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Lazar S, Reurean-Pintilei DV, Ionita I, Avram VF, Herascu A, Timar B. Glycemic Variability and Its Association with Traditional Glycemic Control Biomarkers in Patients with Type 1 Diabetes: A Cross-Sectional, Multicenter Study. J Clin Med 2025; 14:2434. [PMID: 40217883 PMCID: PMC11989622 DOI: 10.3390/jcm14072434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Revised: 03/27/2025] [Accepted: 04/01/2025] [Indexed: 04/14/2025] Open
Abstract
Background/Objectives: Glycemic variability (GV) is a novel concept in the assessment of the quality of glycemic control in patients with diabetes, with its importance emphasized in patients with type 1 diabetes. Its adoption in clinical practice emerged with the increased availability of continuous glycemic monitoring systems. The aim of this study is to evaluate the GV in patients with type 1 diabetes mellitus (T1DM) and to assess its associations with other parameters used to evaluate the glycemic control. Methods: GV indexes and classical glycemic control markers were analyzed for 147 adult patients with T1DM in a multicentric cross-sectional study. Results: Stable glycemia was associated with a higher time in range (TIR) (78% vs. 63%; p < 0.001) and a lower HbA1c (6.8% vs. 7.1%; p = 0.006). The coefficient of variation (CV) was reversely correlated with TIR (Spearman's r = -0.513; p < 0.001) and positively correlated with hemoglobin A1c (HbA1c) (Spearman's r = 0.349; p < 0.001), while TIR was reversely correlated with HbA1c (Spearman's r = -0.637; p < 0.001). The composite GV and metabolic outcome was achieved by 28.6% of the patients. Conclusions: Stable glycemia was associated with a lower HbA1c, average and SD of blood glucose, and a higher TIR. A TIR higher than 70% was associated with a lower HbA1c, and SD and average blood glucose. Only 28.6% of the patients with T1DM achieved the composite GV and metabolic outcome, despite 53.7% of them achieving the HbA1c target, emphasizing thus the role of GV in the assessment of the glycemic control.
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Affiliation(s)
- Sandra Lazar
- Doctoral School of Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (S.L.); (A.H.)
- First Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
- Department of Hematology, Emergency Municipal Hospital, 300254 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (V.-F.A.); (B.T.)
| | - Delia-Viola Reurean-Pintilei
- Department of Medical-Surgical and Complementary Sciences, Faculty of Medicine and Biological Sciences, “Stefan cel Mare” University, 720229 Suceava, Romania
- Consultmed Medical Centre, Department of Diabetes, Nutrition and Metabolic Diseases, 700544 Iasi, Romania
| | - Ioana Ionita
- First Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
- Department of Hematology, Emergency Municipal Hospital, 300254 Timisoara, Romania
- Multidisciplinary Research Center for Malignant Hematological Diseases (CCMHM), Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Vlad-Florian Avram
- Centre for Molecular Research in Nephrology and Vascular Disease, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (V.-F.A.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Department of Diabetes, “Pius Brinzeu” Emergency Hospital, 300723 Timisoara, Romania
| | - Andreea Herascu
- Doctoral School of Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (S.L.); (A.H.)
- Centre for Molecular Research in Nephrology and Vascular Disease, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (V.-F.A.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Department of Diabetes, “Pius Brinzeu” Emergency Hospital, 300723 Timisoara, Romania
| | - Bogdan Timar
- Centre for Molecular Research in Nephrology and Vascular Disease, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (V.-F.A.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Department of Diabetes, “Pius Brinzeu” Emergency Hospital, 300723 Timisoara, Romania
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Rocha GR, de Melo FF. Glucagon-like peptide-1 and impaired counterregulatory responses to hypoglycemia in type 1 diabetes. World J Diabetes 2025; 16:99928. [PMID: 39959274 PMCID: PMC11718485 DOI: 10.4239/wjd.v16.i2.99928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 10/25/2024] [Accepted: 11/04/2024] [Indexed: 12/30/2024] Open
Abstract
This letter comments on a study by Jin et al, published recently in the World Journal of Diabetes. Hypoglycemia is a significant complication of diabetes, with primary defense mechanisms involving the stimulation of glucagon secretion in α-cells and the inhibition of insulin secretion in pancreatic β-cells, which are often compromised in type 1 diabetes mellitus (T1DM) and advanced type 2 diabetes mellitus. Recurrent hypoglycemia predisposes the development of impaired hypoglycemia awareness, a condition underpinned by complex pathophysiological processes, encompassing central nervous system adaptations and several hormonal interactions, including a potential role for glucagon-like peptide-1 (GLP-1) in paracrine and endocrine vias. Experimental evidence indicates that GLP-1 may impair hypoglycemic counterregulation by disrupting the sympathoadrenal system and promoting somatostatin release in pancreatic δ-cells, which inhibits glucagon secretion from neighboring α-cells. However, current trials evaluating GLP-1 receptor agonists (GLP-1 RAs) in T1DM patients have shown promising benefits in reducing insulin requirements and body weight, without increasing the risk of hypoglycemia. Further research is essential to elucidate the specific roles of GLP-1 and GLP-1 RAs in modulating glucagon secretion and the sympathetic-adrenal reflex, and their impact on hypoglycemia unawareness in T1DM patients.
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Affiliation(s)
- Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45065-430, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45065-430, Bahia, Brazil
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Collado A, Jiao T, Kontidou E, Carvalho LRRA, Chernogubova E, Yang J, Zaccagnini G, Zhao A, Tengbom J, Zheng X, Rethi B, Alvarsson M, Catrina SB, Mahdi A, Carlström M, Martelli F, Pernow J, Zhou Z. miR-210 as a therapeutic target in diabetes-associated endothelial dysfunction. Br J Pharmacol 2025; 182:417-431. [PMID: 39402703 DOI: 10.1111/bph.17329] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 07/09/2024] [Accepted: 08/01/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND AND PURPOSE MicroRNA (miR)-210 function in endothelial cells and its role in diabetes-associated endothelial dysfunction are not fully understood. We aimed to characterize the miR-210 function in endothelial cells and study its therapeutic potential in diabetes. EXPERIMENTAL APPROACH Two different diabetic mouse models (db/db and Western diet-induced), miR-210 knockout and transgenic mice, isolated vessels and human endothelial cells were used. KEY RESULTS miR-210 levels were lower in aortas isolated from db/db than in control mice. Endothelium-dependent relaxation (EDR) was impaired in aortas from miR-210 knockout mice, and this was restored by inhibiting miR-210 downstream protein tyrosine phosphatase 1B (PTP1B), mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2), and mitochondrial oxidative stress. Inhibition of these pathways also improved EDR in both diabetic mouse models. High glucose reduced miR-210 levels in endothelial cells and impaired EDR in mouse aortas, effects that were reversed by overexpressing miR-210. However, plasma miR-210 levels were not affected in individuals with type 2 diabetes (T2D) following improved glycaemic status. Of note, genetic overexpression using miR-210 transgenic mice and pharmacological overexpression using miR-210 mimic in vivo ameliorated endothelial dysfunction in both diabetic mouse models by decreasing PTP1B, GPD2 and oxidative stress. Genetic overexpression of miR-210 altered the aortic transcriptome, decreasing genes in pathways involved in oxidative stress. miR-210 mimic restored decreased nitric oxide production by high glucose in endothelial cells. CONCLUSION AND IMPLICATIONS This study unravels the mechanisms by which down-regulated miR-210 by high glucose induces endothelial dysfunction in T2D and demonstrates that miR-210 serves as a novel therapeutic target. LINKED ARTICLES This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.
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Affiliation(s)
- Aida Collado
- Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Tong Jiao
- Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Eftychia Kontidou
- Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | | | - Ekaterina Chernogubova
- Division of Cardiovascular Medicine, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Jiangning Yang
- Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Germana Zaccagnini
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Allan Zhao
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - John Tengbom
- Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Xiaowei Zheng
- Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Bence Rethi
- Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Michael Alvarsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Sergiu-Bogdan Catrina
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Centrum for Diabetes, Academic Specialist Centrum, Stockholm, Sweden
| | - Ali Mahdi
- Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Mattias Carlström
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Fabio Martelli
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - John Pernow
- Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
| | - Zhichao Zhou
- Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
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Veeranki V, Prasad N. Utilising continuous glucose monitoring for glycemic control in diabetic kidney disease. World J Diabetes 2024; 15:2006-2009. [PMID: 39493559 PMCID: PMC11525722 DOI: 10.4239/wjd.v15.i10.2006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/07/2024] [Accepted: 07/09/2024] [Indexed: 09/26/2024] Open
Abstract
In this editorial, we comment on the article by Zhang et al. Chronic kidney disease (CKD) presents a significant challenge in managing glycemic control, especially in diabetic patients with diabetic kidney disease undergoing dialysis or kidney transplantation. Conventional markers like glycated haemoglobin (HbA1c) may not accurately reflect glycemic fluctuations in these populations due to factors such as anaemia and kidney dysfunction. This comprehensive review discusses the limitations of HbA1c and explores alternative methods, such as continuous glucose monitoring (CGM) in CKD patients. CGM emerges as a promising technology offering real-time or retrospective glucose concentration measure-ments and overcoming the limitations of HbA1c. Key studies demonstrate the utility of CGM in different CKD settings, including hemodialysis and peritoneal dialysis patients, as well as kidney transplant recipients. Despite challenges like sensor accuracy fluctuation, CGM proves valuable in monitoring glycemic trends and mitigating the risk of hypo- and hyperglycemia, to which CKD patients are prone. The review also addresses the limitations of CGM in CKD patients, emphasizing the need for further research to optimize its utilization in clinical practice. Altogether, this review advocates for integrating CGM into managing glycemia in CKD patients, highlighting its superiority over traditional markers and urging clinicians to consider CGM a valuable tool in their armamentarium.
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Affiliation(s)
- Vamsidhar Veeranki
- Department of Nephrology and Renal Transplantation, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Narayan Prasad
- Department of Nephrology and Renal Transplantation, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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5
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Hu SY, Xue CD, Li YJ, Li S, Gao ZN, Qin KR. Microfluidic investigation for shear-stress-mediated repair of dysglycemia-induced endothelial cell damage. MECHANOBIOLOGY IN MEDICINE 2024; 2:100069. [PMID: 40395495 PMCID: PMC12082321 DOI: 10.1016/j.mbm.2024.100069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/29/2024] [Accepted: 04/19/2024] [Indexed: 01/03/2025]
Abstract
Dysglycemia causes arterial endothelial damage, which is an early critical event in vascular complications for diabetes patients. Physiologically, moderate shear stress (SS) helps maintain endothelial cell health and normal function. Reactive oxygen species (ROS) and calcium ions (Ca2+) signals are involved in dysglycemia-induced endothelial dysfunction and are also implicated in SS-mediated regulation of endothelial cell function. Therefore, it is urgent to establish in vitro models for studying endothelial biomechanics and mechanobiology, aiming to seek interventions that utilize appropriate SS to delay or reverse endothelial dysfunction. Microfluidic technology, as a novel approach, makes it possible to replicate blood glucose environment and accurate pulsatile SS in vitro. Here, we reviewed the progress of microfluidic systems used for SS-mediated repair of dysglycemia-induced endothelial cell damage (ECD), revealing the crucial roles of ROS and Ca2+ during the processes. It holds significant implications for finding appropriate mechanical intervention methods, such as exercise training, to prevent and treat cardiovascular complications in diabetes.
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Affiliation(s)
- Si-Yu Hu
- School of Mechanical Engineering, Dalian University of Technology, No. 2, Linggong Rd., Dalian 116024, Liaoning Province, China
| | - Chun-Dong Xue
- School of Biomedical Engineering, Faculty of Medicine, Dalian University of Technology, No. 2, Linggong Rd., Dalian 116024, Liaoning Province, China
| | - Yong-Jiang Li
- School of Biomedical Engineering, Faculty of Medicine, Dalian University of Technology, No. 2, Linggong Rd., Dalian 116024, Liaoning Province, China
| | - Shen Li
- Central Hospital of Dalian University of Technology, No. 826, Xinan Rd., Dalian 116033, Liaoning Province, China
| | - Zheng-Nan Gao
- Central Hospital of Dalian University of Technology, No. 826, Xinan Rd., Dalian 116033, Liaoning Province, China
| | - Kai-Rong Qin
- School of Biomedical Engineering, Faculty of Medicine, Dalian University of Technology, No. 2, Linggong Rd., Dalian 116024, Liaoning Province, China
- Central Hospital of Dalian University of Technology, No. 826, Xinan Rd., Dalian 116033, Liaoning Province, China
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6
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Xu S, Liao J, Liu B, Zhang C, Xu X. Aerobic glycolysis of vascular endothelial cells: a novel perspective in cancer therapy. Mol Biol Rep 2024; 51:717. [PMID: 38824197 PMCID: PMC11144152 DOI: 10.1007/s11033-024-09588-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 04/25/2024] [Indexed: 06/03/2024]
Abstract
Vascular endothelial cells (ECs) are monolayers of cells arranged in the inner walls of blood vessels. Under normal physiological conditions, ECs play an essential role in angiogenesis, homeostasis and immune response. Emerging evidence suggests that abnormalities in EC metabolism, especially aerobic glycolysis, are associated with the initiation and progression of various diseases, including multiple cancers. In this review, we discuss the differences in aerobic glycolysis of vascular ECs under normal and pathological conditions, focusing on the recent research progress of aerobic glycolysis in tumor vascular ECs and potential strategies for cancer therapy.
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Affiliation(s)
- Shenhao Xu
- Department of urology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Jiahao Liao
- Department of urology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Bing Liu
- Department of urology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Cheng Zhang
- Department of urology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China.
| | - Xin Xu
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China.
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7
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Mahoney SA, VanDongen NS, Greenberg NT, Venkatasubramanian R, Rossman MJ, Widlansky ME, Brunt VE, Bernaldo de Quirós Y, Seals DR, Clayton ZS. Role of the circulating milieu in age-related arterial dysfunction: a novel ex vivo approach. Am J Physiol Heart Circ Physiol 2024; 326:H1279-H1290. [PMID: 38517225 PMCID: PMC11380963 DOI: 10.1152/ajpheart.00014.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/22/2024] [Accepted: 02/27/2024] [Indexed: 03/23/2024]
Abstract
The circulating milieu, bioactive molecules in the bloodstream, is altered with aging and interfaces constantly with the vasculature. This anatomic juxtaposition suggests that circulating factors may actively modulate arterial function. Here, we developed a novel, translational experimental model that allows for direct interrogation of the influence of the circulating milieu on age-related arterial dysfunction (aortic stiffening and endothelial dysfunction). To do so, we exposed young and old mouse arteries to serum from young and old mice and young and midlife/older (ML/O) adult humans. We found that old mouse and ML/O adult human, but not young, serum stiffened young mouse aortic rings, assessed via elastic modulus (mouse and human serum, P = 0.003 vs. young serum control), and impaired carotid artery endothelial function, assessed by endothelium-dependent dilation (EDD) (mouse serum, P < 0.001; human serum, P = 0.006 vs. young serum control). Furthermore, young mouse and human, but not old, serum reduced aortic elastic modulus (mouse serum, P = 0.009; human serum, P < 0.001 vs. old/MLO serum control) and improved EDD (mouse and human serum, P = 0.015 vs. old/MLO serum control) in old arteries. In human serum-exposed arteries, in vivo arterial function assessed in the human donors correlated with circulating milieu-modulated arterial function in young mouse arteries (aortic stiffness, r = 0.634, P = 0.005; endothelial function, r = 0.609, P = 0.004) and old mouse arteries (aortic stiffness, r = 0.664, P = 0.001; endothelial function, r = 0.637, P = 0.003). This study establishes novel experimental approaches for directly assessing the effects of the circulating milieu on arterial function and implicates changes in the circulating milieu as a mechanism of in vivo arterial aging.NEW & NOTEWORTHY Changes in the circulating milieu with advancing age may be a mechanism underlying age-related arterial dysfunction. Ex vivo exposure of young mouse arteries to the circulating milieu from old mice or midlife/older adults impairs arterial function whereas exposure of old mouse arteries to the circulating milieu from young mice or young adults improves arterial function. These findings establish that the circulating milieu directly influences arterial function with aging.
