|
1
|
Guo L, Zhang J, An R, Wang W, Fen J, Wu Y, Wang Y. The role of estimated glucose disposal rate in predicting cardiovascular risk among general and diabetes mellitus population: a systematic review and meta-analysis. BMC Med 2025; 23:234. [PMID: 40264086 PMCID: PMC12016375 DOI: 10.1186/s12916-025-04064-4] [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: 06/05/2024] [Accepted: 04/10/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Estimated glucose disposal rate (eGDR) is a measure of insulin sensitivity. While recent evidence suggests its role in cardiovascular risk assessment in Type 1 diabetes, its associations with cardiovascular disease (CVD), diabetic microvascular complications (DMC), and mortality across different populations remain unclear. METHODS We systematically searched Medline, EMBASE, Web of Science, and the Cochrane Library up to September 1st, 2024, following PRISMA guidelines. We examined associations between eGDR and CVD, DMC (including diabetic retinopathy, nephropathy, and peripheral neuropathy), and all-cause mortality using random-effects models. Secondary analysis assessed mean eGDR levels in diabetes populations. RESULTS Nineteen observational studies (185,810 participants) examined clinical outcomes, while 50 studies reported mean eGDR values. In patients with Type 1 diabetes (T1DM), each 1-unit (mg/kg/min) increase in eGDR was associated with lower risks of CVD (HR 0.78; 95% CI 0.69-0.87; I2 = 68%) and all-cause mortality (HR 0.83; 95% CI 0.79-0.88; I2 = 0%). The association between eGDR and DMC in T1DM was not statistically significant (HR 0.86; 95% CI 0.72-1.03; I2 = 25%). In patients with Type 2 diabetes (T2DM), each 1-unit (mg/kg/min) increase in eGDR was associated with reduced all-cause mortality (HR 0.90; 95% CI 0.84-0.97; I2 = 62%). Similarly, in the general population, each 1-unit (mg/kg/min) increase in eGDR was associated with decreased mortality risk (HR 0.88; 95% CI 0.82-0.94; I2 = 48%). The pooled mean eGDR was higher in patients with T1DM (8.19 mg/kg/min; 95% CI 7.81-8.57; I2 = 99%) compared to those with T2DM (7.03 mg/kg/min; 95% CI 4.89-9.17; I2 = 100%). CONCLUSIONS Higher eGDR levels were consistently associated with lower risks of CVD and mortality in T1DM, with similar associations observed for mortality in T2DM. In the general population, higher eGDR levels were associated with reduced mortality risk. The relationship between eGDR and DMC requires further investigation, particularly in T2DM. These findings suggest eGDR's potential utility as a risk assessment tool, though its clinical application may vary across different populations.
Collapse
Affiliation(s)
- Lei Guo
- Department of Neurology, Xindu District People's Hospital of Chengdu, Chengdu, Sichuan, 610500, China
| | - Jun Zhang
- Department of Neurology, Xindu District People's Hospital of Chengdu, Chengdu, Sichuan, 610500, China
| | - Ran An
- School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Wenrui Wang
- School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jie Fen
- Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Yanshuang Wu
- Chengdu Xiaojiahe Community Health Center, Chengdu, 610072, China
| | - Yanqing Wang
- School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
- The Second Hospital, Shandong University, Jinan, Shandong, China.
| |
Collapse
|
|
2
|
Gonciarz W, Kozlowska L, Róg J, Chmiela M. Untargeted metabolomic profiling for identifying systemic signatures of helicobacter pylori infection in a guinea pig model. Sci Rep 2025; 15:12889. [PMID: 40234702 PMCID: PMC12000522 DOI: 10.1038/s41598-025-98016-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 04/08/2025] [Indexed: 04/17/2025] Open
Abstract
Infections caused by the Gram-negative bacterium Helicobacter pylori (H. pylori) can lead to gastritis, gastric or duodenal ulcers, and even gastric cancer in humans. Investigating quantitative changes in soluble biomarkers associated with H. pylori infection offers a promising method for monitoring the progression of the infection, inflammatory response and potentially systemic consequences. This study aimed to identify, using an experimental model of H. pylori infection in guinea pigs, the specific metabolomic biomarkers in the serum of H. pylori-infected (32) versus uninfected (32) animals. The H. pylori status was confirmed through histological, molecular, and serological examinations. Metabolomic profiling was conducted using UPLC-QTOF/MS methods. The metabolomic biomarkers significantly associated with H. pylori infection were selected based on volcano plots and traditional univariate receiver operating characteristics (ROC). This study identified 12 unique metabolites significantly differentiating H. pylori-infected guinea pigs from uninfected ones. In summary, the metabolomic profiling of serum samples, in combination with ROC characteristics of the data, enhances the monitoring of H. pylori infection and related inflammatory responses in guinea pigs experimentally infected with these bacteria, with potential applications in humans for prediction the infection course and its systemic effects.
Collapse
Affiliation(s)
- Weronika Gonciarz
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90‑237, Lodz, Poland.
| | - Lucyna Kozlowska
- Laboratory of Human Metabolism Research, Department of Dietetics, Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, 02-776, Warsaw, Poland
| | - Joanna Róg
- Laboratory of Human Metabolism Research, Department of Dietetics, Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, 02-776, Warsaw, Poland
| | - Magdalena Chmiela
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90‑237, Lodz, Poland
| |
Collapse
|
|
3
|
Drygała S, Radzikowski M, Maciejczyk M. β-blockers and metabolic modulation: unraveling the complex interplay with glucose metabolism, inflammation and oxidative stress. Front Pharmacol 2024; 15:1489657. [PMID: 39759452 PMCID: PMC11695285 DOI: 10.3389/fphar.2024.1489657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 12/04/2024] [Indexed: 01/07/2025] Open
Abstract
The growing burden of metabolic disorders manifested by hypertension, type 2 diabetes mellitus, hyperlipidemia, obesity and non-alcoholic fatty liver disease presents a significant global health challenge by contributing to cardiovascular diseases and high mortality rates. Β-blockers are among the most widely used drugs in the treatment of hypertension and acute cardiovascular events. In addition to blocking the receptor sites for catecholamines, third-generation β-blockers with associated vasodilating properties, such as carvedilol and nebivolol, provide a broad spectrum of metabolic effects, including anti-inflammatory and antioxidant properties and a favorable impact on glucose and lipid metabolism. This review aims to report the impact of β-blockers on metabolic modulation based on available literature data. We present an overview of β-blockers and their pleiotropic properties, discuss mechanisms by which these drugs affect cellular metabolism and outline the future perspectives. The influence of β-blockers on glucose metabolism, insulin sensitivity, inflammation and oxidative stress is complex and varies depending on the specific β-blocker used, patient population and underlying health conditions. Recent evidence particularly highlights the potential role of vasodilatory and nitric oxide-mediated properties of nebivolol and carvedilol in improving glycemic control, insulin sensitivity, and lipid metabolism and mitigating oxidative stress and inflammation. It suggests that these drugs may be potential therapeutic options for patients with metabolic disorders, extending beyond their primary role in cardiovascular management.
Collapse
Affiliation(s)
- Szymon Drygała
- Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Bialystok, Poland
| | - Michał Radzikowski
- Biochemistry of Civilisation Diseases’ Students’ Scientific Club at the Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Bialystok, Poland
| | - Mateusz Maciejczyk
- Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Bialystok, Poland
| |
Collapse
|
|
4
|
Hasanpour-Segherlou Z, Butler AA, Candelario-Jalil E, Hoh BL. Role of the Unique Secreted Peptide Adropin in Various Physiological and Disease States. Biomolecules 2024; 14:1613. [PMID: 39766320 PMCID: PMC11674490 DOI: 10.3390/biom14121613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 12/09/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Adropin, a secreted peptide hormone identified in 2008, plays a significant role in regulating energy homeostasis, glucose metabolism, and lipid metabolism. Its expression is linked to dietary macronutrient intake and is influenced by metabolic syndrome, obesity, diabetes, and cardiovascular diseases. Emerging evidence suggests that adropin might be a biomarker for various conditions, including metabolic syndrome, coronary artery disease, and hypertensive disorders complicating pregnancy. In cerebrovascular diseases, adropin demonstrates protective effects by reducing blood-brain barrier permeability, brain edema, and infarct size while improving cognitive and sensorimotor functions in ischemic stroke models. The protective effects of adropin extend to preventing endothelial damage, promoting angiogenesis, and mitigating inflammation, making it a promising therapeutic target for cardiovascular and neurodegenerative diseases. This review provides a comprehensive overview of adropin's multifaceted roles in physiological and pathological conditions, as well as our recent work demonstrating adropin's role in subarachnoid hemorrhage-mediated neural injury and delayed cerebral infarction.
Collapse
Affiliation(s)
| | - Andrew A. Butler
- Department of Pharmacology and Physiological Sciences, Saint Louis University, Saint Louis, MO 63104, USA;
| | - Eduardo Candelario-Jalil
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
| | - Brian L. Hoh
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
| |
Collapse
|
|
5
|
Zhang T, Yi Q, Huang W, Feng J, Liu H. New insights into the roles of Irisin in diabetic cardiomyopathy and vascular diseases. Biomed Pharmacother 2024; 175:116631. [PMID: 38663105 DOI: 10.1016/j.biopha.2024.116631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 04/11/2024] [Accepted: 04/17/2024] [Indexed: 06/03/2024] Open
Abstract
Diabetes mellitus (DM) is a prevalent chronic disease in the 21st century due to increased lifespan and unhealthy lifestyle choices. Extensive research indicates that exercise can play a significant role in regulating systemic metabolism by improving energy metabolism and mitigating various metabolic disorders, including DM. Irisin, a well-known exerkine, was initially reported to enhance energy expenditure by indicating the browning of white adipose tissue (WAT) through peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) signaling. In this review, we summarize the potential mechanisms underlying the beneficial effects of Irisin on glucose dysmetabolism, including reducing gluconeogenesis, enhancing insulin energy expenditure, and promoting glycogenesis. Additionally, we highlight Irisin's potential to improve diabetic vascular diseases by stimulating nitric oxide (NO) production, reducing oxidative and nitrosative stress, curbing inflammation, and attenuating endothelial cell aging. Furthermore, we discuss the potential of Irisin to improve diabetic cardiomyopathy by preventing cardiomyocyte loss and reducing myocardial hypertrophy and fibrosis. Given Irisin's promising functions in managing diabetic cardiomyopathy and vascular diseases, targeting Irisin for therapeutic purposes could be a fruitful avenue for future research and clinical interventions.
