues were addressed by studying new-onset ‘classic’ T1DM (n = 156), LADA (n = 174), T2DM (n = 195) and healthy cohorts (n = 166). Plasma samples were obtained from the four cohorts. We employed isobaric tag for relative and absolute quantitation (iTRAQ) together with liquid chromatography tandem mass spectrometry (LC-MS) to identify plasma proteins with significant changes in LADA. The changes were validated by Western blot and ELISA analyses. Among the four cohorts, 311 unique proteins were identified in three iTRAQ runs, with 157 present across the three data sets. Among them, 49/311 (16.0%) proteins had significant changes in LADA compared with normal controls, including glycoprotein phospholipase D (GPLD1), which was upregulated in LADA. Western blot and ELISA analyses showed that GPLD1 levels were higher in both LADA and T1DM cohorts than in both T2DM and healthy cohorts, while there were no significant differences in the plasma concentrations of GPLD1 between the LADA and T1DM cohorts. GPLD1 is implicated as a potential candidate plasma protein for determining early stage LADA and T2DM.
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Affiliation(s)
- Wen Qin
- Department of pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Yu-Zhen Liang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Bao-Yu Qin
- Department of Elderly Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Jia-Li Zhang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Ning Xia
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
- * E-mail:
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Abstract
Diabetes mellitus is a metabolic homeostasis disease that contributes to additional comorbidities such as cardiovascular disease (CVD) and cancer. It has a long undiagnosed latent period during which there can be irreparable damage to the pancreas and cardiovascular tissues. Recent studies have highlighted the roles of several microRNAs in CVD. Determining the microRNAs that link diabetes mellitus and CVD is an important topic to be explored. In the present review, we discuss the microRNAs that contribute to the progression of diabetes mellitus and CVD and focus on the miR-29 family microRNAs whose expression is upregulated by hyperglycemia and proinflammatory cytokines, the hallmarks of diabetes mellitus. Upregulation of miR-29 expression is a key factor in the loss of pancreatic β cells and development of the first stage of type 1 diabetes mellitus (T1DM). Additionally, miR-29-mediated suppression of myeloid cell leukemia 1 (MCL-1), an important prosurvival protein, underlies Marfan's syndrome, abdominal aortic aneurysm, and diabetes mellitus-associated cardiomyocyte disorganization. Suppression of miR-29 expression and subsequent increase in the prosurvival MCL-1, however, promotes tumor development. Therefore, miR-29 mimics that suppress MCL-1 are hailed as tumor suppressors. The critical question is whether an increase in miR-29 levels is well tolerated in conditions of comorbidities in which insulin resistance is an underlying disease. In light of increasing awareness of the interconnection of diabetes mellitus, CVD, and cancer, it is of utmost importance to understand the mechanism of action of current treatment options on all of the comorbidities and careful evaluation of cardiovascular toxicity must accompany any treatment paradigm that increases miR-29 levels.
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Affiliation(s)
- Anna Ślusarz
- aDepartment of Medicine bDepartment of Biochemistry, University of Missouri cHarry S. Truman Memorial Veterans Affairs Hospital dDepartment of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, USA
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Schwartz SS, Epstein S, Corkey BE, Grant SFA, Gavin JR, Aguilar RB. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell-Centric Classification Schema. Diabetes Care 2016; 39:179-86. [PMID: 26798148 PMCID: PMC5317235 DOI: 10.2337/dc15-1585] [Citation(s) in RCA: 205] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The current classification system presents challenges to the diagnosis and treatment of patients with diabetes mellitus (DM), in part due to its conflicting and confounding definitions of type 1 DM, type 2 DM, and latent autoimmune diabetes of adults (LADA). The current schema also lacks a foundation that readily incorporates advances in our understanding of the disease and its treatment. For appropriate and coherent therapy, we propose an alternate classification system. The β-cell-centric classification of DM is a new approach that obviates the inherent and unintended confusions of the current system. The β-cell-centric model presupposes that all DM originates from a final common denominator-the abnormal pancreatic β-cell. It recognizes that interactions between genetically predisposed β-cells with a number of factors, including insulin resistance (IR), susceptibility to environmental influences, and immune dysregulation/inflammation, lead to the range of hyperglycemic phenotypes within the spectrum of DM. Individually or in concert, and often self-perpetuating, these factors contribute to β-cell stress, dysfunction, or loss through at least 11 distinct pathways. Available, yet underutilized, treatments provide rational choices for personalized therapies that target the individual mediating pathways of hyperglycemia at work in any given patient, without the risk of drug-related hypoglycemia or weight gain or imposing further burden on the β-cells. This article issues an urgent call for the review of the current DM classification system toward the consensus on a new, more useful system.
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Affiliation(s)
- Stanley S Schwartz
- Main Line Health, Wynnewood, PA, and University of Pennsylvania, Philadelphia, PA
| | - Solomon Epstein
- Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Mount Sinai Hospital, New York, NY
| | - Barbara E Corkey
- Department of Medicine, Boston University School of Medicine, Boston, MA
| | - Struan F A Grant
- Division of Human Genetics and Center for Applied Genomics, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Khodabandehloo H, Gorgani-Firuzjaee S, Panahi G, Meshkani R. Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction. Transl Res 2016; 167:228-56. [PMID: 26408801 DOI: 10.1016/j.trsl.2015.08.011] [Citation(s) in RCA: 203] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 08/29/2015] [Accepted: 08/31/2015] [Indexed: 12/13/2022]
Abstract
Obesity is a major public health problem worldwide, and it is associated with an increased risk of developing type 2 diabetes. It is now commonly accepted that chronic inflammation associated with obesity induces insulin resistance and β-cell dysfunction in diabetic patients. Obesity-associated inflammation is characterized by increased abundance of macrophages and enhanced production of inflammatory cytokines in adipose tissue. Adipose tissue macrophages are suggested to be the major source of local and systemic inflammatory mediators such as tumor necrosis factor α, interleukin (IL)-1β, and IL-6. These cytokines induce insulin resistance in insulin target tissues by activating the suppressors of cytokine signaling proteins, several kinases such as c-Jun N-terminal kinase, IκB kinase β, and protein kinase C, inducible nitric oxide synthase, extracellular signal-regulated kinase, and protein tyrosine phosphatases such as protein tyrosine phosphatase 1B. These activated factors impair the insulin signaling at the insulin receptor and the insulin receptor substrates levels. The same process most likely occurs in the pancreas as it contains a pool of tissue-resident macrophages. High concentrations of glucose or palmitate via the chemokine production promote further immune cell migration and infiltration into the islets. These events ultimately induce inflammatory responses leading to the apoptosis of the pancreatic β cells. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation are discussed, with particular attention being placed on the roles of the molecular players linking inflammation to insulin resistance and β-cell dysfunction.