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Affiliation(s)
- Sophia A Mahoney
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
| | - Nicholas S VanDongen
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
| | - Nathan T Greenberg
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
| | | | - Matthew J Rossman
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
| | - Michael E Widlansky
- Department of Medicine and Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Vienna E Brunt
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Yara Bernaldo de Quirós
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
- Institute of Animal Health and Food Safety, Universidad de Las Palmas de Gran Canaria, Canary Islands, Spain
| | - Douglas R Seals
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
| | - Zachary S Clayton
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
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Lee J, König M, Braun G, Escher BI. Water Quality Monitoring with the Multiplexed Assay MitoOxTox for Mitochondrial Toxicity, Oxidative Stress Response, and Cytotoxicity in AREc32 Cells. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024; 58:5716-5726. [PMID: 38503264 PMCID: PMC10993414 DOI: 10.1021/acs.est.3c09844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 03/06/2024] [Accepted: 03/06/2024] [Indexed: 03/21/2024]
Abstract
Mitochondria play a key role in the energy production of cells, but their function can be disturbed by environmental toxicants. We developed a cell-based mitochondrial toxicity assay for environmental chemicals and their mixtures extracted from water samples. The reporter gene cell line AREc32, which is frequently used to quantify the cytotoxicity and oxidative stress response of water samples, was multiplexed with an endpoint of mitochondrial toxicity. The disruption of the mitochondrial membrane potential (MMP) was quantified by high-content imaging and compared to measured cytotoxicity, predicted baseline toxicity, and activation of the oxidative stress response. Mitochondrial complex I inhibitors showed highly specific effects on the MMP, with minor effects on cell viability. Uncouplers showed a wide distribution of specificity on the MMP, often accompanied by specific cytotoxicity (enhanced over baseline toxicity). Mitochondrial toxicity and the oxidative stress response were not directly associated. The multiplexed assay was applied to water samples ranging from wastewater treatment plant (WWTP) influent and effluent and surface water to drinking and bottled water from various European countries. Specific effects on MMP were observed for the WWTP influent and effluent. This new MitoOxTox assay is an important complement for existing in vitro test batteries for water quality testing and has potential for applications in human biomonitoring.
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Affiliation(s)
- Jungeun Lee
- Department
of Cell Toxicology, UFZ—Helmholtz
Centre for Environmental Research, 04318 Leipzig, Germany
| | - Maria König
- Department
of Cell Toxicology, UFZ—Helmholtz
Centre for Environmental Research, 04318 Leipzig, Germany
| | - Georg Braun
- Department
of Cell Toxicology, UFZ—Helmholtz
Centre for Environmental Research, 04318 Leipzig, Germany
| | - Beate I. Escher
- Department
of Cell Toxicology, UFZ—Helmholtz
Centre for Environmental Research, 04318 Leipzig, Germany
- Environmental
Toxicology, Department of Geosciences, Eberhard
Karls University, Schnarrenbergstr.
94-96, 72076 Tübingen, Germany
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Sakamuri SSVP, Sure VN, Oruganti L, Wisen W, Chandra PK, Liu N, Fonseca VA, Wang X, Klein J, Katakam PVG. Acute severe hypoglycemia alters mouse brain microvascular proteome. J Cereb Blood Flow Metab 2024; 44:556-572. [PMID: 37944245 PMCID: PMC10981402 DOI: 10.1177/0271678x231212961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 09/12/2023] [Accepted: 10/05/2023] [Indexed: 11/12/2023]
Abstract
Hypoglycemia increases the risk related to stroke and neurodegenerative diseases, however, the underlying mechanisms are unclear. For the first time, we studied the effect of a single episode (acute) of severe (ASH) and mild (AMH) hypoglycemia on mouse brain microvascular proteome. After four-hour fasting, insulin was administered (i.p) to lower mean blood glucose in mice and induce ∼30 minutes of ASH (∼30 mg/dL) or AMH (∼75 mg/dL), whereas a similar volume of saline was given to control mice (∼130 mg/dL). Blood glucose was allowed to recover over 60 minutes either spontaneously or by 20% dextrose administration (i.p). Twenty-four hours later, the brain microvessels (BMVs) were isolated, and tandem mass tag (TMT)-based quantitative proteomics was performed using liquid chromatography-mass spectrometry (LC/MS). When compared to control, ASH significantly downregulated 13 proteins (p ≤ 0.05) whereas 23 proteins showed a strong trend toward decrease (p ≤ 0.10). When compared to AMH, ASH significantly induced the expression of 35 proteins with 13 proteins showing an increasing trend. AMH downregulated only 3 proteins. ASH-induced downregulated proteins are involved in actin cytoskeleton maintenance needed for cell shape and migration which are critical for blood-brain barrier maintenance and angiogenesis. In contrast, ASH-induced upregulated proteins are RNA-binding proteins involved in RNA splicing, transport, and stability. Thus, ASH alters BMV proteomics to impair cytoskeletal integrity and RNA processing which are critical for cerebrovascular function.
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Affiliation(s)
- Siva SVP Sakamuri
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Venkata N Sure
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Lokanatha Oruganti
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
| | - William Wisen
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Partha K Chandra
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
- Neuroscience Program, Tulane Brain Institute, Tulane University, New Orleans, LA, USA
| | - Ning Liu
- Neuroscience Program, Tulane Brain Institute, Tulane University, New Orleans, LA, USA
- Clinical Neuroscience Research Center, New Orleans, LA, USA
- Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA, USA
| | - Vivian A Fonseca
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Xiaoying Wang
- Neuroscience Program, Tulane Brain Institute, Tulane University, New Orleans, LA, USA
- Clinical Neuroscience Research Center, New Orleans, LA, USA
- Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA, USA
| | - Jennifer Klein
- Department of Biochemistry & Molecular Biology, Louisiana State University School of Medicine, New Orleans, LA, USA
| | - Prasad VG Katakam
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
- Neuroscience Program, Tulane Brain Institute, Tulane University, New Orleans, LA, USA
- Clinical Neuroscience Research Center, New Orleans, LA, USA
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10
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Hossain MI, Haque M, Akter M, Sharmin S, Ahmed A. Blood-brain barrier disruption and edema formation due to prolonged starvation in wild-type mice. Brain Circ 2024; 10:145-153. [PMID: 39036296 PMCID: PMC11259321 DOI: 10.4103/bc.bc_88_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 01/11/2024] [Accepted: 01/29/2024] [Indexed: 07/23/2024] Open
Abstract
INTRODUCTION Different types of diseases have been treated by restricted caloric intake or fasting. Although during this long time, fasting protective measures, for example, supplements, are given to the patients to protect vital organs such as the liver and kidney, little attention is given to the brain. The current research aims to investigate hypoglycemia due to prolonged fasting disrupts blood-brain barrier (BBB) in mice. MATERIALS AND METHODS Immunohistochemistry (IHC) and in situ hybridization (ISH) techniques were used to examine the expression of different genes. Evans blue extravasation and wet-dry technique were performed to evaluate the integrity of BBB and the formation of brain edema, respectively. RESULTS We confirmed that hypoglycemia affected mice fasting brain by examining the increased expression of glucose transporter protein 1 and hyperphosphorylation of tau protein. We subsequently found downregulated expression of some genes, which are involved in maintaining BBB such as vascular endothelial growth factor (VEGF) in astrocytes and claudin-5 (a vital component of BBB) and VEGF receptor (VEGFR1) in endothelial cells by ISH. We also found that prolonged fasting caused the brain endothelial cells to express lipocalin-2, an inflammatory marker of brain endothelial cells. We performed Evans blue extravasation to show more dye was retained in the brain of fasted mice than in control mice as a result of BBB disruption. Finally, wet-dry method showed that the brain of prolonged fasted mice contained significantly higher amount of water confirming the formation of brain edema. Therefore, special attention should be given to the brain during treatment with prolonged fasting for various diseases. CONCLUSIONS Our results demonstrated that hypoglycemia due to prolonged fasting disrupts BBB and produces brain edema in wild-type mice, highlighting the importance of brain health during treatment with prolonged fasting.
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Affiliation(s)
- M. Ibrahim Hossain
- Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Mehjabeen Haque
- Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Maria Akter
- Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Sabrina Sharmin
- Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Asif Ahmed
- Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka, Bangladesh
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Wang JM, Miao MY, Jia YP, Wang XW, Wu XB, Wan ZX, Zheng Y, Qin LQ, Li FR, Chen GC. Effects of intensive glycemic control on microvascular outcomes in type 2 diabetes mellitus are modified by long-term HbA 1c variability: A post hoc analysis of the ACCORD trial. Diabetes Res Clin Pract 2024; 208:111100. [PMID: 38246509 DOI: 10.1016/j.diabres.2024.111100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/04/2024] [Accepted: 01/16/2024] [Indexed: 01/23/2024]
Abstract
AIMS To assess the impact of long-term visit-to-visit variability in HbA1c on microvascular outcomes in type 2 diabetes mellitus (T2DM), and its influence on the effects of intensive glycemic control. METHODS Included were participants with T2DM enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) who had at least three measurements of HbA1c prior to new-onset microvascular outcomes, namely nephropathy, retinopathy and neuropathy. Variability in HbA1c was defined as the coefficient of variation (CV) across HbA1c measurements obtained from enrollment to the transition from intensive to standard glycemic therapy. RESULTS During a median of 22,005, 23,121, and 13,080 person-years of follow-up, 2,905 nephropathy, 2,655 retinopathy, and 1,974 neuropathy cases were recorded, respectively. Median CV (IQR) was 7.91 % (5.66 %-10.76 %) in the standard treatment group and 9.79 % (7.32 %-13.35 %) in the intensive treatment group. In the standard treatment group, lower HbA1c-CV (the first versus the second quartile) was associated with a higher risk of all microvascular outcomes, while higher HbA1c-CV (the fourth quartile) was associated with a higher risk of nephropathy only. In the intensive treatment group, only higher HbA1c-CV was associated with a higher risk of developing the microvascular outcomes. Intensive therapy reduced all microvascular outcomes among individuals with lower HbA1c-CV, but increased the risk among those with the highest HbA1c-CV (all P values for interaction < 0.0001). For example, hazard ratios (95 % CI) of retinopathy comparing intensive with standard treatments were 0.65 (0.56-0.75), 0.84 (0.71-0.98), 0.97 (0.82-1.14) and 1.28 (1.08-1.53) across the lowest to the highest quartiles of HbA1c variability. CONCLUSIONS The effects of intensive glycemic control on microvascular outcomes in T2DM appear to be modified by the variability of HbA1c during the treatment process, suggesting the significance of dynamic monitoring of HbA1c levels and timely adjustments to the therapeutic strategy among individuals with a high HbA1c variability.
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Affiliation(s)
- Jia-Min Wang
- Department of Nutrition and Food Hygiene, MOE Key Laboratory of Geriatric Diseases and Immunology, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China
| | - Meng-Yuan Miao
- Department of Nutrition and Food Hygiene, MOE Key Laboratory of Geriatric Diseases and Immunology, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China
| | - Yi-Ping Jia
- Department of Nutrition and Food Hygiene, MOE Key Laboratory of Geriatric Diseases and Immunology, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China
| | - Xiao-Wen Wang
- Peking University Center for Public Health and Epidemic Preparedness & Response, Peking University, Beijing, China
| | - Xian-Bo Wu
- Department of Epidemiology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), Guangzhou, China
| | - Zhong-Xiao Wan
- Department of Nutrition and Food Hygiene, MOE Key Laboratory of Geriatric Diseases and Immunology, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China
| | - Yan Zheng
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, and School of Life Sciences, Fudan University, Shanghai, China; Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Li-Qiang Qin
- Department of Nutrition and Food Hygiene, MOE Key Laboratory of Geriatric Diseases and Immunology, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China
| | - Fu-Rong Li
- School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, China.
| | - Guo-Chong Chen
- Department of Nutrition and Food Hygiene, MOE Key Laboratory of Geriatric Diseases and Immunology, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China.
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12
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Inoue C, Kusunoki Y, Ohigashi M, Osugi K, Kitajima K, Takagi A, Inoue M, Yagi C, Tsunoda T, Kakutani M, Kadoya M, Konishi K, Katsuno T, Koyama H. Association between brain imaging biomarkers and continuous glucose monitoring-derived glycemic control indices in Japanese patients with type 2 diabetes mellitus. BMJ Open Diabetes Res Care 2024; 12:e003744. [PMID: 38233078 PMCID: PMC10806821 DOI: 10.1136/bmjdrc-2023-003744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 12/19/2023] [Indexed: 01/19/2024] Open
Abstract
INTRODUCTION Although type 2 diabetes mellitus (T2DM) is associated with alterations in brain structure, the relationship between glycemic control indices and brain imaging markers remains unclear. This study aimed to investigate the association between continuous glucose monitoring (CGM)-derived glycemic control indices and brain imaging biomarkers assessed by MRI. RESEARCH DESIGN AND METHODS This cross-sectional study included 150 patients with T2DM. The severity of cerebral white matter lesions (WMLs) was assessed using MRI for deep and subcortical white matter and periventricular hyperintensities. The degree of medial temporal lobe atrophy (MTA) was assessed using voxel-based morphometry. Each participant wore a retrospective CGM for 14 consecutive days, and glycemic control indices, such as time in range (TIR) and glycemia risk index (GRI), were calculated. RESULTS The proportion of patients with severe WMLs showed a decreasing trend with increasing TIR (P for trend=0.006). The proportion of patients with severe WMLs showed an increasing trend with worsening GRI (P for trend=0.011). In contrast, no significant association was observed between the degree of MTA and CGM-derived glycemic control indices, including TIR (P for trend=0.325) and GRI (P for trend=0.447). CONCLUSIONS The findings of this study indicate that the severity of WMLs is associated with TIR and GRI, which are indices of the quality of glycemic control. TRIAL REGISTRATION NUMBER UMIN000032143.
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Affiliation(s)
- Chikako Inoue
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Yoshiki Kusunoki
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Mana Ohigashi
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Keiko Osugi
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Kazuhiro Kitajima
- Department of Radiology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Ayako Takagi
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Maki Inoue
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Chisako Yagi
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Taku Tsunoda
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Miki Kakutani
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Manabu Kadoya
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Kosuke Konishi
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Tomoyuki Katsuno
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Hidenori Koyama
- Department of Diabetes, Endocrinology and Clinical Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
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13
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Kobayashi S, Cox AG, Harvey KF, Hogan BM. Vasculature is getting Hip(po): Hippo signaling in vascular development and disease. Dev Cell 2023; 58:2627-2640. [PMID: 38052179 DOI: 10.1016/j.devcel.2023.11.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 05/29/2023] [Accepted: 11/01/2023] [Indexed: 12/07/2023]
Abstract
The Hippo signaling pathway regulates developmental organ growth, regeneration, and cell fate decisions. Although the role of the Hippo pathway, and its transcriptional effectors YAP and TAZ, has been well documented in many cell types and species, only recently have the roles for this pathway come to light in vascular development and disease. Experiments in mice, zebrafish, and in vitro have uncovered roles for the Hippo pathway, YAP, and TAZ in vasculogenesis, angiogenesis, and lymphangiogenesis. In addition, the Hippo pathway has been implicated in vascular cancers and cardiovascular diseases, thus identifying it as a potential therapeutic target for the treatment of these conditions. However, despite recent advances, Hippo's role in the vasculature is still underappreciated compared with its role in epithelial tissues. In this review, we appraise our current understanding of the Hippo pathway in blood and lymphatic vessel development and highlight the current knowledge gaps and opportunities for further research.