Collapse
Affiliation(s)
- Tiandong Zhang
- Collage of Integration of Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Qian Yi
- Department of Physiology, School of Basic Medical Science, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Wenhua Huang
- Collage of Integration of Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan 646000, China; Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Jianguo Feng
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province 646000, China.
| | - Huan Liu
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China; The Third People's Hospital of Longmatan District, Luzhou, Sichuan 646000, China.
| |
Collapse
|
|
6
|
Rajasekhar S, Subramanyam MVV, Asha Devi S. Grape seed proanthocyanidin extract suppresses oxidative stress in the rat pancreas of type-1 diabetes. Arch Physiol Biochem 2023; 129:1045-1057. [PMID: 33703969 DOI: 10.1080/13813455.2021.1894452] [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: 06/15/2020] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 10/21/2022]
Abstract
AIM This study aimed to elucidate the effects of grape seed proanthocyanidin extract (GSPE) on oxidative stress (OS), antioxidant enzymes, free radicals and cytokines in the pancreas of T1DM rats. METHODS Two-month-old Wistar rats were assigned to the control (CON), CON + GSPE (CON + PA), diabetics (STZ, 60 mg/kg b.w.), diabetes + GSPE (STZ + PA), diabetes + insulin (STZ + INS, 3 U/day) and diabetics + GSPE and INS (STZ + INS + PA) groups. GSPE (75 mg/kg b.w.) was administered daily either alone or with INS for 8 weeks. RESULTS Glutathione was lowest in diabetics while it increased in the STZ + INS + PA (p < .001) group, similar to catalase activity (p < .05). Hydrogen peroxide, superoxide and lipid peroxidation increased with iNOS, TNF-α and IL-1β in the diabetic pancreases, while GSPE decreased (p < .001). Further, reduced β-cells/islet number was improved in diabetics (p < .001) with treatment. CONCLUSION This study suggests that GSPE with INS is effective in minimising OS and pancreatic degeneration in T1DM rats.
Collapse
Affiliation(s)
- Sanna Rajasekhar
- Laboratory of Gerontology, Department of Zoology, Bangalore University, Bangalore, India
| | | | - Sambe Asha Devi
- Laboratory of Gerontology, Department of Zoology, Bangalore University, Bangalore, India
| |
Collapse
|
|
7
|
Zheng HY, Wang YX, Zhou K, Xie HL, Ren Z, Liu HT, Ou YS, Zhou ZX, Jiang ZS. Biological functions of CRTC2 and its role in metabolism-related diseases. J Cell Commun Signal 2023; 17:495-506. [PMID: 36856929 PMCID: PMC10409973 DOI: 10.1007/s12079-023-00730-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 02/01/2023] [Indexed: 03/02/2023] Open
Abstract
CREB-regulated transcription coactivator2 (CRTC2 or TORC2) is a transcriptional coactivator of CREB(cAMP response element binding protein), which affects human energy metabolism through cyclic adenosine phosphate pathway, Mammalian target of rapamycin (mTOR) pathway, Sterol regulatory element binding protein 1(SREBP1), Sterol regulatory element binding protein 2 (SREBP2) and other substances Current studies on CRTC2 mainly focus on glucose and lipid metabolism, relevant studies show that CRTC2 can participate in the occurrence and development of related diseases by affecting metabolic homeostasis. It has been found that Crtc2 acts as a signaling regulator for cAMP and Ca2 + signaling pathways in many cell types, and phosphorylation at ser171 and ser275 can regulate downstream biological functions by controlling CRTC2 shuttling between cytoplasm and nucleus.
Collapse
Affiliation(s)
- Hong-Yu Zheng
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, 421001, China
| | - Yan-Xia Wang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, 421001, China
| | - Kun Zhou
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, 421001, China
| | - Hai-Lin Xie
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, 421001, China
| | - Zhong Ren
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, 421001, China
| | - Hui-Ting Liu
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, 421001, China
| | - Yang-Shao Ou
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, 421001, China
| | - Zhi-Xiang Zhou
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, 421001, China
| | - Zhi-Sheng Jiang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, 421001, China.
| |
Collapse
|
|
8
|
Zhao S, Li H, Jing X, Zhang X, Li R, Li Y, Liu C, Chen J, Li G, Zheng W, Li Q, Wang X, Wang L, Sun Y, Xu Y, Wang S. Identifying subgroups of patients with type 2 diabetes based on real-world traditional chinese medicine electronic medical records. Front Pharmacol 2023; 14:1210667. [PMID: 37456755 PMCID: PMC10339739 DOI: 10.3389/fphar.2023.1210667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 06/15/2023] [Indexed: 07/18/2023] Open
Abstract
Introduction: Type 2 diabetes (T2D) is a multifactorial complex chronic disease with a high prevalence worldwide, and Type 2 diabetes patients with different comorbidities often present multiple phenotypes in the clinic. Thus, there is a pressing need to improve understanding of the complexity of the clinical Type 2 diabetes population to help identify more accurate disease subtypes for personalized treatment. Methods: Here, utilizing the traditional Chinese medicine (TCM) clinical electronic medical records (EMRs) of 2137 Type 2 diabetes inpatients, we followed a heterogeneous medical record network (HEMnet) framework to construct heterogeneous medical record networks by integrating the clinical features from the electronic medical records, molecular interaction networks and domain knowledge. Results: Of the 2137 Type 2 diabetes patients, 1347 were male (63.03%), and 790 were female (36.97%). Using the HEMnet method, we obtained eight non-overlapping patient subgroups. For example, in H3, Poria, Astragali Radix, Glycyrrhizae Radix et Rhizoma, Cinnamomi Ramulus, and Liriopes Radix were identified as significant botanical drugs. Cardiovascular diseases (CVDs) were found to be significant comorbidities. Furthermore, enrichment analysis showed that there were six overlapping pathways and eight overlapping Gene Ontology terms among the herbs, comorbidities, and Type 2 diabetes in H3. Discussion: Our results demonstrate that identification of the Type 2 diabetes subgroup based on the HEMnet method can provide important guidance for the clinical use of herbal prescriptions and that this method can be used for other complex diseases.
Collapse
Affiliation(s)
- Shuai Zhao
- Department of Endocrinology, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Hengfei Li
- Department of Infectious Diseases, Hubei Provincial Hospital of Traditional Chinese Medicine (Affiliated Hospital of Hubei University of Chinese Medicine, Hubei Province Academy of Traditional Chinese Medicine), Wuhan, China
| | - Xuan Jing
- Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang, China
| | - Xuebin Zhang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ronghua Li
- Department of Endocrinology, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yinghao Li
- Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chenguang Liu
- Department of Endocrinology, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jie Chen
- Department of Endocrinology, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Guoxia Li
- Department of Endocrinology, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wenfei Zheng
- Department of Endocrinology, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Qian Li
- Department of Nursing, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xue Wang
- Department of Endocrinology, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Letian Wang
- Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuanyuan Sun
- Department of Obstetrics and Gynecology, Weifang Fangzi District People’s Hospital, Weifang, China
| | - Yunsheng Xu
- Department of Endocrinology, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shihua Wang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| |
Collapse
|
|
9
|
Yadav U, Kumar N, Sarvottam K. Role of obesity related inflammation in pathogenesis of peripheral artery disease in patients of type 2 diabetes mellitus. J Diabetes Metab Disord 2023; 22:175-188. [PMID: 37255816 PMCID: PMC10225462 DOI: 10.1007/s40200-023-01221-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/29/2023] [Indexed: 06/01/2023]
Abstract
Objective Type 2 diabetes mellitus (T2DM) has emerged as one of the greatest global health challenges of twenty-first century. Visceral obesity is one of the most important determinant of insulin resistance (IR) as well as T2DM complications. Therefore this review focuses on the molecular mechanism of obesity induced inflammation, signaling pathways contributing to diabetes, as well as role of lifestyle interventions and medical therapies in the prevention and management of T2DM. Method Articles were searched on digital data base PubMed, Cochrane Library, and Web of Science. The key words used for search included Type 2 diabetes mellitus, obesity, insulin resistance, vascular inflammation and peripheral arterial disease. Result Visceral obesity is associated with chronic low grade inflammation and activation of immune systems which are involved in pathogenesis of obesity related IR and T2DM. Conclusion Metabolic dysregulation of adipose tissue leads to local hypoxia, misfolded/unfolded protein response and increased circulating free fatty acids, which in turn initiate inflammatory signaling cascades in the population of infiltrating cells. Mechanism that relates the role of adipocytokines with insulin sensitivity and glucose homeostasis might throw a light on the development of therapeutic interventions and subsequently might result in the reduction of vascular complications.
Collapse
Affiliation(s)
- Umashree Yadav
- Department of Physiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh 221005 India
| | - Nilesh Kumar
- Department of General Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005 India
| | - Kumar Sarvottam
- Department of Physiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh 221005 India
| |
Collapse
|
|
10
|
Sobolevskaya EV, Shumkov OA, Smagin MA, Guskov AE, Malysheva AV, Atuchin VV, Nimaev VV. Markers of Restenosis after Percutaneous Transluminal Balloon Angioplasty in Patients with Critical Limb Ischemia. Int J Mol Sci 2023; 24:ijms24109096. [PMID: 37240440 DOI: 10.3390/ijms24109096] [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: 03/30/2023] [Revised: 04/14/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
Among cardiovascular diseases, chronic obliterating lesions of the arteries of lower extremities, which are one of the important problems of modern healthcare, are distinguished. In most cases, the cause of damage to the arteries of lower extremities is atherosclerosis. The most severe form is chronic ischemia, characterized by pain at rest and ischemic ulcers, ultimately increasing the risk of limb loss and cardiovascular mortality. Therefore, patients with critical limb ischemia need limb revascularization. Percutaneous transluminal balloon angioplasty is one of the least invasive and safe approaches, with advantages for patients with comorbidities. However, after this procedure, restenosis is still possible. Early detection of changes in the composition of some molecules as markers of restenosis will help screen patients at the risk of restenosis, as well as find ways to apply efforts for further directions of inhibition of this process. The purpose of this review is to provide the most important and up-to-date information on the mechanisms of restenosis development, as well as possible predictors of their occurrence. The information collected in this publication may be useful in predicting outcomes after surgical treatment and will also find new ways for the target implication to the mechanisms of development of restenosis and atherosclerosis.