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Affiliation(s)
- Hadi Khodabandehloo
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Sattar Gorgani-Firuzjaee
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Ghodratollah Panahi
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Reza Meshkani
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.
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Mory DB, Gabbay MAL, Rocco ER, Kasamatsu T, Crispim F, Miranda WL, Dib SA. High frequency of vitamin D receptor gene polymorphism FokI in Brazilian Type 1 diabetes mellitus patients with clinical autoimmune thyroid disease. Diabetol Metab Syndr 2016; 8:29. [PMID: 27011770 PMCID: PMC4804530 DOI: 10.1186/s13098-016-0145-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 03/10/2016] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Polymorphisms of vitamin D receptor (VDR) gene have been studied as genetic markers of type 1 diabetes mellitus (T1DM) and some studies have reported associations with autoimmune thyroid disease. The aim of this study was to evaluate the relationship between VDR FokI polymorphism (rs10735810), thyroid autoimmunity and thyroid dysfunction (TD) in Brazilian T1DM. METHODS One-hundred-eighty T1DM patients were evaluated for age, duration of diabetes (DDM), positivity to TPO Antibody (TPOA), GAD Antibody (GADA), IA2 Antibody (IA2A) and fasting serum C-peptide (FCP) according to diagnosis of TD. PCR-RFLP analyses were carried out for VDR polymorphism FokI. RESULTS TPOA positivity (80.0 vs. 25.0 %, p < 0.001) and GADA positivity (56.0 vs. 30.3 %, p = 0.01) were higher in T1DM patients with TD with the same age and DDM than the group without TD, with no difference of FCP and IA2A positivity. We observed higher prevalence of VDR FokI in T1DM with TD (ff and Ff 73.9 % with TD vs. 52.7 % without TD, p = 0.05). Positivity to TPOA and presence of FokI polymorphism were significantly associated with the concurrence of TD in T1DM patients (OR 18.1; CI 3.7-87.0; p < 0.001). CONCLUSIONS The VDR FokI polymorphism (rs10735810) was associated to persistence of GADA, TPOA positivity and TD in Brazilian T1DM. Positivity to TPOA and VDR polymorphism FokI were strongly associated with concurrence of T1D and TD. These data collaborate to understanding the joint susceptibility genes for TD in T1DM.
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Affiliation(s)
- Denise Barreto Mory
- Endocrinology Division, São Paulo Federal University, Rua Botucatu, 740-Vila Clementino, São Paulo, SP CEP 04034-970 Brazil
| | - Monica Andrade Lima Gabbay
- Endocrinology Division, São Paulo Federal University, Rua Botucatu, 740-Vila Clementino, São Paulo, SP CEP 04034-970 Brazil
| | - Eloá R. Rocco
- Endocrinology Division, São Paulo Federal University, Rua Botucatu, 740-Vila Clementino, São Paulo, SP CEP 04034-970 Brazil
| | - Teresa Kasamatsu
- Endocrinology Division, São Paulo Federal University, Rua Botucatu, 740-Vila Clementino, São Paulo, SP CEP 04034-970 Brazil
| | - Felipe Crispim
- Endocrinology Division, São Paulo Federal University, Rua Botucatu, 740-Vila Clementino, São Paulo, SP CEP 04034-970 Brazil
| | - Walquíria Lopes Miranda
- Endocrinology Division, São Paulo Federal University, Rua Botucatu, 740-Vila Clementino, São Paulo, SP CEP 04034-970 Brazil
| | - Sérgio Atala Dib
- Endocrinology Division, São Paulo Federal University, Rua Botucatu, 740-Vila Clementino, São Paulo, SP CEP 04034-970 Brazil
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Li M, Zhou H, Guan Y, Peng H, Wang S, Zhang P, Su B. Positive hepatitis B surface antibody is associated with reduced risk of diabetes mellitus in retired female Chinese workers. J Diabetes 2016; 8:158-61. [PMID: 26016384 DOI: 10.1111/1753-0407.12317] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Accepted: 05/18/2015] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND To study the relationship between positivity for hepatitis B surface antibody (HBsAb) and the risk of diabetes mellitus in the retired Chinese population. METHODS A cross-sectional analysis was conducted in 900 retired Chinese workers attending a health check-up program. HBsAb, hepatitis B surface antigen, oral glucose tolerance test (OGTT), fasting plasma glucose (FBG), 2-h plasma glucose 2hBG, and insulin levels were collected. RESULTS Participants positive for HBsAb were younger, with lower blood pressure, lower FBG and 2hBG serum uric acid, and glutamic pyruvic transaminase than those who were HbsAb negative. There were 306 subjects with impaired glucose tolerance and 121 with type 2 diabetes (T2D) in the present cohort. Using Chi-squared analysis to assess the risk of diabetes, women positive for HBsAb had a lower prevalence of T2D than those negative for HBsAb (15.7% vs 26.5%, respectively; P < 0.01). Multivariate analysis revealed family history of diabetes, age, and waist circumference were independently associated with a higher prevalence of diabetes, and that HBsAb positivity was independently associated with a lower prevalence of diabetes (odds ratio 0.579; 95% confidence interval 0.388-0.918) when adjusted for sex, family history of hypertension and dyslipidemia, and body mass index. CONCLUSIONS An HBsAb-positive status is associated with a low rate of diabetes and better metabolic status. A prospective study of patients with known vaccination records is needed to investigate whether hepatitis B virus vaccination could protect against the development of diabetes.