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Affiliation(s)
- Sakurako Kobayashi
- Organogenesis and Cancer Program, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Andrew G Cox
- Organogenesis and Cancer Program, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Kieran F Harvey
- Organogenesis and Cancer Program, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia
| | - Benjamin M Hogan
- Organogenesis and Cancer Program, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia.
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14
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Harvengt AA, Polle OG, Martin M, van Maanen A, Gatto L, Lysy PA. Post-Hypoglycemic hyperglycemia are highly relevant markers for stratification of glycemic variability and partial remission status of pediatric patients with new-onset type 1 diabetes. PLoS One 2023; 18:e0294982. [PMID: 38033011 PMCID: PMC10688654 DOI: 10.1371/journal.pone.0294982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 11/14/2023] [Indexed: 12/02/2023] Open
Abstract
AIMS To evaluate whether parameters of post-hypoglycemic hyperglycemia (PHH) correlated with glucose homeostasis during the first year after type 1 diabetes onset and helped to distinguish pediatric patients undergoing partial remission or not. METHODS In the GLUREDIA (GLUcagon Response to hypoglycemia in children and adolescents with new-onset type 1 DIAbetes) study, longitudinal values of clinical parameters, continuous glucose monitoring metrics and residual β-cell secretion from children with new-onset type 1 diabetes were analyzed during the first year after disease onset. PHH parameters were calculated using an in-house algorithm. Correlations between PHH parameters (i.e., PHH frequency, PHH duration, PHH area under the curve [PHHAUC]) and glycemic homeostasis markers were studied using adjusted mixed-effects models. RESULTS PHH parameters were strong markers to differentiate remitters from non-remitters with PHH/Hyperglycemia duration ratio being the most sensitive (ratio<0.02; sensitivity = 86% and specificity = 68%). PHHAUC moderately correlated with parameters of glucose homeostasis including TIR (R2 = 0.35, p-value < 0.05), coefficient of variation (R2 = 0.22, p-value < 0.05) and Insulin-Dose Adjusted A1c (IDAA1C) (R2 = 0.32, p-value < 0.05) and with residual β-cell secretion (R2 = 0.17, p-value < 0.05). Classification of patients into four previously described glucotypes independently validated PHH parameters as reliable markers of glucose homeostasis and improved the segregation of patients with intermediate values of IDAA1C and estimated C-peptide (CPEPEST). Finally, a combination of PHH parameters identified groups of patients with specific patterns of hypoglycemia. CONCLUSION PHH parameters are new minimal-invasive markers to discriminate remitters from non-remitters and evaluate glycemic homeostasis during the first year of type 1 diabetes. PHH parameters may also allow patient-targeted therapeutic management of hypoglycemic episodes.
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Affiliation(s)
- Antoine A. Harvengt
- Pôle PEDI, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
- Specialized Pediatrics Service, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Olivier G. Polle
- Pôle PEDI, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
- Specialized Pediatrics Service, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Manon Martin
- Computational Biology and Bioinformatics (CBIO) Unit, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Aline van Maanen
- Statistical Support Unit, Institut Roi Albert II, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Laurent Gatto
- Computational Biology and Bioinformatics (CBIO) Unit, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Philippe A. Lysy
- Pôle PEDI, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
- Specialized Pediatrics Service, Cliniques universitaires Saint-Luc, Brussels, Belgium
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15
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Nurzhan S, Bekezhankyzy Z, Ding H, Berdigaliyev N, Sergazy S, Gulyayev A, Shulgau Z, Triggle CR, Aljofan M. The Effect of Different Glucose Concentrations on the Antiproliferative Activity of Metformin in MCF-7 Breast Cancer Cells. Pharmaceutics 2023; 15:2186. [PMID: 37765157 PMCID: PMC10537756 DOI: 10.3390/pharmaceutics15092186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/17/2023] [Accepted: 08/17/2023] [Indexed: 09/29/2023] Open
Abstract
The glucose-lowering drug metformin has been reported to have anticancer properties through unknown mechanisms. Other unknown factors that may influence its anticancer potential include the glycemic status of the patient. Therefore, the objective of this study is to determine the effect of different glucose environments on the antiproliferative potency and the cellular mechanism of action of metformin. Human breast cancer cells, MCF-7, were incubated in low, normal, elevated, and high glucose environments and treated with metformin. The antiproliferative potential of metformin and its effect on protein expression as well as its ability to induce cellular apoptosis and autophagy under different glucose environments, were determined using different molecular techniques. Metformin significantly inhibited cellular proliferation in a time- and glucose-concentration-dependent manner. In comparison to elevated glucose, low normal glucose alone induced a significant level of autophagy that was further increased in the presence of metformin. While glucose concentration did not appear to have an effect on the antiproliferative potency of metformin, the cellular basis of action was shown to be glucose-dependent. The antiproliferative mechanism of action of metformin in elevated and low normal glucose environments is mTOR-dependent, whereas, in the high glucose environment, the antiproliferative mechanism is independent of mTOR. This is the first study to report that both the antiproliferative potency and the cellular mechanism of action aredependent on the concentration of glucose.
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Affiliation(s)
- Sholpan Nurzhan
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana Z05H0P9, Kazakhstan; (S.N.); (Z.B.); (N.B.)
- National Center for Biotechnology, Astana Z05K8D5, Kazakhstan; (S.S.); (A.G.)
| | - Zhibek Bekezhankyzy
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana Z05H0P9, Kazakhstan; (S.N.); (Z.B.); (N.B.)
- National Center for Biotechnology, Astana Z05K8D5, Kazakhstan; (S.S.); (A.G.)
| | - Hong Ding
- Department of Pharmacology, Weill Cornell Medicine in Qatar, Education City, Doha P.O. Box 24144, Qatar; (H.D.); (C.R.T.)
| | - Nurken Berdigaliyev
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana Z05H0P9, Kazakhstan; (S.N.); (Z.B.); (N.B.)
- National Center for Biotechnology, Astana Z05K8D5, Kazakhstan; (S.S.); (A.G.)
| | - Shynggys Sergazy
- National Center for Biotechnology, Astana Z05K8D5, Kazakhstan; (S.S.); (A.G.)
- Drug Discovery and Development Laboratory, National Laboratory Astana, Nazarbayev University, Astana Z05H0P9, Kazakhstan
- Research Institute of Balneology and Medical Rehabilitation, Akmola Region, Burabay 021708, Kazakhstan
| | - Alexander Gulyayev
- National Center for Biotechnology, Astana Z05K8D5, Kazakhstan; (S.S.); (A.G.)
- Drug Discovery and Development Laboratory, National Laboratory Astana, Nazarbayev University, Astana Z05H0P9, Kazakhstan
- Research Institute of Balneology and Medical Rehabilitation, Akmola Region, Burabay 021708, Kazakhstan
| | - Zarina Shulgau
- National Center for Biotechnology, Astana Z05K8D5, Kazakhstan; (S.S.); (A.G.)
- Drug Discovery and Development Laboratory, National Laboratory Astana, Nazarbayev University, Astana Z05H0P9, Kazakhstan
| | - Christopher R. Triggle
- Department of Pharmacology, Weill Cornell Medicine in Qatar, Education City, Doha P.O. Box 24144, Qatar; (H.D.); (C.R.T.)
| | - Mohamad Aljofan
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana Z05H0P9, Kazakhstan; (S.N.); (Z.B.); (N.B.)
- Drug Discovery and Development Laboratory, National Laboratory Astana, Nazarbayev University, Astana Z05H0P9, Kazakhstan
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McNeilly AD, Gallagher JR, Evans ML, de Galan BE, Pedersen-Bjergaard U, Thorens B, Dinkova-Kostova AT, Huang JT, Ashford MLJ, McCrimmon RJ. Chronic hyperglycaemia increases the vulnerability of the hippocampus to oxidative damage induced during post-hypoglycaemic hyperglycaemia in a mouse model of chemically induced type 1 diabetes. Diabetologia 2023; 66:1340-1352. [PMID: 37015997 PMCID: PMC10244284 DOI: 10.1007/s00125-023-05907-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 01/26/2023] [Indexed: 04/06/2023]
Abstract
AIMS/HYPOTHESIS Chronic hyperglycaemia and recurrent hypoglycaemia are independently associated with accelerated cognitive decline in type 1 diabetes. Recurrent hypoglycaemia in rodent models of chemically induced (streptozotocin [STZ]) diabetes leads to cognitive impairment in memory-related tasks associated with hippocampal oxidative damage. This study examined the hypothesis that post-hypoglycaemic hyperglycaemia in STZ-diabetes exacerbates hippocampal oxidative stress and explored potential contributory mechanisms. METHODS The hyperinsulinaemic glucose clamp technique was used to induce equivalent hypoglycaemia and to control post-hypoglycaemic glucose levels in mice with and without STZ-diabetes and Nrf2-/- mice (lacking Nrf2 [also known as Nfe2l2]). Subsequently, quantitative proteomics based on stable isotope labelling by amino acids in cell culture and biochemical approaches were used to assess oxidative damage and explore contributory pathways. RESULTS Evidence of hippocampal oxidative damage was most marked in mice with STZ-diabetes exposed to post-hypoglycaemic hyperglycaemia; these mice also showed induction of Nrf2 and the Nrf2 transcriptional targets Sod2 and Hmox-1. In this group, hypoglycaemia induced a significant upregulation of proteins involved in alternative fuel provision, reductive biosynthesis and degradation of damaged proteins, and a significant downregulation of proteins mediating the stress response. Key differences emerged between mice with and without STZ-diabetes following recovery from hypoglycaemia in proteins mediating the stress response and reductive biosynthesis. CONCLUSIONS/INTERPRETATION There is a disruption of the cellular response to a hypoglycaemic challenge in mice with STZ-induced diabetes that is not seen in wild-type non-diabetic animals. The chronic hyperglycaemia of diabetes and post-hypoglycaemic hyperglycaemia act synergistically to induce oxidative stress and damage in the hippocampus, possibly leading to irreversible damage/modification to proteins or synapses between cells. In conclusion, recurrent hypoglycaemia in sub-optimally controlled diabetes may contribute, at least in part, to accelerated cognitive decline through amplifying oxidative damage in key brain regions, such as the hippocampus. DATA AVAILABILITY The datasets generated during and/or analysed during the current study are available in ProteomeXchange, accession no. 1-20220824-173727 ( www.proteomexchange.org ). Additional datasets generated during and/or analysed during the present study are available from the corresponding author upon reasonable request.
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Affiliation(s)
- Alison D McNeilly
- Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK
| | - Jennifer R Gallagher
- Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK
| | - Mark L Evans
- Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Bastiaan E de Galan
- Radboud University Medical Center, Nijmegen, the Netherlands
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands
| | | | - Bernard Thorens
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Albena T Dinkova-Kostova
- Division of Cancer Research, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK
| | - Jeffrey-T Huang
- Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK
- Biomarker and Drug Analysis Core Facility, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK
| | - Michael L J Ashford
- Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK
| | - Rory J McCrimmon
- Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK.
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17
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Brayner B, Perez-Cornago A, Kaur G, Keske MA, Piernas C, Livingstone KM. Cross-sectional associations of dietary patterns characterized by fat type with markers of cardiometabolic health. Nutr Metab Cardiovasc Dis 2023; 33:797-808. [PMID: 36890071 DOI: 10.1016/j.numecd.2023.02.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/16/2023]
Abstract
BACKGROUND AND AIMS Individual dietary fats can differentially impact on cardiometabolic health. However, their impact within a dietary pattern is not well understood, and warrants comparison with diet quality scores with a dietary fat focus. The aim of this study was to investigate cross-sectional associations between a posteriori dietary patterns characterized by fat type and cardiometabolic health markers, and compare these with two diet quality scores. METHODS AND RESULTS UK Biobank adults with ≥two 24-h dietary assessments and data on cardiometabolic health were included (n = 24 553; mean age: 55.9 y). A posteriori dietary patterns (DP1; DP2) were generated through reduced rank regression (response variables: SFA, MUFA, PUFA). Mediterranean Diet Score (MDS) and Dietary Approaches to Stop Hypertension (DASH) dietary patterns were created. Multiple linear regression analyses were used to investigate associations between standardized dietary patterns and cardiometabolic health (total cholesterol, HDL-C, LDL-C and VLDL-C cholesterol, triglycerides, C-reactive protein [CRP], glycated hemoglobin [HbA1c]). DP1, positively correlated with SFAs, MUFAs and PUFAs, characterized by higher nuts, seeds and vegetables intake and lower fruits and low-fat yoghurt intake, was associated with lower HDL-C (β: -0.07; 95% CI: -0.10, -0.03) and triglycerides (-0.17; -0.23, -0.10) and higher LDL-C (0.07; 0.01,0.12), CRP (0.01; 0.01, 0.03) and HbA1c (0.16; 0.11,0.21). DP2, positively correlated with SFAs, negatively correlated with PUFAs, characterized by higher butter and high-fat cheese intake and lower nuts, seeds and vegetable intake, was associated with higher total cholesterol (0.10; 0.01, 0.21), VLDL-C (0.05; 0.02, 0.07), triglycerides (0.07; 0.01, 0.13), CRP (0.03; 0.02, 0,04) and HbA1c (0.06; 0.01, 0.11). Higher adherence to MDS and DASH was associated with favorable cardiometabolic health markers concentration. CONCLUSIONS Irrespective of the method used, dietary patterns that encourage healthy fat consumption were associated with favorable cardiometabolic health biomarkers. This study strengthens the evidence for incorporation of dietary fat type into policy and practice guidelines for CVD prevention.
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Affiliation(s)
- Barbara Brayner
- Deakin University, Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Geelong, Victoria 3220, Australia.
| | - Aurora Perez-Cornago
- University of Oxford, Nuffield Department of Population Health, Medical Sciences Division, Old Road Campus, Headington, Oxford OX3 7LF, United Kingdom.
| | - Gunveen Kaur
- Deakin University, Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Geelong, Victoria 3220, Australia.
| | - Michelle A Keske
- Deakin University, Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Geelong, Victoria 3220, Australia.
| | - Carmen Piernas
- University of Oxford, Nuffield Department of Primary Care Health Sciences, Medical Sciences Division, Old Road Campus, Headington, Oxford OX3 7LF, United Kingdom; Department of Biochemistry and Molecular Biology II, Center for Biomedical Research (CIBM), University of Granada, Spain.
| | - Katherine M Livingstone
- Deakin University, Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Geelong, Victoria 3220, Australia.