Collapse
Affiliation(s)
- Elvira V Sobolevskaya
- Laboratory of Surgical Lymphology and Lymph-Detoxication, Research Institute of Clinical and Experimental Lymphology-Branch of the Institute of Cytology and Genetics, SB RAS, Novosibirsk 630117, Russia
| | - Oleg A Shumkov
- Laboratory of Surgical Lymphology and Lymph-Detoxication, Research Institute of Clinical and Experimental Lymphology-Branch of the Institute of Cytology and Genetics, SB RAS, Novosibirsk 630117, Russia
| | - Mikhail A Smagin
- Laboratory of Surgical Lymphology and Lymph-Detoxication, Research Institute of Clinical and Experimental Lymphology-Branch of the Institute of Cytology and Genetics, SB RAS, Novosibirsk 630117, Russia
| | - Andrey E Guskov
- Laboratory of Scientometrics and Scientific Communications, Russian Research Institute of Economics, Politics and Law in Science and Technology, Moscow 127254, Russia
| | - Alexandra V Malysheva
- Laboratory of Scientometrics and Scientific Communications, Russian Research Institute of Economics, Politics and Law in Science and Technology, Moscow 127254, Russia
| | - Victor V Atuchin
- Laboratory of Optical Materials and Structures, Institute of Semiconductor Physics, SB RAS, Novosibirsk 630090, Russia
- Research and Development Department, Kemerovo State University, Kemerovo 650000, Russia
- Department of Industrial Machinery Design, Novosibirsk State Technical University, Novosibirsk 630073, Russia
- R&D Center "Advanced Electronic Technologies", Tomsk State University, Tomsk 634034, Russia
| | - Vadim V Nimaev
- Laboratory of Surgical Lymphology and Lymph-Detoxication, Research Institute of Clinical and Experimental Lymphology-Branch of the Institute of Cytology and Genetics, SB RAS, Novosibirsk 630117, Russia
| |
Collapse
|
|
11
|
Zhu YX, Li Y, Ma Y, Zhang X, Du X, Gao J, Ding NH, Wang L, Chen N, Luo M, Wu J, Li R. Liraglutide Accelerates Ischemia-Induced Angiogenesis in a Murine Diabetic Model. J Am Heart Assoc 2023; 12:e026586. [PMID: 36789853 PMCID: PMC10111486 DOI: 10.1161/jaha.122.026586] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
Background Severe hindlimb ischemia is a chronic disease with poor prognosis that can lead to amputation or even death. This study aimed to assess the therapeutic effect of liraglutide on hind-limb ischemia in type 2 diabetic mice and to elucidate the underlying mechanism. Methods and Results Blood flow reperfusion and capillary densities after treatment with liraglutide or vehicle were evaluated in a mouse model of lower-limb ischemia in a normal background or a background of streptozotocin-induced diabetes. The proliferation, migration, and tube formation of human umbilical vein endothelial cells were analyzed in vitro upon treatment with liraglutide under normal-glucose and high-glucose conditions. Levels of phospho-Akt, phospho-endothelial nitric oxide synthase, and phospho-extracellular signal-related kinases 1 and 2 under different conditions in human umbilical vein endothelial cells and in ischemic muscle were determined by western blotting. Liraglutide significantly improved perfusion recovery and capillary density in both nondiabetic and diabetic mice. Liraglutide also promoted, in a concentration-dependent manner, the proliferation, migration, and tube formation of normal glucose- and high glucose-treated human umbilical vein endothelial cells, as well as the phosphorylation of Akt, endothelial nitric oxide synthase, and extracellular signal-related kinases 1 and 2 both in vitro and in vivo. The liraglutide antagonist exendin (9-39) reversed the promoting effects of liraglutide on human umbilical vein endothelial cell functions. Furthermore, exendin (9-39), LY294002, and PD98059 blocked the liraglutide-induced activation of Akt/endothelial nitric oxide synthase and extracellular signal-related kinases 1 and 2 signaling pathways. Conclusions These studies identified a novel role of liraglutide in modulating ischemia-induced angiogenesis, possibly through effects on endothelial cell function and activation of Akt/endothelial nitric oxide synthase and extracellular signal-related kinases 1 and 2 signaling, and suggested the glucagon-like peptide-1 receptor may be an important therapeutic target in diabetic hind-limb ischemia.
Collapse
Affiliation(s)
- Yu-Xin Zhu
- Drug Discovery Research Center Southwest Medical University Luzhou Sichuan China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy Southwest Medical University Luzhou Sichuan China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research, Southwest Medical University Luzhou Sichuan China
| | - Yi Li
- Department of Endocrinology The Affiliated Hospital of Southwest Medical University, Southwest Medical University Luzhou Sichuan China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy Southwest Medical University Luzhou Sichuan China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research, Southwest Medical University Luzhou Sichuan China
| | - Yu Ma
- Drug Discovery Research Center Southwest Medical University Luzhou Sichuan China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy Southwest Medical University Luzhou Sichuan China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research, Southwest Medical University Luzhou Sichuan China
| | - Xiao Zhang
- School of Basic Medicine Southwest Medical University Luzhou Sichuan China
| | - Xingrong Du
- Drug Discovery Research Center Southwest Medical University Luzhou Sichuan China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy Southwest Medical University Luzhou Sichuan China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research, Southwest Medical University Luzhou Sichuan China
| | - Jiali Gao
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research, Southwest Medical University Luzhou Sichuan China.,Nucleic Acid Medicine of Luzhou Key Laboratory Southwest Medical University Luzhou Sichuan China
| | - Nian Hui Ding
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research, Southwest Medical University Luzhou Sichuan China.,Nucleic Acid Medicine of Luzhou Key Laboratory Southwest Medical University Luzhou Sichuan China
| | - Liqun Wang
- Drug Discovery Research Center Southwest Medical University Luzhou Sichuan China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy Southwest Medical University Luzhou Sichuan China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research, Southwest Medical University Luzhou Sichuan China
| | - Ni Chen
- Drug Discovery Research Center Southwest Medical University Luzhou Sichuan China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy Southwest Medical University Luzhou Sichuan China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research, Southwest Medical University Luzhou Sichuan China
| | - Mao Luo
- Drug Discovery Research Center Southwest Medical University Luzhou Sichuan China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy Southwest Medical University Luzhou Sichuan China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research, Southwest Medical University Luzhou Sichuan China
| | - Jianbo Wu
- Drug Discovery Research Center Southwest Medical University Luzhou Sichuan China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy Southwest Medical University Luzhou Sichuan China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research, Southwest Medical University Luzhou Sichuan China
| | - Rong Li
- Drug Discovery Research Center Southwest Medical University Luzhou Sichuan China.,Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy Southwest Medical University Luzhou Sichuan China.,Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research, Southwest Medical University Luzhou Sichuan China.,Nucleic Acid Medicine of Luzhou Key Laboratory Southwest Medical University Luzhou Sichuan China
| |
Collapse
|
|
12
|
Sykora D, Firth C, Girardo M, Bhatt S, Tseng A, Chamberlain A, Liedl D, Wennberg P, Shamoun FE. Peripheral artery disease and the risk of venous thromboembolism. VASA 2022; 51:365-371. [DOI: 10.1024/0301-1526/a001029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Summary: Background: Peripheral artery disease (PAD) impacts 3–12% of patients worldwide and is characterized by endothelial dysfunction and inflammatory pathways which are also common to venous thromboembolism (VTE), but there is a paucity of evidence regarding VTE risk in PAD patients. We investigated whether PAD is an independent risk factor for VTE. Patients and methods: We reviewed medical records of patients undergoing ABI studies at Mayo Clinic from 01/1996-02/2020. We classified patients by ABI (low [<1.0], normal [1.0–1.4], or elevated [>1.4]), as well as by specific low ABI subgroup: severely reduced (ABI: 0.00–0.39), moderately reduced (0.40–0.69), mildly reduced (0.70–0.90), and borderline reduced (0.91–0.99). The primary outcome was incident VTE event (acute lower extremity deep vein thrombosis or pulmonary embolism) after ABI measurement. Multivariable Cox proportional regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI) after adjusting for age, sex, active smoking, cancer, previous VTE, thrombophilia, anticoagulation, and revascularization. Results: 39,834 unique patients (mean age 66.3±14.3 years, median follow-up 34 months) were identified. 2,305 VTE events occurred in patients without PAD (13.0%), 2,218 in low ABI patients (13.0%), and 751 in elevated ABI patients (14.8%). After risk factor adjustment, VTE risk was modestly increased for PAD overall (HR: 1.12, 95% CI [1.06, 1.18]), including low ABI (HR: 1.11, 95% CI [1.04, 1.18]) and elevated ABI groups (HR: 1.15, 95% CI [1.04, 1.26]), compared to patients without PAD. The greatest VTE risk was in severely low ABI patients (HR: 1.46, 95% CI [1.31, 1.64]). Conclusions: In a large longitudinal cohort, we present strong clinical evidence of PAD, with low and elevated ABI, as an independent VTE risk factor, with the highest risk seen in patients with severely low ABI. Continued research is required to further investigate this relationship and its intersection with functional performance status to optimize VTE risk reduction or anticoagulation strategies in the PAD population.
Collapse
Affiliation(s)
- Daniel Sykora
- Mayo Clinic School of Graduate Medical Education, Rochester, MN, USA
| | - Christine Firth
- Department of Cardiovascular Diseases, Mayo Clinic, Phoenix, AZ, USA
| | - Marlene Girardo
- Department of Biomedical Statistics and Informatics, Division of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA
| | - Shubhang Bhatt
- Mayo Clinic School of Graduate Medical Education, Scottsdale, AZ, USA
| | - Andrew Tseng
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | | | - David Liedl
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Paul Wennberg
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | | |
Collapse
|
|
13
|
Hypertension and Type 2 Diabetes-The Novel Treatment Possibilities. Int J Mol Sci 2022; 23:ijms23126500. [PMID: 35742943 PMCID: PMC9224227 DOI: 10.3390/ijms23126500] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 06/04/2022] [Accepted: 06/08/2022] [Indexed: 02/04/2023] Open
Abstract
Elevated blood pressure and hyperglycaemia frequently coexist and are both components of metabolic syndrome. Enhanced cardiovascular risk is strongly associated with diabetes and the occurrence of hypertension. Both hypertension and type 2 diabetes, if treated inappropriately, lead to serious complications, increasing the mortality of patients and generating much higher costs of health systems. This is why it is of great importance to find the missing link between hypertension and diabetes development and to simultaneously search for drugs influencing these two disorders or even drugs aimed at their pathological bases. Standard antihypertensive therapy mainly focuses on blood pressure reduction, while novel drugs also possess a wide range of pleiotropic modes of actions, such as cardio- and nephroprotective properties or body weight reduction. These properties are especially desirable in a situation when type 2 diabetes coexists with hypertension. This review describes the connections between diabetes and hypertension development and briefly summarises the current knowledge regarding attempts to define targets for the treatment of high blood pressure in diabetic patients. It also describes the standard hypotensive drugs preferred in patients with type 2 diabetes, as well as novel drugs, such as finerenone, esaxerenone, sodium-glucose co-transporter-2 inhibitors, glucagon-like peptide-1 analogues and sacubitril/valsartan.
Collapse
|
|
14
|
Unwin D, Unwin J, Crocombe D, Delon C, Guess N, Wong C. Renal function in patients following a low carbohydrate diet for type 2 diabetes: a review of the literature and analysis of routine clinical data from a primary care service over 7 years. Curr Opin Endocrinol Diabetes Obes 2021; 28:469-479. [PMID: 34468402 DOI: 10.1097/med.0000000000000658] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW People with T2 Diabetes (T2D) who follow a low carbohydrate diet (LCD) may increase their dietary protein intake. Dietary protein can modulate renal function so there is debate about its role in renal disease. There is concern that higher protein intakes may promote renal damage, and that LCDs themselves may impact on cardiovascular risk. We review the evidence around LCDs, renal and cardiovascular risk factors and compare to results obtained in a real-world, primary care setting. RECENT FINDINGS Chronic kidney disease (CKD) is a well-recognised microvascular complication of T2D caused in part by; chronically increased glomerular pressure, hyperfiltration, increased blood pressure and advanced glycation end products. Hyperglycemia can be seen as central to all of these factors. A LCD is an effective first step in its correction as we demonstrate in our real-world cohort. SUMMARY We found evidence that LCDs for people with T2D may improve many renal and cardiovascular risk factors. In our own LCD cohort of 143 patients with normal renal function or only mild CKD, over an average of 30 months the serum creatinine improved by a significant mean of 4.7 (14.9) μmol/L. What remains to be shown is the effect of the approach on people with T2D and moderate/severe CKD.