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Affiliation(s)
- Ming Li
- Department of Microecology, School of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Hui Zhou
- Department of Endocrinology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Department of Endocrinology and Metabolism, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, China
| | - Yufeng Guan
- Department of Endocrinology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Haiying Peng
- Department of Endocrinology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shunyu Wang
- Department of Endocrinology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Ping Zhang
- Department of Endocrinology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Benli Su
- Department of Endocrinology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
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Subauste A, Gianani R, Chang AM, Plunkett C, Pietropaolo SL, Zhang YJ, Barinas-Mitchell E, Kuller LH, Galecki A, Halter JB, Pietropaolo M. Islet autoimmunity identifies a unique pattern of impaired pancreatic beta-cell function, markedly reduced pancreatic beta cell mass and insulin resistance in clinically diagnosed type 2 diabetes. PLoS One 2014; 9:e106537. [PMID: 25226365 PMCID: PMC4165581 DOI: 10.1371/journal.pone.0106537] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Accepted: 07/31/2014] [Indexed: 01/11/2023] Open
Abstract
There is a paucity of literature describing metabolic and histological data in adult-onset autoimmune diabetes. This subgroup of diabetes mellitus affects at least 5% of clinically diagnosed type 2 diabetic patients (T2DM) and it is termed Latent Autoimmune Diabetes in Adults (LADA). We evaluated indexes of insulin secretion, metabolic assessment, and pancreatic pathology in clinically diagnosed T2DM patients with and without the presence of humoral islet autoimmunity (Ab). A total of 18 patients with at least 5-year duration of clinically diagnosed T2DM were evaluated in this study. In those subjects we assessed acute insulin responses to arginine, a glucose clamp study, whole-body fat mass and fat-free mass. We have also analyzed the pancreatic pathology of 15 T2DM and 43 control cadaveric donors, using pancreatic tissue obtained from all the T2DM organ donors available from the nPOD network through December 31, 2013. The presence of islet Ab correlated with severely impaired β-cell function as demonstrated by remarkably low acute insulin response to arginine (AIR) when compared to that of the Ab negative group. Glucose clamp studies indicated that both Ab positive and Ab negative patients exhibited peripheral insulin resistance in a similar fashion. Pathology data from T2DM donors with Ab or the autoimmune diabetes associated DR3/DR4 allelic class II combination showed reduction in beta cell mass as well as presence of autoimmune-associated pattern A pathology in subjects with either islet autoantibodies or the DR3/DR4 genotype. In conclusion, we provide compelling evidence indicating that islet Ab positive long-term T2DM patients exhibit profound impairment of insulin secretion as well as reduced beta cell mass seemingly determined by an immune-mediated injury of pancreatic β-cells. Deciphering the mechanisms underlying beta cell destruction in this subset of diabetic patients may lead to the development of novel immunologic therapies aimed at halting the disease progression in its early stage.
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Affiliation(s)
- Angela Subauste
- The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
- Division of Endocrinology, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
| | - Roberto Gianani
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Annette M. Chang
- The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Cynthia Plunkett
- The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Susan L. Pietropaolo
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Ying-Jian Zhang
- The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Emma Barinas-Mitchell
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Lewis H. Kuller
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Andrzej Galecki
- Geriatrics Center and Institute of Gerontology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Jeffrey B. Halter
- Geriatrics Center and Institute of Gerontology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Massimo Pietropaolo
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
- * E-mail:
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Masser DR, VanGuilder Starkey HD, Bixler GV, Dunton W, Bronson SK, Freeman WM. Insulin treatment normalizes retinal neuroinflammation but not markers of synapse loss in diabetic rats. Exp Eye Res 2014; 125:95-106. [PMID: 24931083 DOI: 10.1016/j.exer.2014.06.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 05/25/2014] [Accepted: 06/03/2014] [Indexed: 12/30/2022]
Abstract
Diabetic retinopathy is one of the leading causes of blindness in developed countries, and a majority of patients with type I and type II diabetes will develop some degree of vision loss despite blood glucose control regimens. The effects of different insulin therapy regimens on early metabolic, inflammatory and neuronal retinal disease processes such as retinal neuroinflammation and synapse loss have not been extensively investigated. This study compared 3 months non-diabetic and streptozotocin (STZ)-induced diabetic Sprague Dawley rats. Diabetic rats received either no insulin treatment, systemic insulin treatment beginning after 1 week uncontrolled diabetes (early intervention, 11 weeks on insulin), or after 1.5 months uncontrolled diabetes (late intervention, 6 weeks on insulin). Changes in both whole animal metabolic and retinal inflammatory markers were prevented by early initiation of insulin treatment. These metabolic and inflammatory changes were also normalized by the later insulin intervention. Insulin treatment begun 1 week after diabetes induction ameliorated loss of retinal synapse markers. Synapse markers and presumably synapse numbers were equivalent in uncontrolled diabetes and when insulin treatment began at 1.5 months of diabetes. These findings are in agreement with previous demonstrations that retinal synapses are lost within 1 month of uncontrolled diabetes and suggest that synapses are not regained with glycemic control and restoration of insulin signaling. However, increased expression of metabolic and inflammatory markers associated with diabetes was reversed in both groups of insulin treatment. This study also emphasizes the need for insulin treatment groups in diabetic retinopathy studies to provide a more faithful modeling of the human condition.