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18
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He A, Guo Y, Xu Z, Yan J, Xie L, Li Y, Lv D, Luo M. Hypoglycaemia aggravates impaired endothelial-dependent vasodilation in diabetes by suppressing endothelial nitric oxide synthase activity and stimulating inducible nitric oxide synthase expression. Microvasc Res 2023; 146:104468. [PMID: 36513147 DOI: 10.1016/j.mvr.2022.104468] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 11/16/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Diabetes exacerbates vascular injury by triggering endothelial dysfunction. Endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) both play major roles in endothelial dysfunction. However, effects of hypoglycaemia, the main complication of the insulin therapy to the glycemic control in diabetes, on eNOS activity and iNOS expression, and underlying mechanisms in diabetes remain unknown. Hence, we aimed to determine the effects of hypoglycaemia on eNOS activity and iNOS expression in different arterial beds of diabetic rats. METHODS Sprague-Dawley rats were subjected to Streptozotocin (STZ) combined with high fat diet (HFD) to induce diabetes and then received insulin injection to attain acute and recurrent hypoglycaemia. Immunoblotting was used to analyse the phosphorylation and O-glycosylation status of eNOS and iNOS level from thoracic aorta and mesenteric artery tissue. Indicators of oxidative stress from plasm were determined, and endothelial-dependent vasodilation was detected via wire myograph system. RESULTS Hypoglycaemia was associated with a marked increase in eNOS O-GlcNAcylation and decrease in Serine (Ser)-1177 phosphorylation from thoracic aortas and mesenteric arteries. Moreover, hypoglycaemia resulted in elevated phosphorylation of eNOS at Threonine (Thr)-495 site in mesenteric arteries. Besides, changes in these post-translational modifications were associated with increased O-GlcNAc transferase (OGT), decreased phosphorylation of Akt at Ser-473, and increased protein kinase C α subunit (PKCα). iNOS expression was induced in hypoglycaemia. Furthermore, endothelial-dependent vasodilation was impaired under insulin-induced hypoglycaemia, and further in recurrent hypoglycaemia. CONCLUSIONS Conclusively, these findings strongly indicate that hypoglycaemia-dependent vascular dysfunction in diabetes is mediated through altered eNOS activity and iNOS expression. Therefore, this implies that therapeutic modulation of eNOS activity and iNOS expression in diabetics under intensive glucose control may prevent and treat adverse cardiovascular events.
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Affiliation(s)
- An He
- Division of cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yongzheng Guo
- Division of cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhixin Xu
- Division of cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianghong Yan
- Institute of Life Science, Chongqing Medical University, Chongqing, China
| | - Lingyun Xie
- Division of cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuanjing Li
- Division of cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dingyi Lv
- Division of cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Minghao Luo
- Division of cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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19
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Love KM, Barrett EJ, Horton WB. Metformin's Impact on the Microvascular Response to Insulin. Endocrinology 2022; 163:bqac162. [PMID: 36201598 PMCID: PMC10233257 DOI: 10.1210/endocr/bqac162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Indexed: 11/19/2022]
Abstract
Metformin improves insulin's action on whole-body glucose metabolism in various insulin-resistant populations. The detailed cellular mechanism(s) for its metabolic actions are multiple and still incompletely understood. Beyond metabolic actions, metformin also impacts microvascular function. However, the effects of metformin on microvascular function and microvascular insulin action specifically are poorly defined. In this mini-review, we summarize what is currently known about metformin's beneficial impact on both microvascular function and the microvascular response to insulin while highlighting methodologic issues in the literature that limit straightforward mechanistic understanding of these effects. We examine potential mechanisms for these effects based on pharmacologically dosed studies and propose that metformin may improve human microvascular insulin resistance by attenuating oxidative stress, inflammation, and endothelial dysfunction. Finally, we explore several important evidence gaps and discuss avenues for future investigation that may clarify whether metformin's ability to improve microvascular insulin sensitivity is linked to its positive impact on vascular outcomes.
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Affiliation(s)
- Kaitlin M Love
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - Eugene J Barrett
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - William B Horton
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
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20
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Humos B, Mahfoud Z, Dargham S, Al Suwaidi J, Jneid H, Abi Khalil C. Hypoglycemia is associated with a higher risk of mortality and arrhythmias in ST-elevation myocardial infarction, irrespective of diabetes. Front Cardiovasc Med 2022; 9:940035. [PMID: 36299875 PMCID: PMC9588908 DOI: 10.3389/fcvm.2022.940035] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/31/2022] [Indexed: 11/16/2022] Open
Abstract
Aims We aimed to assess the impact of hypoglycemia in ST-elevation myocardial infarction (STEMI). Background Hypoglycemia increases the risk of mortality in patients with diabetes and high cardiovascular risk. Methods We used the National Inpatient Sample (2005–2017) database to identify adult patients with STEMI as the primary diagnosis. The secondary diagnosis was hypoglycemia. We compared cardiovascular and socio-economic outcomes between STEMI patients with and without hypoglycemia and assessed temporal trends. Results Hypoglycemia tends to complicate 0.17% of all cases hospitalized for STEMI. The mean age (±SD) of STEMI patients hospitalized with hypoglycemia decreased from 67 ± 15 in 2005 to 63 ± 12 in 2017 (p = 0.046). Mortality was stable with time, but the prevalence of ventricular tachycardia, ventricular fibrillation, acute renal failure, cardiogenic shock, total charges, and length of stay (LOS) increased with time (p < 0.05 for all). Compared to non-hypoglycemic patients, those who developed hypoglycemia were older and more likely to be black; only 6.7% had diabetes compared to 28.5% of STEMI patients (p = 0.001). Cardiovascular events were more likely to occur in hypoglycemia: mortality risk increased by almost 2.5-fold (adjusted OR = 2.625 [2.095–3.289]). There was a higher incidence of cardiogenic shock (adjusted OR = 1.718 [1.387–2.127]), atrial fibrillation (adjusted OR = 1.284 [1.025–1.607]), ventricular fibrillation (adjusted OR = 1.799 [1.406–2.301]), and acute renal failure (adjusted OR = 2.355 [1.902–2.917]). Patients who developed hypoglycemia were less likely to have PCI (OR = 0.596 [0.491–0.722]) but more likely to have CABG (OR = 1.792 [1.391–2.308]). They also had a longer in-hospital stay and higher charges/stay. Conclusion Hypoglycemia is a rare event in patients hospitalized with STEMI. However, it was found to have higher odds of mortality, arrhythmias, and other comorbidities, irrespective of diabetes.
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Affiliation(s)
- Basel Humos
- Department of Research, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Ziyad Mahfoud
- Department of Research, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Soha Dargham
- Department of Research, Weill Cornell Medicine-Qatar, Doha, Qatar
| | | | - Hani Jneid
- The Michael E. DeBakey VA Medical Centre, Baylor College of Medicine, Houston, TX, United States
| | - Charbel Abi Khalil
- Department of Research, Weill Cornell Medicine-Qatar, Doha, Qatar,Heart Hospital, Hamad Medical Corporation, Doha, Qatar,Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, United States,*Correspondence: Charbel Abi Khalil,
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21
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Papachristoforou E, Kountouri A, Maratou E, Kouretas D, Skaperda Z, Tsoumani M, Efentakis P, Ikonomidis I, Lambadiari V, Makrilakis K. Association of Hypoglycemia with Biomarkers of Oxidative Stress and Antioxidants: An Observational Study. Healthcare (Basel) 2022; 10:healthcare10081509. [PMID: 36011166 PMCID: PMC9408616 DOI: 10.3390/healthcare10081509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/03/2022] [Accepted: 08/08/2022] [Indexed: 11/23/2022] Open
Abstract
Hypoglycemia has been associated with complications from the vasculature. The contributing effects of oxidative stress (OS) on these actions have not been sufficiently studied, especially in daily, routine clinical practice. We examined the association of hypoglycemia encountered in daily clinical practice with biomarkers of OS and endogenous antioxidant activity in persons with diabetes [type 1 (T1D) or type 2 (T2D)], as well as individuals without diabetes, with a history of hypoglycemia. Several biomarkers of OS (MDA, ADMA, ox-LDL, 3-NT, protein carbonyls, 4-HNE, TBARS) and antioxidant capacity (TAC, superoxide scavenging capacity, hydroxyl radical scavenging capacity, reducing power, ABTS) were measured. Blood was drawn at the time of hypoglycemia detection and under euglycemic conditions on a different day. A total of 31 participants (mean age [±SD] 52.2 ± 21.1 years, 45.2% males) were included in the study. There were 14 (45.2%) persons with T2D, 12 (38.7%) with T1D, and 5 (16.1%) without diabetes. We found no differences in the examined biomarkers. Only TBARS, a biomarker of lipid peroxidation, showed lower values during hypoglycemia (p = 0.005). This finding needs confirmation in more extensive studies, given that MDA, another biomarker of lipid peroxidation, was not affected. Our study suggests that hypoglycemia encountered in daily clinical practice does not affect OS.
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Affiliation(s)
- Eleftheria Papachristoforou
- First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Aikaterini Kountouri
- Second Department of Internal Medicine, Research Unit and Diabetes Centre, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Eirini Maratou
- Laboratory of Clinical Biochemistry, Attikon University Hospital, 12462 Athens, Greece
| | - Dimitris Kouretas
- Department of Biochemistry and Biotechnology, University of Thessaly, 41500 Larissa, Greece
| | - Zoi Skaperda
- Department of Biochemistry and Biotechnology, University of Thessaly, 41500 Larissa, Greece
| | - Maria Tsoumani
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece
| | - Panagiotis Efentakis
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece
| | - Ignatios Ikonomidis
- 2nd Department of Cardiology, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Vaia Lambadiari
- Second Department of Internal Medicine, Research Unit and Diabetes Centre, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Konstantinos Makrilakis
- First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Correspondence: ; Tel.: +30-213-2061061; Fax: +30-213-2061794
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22
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Vrebalov Cindro P, Krnić M, Modun D, Vuković J, Tičinović Kurir T, Kardum G, Rušić D, Šešelja Perišin A, Bukić J. Comparison of the Impact of Insulin Degludec U100 and Insulin Glargine U300 on Glycemic Variability and Oxidative Stress in Insulin-Naive Patients With Type 2 Diabetes Mellitus: Pilot Study for a Randomized Trial. JMIR Form Res 2022; 6:e35655. [PMID: 35802405 PMCID: PMC9308081 DOI: 10.2196/35655] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 05/30/2022] [Accepted: 06/01/2022] [Indexed: 11/13/2022] Open
Abstract
Background
There is an ongoing discussion about possible differences between insulin degludec (IDeg-100) and glargine U300 (IGlar-300). There is little data and head-to-head comparison of IDeg-100 and IGlar-300 regarding their simultaneous impact on glycemic variability and oxidative stress in patients with type 2 diabetes mellitus (T2DM).
Objective
In our randomized, open-label, crossover study, we compared the impact of IDeg-100 and IGlar-300 on glycemic variability and oxidative stress in insulin-naive patients with T2DM.
Methods
We recruited a total of 25 adult patients with T2DM (7 females) whose diabetes was uncontrolled (HbA1c ≥7.5%) on two or more oral glucose-lowering drugs; a total of 22 completed the study. Mean age was 57.3 (SD 6.99) years and duration of diabetes was 9.94 (SD 5.01) years. After the washout period, they were randomized alternately to first receive either IDeg-100 or IGlar-300 along with metformin. Each insulin was administered for 12 weeks and then switched. At the beginning and end of each phase, biochemical and oxidative stress parameters were analyzed. On 3 consecutive days prior to each control point, patients performed a 7-point self-monitoring of blood glucose profile. Oxidative stress was assessed by measuring thiol groups and hydroperoxides (determination of reactive oxygen metabolites test) in serum.
Results
IGlar-300 reduced mean glucose by 0.02-0.13 mmol/L, and IDeg-100 reduced glucose by 0.10-0.16 mmol/L, with no significant difference. The reduction of the coefficient of glucose variation also did not show a statistically significant difference. IGlar-300 increased thiols by 0.08 µmol/L and IDeg-100 increased thiols by 0.15 µmol/L, with no significant difference (P=.07) between them. IGlar-300 reduced hydroperoxides by 0.040 CARR U and IDeg-100 increased hydroperoxides by 0.034 CARR U, but the difference was not significant (P=.12).
Conclusions
The results of our study do not show a significant difference regarding glycemic variability between patients receiving either insulin IDeg-100 or IGlar-300, although IGlar-300 showed greater dispersion of data. No significant difference in oxidative stress was observed. In a larger study, doses of insulins should be higher to achieve significant impact on glycemic parameters and consequently on glycemic variability and oxidative stress.
Trial Registration
ClinicalTrials.gov, NCT04692415; https://clinicaltrials.gov/ct2/show/NCT04692415
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Affiliation(s)
| | - Mladen Krnić
- Department of Endocrinology, University Hospital Split, Split, Croatia
- Department of Pathophysiology, School of Medicine, University of Split, Split, Croatia
| | - Darko Modun
- Department of Pharmacy, School of Medicine, University of Split, Split, Croatia
| | - Jonatan Vuković
- Department of Gastroenterology, University Hospital Split, Split, Croatia
| | - Tina Tičinović Kurir
- Department of Endocrinology, University Hospital Split, Split, Croatia
- Department of Pathophysiology, School of Medicine, University of Split, Split, Croatia
| | - Goran Kardum
- Department of Psychology, Faculty of Humanities and Social Sciences, University of Split, Split, Croatia
| | - Doris Rušić
- Department of Pharmacy, School of Medicine, University of Split, Split, Croatia
| | - Ana Šešelja Perišin
- Department of Pharmacy, School of Medicine, University of Split, Split, Croatia
| | - Josipa Bukić
- Department of Pharmacy, School of Medicine, University of Split, Split, Croatia
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23
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Neonatal Anesthesia and Oxidative Stress. Antioxidants (Basel) 2022; 11:antiox11040787. [PMID: 35453473 PMCID: PMC9026345 DOI: 10.3390/antiox11040787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 02/04/2023] Open
Abstract
Neonatal anesthesia, while often essential for surgeries or imaging procedures, is accompanied by significant risks to redox balance in the brain due to the relatively weak antioxidant system in children. Oxidative stress is characterized by concentrations of reactive oxygen species (ROS) that are elevated beyond what can be accommodated by the antioxidant defense system. In neonatal anesthesia, this has been proposed to be a contributing factor to some of the negative consequences (e.g., learning deficits and behavioral abnormalities) that are associated with early anesthetic exposure. In order to assess the relationship between neonatal anesthesia and oxidative stress, we first review the mechanisms of action of common anesthetic agents, the key pathways that produce the majority of ROS, and the main antioxidants. We then explore the possible immediate, short-term, and long-term pathways of neonatal-anesthesia-induced oxidative stress. We review a large body of literature describing oxidative stress to be evident during and immediately following neonatal anesthesia. Moreover, our review suggests that the short-term pathway has a temporally limited effect on oxidative stress, while the long-term pathway can manifest years later due to the altered development of neurons and neurovascular interactions.
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24
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Hypoglycemia induces vascular endothelial dysfunction in subjects with normal glucose tolerance. Sci Rep 2022; 12:2598. [PMID: 35173220 PMCID: PMC8850461 DOI: 10.1038/s41598-022-06450-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/28/2022] [Indexed: 02/04/2023] Open
Abstract
This prospective study determined the effects of hypoglycemic stimulation on vascular endothelial function in non-diabetic patients using reactive hyperemia peripheral arterial tonometry (RH-PAT). The study included non-diabetic patients who were hospitalized for an insulin tolerance test (ITT) for the diagnosis of hypoadrenocorticism or hypopituitarism. Vascular endothelial function was assessed using the reactive hyperemia index (RHI) measured by the RH-PAT. We also measured the levels of anterior pituitary hormone, adrenaline, noradrenaline, and dopamine at the time of hypoglycemia. The primary endpoint was a change in the RHI at 120 min after insulin administration. The study included 27 patients. ITT was associated with significant increases in systolic blood pressure, pulse rate, and the blood levels of adrenocorticotropic hormone, cortisol, growth hormone, adrenaline, noradrenaline, and dopamine. RHI significantly decreased after ITT from 2.24 ± 0.51 to 1.71 ± 0.42. A significant inverse correlation was observed between the change in RHI and change in adrenaline (r = − 0.670, p = 0.012). We concluded that hypoglycemic stimulation altered vascular endothelial function, as measured by RH-PAT, even in patients free of glucose intolerance. The observed deterioration in vascular endothelial function correlated with increases in catecholamine levels during hypoglycemia. Trial registration: UMIN000033244.