Collapse
Affiliation(s)
| | | | - Dominic Crocombe
- Leeds Teaching Hospitals NHS Trust, NNEdPro Global Centre for Nutrition and Health, Cambridge
| | | | - Nicola Guess
- School of Life Sciences University of Westminster, London
| | - Christopher Wong
- Health Sciences Liverpool Hope University, Department of Renal Medicine at Liverpool University Hospitals Foundation Trust, Liverpool, UK
| |
Collapse
|
|
15
|
Cheng C, Xue F, Sui W, Meng L, Xie L, Zhang C, Yang J, Zhang Y. Deletion of natriuretic peptide receptor C alleviates adipose tissue inflammation in hypercholesterolemic Apolipoprotein E knockout mice. J Cell Mol Med 2021; 25:9837-9850. [PMID: 34528389 PMCID: PMC8505842 DOI: 10.1111/jcmm.16931] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/24/2021] [Accepted: 09/01/2021] [Indexed: 12/16/2022] Open
Abstract
The inflammation of adipose tissue is one of the most common secondary pathological changes in atherosclerosis, which in turn influences the process of atherosclerosis. Natriuretic peptides have been revealed important effect in regulating adipose metabolism. However, the relationship between natriuretic peptide receptor C and inflammation of adipose tissue in atherosclerosis remains unknown. This study aims to explore the effect natriuretic peptide receptor C exerts on the regulation of the adipose inflammation in atherosclerotic mice induced by western-type diet and its overlying mechanisms. To clarify the importance of NPRC of adipose inflammation in atherosclerotic mice, NPRC expression was measured in mice fed with chow diet and western-type diet for 12 weeks and we found a considerable increase in adipose tissue of atherosclerotic mice. Global NPRC knockout in mice was bred onto ApoE-/- mice to generate NPRC-/- ApoE-/- mice, which displayed remarked increase in browning of white adipose tissue and lipolysis of adipose tissue and decrease in adipose inflammation manifested by decreased macrophage invasion to form less CLS (crown-like structure), reduced oxidative stress and alleviated expression of TNFα, IL-6, IL-1β and MCP1, but increased expression of adiponectin in adipose tissue. Moreover, our study showed that white adipose tissue browning in NPRC-/- ApoE-/- atherosclerotic mice was associated with decreased inflammatory response through cAMP/PKA signalling activation. These results identify NPRC as a novel regulator for adipose inflammation in atherosclerotic mice by modulating white adipose tissue browning.
Collapse
Affiliation(s)
- Cheng Cheng
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Fei Xue
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wenhai Sui
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Linlin Meng
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lin Xie
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Cheng Zhang
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jianmin Yang
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yun Zhang
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| |
Collapse
|
|
16
|
Association of Gut Hormones and Microbiota with Vascular Dysfunction in Obesity. Nutrients 2021; 13:nu13020613. [PMID: 33668627 PMCID: PMC7918888 DOI: 10.3390/nu13020613] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/25/2021] [Accepted: 02/10/2021] [Indexed: 02/08/2023] Open
Abstract
In the past few decades, obesity has reached pandemic proportions. Obesity is among the main risk factors for cardiovascular diseases, since chronic fat accumulation leads to dysfunction in vascular endothelium and to a precocious arterial stiffness. So far, not all the mechanisms linking adipose tissue and vascular reactivity have been explained. Recently, novel findings reported interesting pathological link between endothelial dysfunction with gut hormones and gut microbiota and energy homeostasis. These findings suggest an active role of gut secretome in regulating the mediators of vascular function, such as nitric oxide (NO) and endothelin-1 (ET-1) that need to be further investigated. Moreover, a central role of brain has been suggested as a main player in the regulation of the different factors and hormones beyond these complex mechanisms. The aim of the present review is to discuss the state of the art in this field, by focusing on the processes leading to endothelial dysfunction mediated by obesity and metabolic diseases, such as insulin resistance. The role of perivascular adipose tissue (PVAT), gut hormones, gut microbiota dysbiosis, and the CNS function in controlling satiety have been considered. Further understanding the crosstalk between these complex mechanisms will allow us to better design novel strategies for the prevention of obesity and its complications.
Collapse
|
|
17
|
Kalra S, Unnikrishnan AG, Baruah MP, Sahay R, Bantwal G. Metabolic and Energy Imbalance in Dysglycemia-Based Chronic Disease. Diabetes Metab Syndr Obes 2021; 14:165-184. [PMID: 33488105 PMCID: PMC7816219 DOI: 10.2147/dmso.s286888] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 12/02/2020] [Indexed: 12/16/2022] Open
Abstract
Metabolic flexibility is the ability to efficiently adapt metabolism based on nutrient availability and requirement that is essential to maintain homeostasis in times of either caloric excess or restriction and during the energy-demanding state. This regulation is orchestrated in multiple organ systems by the alliance of numerous metabolic pathways under the master control of the insulin-glucagon-sympathetic neuro-endocrine axis. This, in turn, regulates key metabolic enzymes and transcription factors, many of which interact closely with and culminate in the mitochondrial energy generation machinery. Metabolic flexibility is compromised due to the continuous mismatch between availability and intake of calorie-dense foods and reduced metabolic demand due to sedentary lifestyle and age-related metabolic slowdown. The resultant nutrient overload leads to mitochondrial trafficking of substrates manifesting as mitochondrial dysfunction characterized by ineffective substrate switching and incomplete substrate utilization. At the systemic level, the manifestation of metabolic inflexibility comprises reduced skeletal muscle glucose disposal rate, impaired suppression of hepatic gluconeogenesis and adipose tissue lipolysis manifesting as insulin resistance. This is compounded by impaired β-cell function and progressively reduced β-cell mass. A consequence of insulin resistance is the upregulation of the mitogen-activated protein kinase pathway leading to a pro-hypertensive, atherogenic, and thrombogenic environment. This is further aggravated by oxidative stress, advanced glycation end products, and inflammation, which potentiates the risk of micro- and macro-vascular complications. This review aims to elucidate underlying mechanisms mediating the onset of metabolic inflexibility operating at the main target organs and to understand the progression of metabolic diseases. This could potentially translate into a pharmacological tool that can manage multiple interlinked conditions of dysglycemia, hypertension, and dyslipidemia by restoring metabolic flexibility. We discuss the breadth and depth of metabolic flexibility and its impact on health and disease.
Collapse
Affiliation(s)
- Sanjay Kalra
- Department of Endocrinology, Bharti Hospital, Karnal, India
- Department of Endocrinology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | | | - Manash P Baruah
- Department of Endocrinology, Excel Hospitals, Guwahati, India
| | - Rakesh Sahay
- Department of Endocrinology, Osmania Medical College, Hyderabad, Telangana, India
| | - Ganapathi Bantwal
- Department of Endocrinology, St. John’s Medical College and Hospital, Bangalore, Karnataka, India
| |
Collapse
|
|
18
|
Salsoso R, Mate A, Toledo F, Vázquez CM, Sobrevia L. Insulin requires A 2B adenosine receptors to modulate the L-arginine/nitric oxide signalling in the human fetoplacental vascular endothelium from late-onset preeclampsia. Biochim Biophys Acta Mol Basis Dis 2020; 1867:165993. [PMID: 33096224 DOI: 10.1016/j.bbadis.2020.165993] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/16/2020] [Accepted: 10/16/2020] [Indexed: 02/07/2023]
Abstract
Late-onset preeclampsia (LOPE) associates with reduced umbilical vein reactivity and endothelial nitric oxide synthase (eNOS) activity but increased human cationic amino acid (hCAT-1)-mediated L-arginine transport involving A2A adenosine receptor in the fetoplacental unit. This study addresses the A2B adenosine receptor (A2BAR)-mediated response to insulin in the fetoplacental vasculature from LOPE. Umbilical veins and HUVECs were obtained from women with normal (n = 37) or LOPE (n = 35) pregnancies. Umbilical vein rings reactivity to insulin was assayed in the absence or presence of adenosine and MRS-1754 (A2BAR antagonist) in a wire myograph. HUVECs were exposed to insulin, MRS-1754, BAY60-6583 (A2BAR agonist), NECA (general adenosine receptors agonist) or NG-nitro-L-arginine methyl ester (NOS inhibitor). A2BAR, hCAT-1, total and phosphorylated eNOS, Akt and p44/42mapk protein abundance were determined by Western blotting. Insulin receptors A (IR-A) and B (IR-B), eNOS and hCAT-1 mRNA were determined by qPCR. Firefly/Renilla luciferase assay was used to determine -1606 bp SLC7A1 (hCAT-1) promoter activity. L-Citrulline content was measured by HPLC, L-[3H]citrulline formation from L-[3H]arginine by the Citrulline assay, and intracellular cGMP by radioimmunoassay. LOPE-reduced dilation of vein rings to insulin was restored by MRS-1754. HUVECs from LOPE showed higher A2BAR, hCAT-1, and IR-A expression, Akt and p44/42mapk activation, and lower NOS activity. MRS-1754 reversed the LOPE effect on A2BAR, hCAT-1, Akt, and eNOS inhibitory phosphorylation. Insulin reversed the LOPE effect on A2BAR, IR-A and eNOS, but increased hCAT-1-mediated transport. Thus, LOPE alters endothelial function, causing an imbalance in the L-arginine/NO signalling pathway to reduce the umbilical vein dilation to insulin requiring A2BAR activation in HUVECs.
Collapse
Affiliation(s)
- Rocío Salsoso
- Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil; Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, Seville E-41012, Spain
| | - Alfonso Mate
- Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, Seville E-41012, Spain
| | - Fernando Toledo
- Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Basic Sciences, Faculty of Sciences, Universidad del Bío-Bío, Chillán 3780000, Chile
| | - Carmen M Vázquez
- Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, Seville E-41012, Spain.
| | - Luis Sobrevia
- Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, Seville E-41012, Spain; Medical School (Faculty of Medicine), São Paulo State University (UNESP), Brazil; University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, Herston, QLD, 4029, Australia.
| |
Collapse
|
|
19
|
Kim HW, Shi H, Winkler MA, Lee R, Weintraub NL. Perivascular Adipose Tissue and Vascular Perturbation/Atherosclerosis. Arterioscler Thromb Vasc Biol 2020; 40:2569-2576. [PMID: 32878476 DOI: 10.1161/atvbaha.120.312470] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Atherosclerosis is orchestrated by complex interactions between vascular and inflammatory cells. Traditionally, it has been considered to be an intimal inflammatory disease, characterized by endothelial dysfunction, inflammatory cell recruitment, lipid oxidation, and foam cell formation. This inside-out signaling paradigm has been accepted as dogma for many years, despite the fact that inflammatory cells are far more prevalent in the adventitia compared with the intima. For decades, the origin of adventitial inflammation in atherosclerosis was unknown. The fact that these inflammatory cells were observed to cluster at the margin of perivascular adipose tissues-a unique and highly inflammatory adipose depot that surrounds most atherosclerosis-prone blood vessels-has stimulated interest in perivascular adipose tissue-mediated outside-in signaling in vascular pathophysiology, including atherosclerosis. The phenotype of perivascular adipocytes underlies the functional characteristics of this depot, including its role in adventitial inflammatory cell recruitment, trafficking to the intima via the vasa vasorum, and atherosclerosis perturbation. This review is focused on emerging concepts pertaining to outside-in signaling in atherosclerosis driven by dysfunctional perivascular adipose tissues during diet-induced obesity and recent strategies for atherosclerosis prediction and prognostication based upon this hypothesis.