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Affiliation(s)
- Dustin R Masser
- Department of Pharmacology, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA; Department of Physiology, BMSB 653, P.O. Box 26901, Oklahoma University Health Sciences Center, Oklahoma City, OK 73216, USA; Reynolds Oklahoma Center on Aging, SLY-BRC 1370, 975 NE 10th St, Oklahoma City, OK 73104, USA.
| | - Heather D VanGuilder Starkey
- Department of Pharmacology, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA; Penn State Hershey Eye Center, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA.
| | - Georgina V Bixler
- Department of Pharmacology, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA.
| | - Wendy Dunton
- Department of Cellular and Molecular Physiology, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA.
| | - Sarah K Bronson
- Penn State Hershey Eye Center, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA; Department of Cellular and Molecular Physiology, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA.
| | - Willard M Freeman
- Department of Pharmacology, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA; Department of Physiology, BMSB 653, P.O. Box 26901, Oklahoma University Health Sciences Center, Oklahoma City, OK 73216, USA; Reynolds Oklahoma Center on Aging, SLY-BRC 1370, 975 NE 10th St, Oklahoma City, OK 73104, USA; Penn State Hershey Eye Center, 500 University Drive, Penn State College of Medicine, Hershey, PA 17033, USA.
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Li MF, Ren Y, Zhao CC, Zhang R, Li LX, Liu F, Lu JX, Tu YF, Zhao WJ, Bao YQ, Jia WP. Prevalence and clinical characteristics of lower limb atherosclerotic lesions in newly diagnosed patients with ketosis-onset diabetes: a cross-sectional study. Diabetol Metab Syndr 2014; 6:71. [PMID: 24926320 PMCID: PMC4054910 DOI: 10.1186/1758-5996-6-71] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 05/26/2014] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND The clinical features of atherosclerotic lesions in ketosis-onset diabetes are largely absent. We aimed to compare the characteristics of lower limb atherosclerotic lesions among type 1, ketosis-onset and non-ketotic type 2 diabetes. METHODS A cross-sectional study was performed in newly diagnosed Chinese patients with diabetes, including 53 type 1 diabetics with positive islet-associated autoantibodies, 208 ketosis-onset diabetics without islet-associated autoantibodies, and 215 non-ketotic type 2 diabetics. Sixty-two subjects without diabetes were used as control. Femoral intima-media thickness (FIMT), lower limb atherosclerotic plaque and stenosis were evaluated and compared among the four groups based on ultrasonography. The risk factors associated with lower limb atherosclerotic plaque were evaluated via binary logistic regression in patients with diabetes. RESULTS After adjusting for age and sex, the prevalence of lower limb plaque in the patients with ketosis-onset diabetes (47.6%) was significantly higher than in the control subjects (25.8%, p = 0.013), and showed a higher trend compared with the patients with type 1 diabetes (39.6%, p = 0.072), but no difference was observed in comparison to the patients with non-ketotic type 2 diabetes (62.3%, p = 0.859). The mean FIMT in the ketosis-onset diabetics (0.73 ± 0.17 mm) was markedly greater than that in the control subjects (0.69 ± 0.13 mm, p = 0.045) after controlling for age and sex, but no significant differences were found between the ketosis-onset diabetics and the type 1 diabetics (0.71 ± 0.16 mm, p = 0.373), and the non-ketotic type 2 diabetics (0.80 ± 0.22 mm, p = 0.280), respectively. Age and FIMT were independent risk factors for the presence of lower limb plaque in both the ketosis-onset and non-ketotic type 2 diabetic patients, while sex and age in the type 1 diabetic patients. CONCLUSIONS The prevalence and risk of lower limb atherosclerotic plaque in the ketosis-onset diabetes were remarkably higher than in the control subjects without diabetes. The features and risk factors of lower limb atherosclerotic lesions in the ketosis-onset diabetes resembled those in the non-ketotic type 2 diabetes, but different from those in the type 1 diabetes. Our findings provide further evidences to support the classification of ketosis-onset diabetes as a subtype of type 2 diabetes rather than idiopathic type 1 diabetes.
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Affiliation(s)
- Mei-Fang Li
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center for Diabetes; Shanghai key Laboratory of Diabetes Mellitus, 600 Yishan Road, Shanghai 200233, China
| | - Ying Ren
- Department of VIP, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Cui-Chun Zhao
- Department of VIP, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Rong Zhang
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center for Diabetes; Shanghai key Laboratory of Diabetes Mellitus, 600 Yishan Road, Shanghai 200233, China
| | - Lian-Xi Li
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center for Diabetes; Shanghai key Laboratory of Diabetes Mellitus, 600 Yishan Road, Shanghai 200233, China
| | - Fang Liu
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center for Diabetes; Shanghai key Laboratory of Diabetes Mellitus, 600 Yishan Road, Shanghai 200233, China
| | - Jun-Xi Lu
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center for Diabetes; Shanghai key Laboratory of Diabetes Mellitus, 600 Yishan Road, Shanghai 200233, China
| | - Yin-Fang Tu
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center for Diabetes; Shanghai key Laboratory of Diabetes Mellitus, 600 Yishan Road, Shanghai 200233, China
| | - Wei-Jing Zhao
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center for Diabetes; Shanghai key Laboratory of Diabetes Mellitus, 600 Yishan Road, Shanghai 200233, China
| | - Yu-Qian Bao
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center for Diabetes; Shanghai key Laboratory of Diabetes Mellitus, 600 Yishan Road, Shanghai 200233, China
| | - Wei-Ping Jia
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center for Diabetes; Shanghai key Laboratory of Diabetes Mellitus, 600 Yishan Road, Shanghai 200233, China
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Jaberi-Douraki M, Pietropaolo M, Khadra A. Predictive models of type 1 diabetes progression: understanding T-cell cycles and their implications on autoantibody release. PLoS One 2014; 9:e93326. [PMID: 24705439 PMCID: PMC3976292 DOI: 10.1371/journal.pone.0093326] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Accepted: 02/28/2014] [Indexed: 02/06/2023] Open
Abstract
Defining the role of T-cell avidity and killing efficacy in forming immunological response(s), leading to relapse-remission and autoantibody release in autoimmune type 1 diabetes (T1D), remains incompletely understood. Using competition-based population models of T- and B-cells, we provide a predictive tool to determine how these two parametric quantities, namely, avidity and killing efficacy, affect disease outcomes. We show that, in the presence of T-cell competition, successive waves along with cyclic fluctuations in the number of T-cells are exhibited by the model, with the former induced by transient bistability and the latter by transient periodic orbits. We hypothesize that these two immunological processes are responsible for making T1D a relapsing-remitting disease within prolonged but limited durations. The period and the number of peaks of these two processes differ, making them potential candidates to determine how plausible waves and cyclic fluctuations are in producing such effects. By assuming that T-cell and B-cell avidities are correlated, we demonstrate that autoantibodies associated with the higher avidity T-cell clones are first to be detected, and they reach their detectability level faster than those associated with the low avidity clones, independent of what T-cell killing efficacies are. Such outcomes are consistent with experimental observations in humans and they provide a rationale for observing rapid and slow progressors of T1D in high risk subjects. Our analysis of the models also reveals that it is possible to improve disease outcomes by unexpectedly increasing the avidity of certain subclones of T-cells. The decline in the number of β-cells in these cases still occurs, but it terminates early, leaving sufficient number of functioning β-cells in operation and the affected individual asymptomatic. These results indicate that the models presented here are of clinical relevance because of their potential use in developing predictive algorithms of rapid and slow progression to clinical T1D.