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25
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Abstract
The goal of diabetes treatment is to maintain good glycemic control, prevent the development and progression of diabetic complications, and ensure the same quality of life and life expectancy as healthy people. Hemoglobin A1c (HbA1c) is used as an index of glycemic control, but strict glycemic control using HbA1c as an index may lead to severe hypoglycemia and cardiovascular death. Glycemic variability (GV), such as excessive hyperglycemia and hypoglycemia, is associated with diabetic vascular complications and has been recognized as an important index of glycemic control. Here, we reviewed the definition and evaluated the clinical usefulness of GV, and its relationship with diabetic complications and therapeutic strategies to reduce GV.
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Affiliation(s)
- Yoshiki Kusunoki
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Japan
| | - Kosuke Konishi
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Japan
| | - Taku Tsunoda
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Japan
| | - Hidenori Koyama
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Japan
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26
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Torimoto K, Okuno K, Kuroda R, Shanas N, Cicalese SM, Eguchi K, Elliott KJ, Kawai T, Corbett CB, Peluzzo AM, St. Paul AK, Autieri MV, Scalia R, Rizzo V, Hashimoto T, Eguchi S. Glucose consumption of vascular cell types in culture: toward optimization of experimental conditions. Am J Physiol Cell Physiol 2022; 322:C73-C85. [PMID: 34817269 PMCID: PMC8791793 DOI: 10.1152/ajpcell.00257.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
In this study, we have looked for an optimum media glucose concentration and compared glucose consumption in three vascular cell types, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and adventitial fibroblasts (AFs) with or without angiotensin II (AngII) stimulation. In a subconfluent 6-well experiment in 1 mL DMEM with a standard low (100 mg/dL), a standard high (450 mg/dL), or a mixed middle (275 mg/dL) glucose concentration, steady and significant glucose consumption was observed in all cell types. After 48-h incubation, media that contained low glucose was reduced to almost 0 mg/dL, media that contained high glucose remained significantly higher at ∼275 mg/dL, and media that contained middle glucose remained closer to physiological range. AngII treatment enhanced glucose consumption in AFs and VSMCs but not in ECs. Enhanced extracellular acidification rate by AngII was also observed in AFs. In AFs, AngII induction of target proteins at 48 h varied depending on the glucose concentration used. In low glucose media, induction of glucose regulatory protein 78 or hexokinase II was highest, whereas induction of VCAM-1 was lowest. Utilization of specific inhibitors further suggests essential roles of angiotensin II type-1 receptor and glycolysis in AngII-induced fibroblast activation. Overall, this study demonstrates a high risk of hypo- or hyperglycemic conditions when standard low or high glucose media is used with vascular cells. Moreover, these conditions may significantly alter experimental outcomes. Media glucose concentration should be monitored during any culture experiments and utilization of middle glucose media is recommended for all vascular cell types.
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Affiliation(s)
- Keiichi Torimoto
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Keisuke Okuno
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Ryohei Kuroda
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - No’Ad Shanas
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Stephanie M. Cicalese
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Kunie Eguchi
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Katherine J. Elliott
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Tatsuo Kawai
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Cali B. Corbett
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Amanda M. Peluzzo
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Amanda K. St. Paul
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Michael V. Autieri
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Rosario Scalia
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Victor Rizzo
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Tomoki Hashimoto
- 2Barrow Aneurysm and AVM Research Center, Departments of Neurosurgery and Neurobiology, Barrow Neurological Institute, Phoenix, Arizona
| | - Satoru Eguchi
- 1Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
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27
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Love KM, Barrett EJ, Malin SK, Reusch JEB, Regensteiner JG, Liu Z. Diabetes pathogenesis and management: the endothelium comes of age. J Mol Cell Biol 2021; 13:500-512. [PMID: 33787922 PMCID: PMC8530521 DOI: 10.1093/jmcb/mjab024] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/10/2021] [Accepted: 02/25/2021] [Indexed: 12/03/2022] Open
Abstract
Endothelium, acting as a barrier, protects tissues against factors that provoke insulin resistance and type 2 diabetes and itself responds to the insult of insulin resistance inducers with altered function. Endothelial insulin resistance and vascular dysfunction occur early in the evolution of insulin resistance-related disease, can co-exist with and even contribute to the development of metabolic insulin resistance, and promote vascular complications in those affected. The impact of endothelial insulin resistance and vascular dysfunction varies depending on the blood vessel size and location, resulting in decreased arterial plasticity, increased atherosclerosis and vascular resistance, and decreased tissue perfusion. Women with insulin resistance and diabetes are disproportionately impacted by cardiovascular disease, likely related to differential sex-hormone endothelium effects. Thus, reducing endothelial insulin resistance and improving endothelial function in the conduit arteries may reduce atherosclerotic complications, in the resistance arteries lead to better blood pressure control, and in the microvasculature lead to less microvascular complications and more effective tissue perfusion. Multiple diabetes therapeutic modalities, including medications and exercise training, improve endothelial insulin action and vascular function. This action may delay the onset of type 2 diabetes and/or its complications, making the vascular endothelium an attractive therapeutic target for type 2 diabetes and potentially type 1 diabetes.
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MESH Headings
- Age Factors
- Cardiovascular Diseases/epidemiology
- Cardiovascular Diseases/ethnology
- Cardiovascular Diseases/metabolism
- Cardiovascular Diseases/physiopathology
- Comorbidity
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/epidemiology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/physiopathology
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/epidemiology
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/physiopathology
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/physiopathology
- Exercise
- Female
- Humans
- Hypoglycemic Agents/pharmacology
- Hypoglycemic Agents/therapeutic use
- Insulin Resistance
- Male
- Racial Groups
- Risk Factors
- Sex Factors
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Affiliation(s)
- Kaitlin M Love
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Eugene J Barrett
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Steven K Malin
- Department of Kinesiology and Health, Rutgers University, New Brunswick, NJ, USA
- Division of Endocrinology, Metabolism and Nutrition, Rutgers University, New Brunswick, NJ, USA
- New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ, USA
- Institute of Translational Medicine and Research, Rutgers University, New Brunswick, NJ, USA
| | - Jane E B Reusch
- Center for Women’s Health Research, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA
| | - Judith G Regensteiner
- Center for Women’s Health Research, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Zhenqi Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
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Vashisht A, Ahluwalia PK, Gahlay GK. A Comparative Analysis of the Altered Levels of Human Seminal Plasma Constituents as Contributing Factors in Different Types of Male Infertility. Curr Issues Mol Biol 2021; 43:1307-1324. [PMID: 34698062 PMCID: PMC8929149 DOI: 10.3390/cimb43030093] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 09/09/2021] [Accepted: 09/16/2021] [Indexed: 11/23/2022] Open
Abstract
(1) Background: The relationships between the biochemical and immunological components in seminal plasma and their physiological effects on male reproductive system have been underreported. In this study, we evaluated the potential of several seminal plasma biochemical and immunological markers in the pathophysiological developments of the infertile male patients. The study was designed to identify and assess different markers that may be associated with semen functions in different types of male infertility. (2) Methods: A total of 50 infertile male patients who underwent checkup for fertility assessment and 50 fertile controls were included in this study. The complete medical history of each recruited participant was reviewed. The infertile sub-groups (non-obstructive azoospermia (NOA), asthenozoospermia (AS), normozoospermic infertile (NI), and oligozoospermia (OZ)) were characterized based on sperm motility and concentration, while NI patients were included after a thorough check up of their female partners as well. We investigated each sample for 21 different analytes, enzymes, trace elements, and immunological markers to find crucial markers posing as contributing factors to a specific type of male infertility. (3) Results: The levels of 15 out of 21 markers, assayed from the seminal plasma of infertile males, were significantly altered in comparison to fertile controls (p < 0.05). For the first time, microprotein levels were also analyzed. The presence of monocytes, lymphocytes, and granulocytes was limited to semen from NOA patients, while a significant increase in the level of platelets was observed in AS. Hierarchical clustering and ROC-AUC analysis identified the three most significant markers (zinc, LDH, and TG) for the healthy control group and asthenozoospermic group (AUC, of 0.92 and 0.81, respectively). (4) Conclusions: The altered levels of biochemical and immunological markers in seminal plasma might be associated with the different male infertility profiles and could be required for the sperm metabolism and maintenance. However, a larger sample size and follow up analysis is required for establishing the hypothesized panel of markers as biomarkers at clinical stage.
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Affiliation(s)
- Ashutosh Vashisht
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India;
| | - Pankaj Kumar Ahluwalia
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA;
| | - Gagandeep Kaur Gahlay
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India;
- Correspondence: ; Tel.: +91-9878755211
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Hsing SC, Lin C, Chen JT, Chen YH, Fang WH. Glycemic Gap as a Useful Surrogate Marker for Glucose Variability and Progression of Diabetic Retinopathy. J Pers Med 2021; 11:jpm11080799. [PMID: 34442443 PMCID: PMC8401120 DOI: 10.3390/jpm11080799] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/13/2021] [Accepted: 08/14/2021] [Indexed: 12/22/2022] Open
Abstract
(1) Background: Recent studies have reported that the glucose variability (GV), irrespective of glycosylated hemoglobin (HbA1c), could be an additional risk factor for the development of diabetic retinopathy (DR). However, measurements for GV, such as continuous glucose monitoring (CGM) and fasting plasma glucose (FPG) variability, are expensive and time consuming. (2) Methods: This present study aims to explore the correlation between the glycemic gap as a measurement of GV, and DR. In total, 2565 patients were included in this study. We evaluated the effect of the different types of glycemic gaps on DR progression. (3) Results: We found that the area under the curve (AUC) values of both the glycemic gap and negative glycemic gap showed an association with DR progression. (4) Conclusions: On eliminating the possible influences of chronic blood glucose controls, the results show that GV has deleterious effects that are associated with the progression of DR. The glycemic gap is a simple measurement of GV, and the predictive value of the negative glycemic gap in DR progression shows that GV and treatment-related hypoglycemia may cause the development of DR. Individual treatment goals with a reasonable HbA1c and minimal glucose fluctuations may help in preventing DR.
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Affiliation(s)
- Shi-Chue Hsing
- National Defense Medical Center, Department of Internal Medicine, Tri-Service General Hospital, Taipei 11490, Taiwan;
| | - Chin Lin
- National Defense Medical Center, Graduate Institute of Life Sciences, Taipei 11490, Taiwan;
- National Defense Medical Center, School of Medicine, Taipei 11490, Taiwan
- National Defense Medical Center, School of Public Health, Taipei 11490, Taiwan
| | - Jiann-Torng Chen
- National Defense Medical Center, Department of Ophthalmology, Tri-Service General Hospital, Taipei 11490, Taiwan; (J.-T.C.); (Y.-H.C.)
| | - Yi-Hao Chen
- National Defense Medical Center, Department of Ophthalmology, Tri-Service General Hospital, Taipei 11490, Taiwan; (J.-T.C.); (Y.-H.C.)
| | - Wen-Hui Fang
- National Defense Medical Center, Department of Family and Community Medicine, Tri-Service General Hospital, No.161, Min-Chun E. Rd., Sec. 6, Neihu, Taipei 11490, Taiwan
- Correspondence: ; Tel.: +886-2-87923311 (ext. 12322); Fax: +886-2-66012632
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Hansen C, Olsen K, Pilegaard H, Bangsbo J, Gliemann L, Hellsten Y. High metabolic substrate load induces mitochondrial dysfunction in rat skeletal muscle microvascular endothelial cells. Physiol Rep 2021; 9:e14855. [PMID: 34288561 PMCID: PMC8290479 DOI: 10.14814/phy2.14855] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 12/21/2022] Open
Abstract
The influence of glucose and palmitic acid (PA) on mitochondrial respiration and emission of hydrogen peroxide (H2 O2 ) was determined in skeletal muscle-derived microvascular endothelial cells. Measurements were assessed in intact and permeabilized (cells treated with 0.025% saponin) low passage endothelial cells with acute-or prolonged (3 days) incubation with regular (1.7 mM) or elevated (2.2 mM) PA concentrations and regular (5 mM) or elevated (11 mM) glucose concentrations. In intact cells, acute incubation with 1.7 mM PA alone or with 1.7 mM PA + 5 mM glucose (p < .001) led to a lower mitochondrial respiration (p < 0.01) and markedly higher H2 O2 /O2 emission (p < 0.05) than with 5 mM glucose alone. Prolonged incubation of intact cells with 1.7 mM PA +5 mM glucose led to 34% (p < 0.05) lower respiration and 2.5-fold higher H2 O2 /O2 emission (p < 0.01) than incubation with 5 mM glucose alone. Prolonged incubation of intact cells with elevated glucose led to 60% lower (p < 0.05) mitochondrial respiration and 4.6-fold higher H2 O2 /O2 production than incubation with 5 mM glucose in intact cells (p < 0.001). All effects observed in intact cells were present also in permeabilized cells (State 2). In conclusion, our results show that acute and prolonged lipid availability, as well as prolonged hyperglycemia, induces mitochondrial dysfunction as evidenced by lower mitochondrial respiration and enhanced H2 O2/ O2 emission. Elevated plasma substrate availability may lead to microvascular dysfunction in skeletal muscle by impairing endothelial mitochondrial function.
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Affiliation(s)
- Camilla Hansen
- Department of Nutrition, Exercise and SportsCardiovascular Physiology GroupSection of Integrative PhysiologyUniversity of CopenhagenCopenhagenDenmark
| | - Karina Olsen
- Department of Nutrition, Exercise and SportsCardiovascular Physiology GroupSection of Integrative PhysiologyUniversity of CopenhagenCopenhagenDenmark
| | - Henriette Pilegaard
- Department of BiologySection of Cell Biology and PhysiologyUniversity of CopenhagenCopenhagenDenmark
| | - Jens Bangsbo
- Department of Nutrition, Exercise and SportsSection of Integrative PhysiologyUniversity of CopenhagenCopenhagenDenmark
| | - Lasse Gliemann
- Department of Nutrition, Exercise and SportsCardiovascular Physiology GroupSection of Integrative PhysiologyUniversity of CopenhagenCopenhagenDenmark
| | - Ylva Hellsten
- Department of Nutrition, Exercise and SportsCardiovascular Physiology GroupSection of Integrative PhysiologyUniversity of CopenhagenCopenhagenDenmark
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Dai L, Ren M, Lin W. Development of a novel NIR viscosity fluorescent probe for visualizing the kidneys in diabetic mice. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2021; 254:119627. [PMID: 33714915 DOI: 10.1016/j.saa.2021.119627] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/22/2021] [Accepted: 02/09/2021] [Indexed: 06/12/2023]
Abstract
Viscosity is an important parameter for evaluating cell health, and abnormal viscosity can cause a variety of intracellular organelle function disorders. The mitochondria are a key organelle in cells, and the viscosity of the mitochondria determines the state of the cell. In this work, we report a novel near-infrared fluorescent probe, referred to as NI-VD, that has a large Stokes-shift and a satisfactory response multiple. NI-VD can sensitively detect changes in cell viscosity in cells and tissues, and it can effectively avoid interference from the overlap of excitation and emission light. The fluorescence spectrum shows that NI-VD has maximum emission peaks at 730 nm, and the fluorescence intensity is amplified with an increase in the solution viscosity. The response from pure PBS solution to glycerol changes by 13-fold. After confirmation in a variety of cell and biological models, NI-VD can detect the changes in viscosity in mitochondria. Most importantly, this study is the first to visualize the differences between the kidneys of diabetic mice and normal mice. This approach is a new solution for the diagnosis and treatment of diabetic nephropathy.