Collapse
Affiliation(s)
- Ha Won Kim
- Department of Medicine (H.W.K., H.S., N.L.W.), Medical College of Georgia at Augusta University.,Vascular Biology Center (H.W.K., H.S., N.L.W.), Medical College of Georgia at Augusta University
| | - Hong Shi
- Department of Medicine (H.W.K., H.S., N.L.W.), Medical College of Georgia at Augusta University.,Vascular Biology Center (H.W.K., H.S., N.L.W.), Medical College of Georgia at Augusta University
| | - Michael A Winkler
- Department of Radiology (M.A.W.), Medical College of Georgia at Augusta University
| | - Richard Lee
- Department of Surgery (R.L.), Medical College of Georgia at Augusta University
| | - Neal L Weintraub
- Department of Medicine (H.W.K., H.S., N.L.W.), Medical College of Georgia at Augusta University.,Vascular Biology Center (H.W.K., H.S., N.L.W.), Medical College of Georgia at Augusta University
| |
Collapse
|
|
20
|
Muniyappa R, Chen H, Montagnani M, Sherman A, Quon MJ. Endothelial dysfunction due to selective insulin resistance in vascular endothelium: insights from mechanistic modeling. Am J Physiol Endocrinol Metab 2020; 319:E629-E646. [PMID: 32776829 PMCID: PMC7642854 DOI: 10.1152/ajpendo.00247.2020] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Previously, we have used mathematical modeling to gain mechanistic insights into insulin-stimulated glucose uptake. Phosphatidylinositol 3-kinase (PI3K)-dependent insulin signaling required for metabolic actions of insulin also regulates endothelium-dependent production of the vasodilator nitric oxide (NO). Vasodilation increases blood flow that augments direct metabolic actions of insulin in skeletal muscle. This is counterbalanced by mitogen-activated protein kinase (MAPK)-dependent insulin signaling in endothelium that promotes secretion of the vasoconstrictor endothelin-1 (ET-1). In the present study, we extended our model of metabolic insulin signaling into a dynamic model of insulin signaling in vascular endothelium that explicitly represents opposing PI3K/NO and MAPK/ET-1 pathways. Novel NO and ET-1 subsystems were developed using published and new experimental data to generate model structures/parameters. The signal-response relationships of our model with respect to insulin-stimulated NO production, ET-1 secretion, and resultant vascular tone, agree with published experimental data, independent of those used for model development. Simulations of pathological stimuli directly impairing only insulin-stimulated PI3K/Akt activity predict altered dynamics of NO and ET-1 consistent with endothelial dysfunction in insulin-resistant states. Indeed, modeling pathway-selective impairment of PI3K/Akt pathways consistent with insulin resistance caused by glucotoxicity, lipotoxicity, or inflammation predict diminished NO production and increased ET-1 secretion characteristic of diabetes and endothelial dysfunction. We conclude that our mathematical model of insulin signaling in vascular endothelium supports the hypothesis that pathway-selective insulin resistance accounts, in part, for relationships between insulin resistance and endothelial dysfunction. This may be relevant for developing novel approaches for the treatment of diabetes and its cardiovascular complications.
Collapse
Affiliation(s)
- Ranganath Muniyappa
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
| | - Hui Chen
- Clinical and Integrative Diabetes and Obesity Integrated Review Group, Center for Scientific Review, National Institutes of Health, Bethesda, Maryland
| | - Monica Montagnani
- Department of Biomedical Sciences and Human Oncology, Pharmacology Section, Medical School, University of Bari "Aldo Moro", Bari, Italy
| | - Arthur Sherman
- Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
| | - Michael J Quon
- Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
21
|
Adenan DM, Jaafar Z, Jayapalan JJ, Abdul Aziz A. Plasma antioxidants and oxidative stress status in obese women: correlation with cardiopulmonary response. PeerJ 2020; 8:e9230. [PMID: 32477840 PMCID: PMC7243812 DOI: 10.7717/peerj.9230] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 04/30/2020] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION A high body fat coupled with low cardiopulmonary fitness and an increase in oxidative stress has been connoted as contributing factors in developing cardiovascular comorbidities. This study aimed to investigate the correlation between antioxidants and oxidative stress status with cardiopulmonary responses in women of different body mass index (BMI). SUBJECTS AND METHODS Eighty female adults were recruited and divided into three groups; normal weight (n = 23), overweight (n = 28) and obese (n = 29), according to their BMI. Blood samples were obtained prior to cardiopulmonary exercise testing. Plasma samples were separated by centrifugation and analysed for enzymatic antioxidant activity including catalase, glutathione peroxidase and superoxide dismutase. Non-enzymatic antioxidant activities were assessed using 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical scavenging and ferric reducing ability of plasma (FRAP) assays. To evaluate the oxidative stress status of subjects, levels of reactive oxygen species and malondialdehyde, the by-product of lipid peroxidation, were measured. Cardiopulmonary responses were analysed using cardiopulmonary exercise testing (CPET) which involved 15 various parameters such as peak oxygen consumption, metabolic equivalents and respiratory exchange ratio. RESULTS The obese group had significantly lower ABTS radical scavenging and FRAP activities than the normal weight group. A higher catalase activity was observed in the obese group than the normal weight group. Spearman's correlation showed an inverse relationship between catalase and peak oxygen consumption, while partial correlation analysis showed inverse correlations between superoxide dismutase and respiratory frequency, ABTS activity and oxygen pulse, and between ABTS activity and cardiac output. CONCLUSION Our results demonstrate a lower cardiovascular fitness and antioxidant capacity in obese women; the higher catalase activity may be a compensatory mechanism. The negative correlations found between these two parameters may indicate the potential effect of antioxidants on the cardiopulmonary system and deserve further analysis in a larger population. Nevertheless, this study provides the basis for future studies to further explore the relationships between redox status and cardiopulmonary responses. This can potentially be used to predict future risk of developing diseases associated with oxidative stress, especially pulmonary and cardiovascular diseases.
Collapse
Affiliation(s)
- Dyg Mastura Adenan
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Zulkarnain Jaafar
- Department of Sports Medicine, University Malaya Medical Centre, Lembah Pantai, Kuala Lumpur, Malaysia
| | | | - Azlina Abdul Aziz
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| |
Collapse
|
|
22
|
Katsiki N, Anagnostis P, Kotsa K, Goulis DG, Mikhailidis DP. Obesity, Metabolic Syndrome and the Risk of Microvascular Complications in Patients with Diabetes mellitus. Curr Pharm Des 2020; 25:2051-2059. [PMID: 31298151 DOI: 10.2174/1381612825666190708192134] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 06/24/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Obesity frequently co-exists with type 2 diabetes mellitus (T2DM), leading to the socalled "diabesity epidemic". The metabolic syndrome (MetS), a cluster of central obesity, hypertension, dysglycemia, insulin resistance and/or atherogenic dyslipidemia, as well as non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of MetS, has been associated with increased cardiovascular disease (CVD), T2DM and chronic kidney disease (CKD) incidence. However, the association between obesity, MetS (including NAFLD) and diabetic microvascular complications is less evident. METHODS The present narrative review discusses the associations of obesity, MetS and NAFLD with diabetic kidney disease (DKD), diabetic retinopathy (DR) and diabetic peripheral neuropathy (DPN) as well as cardiac autonomic neuropathy (CAN). The available data on the effects of lifestyle measures and bariatric surgery on these diabetic complications are also briefly discussed. RESULTS Overall, both obesity and MetS have been related to DKD, DR and DPN, although conflicting results exist. Links between NAFLD and diabetic microvascular complications have also been reported but data are still limited. Lifestyle intervention and bariatric surgery may prevent the development and/or progression of these microvascular complications but more evidence is needed. CONCLUSION Clinicians should be aware of the frequent co-existence of MetS and/or NAFLD in T2DM patients to prevent or treat these metabolic disorders, thus potentially minimizing the risk for both CVD and diabetic microvascular complications.
Collapse
Affiliation(s)
- Niki Katsiki
- First Department of Internal Medicine, Division of Endocrinology and Metabolism, Diabetes Center, Medical School, AHEPA University Hospital, Thessaloniki, Greece
| | - Panagiotis Anagnostis
- Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kalliopi Kotsa
- First Department of Internal Medicine, Division of Endocrinology and Metabolism, Diabetes Center, Medical School, AHEPA University Hospital, Thessaloniki, Greece
| | - Dimitrios G Goulis
- Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom
| |
Collapse
|
|
23
|
Dragic S, Momcicevic D, Zlojutro B, Jandric M, Kovacevic T, Djajić V, Gajić A, Talić G, Kovacevic P. Serum levels of nitric oxide and endothelin-1 in vasculopathy managed with hyperbaric oxygen therapy. Clin Hemorheol Microcirc 2020; 75:233-241. [PMID: 32116239 DOI: 10.3233/ch-190796] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Roles of nitric oxide (NO) and endothelin-1 (ET-1) in the local regulation of blood flow under physiological conditions are important and well known, while data on their effects and interactions in conditions of hyperbaric hyperoxia is still insufficient. This was a prospective observational study which included patients who underwent hyperbaric oxygen therapy (HBOT) in accordance with existing therapeutic protocol for peripherial arterial disease (PAD) during time period of six months, between january and july of 2016. Clinical stage of PAD according to Fontain was taken into account, as well as risk factors, demographic, anthropometric and clinical characteristics of studied patients. The study included 64 patients with a mean age (±Sd) 60.2±12.7 years, of whom 28 were female. Patients' NO serum levels in all observed categories before and after HBOT were not signifficantly different, except for stage II PAD (NObefore HBOT 21.9±9.6 vs. NOafter HBOT 26.2±12.1 (p = 0.04)). On the contrary, in all studied patients ET-1 level increased signifficantly after HBOT (ET-1before HBOT 4.2±11.6 vs. ET-1after 18.3±21.0 (p < 0.001)). Treatment of PAD using HBOT leads to the predominance of vasoconstrictor effects probably caused by elevation of serum ET-1 concentrations, while other factors such as exposure time to hyperbaric conditions, activation of antioxidant molecules, and the influx of other interfering substances must be considered in interpreting the effects of NO molecules.
Collapse
Affiliation(s)
- Sasa Dragic
- Medical Intensive Care Unit, University Clinical Centre of Republic of Srpska, Banja Luka, Republic of Srpska, Bosnia and Herzegovina.,Pan- European University "Apeiron", College of Health Sciences, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Danica Momcicevic
- Medical Intensive Care Unit, University Clinical Centre of Republic of Srpska, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Biljana Zlojutro
- Medical Intensive Care Unit, University Clinical Centre of Republic of Srpska, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Milka Jandric
- Medical Intensive Care Unit, University Clinical Centre of Republic of Srpska, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Tijana Kovacevic
- Pharmacy Department, University Clinical Centre of Republic of Srpska, Banja Luka, Republic of Srpska, Bosnia and Herzegovina.,Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Vlado Djajić
- Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Aleksandar Gajić
- Institute for the Physical Medicine and Rehabilitation "dr. Miroslav Zotovic" Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Goran Talić
- Institute for the Physical Medicine and Rehabilitation "dr. Miroslav Zotovic" Banja Luka, Republic of Srpska, Bosnia and Herzegovina.,Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Pedja Kovacevic
- Medical Intensive Care Unit, University Clinical Centre of Republic of Srpska, Banja Luka, Republic of Srpska, Bosnia and Herzegovina.,Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| |
Collapse
|
|
24
|
Agboghoroma OF, Akemokwe FM, Puepet FH. Peripheral arterial disease and its correlates in patients with type 2 diabetes mellitus in a teaching hospital in northern Nigeria: a cross-sectional study. BMC Cardiovasc Disord 2020; 20:102. [PMID: 32111165 PMCID: PMC7049182 DOI: 10.1186/s12872-020-01395-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 02/21/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Peripheral arterial disease (PAD) is a risk factor for diabetic foot ulcer, limb amputation as well as coronary heart disease. It is more common in patients with diabetes mellitus (DM) and co-exists with peripheral neuropathy. Prevalence of PAD in type 2 DM patients in northern Nigeria is largely unknown. We investigated the occurrence and factors associated with PAD among patients with type 2 DM in a tertiary hospital in northern Nigeria. METHODS This was a cross- sectional analytic study. We recruited 200 patients with type 2 DM consecutively from the diabetes clinic of the Jos University Teaching Hospital. Ankle brachial index was assessed for each participant. Clinical information, anthropometric indices and blood samples were collected for assay. Data was analysed using CDC Epi-Info and logistic regression analysis was used to determine independent correlates of PAD. RESULTS PAD was present in 38.5%(n = 77) of subjects and it was associated with the female sex, age ≥ 50 years, Body mass index (BMI) ≥ 25 kg/m2 and low HDL cholesterol levels. However, on multiple logistic regression, a BMI ≥ 25 kg/m2 and a low HDL cholesterol level were independent correlates of PAD(adjusted OR = 2.13,95% CI = 1.04-4.36 and adjusted OR = 2.31, 95% CI = 1.04-5.15, respectively). CONCLUSION PAD is present in more than a third of patients with type 2 DM in a tertiary hospital in northern Nigeria. A BMI of ≥25 kg/m2 and low HDL cholesterol levels were independent correlates of PAD.