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Affiliation(s)
| | - Massimo Pietropaolo
- Laboratory of Immunogenetics, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Anmar Khadra
- Department of Physiology, McGill University, Montreal, QC, Canada
- * E-mail:
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Chatzopoulou M, Pegklidou K, Papastavrou N, Demopoulos VJ. Development of aldose reductase inhibitors for the treatment of inflammatory disorders. Expert Opin Drug Discov 2013; 8:1365-80. [PMID: 24090200 DOI: 10.1517/17460441.2013.843524] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Accumulating evidence attributes a significant role to aldose reductase (ALR2) in the pathogenesis of several inflammatory pathologies. Aldose reductase inhibitors (ARIs) were found to attenuate reactive oxygen species (ROS) production both in vitro and in vivo. Thus, they disrupt signaling cascades that lead to the production of cytokines/chemokines, which induce and exacerbate inflammation. As a result, ARIs might hold a significant therapeutic potential as alternate anti-inflammatory drugs. AREAS COVERED The authors present a comprehensive review of the current data that support the central role of ALR2 in several inflammatory pathologies (i.e., diabetes, cancer, sepsis, asthma and ocular inflammation). Further, the authors describe the potential underlying molecular mechanisms and provide a commentary on the status of ARIs in this field. EXPERT OPINION It is important that future efforts focus on delineating all the steps of the molecular mechanism that implicates ALR2 in inflammatory pathologies. At the same time, utilizing the previous efforts in the field of ARIs, several candidates that have been proven safe in the clinic may be evaluated for their clinical significance as anti-inflammatory medication. Finally, structurally novel ARIs, designed to target specifically the proinflammatory subpocket of ALR2, should be pursued.
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Affiliation(s)
- Maria Chatzopoulou
- Aristotle University of Thessaloniki, School of Pharmacy, Department of Pharmaceutical Chemistry , 54124 Thessaloniki , Greece ;
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Abstract
Traumatic brain injury (TBI) has been associated with various neurological disorders. However, the role of cerebrovascular dysfunction and its mechanisms associated with TBI are still not well understood. Inflammation is the main cause of vascular dysfunction. It affects properties of blood components and the vascular wall leading to changes in blood flow and in interaction of blood components and vascular endothelium exacerbating microcirculatory complications during inflammatory diseases. One of the markers of inflammation is a plasma adhesion protein, fibrinogen (Fg). At elevated levels, Fg can also cause inflammatory responses. One of the manifestations of inflammatory responses is an increase in microvascular permeability leading to accumulation of plasma proteins in the subendothelial matrix and causing vascular remodelling. This has a most devastating effect on cerebral circulation after TBI that is accompanied with an elevation of plasma level of Fg and with an increased cerebrovascular permeability in injury penumbra impairing the normal healing process. This study reviews cerebrovascular alterations after TBI, considers the consequences of increased blood-brain barrier permeability, defines the role of elevated level of Fg and discusses the potential mechanisms of its action leading to vascular dysfunction, which subsequently can cause impairment in neuronal function. Thus, possible mechanisms of vasculo-neuronal dysfunction after TBI are considered.
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Affiliation(s)
- Nino Muradashvili
- Department of Physiology and Biophysics, University of Louisville, School of Medicine , Louisville, KY , USA
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Francés DE, Ingaramo PI, Ronco MT, Carnovale CE. Diabetes, an inflammatory process: Oxidative Stress and TNF-alpha involved in hepatic complication. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/jbise.2013.66079] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Abdulrhman M, El Hefnawy M, Ali R, Abdel Hamid I, Abou El-Goud A, Refai D. Effects of honey, sucrose and glucose on blood glucose and C-peptide in patients with type 1 diabetes mellitus. Complement Ther Clin Pract 2012; 19:15-9. [PMID: 23337559 DOI: 10.1016/j.ctcp.2012.08.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 08/29/2012] [Indexed: 12/18/2022]
Abstract
UNLABELLED This study was a case control cross sectional study that was conducted on 50 patients with type 1 diabetes mellitus and 30 controls without diabetes. The mean age of patients was 10.02 years. Oral sugar tolerance tests using glucose, sucrose and honey and measurement of fasting and postprandial serum C-peptide levels were done for all subjects in three separate sittings. The glycemic index (GI) and the peak incremental index (PII) were then calculated for each subject. Honey, compared to sucrose, had lower GI and PII in both patients and controls (P < 0.01). In both patients and controls, the increase in the level of C-peptide after honey was significant when compared with either glucose or sucrose (P < 0.01). CONCLUSION Because of its possible stimulatory effect on diseased beta cells, honey might be considered in future therapeutic trials targeting beta cells of pancreas.