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Affiliation(s)
- Lixuan Dai
- Institute of Fluorescent Probes for Biological Imaging, School of Chemistry and Chemical Engineering, School of Materials Science and Engineering, University of Jinan, Jinan, Shandong 250022, China
| | - Mingguang Ren
- Institute of Fluorescent Probes for Biological Imaging, School of Chemistry and Chemical Engineering, School of Materials Science and Engineering, University of Jinan, Jinan, Shandong 250022, China; State Key Laboratory of Biobased Material and Green Papermaking, Shandong Academy of Sciences, Qilu University of Technology, Jinan 250353, China
| | - Weiying Lin
- Institute of Fluorescent Probes for Biological Imaging, School of Chemistry and Chemical Engineering, School of Materials Science and Engineering, University of Jinan, Jinan, Shandong 250022, China; Guangxi Key Laboratory of Electrochemical Energy Materials, Institute of Optical Materials and Chemical Biology, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi 530004, China.
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Age and sex modify cellular proliferation responses to oxidative stress and glucocorticoid challenges in baboon cells. GeroScience 2021; 43:2067-2085. [PMID: 34089175 DOI: 10.1007/s11357-021-00395-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 05/27/2021] [Indexed: 10/21/2022] Open
Abstract
Aging is associated with progressive loss of cellular homeostasis resulting from intrinsic and extrinsic challenges. Lack of a carefully designed, well-characterized, precise, translational experimental model is a major limitation to understanding the cellular perturbations that characterize aging. Here, we tested the feasibility of primary fibroblasts isolated from nonhuman primates (baboons) as a model of cellular resilience in response to homeostatic challenge. Using a real-time live-cell imaging system, we precisely defined a protocol for testing effects of prooxidant compounds (e.g., hydrogen peroxide (H2O2), paraquat), thapsigargin, dexamethasone, and a low glucose environment on cell proliferation in fibroblasts derived from baboons across the life course (n = 11/sex). Linear regression analysis indicated that donor age significantly reduced the ability of cells to proliferate following exposure to H2O2 (50 and 100 µM) and paraquat (100 and 200 µM) challenges in cells from males (6.4-21.3 years; average lifespan 21 years) but not cells from females (4.3-15.9 years). Inhibitory effects of thapsigargin on cell proliferation were dependent on challenge duration (2 vs 24 h) and concentration (0.1 and 1 µM). Cells from older females (14.4-15.9 years) exhibited greater resilience to thapsigargin (1 µM; 24 h) and dexamethasone (500 µM) challenges than did those from younger females (4.3-6.7 years). The cell proliferation response to low glucose (1 mM) was reduced with age in both sexes. These data indicate that donor's chronological age and sex are important variables in determining fibroblast responses to metabolite and other challenges.
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Cindro PV, Krnić M, Modun D, Smajić B, Vuković J. The differences between insulin glargine U300 and insulin degludec U100 in impact on the glycaemic variability, arterial stiffness and the lipid profiles in insulin naïve patients suffering from type two diabetes mellitus - outcomes from cross-over open-label randomized trial. BMC Endocr Disord 2021; 21:86. [PMID: 33926446 PMCID: PMC8082786 DOI: 10.1186/s12902-021-00746-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/12/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND AIMS Diabetes mellitus type two is one of the major cardiovascular risk factors. Treatment of diabetes can reduce this risk, but the treatment options differ a lot in their risk-reducing capabilities. We compared the impact of insulin degludec (IDeg-100) and insulin glargine U300 (IGlar-300) on cardiovascular risk parameters - glycaemic variability (GV), arterial stiffness and lipid parameters - in insulin naive patients with DMT2. METHODS To 23 individuals who previously had uncontrolled DMT2 on two or more oral antidiabetic drugs, IGlar-300 and IDeg-100 were applied for 12 weeks and then switched in a cross over design manner. Prior and after of each insulin phase, we analysed biochemical parameters,7-point SMBG profile over three days and arterial stiffness which was assessed indirectly by measuring the augmentation index (AIx) on the principles of applanation tonometry. RESULTS There were no significant differences between IGlar-300 and IDeg-100 regarding reduction of mean glucose values and coefficient of variation (CV). Both insulins insignificantly reduced AIx for standardised pulse of 75 beats/min and without differences between them. IGlar-300 and IDeg-100 reduced triglycerides and increased HDL with no significant difference between the two insulins. IGlar-300 increased the total cholesterol level and IDeg-100 decreased total cholesterol, but without statistically significant difference. IGlar-300 increased LDL level by 0.508 mmol/L and IDeg-100 decreased LDL by 0.217 mmol/L, with statistically significant difference (p = 0.0215). CONCLUSIONS This study did not show significant difference between IGlar-300 and IDeg-100 regarding glycaemic parameters and augmentation index using the same dose of 0.2 IU/kg for both insulins, but it has revealed possible differences in impact on lipid profile. TRIAL REGISTRATION Clinicaltrials.gov, NCT04692415 . Retrospectively registered on December 31th 2020.
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Affiliation(s)
- Pavle Vrebalov Cindro
- Department of Gastroenterology, University Hospital Split, Spinčićeva 1, 21000, Split, Croatia
| | - Mladen Krnić
- Department of Endocrinology, University Hospital Split, Šoltanska 1, 21000, Split, Croatia.
- Department of Pathophysiology, University of Split School of Medicine, Šoltanska 2, 21000, Split, Croatia.
| | - Darko Modun
- Department of Pharmacy, University of Split School of Medicine, Šoltanska 2, 21000, Split, Croatia
| | - Božo Smajić
- Medical Student, University of Split School of Medicine, Šoltanska 2, 21000, Split, Croatia
| | - Jonatan Vuković
- Department of Gastroenterology, University Hospital Split, Spinčićeva 1, 21000, Split, Croatia
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Akhan O, Ardahanli I. Hypoglycemia in the emergency, is there any effect on endothelial and diastolic functions? Echocardiography 2021; 38:450-459. [PMID: 33539572 DOI: 10.1111/echo.14988] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/16/2021] [Accepted: 01/18/2021] [Indexed: 01/14/2023] Open
Abstract
INTRODUCTION Several homeostatic changes like an increase in sympathoadrenal response and oxidative stress occur in hypoglycemia. As a result of these findings, an increase in inflammation and preatherogenic factors is observed, and these changes may lead to endothelial dysfunction. AIM Our study aims to reveal possible cardiac risks (systolic-diastolic functions and endothelial dysfunctions) in patients who have applied to the emergency department with hypoglycemia. METHODS This cross-sectional, case-control study included 46 hypoglycemia patients who admitted to the emergency with symptoms compatible with hypoglycemia and diagnosed with hypoglycemia and 30 healthy volunteers. All patients were evaluated with baseline echocardiography, tissue-Doppler imaging (carotid and brachial artery). Also, the fasting blood tests of the patients referred to the internal medicine department were examined. RESULTS There were no differences between the groups regarding age, weight, body mass index, and systolic blood pressure. Total cholesterol, LDL, HDL, Vitamin B12, TSH, and fasting blood glucose levels were similar in the groups' blood tests (all P values > .05). We observed a statistically significant decrease in diastolic dysfunction parameters: E/A and E/e' ratios (respectively, P = .020 and 0.026). It was shown that insulin resistance was influential in forming these considerable differences. The patient group observed that the carotid intima-media thickness was more remarkable (P = .001), and the brachial flow-mediated dilatation value was smaller (P = .003), giving an idea about endothelial functions. CONCLUSION As a message, we can say that hypoglycemia may affect diastolic functions in addition to endothelial dysfunction. Therefore, even young individuals without any chronic diseases may need follow-up in terms of possible risks.
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Affiliation(s)
- Onur Akhan
- Cardiology, Bilecik Training and Research Hospital, Bilecik, Turkey
| | - Isa Ardahanli
- Cardiology, Bilecik Training and Research Hospital, Bilecik, Turkey
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35
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Endothelial response to glucose: dysfunction, metabolism, and transport. Biochem Soc Trans 2021; 49:313-325. [PMID: 33522573 DOI: 10.1042/bst20200611] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 12/23/2020] [Accepted: 01/04/2021] [Indexed: 02/07/2023]
Abstract
The endothelial cell response to glucose plays an important role in both health and disease. Endothelial glucose-induced dysfunction was first studied in diabetic animal models and in cells cultured in hyperglycemia. Four classical dysfunction pathways were identified, which were later shown to result from the common mechanism of mitochondrial superoxide overproduction. More recently, non-coding RNA, extracellular vesicles, and sodium-glucose cotransporter-2 inhibitors were shown to affect glucose-induced endothelial dysfunction. Endothelial cells also metabolize glucose for their own energetic needs. Research over the past decade highlighted how manipulation of endothelial glycolysis can be used to control angiogenesis and microvascular permeability in diseases such as cancer. Finally, endothelial cells transport glucose to the cells of the blood vessel wall and to the parenchymal tissue. Increasing evidence from the blood-brain barrier and peripheral vasculature suggests that endothelial cells regulate glucose transport through glucose transporters that move glucose from the apical to the basolateral side of the cell. Future studies of endothelial glucose response should begin to integrate dysfunction, metabolism and transport into experimental and computational approaches that also consider endothelial heterogeneity, metabolic diversity, and parenchymal tissue interactions.
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36
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Lee S, Liu T, Zhou J, Zhang Q, Wong WT, Tse G. Predictions of diabetes complications and mortality using hba1c variability: a 10-year observational cohort study. Acta Diabetol 2021; 58:171-180. [PMID: 32939583 DOI: 10.1007/s00592-020-01605-6] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 09/09/2020] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Emerging evidence suggests that HbA1c variability, in addition to HbA1c itself, can be used as a predictor for mortality. The present study aims to examine the predictive power of mean HbA1c and HbA1c variability measures for diabetic complications as well as mortality. METHODS The retrospective observational study analyzed diabetic patients who were prescribed insulin at outpatient clinics of the Prince of Wales Hospital and Shatin Hospital, Hong Kong, from 1 January to 31 December, 2009. Standard deviation (SD), root mean square (RMS), and coefficient of variation were used as measures of HbA1c variability. The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes were diabetes-related complications. RESULTS The study cohort consists of 3424 patients, including 3137 patients with at least three HbA1c measurements. The low mean HbA1c subgroup had significantly shorter time-to-death for all-cause mortality (P < 0.001) but not cardiovascular mortality (P = 0.920). The high Hba1c subgroup showed shorter time-to-death for all-cause (P < 0.001) and cardiovascular mortality (P < 0.001). Mean Hba1c and Hba1c variability predicted all-cause as well as cardiovascular-specific mortality. In terms of secondary outcomes, mean HbA1c and HbA1c variability significantly predicted diabetic ketoacidosis/hyperosmolar hyperglycemic state/diabetic coma, neurological, ophthalmological, and renal complications. A significant association between dichotomized HbA1c variability and hypoglycemia frequency was found (P < 0.0001). CONCLUSION High HbA1c variability is associated with increased risk of all-cause and cardiovascular mortality, as well as diabetic complications. The association between hypoglycemic frequency, HbA1c variability, and mortality suggests that intermittent hypoglycemia resulting in poorer outcomes in diabetic patients.
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Affiliation(s)
- Sharen Lee
- Laboratory of Cardiovascular Physiology, Li Ka Shing Institute of Health Sciences, Hong Kong, China
| | - Tong Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People's Republic of China
| | - Jiandong Zhou
- School of Data Science, City University of Hong Kong, Hong Kong, China
| | - Qingpeng Zhang
- School of Data Science, City University of Hong Kong, Hong Kong, China
| | - Wing Tak Wong
- School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China.
| | - Gary Tse
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People's Republic of China.
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Mani BK, Osborne-Lawrence S, Metzger N, Zigman JM. Lowering oxidative stress in ghrelin cells stimulates ghrelin secretion. Am J Physiol Endocrinol Metab 2020; 319:E330-E337. [PMID: 32543942 PMCID: PMC7473909 DOI: 10.1152/ajpendo.00119.2020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Ghrelin is a predominantly stomach-derived peptide hormone with many actions including regulation of food intake, body weight, and blood glucose. Plasma ghrelin levels are robustly regulated by feeding status, with its levels increasing upon caloric restriction and decreasing after food intake. At least some of this regulation might be due to direct responsiveness of ghrelin cells to changes in circulating nutrients, including glucose. Indeed, oral and parental glucose administration to humans and mice lower plasma ghrelin. Also, dissociated mouse gastric mucosal cell preparations, which contain ghrelin cells, decrease ghrelin secretion when cultured in high ambient glucose. Here, we used primary cultures of mouse gastric mucosal cells in combination with an array of pharmacological tools to examine the potential role of changed intracellular oxidative stress in glucose-restricted ghrelin secretion. The antioxidants resveratrol, SRT1720, and curcumin all markedly increased ghrelin secretion. Furthermore, three different selective activators of Nuclear factor erythroid-derived-2-like 2 (Nrf2), a master regulator of the antioxidative cellular response to oxidative stress, increased ghrelin secretion. These antioxidant compounds blocked the inhibitory effects of glucose on ghrelin secretion. Therefore, we conclude that lowering oxidative stress within ghrelin cells stimulates ghrelin secretion and blocks the direct effects of glucose on ghrelin cells to inhibit ghrelin secretion.
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Affiliation(s)
- Bharath K Mani
- Center for Hypothalamic Research and Division of Endocrinology, Department of Internal Medicine and Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Sherri Osborne-Lawrence
- Center for Hypothalamic Research and Division of Endocrinology, Department of Internal Medicine and Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Nathan Metzger
- Center for Hypothalamic Research and Division of Endocrinology, Department of Internal Medicine and Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jeffrey M Zigman
- Center for Hypothalamic Research and Division of Endocrinology, Department of Internal Medicine and Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
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Wright WS, Eshaq RS, Lee M, Kaur G, Harris NR. Retinal Physiology and Circulation: Effect of Diabetes. Compr Physiol 2020; 10:933-974. [PMID: 32941691 PMCID: PMC10088460 DOI: 10.1002/cphy.c190021] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
In this article, we present a discussion of diabetes and its complications, including the macrovascular and microvascular effects, with the latter of consequence to the retina. We will discuss the anatomy and physiology of the retina, including aspects of metabolism and mechanisms of oxygenation, with the latter accomplished via a combination of the retinal and choroidal blood circulations. Both of these vasculatures are altered in diabetes, with the retinal circulation intimately involved in the pathology of diabetic retinopathy. The later stages of diabetic retinopathy involve poorly controlled angiogenesis that is of great concern, but in our discussion, we will focus more on several alterations in the retinal circulation occurring earlier in the progression of disease, including reductions in blood flow and a possible redistribution of perfusion that may leave some areas of the retina ischemic and hypoxic. Finally, we include in this article a more recent area of investigation regarding the diabetic retinal vasculature, that is, the alterations to the endothelial surface layer that normally plays a vital role in maintaining physiological functions. © 2020 American Physiological Society. Compr Physiol 10:933-974, 2020.