Collapse
Affiliation(s)
- Orighomisan Freda Agboghoroma
- Jos University Teaching Hospital, Jos, Plateau State Nigeria
- Present address: Medical Research Council at the London School of Hygiene and Tropical Medicine, Fajara, Gambia
| | - Fatai Momodu Akemokwe
- Present address: Medical Research Council at the London School of Hygiene and Tropical Medicine, Fajara, Gambia
| | | |
Collapse
|
|
25
|
Antioxidant Effects and Mechanisms of Medicinal Plants and Their Bioactive Compounds for the Prevention and Treatment of Type 2 Diabetes: An Updated Review. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:1356893. [PMID: 32148647 PMCID: PMC7042557 DOI: 10.1155/2020/1356893] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/31/2019] [Accepted: 01/16/2020] [Indexed: 12/14/2022]
Abstract
Diabetes mellitus is a metabolic disorder that majorly affects the endocrine gland, and it is symbolized by hyperglycemia and glucose intolerance owing to deficient insulin secretory responses and beta cell dysfunction. This ailment affects as many as 451 million people worldwide, and it is also one of the leading causes of death. In spite of the immense advances made in the development of orthodox antidiabetic drugs, these drugs are often considered not successful for the management and treatment of T2DM due to the myriad side effects associated with them. Thus, the exploration of medicinal herbs and natural products as therapeutic sources for the treatment of T2DM is promoted because they have little or no side effects. Bioactive molecules isolated from natural sources have been proven to lower blood glucose levels via regulating one or more of the following mechanisms: improvement of beta cell function, insulin resistance, glucose (re)absorption, and glucagon-like peptide-1 homeostasis. In recent times, the mechanisms of action of different bioactive molecules with antidiabetic properties and phytochemistry are gaining a lot of attention in the area of drug discovery. This review article presents an update of the findings from clinical research into medicinal plant therapy for T2DM.
Collapse
|
|
26
|
Gamil NM, Abd El Fattah MA, Ahmed MAE, Maklad YA, Gamal El Din AA, Eid NI. Lansoprazole enhances the antidiabetic effect of dapagliflozin in fortified diet-fed streptozotocin-treated diabetic rats. J Biochem Mol Toxicol 2020; 34:e22451. [PMID: 31975531 DOI: 10.1002/jbt.22451] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 11/29/2019] [Accepted: 01/08/2020] [Indexed: 12/19/2022]
Abstract
Dapagliflozin (DAPA) is used for treating type 2 diabetes, whereas lansoprazole (LPZ) is used as a traditional antiulcer drug. The present study investigated the possible antidiabetic effects of LPZ on fortified diet-fed streptozotocin (FDF/STZ)-induced insulin-resistant diabetic rats. On the basis of the current results, it can be concluded that LPZ could be used as an add-on drug along with the conventional treatment for T2D as it showed beneficial effects in the current experimental model of insulin resistance.
Collapse
Affiliation(s)
- Noha M Gamil
- Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, Egypt
| | - Mai A Abd El Fattah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Maha A E Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, Egypt
| | - Yousreya A Maklad
- Medicinal and Pharmaceutical Chemistry Department (Pharmacology Group), Pharmaceutical and Drug Industries Research Division, National Research Centre, Giza, Egypt
| | - Amina A Gamal El Din
- Medical Research Division, Pathology Department, National Research Centre, Giza, Egypt
| | - Nihad I Eid
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| |
Collapse
|
|
27
|
Heyman E, Daussin F, Wieczorek V, Caiazzo R, Matran R, Berthon P, Aucouturier J, Berthoin S, Descatoire A, Leclair E, Marais G, Combes A, Fontaine P, Tagougui S. Muscle Oxygen Supply and Use in Type 1 Diabetes, From Ambient Air to the Mitochondrial Respiratory Chain: Is There a Limiting Step? Diabetes Care 2020; 43:209-218. [PMID: 31636081 DOI: 10.2337/dc19-1125] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 09/25/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Long before clinical complications of type 1 diabetes (T1D) develop, oxygen supply and use can be altered during activities of daily life. We examined in patients with uncomplicated T1D all steps of the oxygen pathway, from the lungs to the mitochondria, using an integrative ex vivo (muscle biopsies) and in vivo (during exercise) approach. RESEARCH DESIGN AND METHODS We compared 16 adults with T1D with 16 strictly matched healthy control subjects. We assessed lung diffusion capacity for carbon monoxide and nitric oxide, exercise-induced changes in arterial O2 content (SaO2, PaO2, hemoglobin), muscle blood volume, and O2 extraction (via near-infrared spectroscopy). We analyzed blood samples for metabolic and hormonal vasoactive moieties and factors that are able to shift the O2-hemoglobin dissociation curve. Mitochondrial oxidative capacities were assessed in permeabilized vastus lateralis muscle fibers. RESULTS Lung diffusion capacity and arterial O2 transport were normal in patients with T1D. However, those patients displayed blunted exercise-induced increases in muscle blood volume, despite higher serum insulin, and in O2 extraction, despite higher erythrocyte 2,3-diphosphoglycerate. Although complex I- and complex II-supported mitochondrial respirations were unaltered, complex IV capacity (relative to complex I capacity) was impaired in patients with T1D, and this was even more apparent in those with long-standing diabetes and high HbA1c. [Formula: see text]O2max was lower in patients with T1D than in the control subjects. CONCLUSIONS Early defects in microvascular delivery of blood to skeletal muscle and in complex IV capacity in the mitochondrial respiratory chain may negatively impact aerobic fitness. These findings are clinically relevant considering the main role of skeletal muscle oxidation in whole-body glucose disposal.
Collapse
Affiliation(s)
- Elsa Heyman
- EA7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, Lille, France
| | - Frédéric Daussin
- EA7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, Lille, France
| | | | - Robert Caiazzo
- Service de Chirurgie Générale et Endocrinienne, University Hospital of Lille, Lille, France.,UMR_1190 Recherche Translationnelle sur le Diabète, Faculté de Médecine de Lille, INSERM, Lille, France
| | - Régis Matran
- Department of Physiology, EA 2689 and IFR 22, Lille, France
| | - Phanélie Berthon
- Inter-university Laboratory of Human Movement Sciences EA7424, University of Savoie Mont Blanc, Chambéry, France
| | - Julien Aucouturier
- EA7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, Lille, France
| | - Serge Berthoin
- EA7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, Lille, France
| | | | - Erwan Leclair
- EA7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, Lille, France.,Réseau québécois de recherche sur la douleur, Université de Sherbrooke, Montreal, Quebec, Canada
| | - Gaëlle Marais
- EA7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, Lille, France
| | - Adrien Combes
- EA7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, Lille, France
| | - Pierre Fontaine
- Department of Diabetology, Lille University Hospital, EA 4489, Lille, France
| | - Sémah Tagougui
- EA7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, Lille, France.,Metabolic Diseases, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
| |
Collapse
|
|
28
|
Piri R, Naghavi-Behzad M, Gerke O, Høilund-Carlsen PF, Vafaee MS. Investigations of possible links between Alzheimer’s disease and type 2 diabetes mellitus by positron emission tomography: a systematic review. Clin Transl Imaging 2019. [DOI: 10.1007/s40336-019-00339-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
|
|
29
|
Tekwe CD, Yao K, Lei J, Li X, Gupta A, Luan Y, Meininger CJ, Bazer FW, Wu G. Oral administration of α-ketoglutarate enhances nitric oxide synthesis by endothelial cells and whole-body insulin sensitivity in diet-induced obese rats. Exp Biol Med (Maywood) 2019; 244:1081-1088. [PMID: 31357871 DOI: 10.1177/1535370219865229] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Obesity is a risk factor for many chronic diseases, including hypertension, type-2 diabetes, and cancer. Interestingly, concentrations of branched-chain amino acids (BCAAs) in plasma are commonly associated with endothelial dysfunction in humans and animals with obesity. Because L-leucine inhibits nitric oxide synthesis by endothelial cells (EC), we hypothesized that dietary supplementation with AKG (a substrate for BCAA transaminase) may stimulate BCAA catabolism in the small intestine and extra-intestinal tissues, thereby reducing the circulating concentrations of BCAAs and increasing nitric oxide synthesis by endothelial cells. Beginning at four weeks of age, male Sprague-Dawley rats were fed a low-fat or a high-fat diet for 15 weeks. At 19 weeks of age, lean or obese rats continued to be fed for 12 weeks their respective diets and received drinking water containing 0 or 1% AKG ( n = 8/group). At 31 weeks of age, the rats were euthanized to obtain tissues. Food intake did not differ ( P > 0.05) between rats supplemented with or without AKG. Oral administration of AKG (250 mg/kg BW per day) reduced ( P < 0.05) concentrations of BCAAs, glucose, ammonia, and triacylglycerols in plasma, adiposity, and glutamine:fructose-6-phosphate transaminase activity in endothelial cells, and enhanced ( P < 0.05) concentrations of the reduced form of glutathione in tissues, nitric oxide synthesis by endothelial cells, and whole-body insulin sensitivity (indicated by oral glucose tolerance test) in both low-fat and high-fat rats. AKG administration reduced ( P < 0.05) white adipose tissue weights of rats in the low-fat and high-fat groups. These novel results indicate that AKG can reduce adiposity and increase nitric oxide production by endothelial cells in diet-induced obese rats. Impact statement Obesity is associated with elevated concentrations of branched-chain amino acids, including L-leucine. L-Leucine inhibits the synthesis of nitric oxide from L-arginine by endothelial cells, contributing to impairments in angiogenesis, blood flow, and vascular dysfunction, as well as insulin resistance. Reduction in the circulating levels of branched-chain amino acids through dietary supplementation with α-ketoglutarate to promote their transamination in the small intestine and other tissues can restore nitric oxide synthesis in the vasculature and reduce the weights of white adipose tissues, thereby improving metabolic profiles and whole-body insulin sensitivity (indicated by oral glucose tolerance test) in diet-induced obese rats. Our findings provide a simple and effective nutritional means to alleviate metabolic syndrome in obese subjects. This is highly significant to combat the current obesity epidemic and associated health problems in humans worldwide.