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Affiliation(s)
- Mamdouh Abdulrhman
- Pediatric Department, Faculty of Medicine, Ain Shams University, Abbasia, Cairo, Egypt.
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Pietropaolo M, Towns R, Eisenbarth GS. Humoral autoimmunity in type 1 diabetes: prediction, significance, and detection of distinct disease subtypes. Cold Spring Harb Perspect Med 2012; 2:a012831. [PMID: 23028135 PMCID: PMC3475400 DOI: 10.1101/cshperspect.a012831] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Type 1 diabetes mellitus (T1D) is an autoimmune disease encompassing the T-cell-mediated destruction of pancreatic β cells and the production of autoantibodies against islet proteins. In humoral autoimmunity in T1D, the detection of islet autoantibodies and the examination of their associations with genetic factors and cellular autoimmunity constitute major areas in both basic research and clinical practice. Although insulin is a key autoantigen and may be primus inter pares in importance among T1D autoantigens, an abundant body of research has also revealed other autoantigens associated with the disease process. Solid evidence indicates that autoantibodies against islet targets serve as key markers to enroll newly diagnosed T1D patients and their family members in intervention trials aimed at preventing or halting the disease process. The next challenge is perfecting mechanistic bioassays to be used as end points for disease amelioration following immunomodulatory therapies aimed at blocking immune-mediated β-cell injury and, in turn, preserving β-cell function in type 1 diabetes mellitus.
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Affiliation(s)
- Massimo Pietropaolo
- Laboratory of Immunogenetics, The Brehm Center for Diabetes Research, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA
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Arvan P, Pietropaolo M, Ostrov D, Rhodes CJ. Islet autoantigens: structure, function, localization, and regulation. Cold Spring Harb Perspect Med 2012; 2:cshperspect.a007658. [PMID: 22908193 DOI: 10.1101/cshperspect.a007658] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Islet autoantigens associated with autoimmune type 1 diabetes (T1D) are expressed in pancreatic β cells, although many show wider patterns of expression in the neuroendocrine system. Within pancreatic β cells, every T1D autoantigen is in one way or another linked to the secretory pathway. Together, these autoantigens play diverse roles in glucose regulation, metabolism of biogenic amines, as well as the regulation, formation, and packaging of secretory granules. The mechanism(s) by which immune tolerance to islet-cell antigens is lost during the development of T1D, remains unclear. Antigenic peptide creation for immune presentation may potentially link to the secretory biology of β cells in a number of ways, including proteasomal digestion of misfolded products, exocytosis and endocytosis of cell-surface products, or antigen release from dying β cells during normal or pathological turnover. In this context, we evaluate the biochemical nature and immunogenicity of the major autoantigens in T1D including (pro)insulin, GAD65, ZnT8, IA2, and ICA69.
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Affiliation(s)
- Peter Arvan
- Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
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Mitianina VA, Kuptsov VN, Savel'ev SV, Shvets VI, Selishcheva AA. [Erythrocyte lipid composition at different stages of type 1 diabetes in children]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2012; 58:95-103. [PMID: 22642156 DOI: 10.18097/pbmc20125801095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Complete profiles of phospholipid and ceramide molecular species from erythrocyte lipid extracts of children without carbohydrate metabolism disorders, and children with type 1 diabetes were compared by means of high performance liquid chromatography/mass spectrometry. For the first time a statistically significant increase (p<0.05) of lysophosphatidylcholine content in two groups of diabetic children with different duration of the disease (less than one year and more than one year) was found. Statistically significant changes in other lipid classes were not observed. The dependence of the content of phosphatidylcholine and phosphatidylethanolamine molecular species containing arachidonic acid residue (20:4) on the duration of the disease was found. The observed shift in lipid metabolism suggests of phospholipase A2 and chronic inflammatory process at different stages of diabetes mellitus, in cells (erythrocytes), which aer not involved in the immune response.
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Abstract
Human diseases can be caused by complex mechanisms involving aberrations in numerous proteins and pathways. With recent advances in genomics, elucidating the molecular basis of disease on a personalized level has become an attainable goal. In many cases, relevant molecular targets will be identified for which approved drugs already exist, and the potential repositioning of these drugs to a new indication can be investigated. Repositioning is an accelerated route for drug discovery because existing drugs have established clinical and pharmacokinetic data. Personalized medicine and repositioning both aim to improve the productivity of current drug discovery pipelines, which expend enormous time and cost to develop new drugs, only to have them fail in clinical trials because of lack of efficacy or toxicity. Here, we discuss the current state of research in these two fields, focusing on recent large-scale efforts to systematically find repositioning candidates and elucidate individual disease mechanisms in cancer. We also discuss scenarios in which personalized drug repositioning could be particularly rewarding, such as for diseases that are rare or have specific mutations, as well as current challenges in this field. With an increasing number of drugs being approved for rare cancer subtypes, personalized medicine and repositioning approaches are poised to significantly alter the way we diagnose diseases, infer treatments and develop new drugs.