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Affiliation(s)
- William S Wright
- Department of Biomedical Sciences, University of South Carolina School of Medicine Greenville, Greenville, South Carolina, USA
| | - Randa S Eshaq
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, Louisiana, USA
| | - Minsup Lee
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, Louisiana, USA
| | - Gaganpreet Kaur
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, Louisiana, USA
| | - Norman R Harris
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, Louisiana, USA
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Jansen T, Kvandová M, Daiber A, Stamm P, Frenis K, Schulz E, Münzel T, Kröller-Schön S. The AMP-Activated Protein Kinase Plays a Role in Antioxidant Defense and Regulation of Vascular Inflammation. Antioxidants (Basel) 2020; 9:antiox9060525. [PMID: 32560060 PMCID: PMC7346208 DOI: 10.3390/antiox9060525] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/10/2020] [Accepted: 06/11/2020] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases represent the leading cause of global deaths and life years spent with a severe disability. Endothelial dysfunction and vascular oxidative stress are early precursors of atherosclerotic processes in the vascular wall, all of which are hallmarks in the development of cardiovascular diseases and predictors of future cardiovascular events. There is growing evidence that inflammatory processes represent a major trigger for endothelial dysfunction, vascular oxidative stress and atherosclerosis and clinical data identified inflammation as a cardiovascular risk factor on its own. AMP-activated protein kinase (AMPK) is a central enzyme of cellular energy balance and metabolism that has been shown to confer cardio-protection and antioxidant defense which thereby contributes to vascular health. Interestingly, AMPK is also redox-regulated itself. We have previously shown that AMPK largely contributes to a healthy endothelium, confers potent antioxidant effects and prevents arterial hypertension. Recently, we provided deep mechanistic insights into the role of AMPK in cardiovascular protection and redox homeostasis by studies on arterial hypertension in endothelial and myelomonocytic cell-specific AMPK knockout (Cadh5CrexAMPKfl/fl and LysMCrexAMPKfl/fl) mice. Using these cell-specific knockout mice, we revealed the potent anti-inflammatory properties of AMPK representing the molecular basis of the antihypertensive effects of AMPK. Here, we discuss our own findings in the context of literature data with respect to the anti-inflammatory and antioxidant effects of AMPK in the specific setting of arterial hypertension as well as cardiovascular diseases in general.
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Affiliation(s)
- Thomas Jansen
- Center for Cardiology, Department of Cardiology 1—Molecular Cardiology, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany; (T.J.); (M.K.); (P.S.); (K.F.); (T.M.)
| | - Miroslava Kvandová
- Center for Cardiology, Department of Cardiology 1—Molecular Cardiology, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany; (T.J.); (M.K.); (P.S.); (K.F.); (T.M.)
| | - Andreas Daiber
- Center for Cardiology, Department of Cardiology 1—Molecular Cardiology, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany; (T.J.); (M.K.); (P.S.); (K.F.); (T.M.)
- Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Langenbeckstr. 1, 55131 Mainz, Germany
- Correspondence: (A.D.); (S.K.-S); Tel.: +49-(0)6131-176280 (A.D.); Fax: +49-(0)6131-176293 (A.D.)
| | - Paul Stamm
- Center for Cardiology, Department of Cardiology 1—Molecular Cardiology, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany; (T.J.); (M.K.); (P.S.); (K.F.); (T.M.)
| | - Katie Frenis
- Center for Cardiology, Department of Cardiology 1—Molecular Cardiology, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany; (T.J.); (M.K.); (P.S.); (K.F.); (T.M.)
| | - Eberhard Schulz
- Department of Cardiology, Allgemeines Krankenhaus Celle, 29223 Celle, Germany;
| | - Thomas Münzel
- Center for Cardiology, Department of Cardiology 1—Molecular Cardiology, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany; (T.J.); (M.K.); (P.S.); (K.F.); (T.M.)
- Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Langenbeckstr. 1, 55131 Mainz, Germany
| | - Swenja Kröller-Schön
- Center for Cardiology, Department of Cardiology 1—Molecular Cardiology, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany; (T.J.); (M.K.); (P.S.); (K.F.); (T.M.)
- Correspondence: (A.D.); (S.K.-S); Tel.: +49-(0)6131-176280 (A.D.); Fax: +49-(0)6131-176293 (A.D.)
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Zhang C, Tang M, Lu X, Zhou Y, Zhao W, Liu Y, Liu Y, Guo X. Relationship of ankle-brachial index, vibration perception threshold, and current perception threshold to glycemic variability in type 2 diabetes. Medicine (Baltimore) 2020; 99:e19374. [PMID: 32195933 PMCID: PMC7220673 DOI: 10.1097/md.0000000000019374] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
To explore the relationship of glycemic variability with lower extremity arterial disease (LEAD) and diabetic peripheral neuropathy (DPN).Seventy-eight patients with type 2 diabetes were enrolled. All patients underwent 72-hour dynamic blood glucose monitoring and obtained mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD), standard deviation of blood glucose (SD), largest amplitude of glycemic excursion (LAGE), mean blood glucose (MBG), T≥10.0 (percentage of time for blood glucose levels ≥10.0 mmol/L), T≤3.9 (percentage of time for blood glucose levels ≤3.9 mmol/L), and other glycemic variability parameters. In the meanwhile, in order to explore the correlation of glycemic variability parameters with ankle-brachial index (ABI), vibration perception threshold (VPT), and current perception threshold (CPT), all patients underwent quantitative diabetic foot screening, including ABI for quantitative assessment of lower extremity arterial lesions and VPT and CPT for quantitative assessment of peripheral neuropathy.Patients were divided into abnormal CPT group (n = 21) and normal CPT group (n = 57) according to the CPT values. Compared with the normal CPT group, abnormal CPT group showed significantly higher levels of HbA1c, longer duration of diabetes, and higher levels of T≤3.9 (P < .05). However, there was no significant difference of MAGE, SD, LAGE, MODD, and other glycemic variability parameters between abnormal CPT group and normal CPT group (P > .05). Pearson correlation analysis or Spearman correlation analysis showed that ABI negatively correlated with MBG, T≥10.0, SD, LAGE, and MAGE (P < .05), but no correlation of ABI with T≤3.9 and MODD (P > .05) was shown. VPT showed a positive correlation with T≥10.0 (P < .05), but no correlation with other glycemic variability parameters (P > .05). There was no correlation between the other CPT values and the glycemic variability parameters (P > .05), except that the left and right 250 Hz CPT values were positively correlated with T≤3.9 (P > .05).The higher the blood glucose levels, the severer the degree of LEAD and DPN lesions; the higher the incidence of hypoglycemia, the severer the degree of DPN lesions; the greater the fluctuation of blood glucose, the severer the degree of LEAD lesions. However, the glycemic variability was not significantly correlated with DPN.
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Affiliation(s)
- Chuangbiao Zhang
- Department of Endocrinology, First Affiliated Hospital of Jinan University
| | - Meili Tang
- Department of Endocrinology, First Affiliated Hospital of Jinan University
| | - Xiaohua Lu
- Department of Endocrinology, First Affiliated Hospital of Jinan University
| | - Yan Zhou
- Department of Endocrinology, First Affiliated Hospital of Jinan University
- College of Nursing, Jinan University, Guangzhou
| | - Wane Zhao
- Department of Endocrinology, First Affiliated Hospital of Jinan University
- College of Nursing, Jinan University, Guangzhou
| | - Yu Liu
- Department of Endocrinology, First Affiliated Hospital of Jinan University
- College of Nursing, Jinan University, Guangzhou
| | - Yan Liu
- Department of Endocrinology, First Affiliated Hospital of Jinan University
- College of Nursing, Jinan University, Guangzhou
| | - Xiujie Guo
- Department of Endocrinology, Qingyuan People's Hospital, Qingyuan, Guangdong Province, China
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Bøtker HE, Cabrera-Fuentes HA, Ruiz-Meana M, Heusch G, Ovize M. Translational issues for mitoprotective agents as adjunct to reperfusion therapy in patients with ST-segment elevation myocardial infarction. J Cell Mol Med 2020; 24:2717-2729. [PMID: 31967733 PMCID: PMC7077531 DOI: 10.1111/jcmm.14953] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 11/26/2019] [Accepted: 11/27/2019] [Indexed: 12/16/2022] Open
Abstract
Pre‐clinical studies have indicated that mitoprotective drugs may add cardioprotection beyond rapid revascularization, antiplatelet therapy and risk modification. We review the clinical efficacy of mitoprotective drugs that have progressed to clinical testing comprising cyclosporine A, KAI‐9803, MTP131 and TRO 40303. Whereas cyclosporine may reduce infarct size in patients undergoing primary angioplasty as evaluated by release of myocardial ischaemic biomarkers and infarct size imaging, the other drugs were not capable of demonstrating this effect in the clinical setting. The absent effect leaves the role of the mitochondrial permeability transition pore for reperfusion injury in humans unanswered and indicates that targeting one single mechanism to provide mitoprotection may not be efficient. Moreover, the lack of effect may relate to favourable outcome with current optimal therapy, but conditions such as age, sex, diabetes, dyslipidaemia and concurrent medications may also alter mitochondrial function. However, as long as the molecular structure of the pore remains unknown and specific inhibitors of its opening are lacking, the mitochondrial permeability transition pore remains a target for alleviation of reperfusion injury. Nevertheless, taking conditions such as ageing, sex, comorbidities and co‐medication into account may be of paramount importance during the design of pre‐clinical and clinical studies testing mitoprotective drugs.
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Affiliation(s)
- Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark
| | - Hector Alejandro Cabrera-Fuentes
- SingHealth Duke-NUS Cardiovascular Sciences Academic Clinical Programme and Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.,National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore.,Institute of Biochemistry, Medical School, Justus-Liebig University, Giessen, Germany.,Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Monterrey, Mexico.,Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russian Federation
| | - Marisol Ruiz-Meana
- Vall d'Hebron Institut de Recerca, University Hospital Vall d'Hebron-Universitat Autònoma, Barcelona, Spain.,Centro de Investigación Biomédica en Red-CV, CIBER-CV, Spain
| | - Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen. Medical School, Essen, Germany
| | - Michel Ovize
- CarMeN Laboratory, Hôpital Louis Pradel, Hospices Civils de Lyon, Université de Lyon and Explorations Fonctionnelles Cardiovasculaires, INSERM U1060, Lyon, France
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Jegal ME, Jung SY, Han YS, Kim YJ. C-terminal truncated HBx reduces doxorubicin cytotoxicity via ABCB1 upregulation in Huh-7 hepatocellular carcinoma cells. BMB Rep 2019. [PMID: 30982500 PMCID: PMC6549916 DOI: 10.5483/bmbrep.2019.52.5.312] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV) encoding the HBV x protein (HBx) is a known causative agent of hepatocellular carcinoma (HCC). Its pathogenic activities in HCC include interference with several signaling pathways associated with cell proliferation and apoptosis. Mutant C-terminal-truncated HBx isoforms are frequently found in human HCC and have been shown to enhance proliferation and invasiveness leading to HCC malignancy. We investigated the molecular mechanism of the reduced doxorubicin cytotoxicity by C-terminal truncated HBx. Cells transfected with C-terminal truncated HBx exhibited reduced cytotoxicity to doxorubicin compared to those transfected with full-length HBx. The doxorubicin resistance of cells expressing C-terminal truncated HBx correlated with upregulation of the ATP binding cassette subfamily B member 1(ABCB1) transporter, resulting in the enhanced efflux of doxorubicin. Inhibiting the activity of ABCB1 and silencing ABCB1 expression by small interfering ribonucleic acid (siRNA) increased the cytotoxicity of doxorubicin. These results indicate that elevated ABCB1 expression induced by C-terminal truncation of HBx was responsible for doxorubicin resistance in HCC. Hence, co-treatment with an ABCB1 inhibitor and an anticancer agent may be effective for the treatment of patients with liver cancer containing the C-terminal truncated HBx.
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Affiliation(s)
- Myeong-Eun Jegal
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Korea
| | - Seung-Youn Jung
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Korea
| | - Yu-Seon Han
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Korea
| | - Yung-Jin Kim
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Korea
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Kakarla M, Puppala VK, Tyagi S, Anger A, Repp K, Wang J, Ying R, Widlansky ME. Circulating levels of mitochondrial uncoupling protein 2, but not prohibitin, are lower in humans with type 2 diabetes and correlate with brachial artery flow-mediated dilation. Cardiovasc Diabetol 2019; 18:148. [PMID: 31706320 PMCID: PMC6842161 DOI: 10.1186/s12933-019-0956-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 10/28/2019] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Excessive reactive oxygen species from endothelial mitochondria in type 2 diabetes individuals (T2DM) may occur through multiple related mechanisms, including production of mitochondrial reactive oxygen species (mtROS), inner mitochondrial membrane (Δψm) hyperpolarization, changes in mitochondrial mass and membrane composition, and fission of the mitochondrial networks. Inner mitochondrial membrane proteins uncoupling protein-2 (UCP2) and prohibitin (PHB) can favorably impact mtROS and mitochondrial membrane potential (Δψm). Circulating levels of UCP2 and PHB could potentially serve as biomarker surrogates for vascular health in patients with and without T2DM. METHODS Plasma samples and data from a total of 107 individuals with (N = 52) and without T2DM (N = 55) were included in this study. Brachial artery flow mediated dilation (FMD) was measured by ultrasound. ELISA was performed to measure serum concentrations of PHB1 and UCP2. Mitochondrial membrane potential was measured from isolated leukocytes using JC-1 dye. RESULTS Serum UCP2 levels were significantly lower in T2DM subjects compared to control subjects (3.01 ± 0.34 vs. 4.11 ± 0.41 ng/mL, P = 0.04). There were no significant differences in levels of serum PHB. UCP2 levels significantly and positively correlated with FMDmm (r = 0.30, P = 0.03) in T2DM subjects only and remained significant after multivariable adjustment. Within T2DM subjects, serum PHB levels were significantly and negatively correlated with UCP2 levels (ρ = - 0.35, P = 0.03). CONCLUSION Circulating UCP2 levels are lower in T2DM patients and correlate with endothelium-dependent vasodilation in conduit vessels. UCP2 could be biomarker surrogate for overall vascular health in patients with T2DM and merits additional investigation.
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Affiliation(s)
- Mamatha Kakarla
- Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Hub for Collaborative Medicine, 5th Floor A5743, 8701 W. Watertown Plank Road, Milwaukee, WI, 53226, USA.
| | - Venkata K Puppala
- Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Hub for Collaborative Medicine, 5th Floor A5743, 8701 W. Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Sudhi Tyagi
- Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Hub for Collaborative Medicine, 5th Floor A5743, 8701 W. Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Amberly Anger
- Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Hub for Collaborative Medicine, 5th Floor A5743, 8701 W. Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Kathryn Repp
- Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Hub for Collaborative Medicine, 5th Floor A5743, 8701 W. Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Jingli Wang
- Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Hub for Collaborative Medicine, 5th Floor A5743, 8701 W. Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Rong Ying
- Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Hub for Collaborative Medicine, 5th Floor A5743, 8701 W. Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Michael E Widlansky
- Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Hub for Collaborative Medicine, 5th Floor A5743, 8701 W. Watertown Plank Road, Milwaukee, WI, 53226, USA.,Department of Pharmacology, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
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Nyunt T, Britton M, Wanichthanarak K, Budamagunta M, Voss JC, Wilson DW, Rutledge JC, Aung HH. Mitochondrial oxidative stress-induced transcript variants of ATF3 mediate lipotoxic brain microvascular injury. Free Radic Biol Med 2019; 143:25-46. [PMID: 31356870 PMCID: PMC6848793 DOI: 10.1016/j.freeradbiomed.2019.07.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 06/30/2019] [Accepted: 07/23/2019] [Indexed: 12/06/2022]
Abstract
Elevation of blood triglycerides, primarily triglyceride-rich lipoproteins (TGRL), is an independent risk factor for cardiovascular disease and vascular dementia (VaD). Accumulating evidence indicates that both atherosclerosis and VaD are linked to vascular inflammation. However, the role of TGRL in vascular inflammation, which increases risk for VaD, remains largely unknown and its underlying mechanisms are still unclear. We strived to determine the effects of postprandial TGRL exposure on brain microvascular endothelial cells, the potential risk factor of vascular inflammation, resulting in VaD. We showed in Aung et al., J Lipid Res., 2016 that postprandial TGRL lipolysis products (TL) activate mitochondrial reactive oxygen species (ROS) and increase the expression of the stress-responsive protein, activating transcription factor 3 (ATF3), which injures human brain microvascular endothelial cells (HBMECs) in vitro. In this study, we deployed high-throughput sequencing (HTS)-based RNA sequencing methods and mito stress and glycolytic rate assays with an Agilent Seahorse XF analyzer and profiled the differential expression of transcripts, constructed signaling pathways, and measured mitochondrial respiration, ATP production, proton leak, and glycolysis of HBMECs treated with TL. Conclusions: TL potentiate ROS by mitochondria which activate mitochondrial oxidative stress, decrease ATP production, increase mitochondrial proton leak and glycolysis rate, and mitochondria DNA damage. Additionally, CPT1A1 siRNA knockdown suppresses oxidative stress and prevents mitochondrial dysfunction and vascular inflammation in TL treated HBMECs. TL activates ATF3-MAPKinase, TNF, and NRF2 signaling pathways. Furthermore, the NRF2 signaling pathway which is upstream of the ATF3-MAPKinase signaling pathway, is also regulated by the mitochondrial oxidative stress. We are the first to report differential inflammatory characteristics of transcript variants 4 (ATF3-T4) and 5 (ATF3-T5) of the stress responsive gene ATF3 in HBMECs induced by postprandial TL. Specifically, our data indicates that ATF3-T4 predominantly regulates the TL-induced brain microvascular inflammation and TNF signaling. Both siRNAs of ATF3-T4 and ATF3-T5 suppress cells apoptosis and lipotoxic brain microvascular endothelial cells. These novel signaling pathways triggered by oxidative stress-responsive transcript variants, ATF3-T4 and ATF3-T5, in the brain microvascular inflammation induced by TGRL lipolysis products may contribute to pathophysiological processes of vascular dementia.