Collapse
Affiliation(s)
- Carmen D Tekwe
- Department of Animal Science, Texas A&M University, College Station, TX 77843, USA.,Department of Epidemiology and Biostatistics, Texas A&M University, College Station, TX 77843, USA
| | - Kang Yao
- Department of Animal Science, Texas A&M University, College Station, TX 77843, USA
| | - Jian Lei
- Department of Animal Science, Texas A&M University, College Station, TX 77843, USA
| | - Xilong Li
- Department of Animal Science, Texas A&M University, College Station, TX 77843, USA
| | - Anand Gupta
- Department of Epidemiology and Biostatistics, Texas A&M University, College Station, TX 77843, USA
| | - Yuanyuan Luan
- Department of Epidemiology and Biostatistics, Texas A&M University, College Station, TX 77843, USA
| | - Cynthia J Meininger
- Department of Medical Physiology, Texas A&M Health Science Center, College Station, TX 77843, USA
| | - Fuller W Bazer
- Department of Animal Science, Texas A&M University, College Station, TX 77843, USA
| | - Guoyao Wu
- Department of Animal Science, Texas A&M University, College Station, TX 77843, USA.,Department of Medical Physiology, Texas A&M Health Science Center, College Station, TX 77843, USA
| |
Collapse
|
|
30
|
Green S, O'Connor E, Kiely C, O'Shea D, Egaña M. Effect of obesity on oxygen uptake and cardiovascular dynamics during whole-body and leg exercise in adult males and females. Physiol Rep 2019; 6:e13705. [PMID: 29756296 PMCID: PMC5949330 DOI: 10.14814/phy2.13705] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 04/13/2018] [Indexed: 12/02/2022] Open
Abstract
Obesity has been associated with a slowing of V˙O2 dynamics in children and adolescents, but this problem has not been studied in adults. Cardiovascular mechanisms underlying this effect are not clear. In this study, 48 adults (18 males, 30 females) grouped according to body mass index (BMI) (lean < 25 kg·m−2, overweight = 25–29.9 kg·m−2, obese ≥30 kg·m−2) provided a fasting blood sample, completed a maximal graded exercise test and six bouts of submaximal exercise on a cycle ergometer, and performed two protocols of calf exercise. Dynamic response characteristics of V˙O2 and leg vascular conductance (LVC) were assessed during cycling (80% ventilatory threshold) and calf exercise (30% MVC), respectively. Dynamic responses of cardiac output, mean arterial pressure and total systemic vascular conductance were also assessed during cycling based on measurements at 30 and 240 sec. The time constant of the second phase of the V˙O2 response was significantly greater in obese than lean subjects (39.4 (9.2) vs. 29.1 (7.6) sec); whereas dynamic responses of cardiac output and systemic vascular conductance were not affected by BMI. For calf exercise, the time constant of the second growth phase of LVC was slowed significantly in obese subjects (22.1 (12.7) sec) compared with lean and overweight subjects (11.6 (4.5) sec and 13.4 (6.7) sec). These data show that obesity slows dynamic responses of V˙O2 during cycling and the slower phase of vasodilation in contracting muscles of male and female adults.
Collapse
Affiliation(s)
- Simon Green
- School of Science and Health, Western Sydney University, Sydney, Australia
| | - Eamon O'Connor
- School of Medicine, Department of Physiology, Trinity College Dublin, Dublin, Ireland
| | - Catherine Kiely
- School of Medicine, Department of Physiology, Trinity College Dublin, Dublin, Ireland
| | - Donal O'Shea
- Endocrinology, St. Columcille's and St. Vincent's Hospitals, Dublin, Ireland
| | - Mikel Egaña
- School of Medicine, Department of Physiology, Trinity College Dublin, Dublin, Ireland
| |
Collapse
|
|
31
|
Editorial commentary: Metabolic effects of cardiovascular medication: Does it matter? Trends Cardiovasc Med 2019; 29:188-189. [DOI: 10.1016/j.tcm.2018.09.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 09/21/2018] [Indexed: 11/20/2022]
|
|
32
|
Saunders DJ, Bleasdale L, Summerton L, Hancock A, Homer-Vanniasinkam S, Russell DA. Assessment of the Utility of a Vascular Early Warning System Device in the Assessment of Peripheral Arterial Disease in Patients with Diabetes and Incompressible Vessels. Ann Vasc Surg 2019; 58:160-165. [PMID: 30769053 DOI: 10.1016/j.avsg.2018.11.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 11/13/2018] [Accepted: 11/20/2018] [Indexed: 10/27/2022]
Abstract
BACKGROUND The objective of this study was to assess the ability of a novel, automated Conformité Européenne marked vascular early warning system (VEWS) device to detect peripheral arterial disease in patients with incompressible ankle arteries and non-measurable ankle brachial pressure index (ABPI) secondary to diabetes. METHODS Recruited patients had diabetes, recent magnetic resonance angiography evidence of peripheral arterial disease (PAD), and incompressible vessels on ABPI. VEWS indices of each leg were automatically calculated by using optical infrared and red sensors applied to the foot, with readings obtained with the subject's leg both flat and elevated. Indices <1.03 and ≤0.94 were considered upper and lower diagnostic cutoff limits for PAD. Bollinger scores were calculated from the magnetic resonance angiography. A Best Bollinger Score (BBS) of <4 was defined as no significant PAD. RESULTS All patients had tissue loss. Per protocol analysis of 28 limbs in 14 patients: VEWS had a sensitivity of 94% and specificity 20% for the detection of PAD at <1.03 cutoff and sensitivity 89% and specificity 80% at ≤0.94 cutoff. There was a good correlation between the VEWS index and BBS (-0.637; P = 0.0003). CONCLUSION VEWS is a safe, simple-to-use, promising tool to assist in the diagnosis of PAD in patients with incompressible vessels due to diabetes.
Collapse
Affiliation(s)
| | | | | | | | | | - David A Russell
- Leeds Vascular Institute, Leeds General Infirmary, Leeds, UK; Leeds Diabetes Limb Salvage Unit, St James' University Hospital, Leeds, UK; Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| |
Collapse
|
|
33
|
Schinzari F, Tesauro M, Cardillo C. Increased endothelin-1-mediated vasoconstrictor tone in human obesity: effects of gut hormones. Physiol Res 2018; 67:S69-S81. [PMID: 29947529 DOI: 10.33549/physiolres.933821] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. Impaired vasodilator reactivity has been recognized as an early hemodynamic abnormality in obese patients, but also increased vasoconstrictor tone importantly contributes to their vascular damage. In particular, upregulation of the endothelin (ET)-1 system, consistently reported in these patients, might accelerate atherosclerosis and its complication, given the pro-inflammatory and mitogenic properties of ET-1. In recent years, a number of gut hormones, in addition to their role as modulators of food intake, energy balance, glucose and lipid metabolism, and insulin secretion and action, have demonstrated favorable vascular actions. They increase the bioavailability of vasodilator mediators like nitric oxide, but they have also been shown to inhibit the ET-1 system. These features make gut hormones promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant advantages. Therefore, there is real hope that better understanding of the properties of gut-derived substances might provide more effective therapies for the obesity-related cardiometabolic syndrome.
Collapse
Affiliation(s)
- F Schinzari
- Policlinico A. Gemelli, Rome, Italy, Istituto di Patologia Speciale Medica e Semeiotica Medica, Universita Cattolica del Sacro Cuore, Rome, Italy.
| | | | | |
Collapse
|
|
34
|
Chatterjee S, Bandyopadhyay D, Ghosh RK, Majumdar U, Aneja A, Lavie CJ, Deedwania P. SGLT-2 Inhibitors and Peripheral Artery Disease: A Statistical Hoax or Reality? Curr Probl Cardiol 2018; 44:207-222. [PMID: 30195639 DOI: 10.1016/j.cpcardiol.2018.06.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 06/29/2018] [Indexed: 12/14/2022]
Abstract
Inhibitors of sodium-glucose cotransporters type-2 are the most recent addition to the armamentarium of oral antidiabetic agents. This class of drugs has shown promising results in glycemic control and most importantly to reduce cardiovascular disease (CVD) mortality risk. Despite the encouraging data, there is concern regarding their potential for causing or worsening peripheral artery disease (PAD), which may increase the risk of lower extremity amputations. Following the publication of results of CANVAS and CANVAS-R trials, which revealed that leg and mid-foot amputations occurred about twice as often in patients treated with canagliflozin compared to placebo, the Food and Drug Administration (FDA) in the United States issued a black box warning of leg and foot amputations associated with canagliflozin use. In this article, our main aim is to review the available evidence in preclinical and clinical studies regarding SGLT-2 inhibitors and PAD events, the possible mechanisms related to increased risk of amputation, to evaluate whether it is a class effect or individual drug effect, and most importantly, implications for their continued use as antidiabetic agents. It also raises the issue of including PAD events among the end-points when assessing future antihyperglycemic agents. Thus, we also tried to analyze whether outcomes of SGLT2 inhibitors trials mostly focused on stroke, myocardial infarction, heart failure, and peripheral vascular disease-related outcomes remained underrated.
Collapse
|
|
35
|
Leech RM, Timperio A, Worsley A, McNaughton SA. Eating patterns of Australian adults: associations with blood pressure and hypertension prevalence. Eur J Nutr 2018; 58:1899-1909. [PMID: 29876653 PMCID: PMC6647126 DOI: 10.1007/s00394-018-1741-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 06/05/2018] [Indexed: 11/28/2022]
Abstract
PURPOSE Eating patterns have been linked to obesity, an established risk factor for hypertension; however, their contribution to hypertension is poorly understood. This study aimed to examine associations of frequency of meals, snacks and all eating occasions (EO), and temporal eating patterns, with blood pressure (BP) and hypertension. METHODS Dietary data collected via two 24-h recalls during the 2011-2012 Australian National Nutrition and Physical Activity Survey (n = 4482 adults, ≥ 19 years) were analysed. Frequencies of EO, meals, and snacks were calculated. Temporal eating patterns were determined using latent class analysis. Multivariate regression models assessed associations of eating patterns with systolic BP (SBP), diastolic BP (DBP), and hypertension prevalence. RESULTS Among men, a higher snack frequency was inversely associated with DBP [β = - 0.59, 95% confidence interval (CI) (- 1.12, - 0.07)] and hypertension [odds ratio (OR) 0.86, 95% CI (0.75, 0.98)] after adjustment for covariates and BMI. However, these associations disappeared after additional adjustment for total energy intake and overall diet quality. Among women, a temporal eating pattern characterized by a later "lunch" meal was associated with SBP [β = 2.45, 95% CI (0.05, 4.84)], DBP [β = 1.69, 95% CI (0.25, 3.13)], and hypertension [OR = 1.49, 95% CI (1.00, 2.22)], when compared to a "conventional" eating pattern. CONCLUSIONS In this study, an inverse association found between snack frequency and BP among men disappeared after adjustment for dietary factors and a "later lunch" pattern was associated with higher BP in women. Future research is needed to understand the relationship and potential mechanistic pathways between eating patterns and BP.