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Affiliation(s)
- Yvonne Y Li
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada
| | - Steven Jm Jones
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada
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Khadra A, Pietropaolo M, Nepom GT, Sherman A. Investigating the role of T-cell avidity and killing efficacy in relation to type 1 diabetes prediction. PLoS One 2011; 6:e14796. [PMID: 21573001 PMCID: PMC3091860 DOI: 10.1371/journal.pone.0014796] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Accepted: 03/05/2011] [Indexed: 12/15/2022] Open
Abstract
During the progression of the clinical onset of Type 1 Diabetes (T1D), high-risk individuals exhibit multiple islet autoantibodies and high-avidity T cells which progressively destroy beta cells causing overt T1D. In particular, novel autoantibodies, such as those against IA-2 epitopes (aa1-577), had a predictive rate of 100% in a 10-year follow up (rapid progressors), unlike conventional autoantibodies that required 15 years of follow up for a 74% predictive rate (slow progressors). The discrepancy between these two groups is thought to be associated with T-cell avidity, including CD8 and/or CD4 T cells. For this purpose, we build a series of mathematical models incorporating first one clone then multiple clones of islet-specific and pathogenic CD8 and/or CD4 T cells, together with B lymphocytes, to investigate the interaction of T-cell avidity with autoantibodies in predicting disease onset. These models are instrumental in examining several experimental observations associated with T-cell avidity, including the phenomenon of avidity maturation (increased average T-cell avidity over time), based on intra- and cross-clonal competition between T cells in high-risk human subjects. The model shows that the level and persistence of autoantibodies depends not only on the avidity of T cells, but also on the killing efficacy of these cells. Quantification and modeling of autoreactive T-cell avidities can thus determine the level of risk associated with each type of autoantibodies and the timing of T1D disease onset in individuals that have been tested positive for these autoantibodies. Such studies may lead to early diagnosis of the disease in high-risk individuals and thus potentially serve as a means of staging patients for clinical trials of preventive or interventional therapies far before disease onset.
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Affiliation(s)
- Anmar Khadra
- Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
- * E-mail:
| | - Massimo Pietropaolo
- Laboratory of Immunogenetics, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Gerald T. Nepom
- Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America
| | - Arthur Sherman
- Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
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Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stress-induced hydroxyl radical formation in mitochondria. J Mol Med (Berl) 2011; 89:785-98. [PMID: 21487676 DOI: 10.1007/s00109-011-0747-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2010] [Revised: 02/22/2011] [Accepted: 03/07/2011] [Indexed: 01/27/2023]
Abstract
Although nitric oxide (NO) and oxidative stress both contribute to proinflammatory cytokine toxicity in pancreatic β-cells during type 1 diabetes mellitus (T1DM) development, the interactions between NO and reactive oxygen species (ROS) in cytokine-mediated β-cell death have not been clarified. Exposure of insulin-producing RINm5F cells to IL-1β generated NO, while exposure to a combination of IL-1β, TNF-α, and IFN-γ, which simulates T1DM conditions, generated both NO and ROS. In theory, two reactions between NO and ROS are possible, one with the superoxide radical yielding peroxynitrite, and the other with hydrogen peroxide (H(2)O(2)) yielding hydroxyl radicals. Results of the present work exclude peroxynitrite involvement in cytokine toxicity to β-cells because its generation did not correlate with the toxic action of cytokines. On the other hand, we show that H(2)O(2), produced upon exposure of insulin-producing cell clones and primary rat islet cells to cytokines almost exclusively in the mitochondria, reacted in the presence of trace metal (Fe(++)) with NO forming highly toxic hydroxyl radicals, thus explaining the severe toxicity that causes apoptotic β-cell death. Expression of the H(2)O(2)-inactivating enzyme catalase in mitochondria protected against cytokine toxicity by preventing hydroxyl radical formation. We therefore conclude that proinflammatory cytokine-mediated β-cell death is due to nitro-oxidative stress-mediated hydroxyl radical formation in the mitochondria.
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Towns R, Pietropaolo M. GAD65 autoantibodies and its role as biomarker of Type 1 diabetes and Latent Autoimmune Diabetes in Adults (LADA). DRUG FUTURE 2011; 36:847. [PMID: 22869930 DOI: 10.1358/dof.2011.036.11.1710754] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
One of the hallmarks of autoimmune diabetes is the presence of adaptive responses directed to neuroendocrine proteins. One of these proteins is glutamic acid decarboxylase (GAD). While GAD is widely distributed in neuroendocrine tissues, its specific significance in diabetes has paralleled the advances in understanding humoral and cellular immunity in Type 1 diabetes (T1D) and in a subset of Type 2 diabetes (T2D), going from the seminal discoveries of islet autoantibodies to the development and standardization of bioassays as diagnostic tools, to studies on the structure of GAD and its antigenic determinants. GAD65 autoantibodies can accurately predict T1D development in combination with other surrogate humoral biomarkers and they are considered the most sensitive and specific biomarker which identifies a subset of clinically diagnosed T2D termed Latent Autoimmune Diabetes in Adults (LADA). We and others provided evidence indicating that GAD65 autoantibody detection should be part of the diagnostic assessment for clinically diagnosed T2DM mainly because it predicts the rate of progression to insulin requirement in patients affected by LADA. More recently GAD has been used as a "tolerogenic vaccine" to preserve beta cell function in autoimmune diabetes. While the results of Phase III clinical trials did not substantiate the earlier promise of Phase I and II trials, there are still many unanswered questions and approaches that need to be investigated in the applications of GAD in the therapy of T1D and LADA.
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Affiliation(s)
- Roberto Towns
- Laboratory of Immunogenetics, The Brehm Center for Diabetes Research, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
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Abstract
CONTEXT Autoantibodies that are reactive to islet antigens are present at the time of diagnosis in most patients with type 1 diabetes. Additionally, approximately 10% of phenotypic type 2 diabetic patients are positive for at least one of the islet autoantibodies, and this group is often referred to as "latent autoimmune diabetes in adults (LADA)." These patients share many genetic and immunological similarities with type 1 diabetes, suggesting that LADA, like type 1 diabetes, is an autoimmune disease. However, there are differences in autoantibody clustering, T cell reactivity, and genetic susceptibility and protection between type 1 diabetes and LADA, implying important differences in the underlying disease processes. EVIDENCE ACQUISITION AND SYNTHESIS In this clinical review, we will summarize the current understanding of LADA based on the MEDLINE search of all peer-reviewed publications (original articles and reviews) on this topic between 1974 and 2009. CONCLUSIONS In LADA, diabetes occurs earlier in the beta-cell-destructive process because of the greater insulin resistance. Complexities arise also because of variable definitions of LADA and type 1 diabetes in adults. As immunomodulatory therapies that slow or halt the type 1 diabetes disease process are discovered, testing these therapies in LADA will be essential.