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Affiliation(s)
- Tun Nyunt
- Division of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, University of California, Davis, Davis, CA, 95616, USA
| | - Monica Britton
- Genome Center and Bioinformatics Core Facility, University of California, Davis, CA, 95616, USA
| | - Kwanjeera Wanichthanarak
- West Coast Metabolomics Center, Genome Center, University of California Davis, Davis, CA, USA; Department of Biochemistry and Siriraj Metabolomics and Phenomics Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Madhu Budamagunta
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, 95616, USA
| | - John C Voss
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, 95616, USA
| | - Dennis W Wilson
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA, 95616, USA
| | - John C Rutledge
- Division of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, University of California, Davis, Davis, CA, 95616, USA
| | - Hnin H Aung
- Division of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, University of California, Davis, Davis, CA, 95616, USA.
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Shah FA, Mahmud H, Gallego-Martin T, Jurczak MJ, O’Donnell CP, McVerry BJ. Therapeutic Effects of Endogenous Incretin Hormones and Exogenous Incretin-Based Medications in Sepsis. J Clin Endocrinol Metab 2019; 104:5274-5284. [PMID: 31216011 PMCID: PMC6763279 DOI: 10.1210/jc.2019-00296] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 06/13/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Sepsis, a complex disorder characterized by a dysregulated immune response to an inciting infection, affects over one million Americans annually. Dysglycemia during sepsis hospitalization confers increased risk of organ dysfunction and death, and novel targets for the treatment of sepsis and maintenance of glucose homeostasis are needed. Incretin hormones are secreted by enteroendocrine cells in response to enteral nutrients and potentiate insulin release from pancreatic β cells in a glucose-dependent manner, thereby reducing the risk of insulin-induced hypoglycemia. Incretin hormones also reduce systemic inflammation in preclinical studies, but studies of incretins in the setting of sepsis are limited. METHODS In this bench-to-bedside mini-review, we detail the evidence to support incretin hormones as a therapeutic target in patients with sepsis. We performed a PubMed search using the medical subject headings "incretins," "glucagon-like peptide-1," "gastric inhibitory peptide," "inflammation," and "sepsis." RESULTS Incretin-based therapies decrease immune cell activation, inhibit proinflammatory cytokine release, and reduce organ dysfunction and mortality in preclinical models of sepsis. Several small clinical trials in critically ill patients have suggested potential benefit in glycemic control using exogenous incretin infusions, but these studies had limited power and were performed in mixed populations. Further clinical studies examining incretins specifically in septic populations are needed. CONCLUSIONS Targeting the incretin hormone axis in sepsis may provide a means of not only promoting euglycemia in sepsis but also attenuating the proinflammatory response and improving clinical outcomes.
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Affiliation(s)
- Faraaz Ali Shah
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Veteran Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
- Correspondence and Reprint Requests: Faraaz Ali Shah, MD, MPH, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, 3459 Fifth Avenue NW, 628 MUH, Pittsburgh, Pennsylvania 15213. E-mail:
| | - Hussain Mahmud
- Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Teresa Gallego-Martin
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michael J Jurczak
- Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Christopher P O’Donnell
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Bryan J McVerry
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Center for Medicine and the Microbiome, University of Pittsburgh, Pittsburgh, Pennsylvania
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Torimoto K, Okada Y, Tanaka Y. Hypoglycemia Abrogates the Vascular Endothelial Protective Effect of Exenatide in Type 2 Diabetes Mellitus. Diabetes Ther 2019; 10:1127-1132. [PMID: 30875066 PMCID: PMC6531533 DOI: 10.1007/s13300-019-0596-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Indexed: 12/25/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists improve postprandial glucose, lipid metabolism, and vascular endothelial function. However, little is known about the effect of hypoglycemia on vascular endothelial function in patients on GLP-1 receptor agonist therapy. The aim of the present study was to determine the effect of hypoglycemia on vascular endothelial function in patients with type 2 diabetes mellitus (T2DM) treated with exenatide. Seventeen patients with T2DM underwent a meal tolerance test to examine the changes in vascular endothelial function and in glucose metabolism, both without exenatide and after a single subcutaneous injection of 10 μg exenatide. Vascular endothelial function was evaluated using reactive hyperemia index (RHI) measured by peripheral arterial tonometry before and 120 min after the meal loading test. The primary endpoint was the difference in changes in postprandial vascular endothelial function between the baseline and exenatide test. The results were analyzed in relation to the presence of absence of hypoglycemia. The natural logarithmically scaled RHI (L_RHI) was significantly lower after the baseline meal test but not in the exenatide test. Administration of exenatide caused symptomatic hypoglycemia in two patients during the meal tolerance test. The difference in the change in L_RHI was 0.125 ± 0.085 in the non-hypoglycemic group, whereas it was lower, - 0.487 ± 0.061, in the hypoglycemic group. The results of this study also suggest that the presence of hypoglycemia induces vascular endothelial dysfunction even during GLP-1 receptor agonist therapy.Trial registration: UMIN000015699.
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Affiliation(s)
- Keiichi Torimoto
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushyu, 807-8555, Japan
| | - Yosuke Okada
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushyu, 807-8555, Japan
| | - Yoshiya Tanaka
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushyu, 807-8555, Japan.
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Different Types of Cellular Stress Affect the Proteome Composition of Small Extracellular Vesicles: A Mini Review. Proteomes 2019; 7:proteomes7020023. [PMID: 31126168 PMCID: PMC6631412 DOI: 10.3390/proteomes7020023] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 05/14/2019] [Accepted: 05/19/2019] [Indexed: 12/27/2022] Open
Abstract
Extracellular vesicles (EVs) are well-known mediators of the cellular response to different stress factors, yet the exact mechanism of their action remains unclear. Hence, the characterization of their cargo, consisting of proteins, nucleic acids, and different classes of metabolites, helps to elucidate an understanding of their function in stress-related communication. The unexpected diversity and complexity of these vesicles requires the incorporation of multiple technologically advanced approaches in EV-oriented studies. This mini review focuses on the invaluable role of proteomics, especially mass spectrometry-based tools, in the investigation of the role of small EVs in their response to stress. Though relatively few experimental works address this issue to date, the available data indicate that stress conditions would affect the composition of protein cargo of vesicles released by stressed cells, as evidenced by the functional importance of such changes in the context of the response of recipient cells.
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Lopes-da-Silva M, McCormack JJ, Burden JJ, Harrison-Lavoie KJ, Ferraro F, Cutler DF. A GBF1-Dependent Mechanism for Environmentally Responsive Regulation of ER-Golgi Transport. Dev Cell 2019; 49:786-801.e6. [PMID: 31056345 PMCID: PMC6764485 DOI: 10.1016/j.devcel.2019.04.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 02/19/2019] [Accepted: 04/04/2019] [Indexed: 12/17/2022]
Abstract
How can anterograde membrane trafficking be modulated by physiological cues? A screen of Golgi-associated proteins revealed that the ARF-GEF GBF1 can selectively modulate the ER-Golgi trafficking of prohaemostatic von Willebrand factor (VWF) and extracellular matrix (ECM) proteins in human endothelial cells and in mouse fibroblasts. The relationship between levels of GBF1 and the trafficking of VWF into forming secretory granules confirmed GBF1 is a limiting factor in this process. Further, GBF1 activation by AMPK couples its control of anterograde trafficking to physiological cues; levels of glucose control GBF1 activation in turn modulating VWF trafficking into secretory granules. GBF1 modulates both ER and TGN exit, the latter dramatically affecting the size of the VWF storage organelles, thereby influencing the hemostatic capacity of the endothelium. The role of AMPK as a central integrating element of cellular pathways with intra- and extra-cellular cues can now be extended to modulation of the anterograde secretory pathway.
The Arf-GEF GBF1 modulates anterograde trafficking of VWF and ECM proteins Loss of GBF1 slows ER and TGN exit, producing swollen ER and giant WPBs Activation of GBF1 via AMPK reduces endothelial WPB size and secretion Metabolic change alters anterograde trafficking and cargo secretion via AMPK-GBF1
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Affiliation(s)
- Mafalda Lopes-da-Silva
- Endothelial Cell Biology Laboratory, MRC Laboratory for Molecular Cell Biology, University College London, London, UK.
| | - Jessica J McCormack
- Endothelial Cell Biology Laboratory, MRC Laboratory for Molecular Cell Biology, University College London, London, UK
| | - Jemima J Burden
- Electron Microscopy Laboratory, MRC Laboratory for Molecular Cell Biology, University College London, London, UK
| | - Kimberly J Harrison-Lavoie
- Endothelial Cell Biology Laboratory, MRC Laboratory for Molecular Cell Biology, University College London, London, UK
| | - Francesco Ferraro
- Endothelial Cell Biology Laboratory, MRC Laboratory for Molecular Cell Biology, University College London, London, UK
| | - Daniel F Cutler
- Endothelial Cell Biology Laboratory, MRC Laboratory for Molecular Cell Biology, University College London, London, UK.
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Ahmad I, Zelnick LR, Batacchi Z, Robinson N, Dighe A, Manski-Nankervis JAE, Furler J, O'Neal DN, Little R, Trence D, Hirsch IB, Bansal N, de Boer IH. Hypoglycemia in People with Type 2 Diabetes and CKD. Clin J Am Soc Nephrol 2019; 14:844-853. [PMID: 30996047 PMCID: PMC6556736 DOI: 10.2215/cjn.11650918] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 03/22/2019] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Among people with diabetes mellitus, CKD may promote hypoglycemia through altered clearance of glucose-lowering medications, decreased kidney gluconeogenesis, and blunted counter-regulatory response. We conducted a prospective observational study of hypoglycemia among 105 individuals with type 2 diabetes treated with insulin or a sulfonylurea using continuous glucose monitors. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS We enrolled 81 participants with CKD, defined as eGFR<60 ml/min per 1.73 m2, and 24 control participants with eGFR≥60 ml/min per 1.73 m2 frequency-matched on age, duration of diabetes, hemoglobin A1c, and glucose-lowering medications. Each participant wore a continuous glucose monitor for two 6-day periods. We examined rates of sustained level 1 hypoglycemia (<70 mg/dl) and level 2 hypoglycemia (<54 mg/dl) among participants with CKD. We then tested differences compared with control participants as well as a second control population (n=73) using Poisson and linear regression, adjusting for age, sex, and race. RESULTS Over 890 total days of continuous glucose monitoring, participants with CKD were observed to have 255 episodes of level 1 hypoglycemia, of which 68 episodes reached level 2 hypoglycemia. Median rate of hypoglycemic episodes was 5.3 (interquartile range, 0.0-11.7) per 30 days and mean time spent in hypoglycemia was 28 (SD 37) minutes per day. Hemoglobin A1c and the glucose management indicator were the main clinical correlates of time in hypoglycemia (adjusted differences 6 [95% confidence interval, 2 to 10] and 13 [95% confidence interval, 7 to 20] fewer minutes per day per 1% higher hemoglobin A1c or glucose management indicator, respectively). Compared with control populations, participants with CKD were not observed to have significant differences in time in hypoglycemia (adjusted differences 4 [95% confidence interval, -12 to 20] and -12 [95% confidence interval, -29 to 5] minutes per day). CONCLUSIONS Among people with type 2 diabetes and moderate to severe CKD, hypoglycemia was common, particularly with tighter glycemic control, but not significantly different from groups with similar clinical characteristics and preserved eGFR.
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Affiliation(s)
- Iram Ahmad
- Division of Endocrinology, Banner-MD Anderson Cancer Center, Gilbert, Arizona;
| | | | - Zona Batacchi
- Kidney Research Institute.,Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, Washington
| | | | | | | | - John Furler
- Department of General Practice, University of Melbourne, Carlton, Victoria, Australia
| | - David N O'Neal
- Department of Medicine, St Vincent's Hospital Melbourne, University of Melbourne, Fitzroy, Victoria, Australia
| | - Randie Little
- Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri; and
| | - Dace Trence
- Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, Washington
| | - Irl B Hirsch
- Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, Washington
| | - Nisha Bansal
- Kidney Research Institute.,Division of Nephrology, and
| | - Ian H de Boer
- Kidney Research Institute.,Division of Nephrology, and.,Puget Sound Veterans Affairs Health Care System, Seattle, Washington
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Yang D, Xiao C, Long F, Wu W, Huang M, Qu L, Liu X, Zhu Y. Fra‐1 plays a critical role in angiotensin II—induced vascular senescence. FASEB J 2019; 33:7603-7614. [DOI: 10.1096/fj.201801671rrrr] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Di Yang
- Department of PharmacologyShanghai Key Laboratory of Bioactive Small MoleculesSchool of PharmacyFudan UniversityShanghaiChina
- State Key Laboratory of Quality Research in Chinese MedicineSchool of PharmacyMacau University of Science and TechnologyMacauChina
| | - Chenxi Xiao
- Department of PharmacologyShanghai Key Laboratory of Bioactive Small MoleculesSchool of PharmacyFudan UniversityShanghaiChina
| | - Fen Long
- Department of PharmacologyShanghai Key Laboratory of Bioactive Small MoleculesSchool of PharmacyFudan UniversityShanghaiChina
| | - Weijun Wu
- Department of PharmacologyShanghai Key Laboratory of Bioactive Small MoleculesSchool of PharmacyFudan UniversityShanghaiChina
| | - Mengwei Huang
- Department of PharmacologyShanghai Key Laboratory of Bioactive Small MoleculesSchool of PharmacyFudan UniversityShanghaiChina
| | - Lefeng Qu
- Department of Vascular SurgeryChangzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Xinhua Liu
- Department of PharmacologyShanghai Key Laboratory of Bioactive Small MoleculesSchool of PharmacyFudan UniversityShanghaiChina
| | - Yizhun Zhu
- Department of PharmacologyShanghai Key Laboratory of Bioactive Small MoleculesSchool of PharmacyFudan UniversityShanghaiChina
- State Key Laboratory of Quality Research in Chinese MedicineSchool of PharmacyMacau University of Science and TechnologyMacauChina
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