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Affiliation(s)
- Ramachandra G Naik
- Charles River Clinical Services Northwest, Tacoma, Washington 98418, USA
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Wegner M, Araszkiewicz A, Pioruńska-Mikołajczak A, Zozulińska-Ziółkiewicz D, Wierusz-Wysocka B, Pioruńska-Stolzmann M. The evaluation of IL-12 concentration, PAF-AH, and PLA2 activity in patients with type 1 diabetes treated with intensive insulin therapy. Clin Biochem 2009; 42:1621-7. [DOI: 10.1016/j.clinbiochem.2009.07.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2009] [Revised: 06/29/2009] [Accepted: 07/17/2009] [Indexed: 12/29/2022]
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Abstract
OBJECTIVE To examine whether depressive symptoms are differentially associated with visceral adipose tissue (VAT), which is more metabolically active and confers greater cardiovascular risk than subcutaneous fat (SAT). Prior research has shown an association between depression and central adiposity. Mechanisms underlying the association between depression and increased cardiovascular risk remain poorly understood. Central adiposity is one potential pathway. METHODS We investigated the cross-sectional association between depressive symptoms, assessed by the Center for Epidemiological Studies Depression Scale (CES-D), and VAT and SAT, assessed by computed tomography, in a sample of 409 middle-aged women (44.7% African-Americans, 55.3% Whites; mean age = 50.4 years) participating in the Chicago site of the Study of Women's Health Across the Nation (SWAN). RESULTS With adjustments for age, race, total percent fat, and sex hormone binding globulin (SHBG), each 1-point higher score on the CES-D was associated with 1.03-cm(2) greater VAT (p < .001). Women with a CES-D score of >or=16, indicative of clinically relevant depressive symptomatology, had 24.5% more VAT than women with lower CES-D scores (p < .001). Further adjustment for Framingham Risk Score and physical activity did not alter the findings, and associations did not vary by race. Associations were strongest in obese and overweight women. Depressive symptoms were unrelated to SAT. CONCLUSIONS Increased visceral fat may be one pathway by which depression contributes to excess risk for cardiovascular disease and diabetes. Further research is needed to examine whether depressive symptoms influence accumulation of VAT over time.
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Morran MP, Omenn GS, Pietropaolo M. Immunology and genetics of type 1 diabetes. ACTA ACUST UNITED AC 2009; 75:314-27. [PMID: 18729178 DOI: 10.1002/msj.20052] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Type 1 diabetes is one of the most well-characterized autoimmune diseases. Type 1 diabetes compromises an individual's insulin production through the autoimmune destruction of pancreatic beta-cells. Although much is understood about the mechanisms of this disease, multiple potential contributing factors are thought to play distinct parts in triggering type 1 diabetes. The immunological diagnosis of type 1 diabetes relies primarily on the detection of autoantibodies against islet antigens in the serum of type 1 diabetes mellitus patients. Genetic analyses of type 1 diabetes have linked human leukocyte antigen, specifically class II alleles, to susceptibility to disease onset. Environmental catalysts include various possible factors, such as viral infections, although the evidence linking infections with type 1 diabetes remains inconclusive. Imbalances within the immune system's system of checks and balances may promote immune activation, while undermining immune regulation. A lack of proper regulation and overactive pathogenic responses provide a framework for the development of autoimmune abnormalities. Type 1 diabetes is a predictable and potentially treatable disease that still requires much research to fully understand and pinpoint the exact triggering events leading to autoimmune activation. In silico research can aid the comprehension of the etiology of complex disease pathways, including Type I diabetes, in order to and help predict the outcome of therapeutic strategies aimed at preserving beta-cell function.
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Affiliation(s)
- Michael P Morran
- Department of Internal Medicine, Division of Metabolism, Laboratory of Immunogenetics, Brehm Center for Type 1 Diabetes Research and Analysis, University of Michigan Medical School, Ann Arbor, MI, USA
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Hawa MI, Thivolet C, Mauricio D, Alemanno I, Cipponeri E, Collier D, Hunter S, Buzzetti R, de Leiva A, Pozzilli P, Leslie RDG. Metabolic syndrome and autoimmune diabetes: action LADA 3. Diabetes Care 2009; 32:160-4. [PMID: 18945926 PMCID: PMC2606853 DOI: 10.2337/dc08-1419] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The purpose of this study was to estimate whether prevalence of metabolic syndrome in adult European diabetic patients is associated with type of diabetes. RESEARCH DESIGN AND METHODS A consecutive series of patients attending hospital-based diabetes clinics were assessed for the frequency of metabolic syndrome and compared with population-based control subjects as part of the Action LADA study. In total, 2,011 subjects (aged 30-70 years) were studied, including 1,247 patients with recent-onset type 2 diabetes without glutamic acid decarboxylase autoantibodies (GADAs), 117 non-insulin-requiring patients with GADAs who had not received insulin therapy for at least 6 months after diagnosis (designated latent autoimmune diabetes of adults [LADA]), 288 type 1 diabetic patients, and 359 normal subjects. RESULTS Frequency of metabolic syndrome was significantly different in patients with type 1 diabetes (31.9%) and LADA (41.9%) (P = 0.015) and in both conditions was less frequent than in type 2 diabetic patients (88.8%) (P < 0.0001 for each). Eliminating glucose as a variable, the prevalence of metabolic syndrome was similar in patients with autoimmune diabetes (type 1 diabetes and/or LADA) (17.3%) and control subjects (23.7%) but remained more common in type 2 diabetic patients (47.8%) (P = 0.001 for all groups). In both type 1 diabetic patients and those with LADA, individual components of metabolic syndrome were similar but less common than in type 2 diabetic patients (P < 0.0001 for each). CONCLUSIONS The prevalence of metabolic syndrome is significantly higher in type 2 diabetic patients than in patients with LADA or adults with type 1 diabetes. Excluding glucose as a variable, metabolic syndrome is not more prevalent in patients with autoimmune diabetes than in control subjects. Metabolic syndrome is not a characteristic of autoimmune diabetes.
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