Collapse
Affiliation(s)
- Rebecca M Leech
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, 75 Pigdons Rd, Waurn Ponds, Geelong, 3216, Australia.
| | - Anna Timperio
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, 75 Pigdons Rd, Waurn Ponds, Geelong, 3216, Australia
| | - Anthony Worsley
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, 75 Pigdons Rd, Waurn Ponds, Geelong, 3216, Australia
| | - Sarah A McNaughton
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, 75 Pigdons Rd, Waurn Ponds, Geelong, 3216, Australia
| |
Collapse
|
|
36
|
Chen XM, Zhang WQ, Tian Y, Wang LF, Chen CC, Qiu CM. Liraglutide suppresses non-esterified free fatty acids and soluble vascular cell adhesion molecule-1 compared with metformin in patients with recent-onset type 2 diabetes. Cardiovasc Diabetol 2018; 17:53. [PMID: 29636047 PMCID: PMC5891985 DOI: 10.1186/s12933-018-0701-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 04/05/2018] [Indexed: 01/28/2023] Open
Abstract
Background It has been suggested that liraglutide could have an impact on glucose and lipid metabolism disorder and adhesion molecule activation, which may play important roles in the vascular damage of diabetes. In this study, we examined the effects of liraglutide versus metformin on non-esterified free fatty acids, beta-cell insulin secretion, and adhesion molecule levels in patients with recent-onset type 2 diabetes mellitus. Methods In this study, 60 patients newly diagnosed with type 2 diabetes mellitus (mean age 33.97 ± 5.67 years) were randomly assigned to receive once-daily subcutaneous liraglutide or oral metformin. Before the study and after the 8-week treatment period, a 75 g oral glucose tolerance test was performed. Plasma glucose, lipids and lipoprotein, plasma insulin, glycaemic and insulin responses, non-esterified free fatty acids (NEFA), and soluble vascular cell adhesion molecule-1 (sVCAM-1) levels were evaluated. Results After 8 weeks, 120 min of NEFA (155 ± 125 vs 99 ± 73 µmol/L, P = 0.026) and the levels of sVCAM-1 (465 ± 136 vs 382 ± 131 ng/ml, P = 0.013) significantly decreased, while the early phase insulin secretion index (24.94 [7.78, 38.89] vs. 31.13 [17.67, 59.09], P = 0.031), fasting plasma insulin (104 [51, 123] vs 113 [54, 171] mIU/L, P = 0.015), 60 min plasma insulin (326 [165, 441] vs 471 [334, 717] mIU/L, P = 0.005), 120 min plasma insulin (401 [193, 560] vs 500 [367, 960] mIU/L, P = 0.047), and insulin area under the curve (AUCins) (648 [321, 742] vs 738 [451, 1118] mIU/L, P = 0.005) remarkably increased for patients in the liraglutide treatment group. The levels of sVCAM-1 dramatically decreased after 8 weeks of liraglutide treatment (503 ± 182 vs 382 ± 131 ng/ml, P = 0.046) compared to that of the metformin treatment group. At the same time, the differences before and after liraglutide treatment in 120 min of NEFA (− 32 [− 96, − 5] vs 5 [− 35, 38] µmol/L, P = 0.033) and AUCins (738 [451, 1118] vs 594 [357, 1216] mIU/L, P = 0.014) were remarkably enhanced compared to that of the metformin therapy. Nevertheless, there were no significant differences in fasting NEFA after liraglutide or metformin treatment. The reduction of 120 min NEFA (ΔNEFA) was positively correlated with the decrease of sVCAM-1 (ΔsVCAM-1) after 8 weeks of liraglutide treatment (r = 0.523, P = 0.003). Conclusions Our results demonstrate that liraglutide administration is more effective than metformin in reducing 120 min NEFA and suppressing sVCAM-1 levels for recent-onset type 2 diabetes mellitus. We suggest that this outcome may be because liraglutide is associated with potentiating insulin secretion capacity, inhibiting vascular inflammatory cytokines, and antagonizing atherosclerosis. Electronic supplementary material The online version of this article (10.1186/s12933-018-0701-4) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Xiao-Min Chen
- Department of Endocrinology and Metabolism, Zhongshan Hospital Xiamen University, 201-209 Hubin South Road, Xiamen, 361004, People's Republic of China.
| | - Wen-Qiang Zhang
- Department of Endocrinology and Metabolism, Zhongshan Hospital Xiamen University, 201-209 Hubin South Road, Xiamen, 361004, People's Republic of China
| | - Yuan Tian
- Department of Endocrinology and Metabolism, Zhongshan Hospital Xiamen University, 201-209 Hubin South Road, Xiamen, 361004, People's Republic of China
| | - Li-Fen Wang
- Guangzhou Medicine University Second Affiliated Hospital, 250-296 Changgang East Road, Guangzhou, 510260, People's Republic of China
| | - Chan-Chan Chen
- Department of Endocrinology and Metabolism, Zhongshan Hospital Xiamen University, 201-209 Hubin South Road, Xiamen, 361004, People's Republic of China
| | - Chuan-Mei Qiu
- Department of Endocrinology and Metabolism, Zhongshan Hospital Xiamen University, 201-209 Hubin South Road, Xiamen, 361004, People's Republic of China
| |
Collapse
|
|
37
|
Roh HT, So WY. The effects of aerobic exercise training on oxidant-antioxidant balance, neurotrophic factor levels, and blood-brain barrier function in obese and non-obese men. JOURNAL OF SPORT AND HEALTH SCIENCE 2017; 6:447-453. [PMID: 30356625 PMCID: PMC6189263 DOI: 10.1016/j.jshs.2016.07.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2015] [Revised: 04/02/2016] [Accepted: 04/18/2016] [Indexed: 05/24/2023]
Abstract
PURPOSE The purpose of this study was to investigate the effects of obesity and aerobic exercise training on oxidant-antioxidant balance, neurotrophic factor levels, and blood-brain barrier (BBB) function. METHODS Ten non-obese healthy men (body mass index < 25 kg/m2) and 10 obese men (body mass index ≥ 25 kg/m2) were included in the study. Both groups performed treadmill exercise for 40 min 3 times weekly for 8 weeks at 70% heart rate reserve. Blood samples were collected to examine oxidant-antioxidant balance (reactive oxygen species (ROS) and superoxide dismutase (SOD) activity levels), neurotrophic factors (brain-derived neurotrophic factor (BDNF), nerve growth factor, and glial cell line-derived neurotrophic factor levels), and BBB function (S100β and neuron-specific enolase (NSE) levels) before and after exercise training. RESULTS The obese group showed significantly greater changes than the non-obese group in serum ROS (-0.46 ± 0.31 mmol/L vs. -0.10 ± 0.17 mmol/L, p = 0.005), serum S100β levels (-8.50 ± 5.92 ng/L vs. -0.78 ± 5.45 ng/L, p = 0.007), and serum NSE levels (-0.89 ± 0.54 µg/L vs. -0.01 ± 0.74 µg/L, p = 0.007) after training. At baseline, the obese group showed significantly higher serum ROS and S100β levels and significantly lower serum SOD activity and BDNF levels than the non-obese group (p < 0.05). The obese group showed significantly lower serum ROS, S100β, and NSE levels and significantly higher serum SOD activity and BDNF levels after training compared with baseline (p < 0.05). CONCLUSION These results suggest that obesity can reduce serum neurotrophic factor levels and can induce BBB dysfunction. On the other hand, aerobic exercise can improve an oxidant-antioxidant imbalance in obese subjects and limit BBB dysfunction.
Collapse
Affiliation(s)
- Hee-Tae Roh
- Department of Physical Education, College of Arts and Physical Education, Dong-A University, Busan 604-714, Republic of Korea
| | - Wi-Young So
- Sports and Health Care Major, College of Humanities and Arts, Korea National University of Transportation, Chungju-si 380-702, Republic of Korea
| |
Collapse
|
|
38
|
Abstract
Blood pressure management in hypertensive patients with metabolic abnormalities is challenging, since many of the antihypertensive drugs adversely affect metabolism. Besides effective control of blood pressure in patients with hypertension, third-generation beta-blockers such as nebivolol offer additional benefits for central hemodynamics and neutral or beneficial effects on metabolism. Emerging clinical data suggest that nebivolol also has similar effects on metabolism in obese hypertensive and hypertensive diabetic patients. The present article will provide a systematic analysis of the pathophysiological links among hypertension, insulin resistance, and metabolic syndrome. We will also summarize the available clinical evidence regarding the metabolic effects of beta-blockers in hypertensive patients, with an emphasis on nebivolol. Nebivolol exerts neutral or beneficial effects on insulin sensitivity and lipid metabolism in hypertensive patients, owing to its nitric oxide-mediated vasodilatory and antioxidative properties. Thus, nebivolol could be a favorable therapeutic option for the treatment of hypertension in patients with impaired glucose and lipid metabolism.
Collapse
|
|
39
|
Ghosh A, Gao L, Thakur A, Siu PM, Lai CWK. Role of free fatty acids in endothelial dysfunction. J Biomed Sci 2017; 24:50. [PMID: 28750629 PMCID: PMC5530532 DOI: 10.1186/s12929-017-0357-5] [Citation(s) in RCA: 279] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 07/24/2017] [Indexed: 02/06/2023] Open
Abstract
Plasma free fatty acids levels are increased in subjects with obesity and type 2 diabetes, playing detrimental roles in the pathogenesis of atherosclerosis and cardiovascular diseases. Increasing evidence showing that dysfunction of the vascular endothelium, the inner lining of the blood vessels, is the key player in the pathogenesis of atherosclerosis. In this review, we aimed to summarize the roles and the underlying mechanisms using the evidence collected from clinical and experimental studies about free fatty acid-mediated endothelial dysfunction. Because of the multifaceted roles of plasma free fatty acids in mediating endothelial dysfunction, elevated free fatty acid level is now considered as an important link in the onset of endothelial dysfunction due to metabolic syndromes such as diabetes and obesity. Free fatty acid-mediated endothelial dysfunction involves several mechanisms including impaired insulin signaling and nitric oxide production, oxidative stress, inflammation and the activation of the renin-angiotensin system and apoptosis in the endothelial cells. Therefore, targeting the signaling pathways involved in free fatty acid-induced endothelial dysfunction could serve as a preventive approach to protect against the occurrence of endothelial dysfunction and the subsequent complications such as atherosclerosis.
Collapse
Affiliation(s)
- Arijit Ghosh
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, HKSAR, China
- Department of Biomedical Sciences, City University of Hong Kong, HKSAR, China
| | - Lei Gao
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, HKSAR, China
| | - Abhimanyu Thakur
- Department of Biomedical Sciences, City University of Hong Kong, HKSAR, China
| | - Parco M. Siu
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, HKSAR, China
| | - Christopher W. K. Lai
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, HKSAR, China
| |
Collapse
|
|
40
|
Endothelial and Perivascular Adipose Tissue Abnormalities in Obesity-Related Vascular Dysfunction: Novel Targets for Treatment. J Cardiovasc Pharmacol 2017; 69:360-368. [DOI: 10.1097/fjc.0000000000000469] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|
|
41
|
Niedzwiecki P, Naskret D, Pilacinski S, Pempera M, Uruska A, Adamska A, Zozulinska-Ziolkiewicz D. The Higher the Insulin Resistance the Lower the Cardiac Output in Men with Type 1 Diabetes During the Maximal Exercise Test. Metab Syndr Relat Disord 2017; 15:252-257. [PMID: 28394194 DOI: 10.1089/met.2017.0007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND The aim of this study was to assess the hemodynamic parameters analyzed in bioimpedance cardiography during maximal exercise in patients with type 1 diabetes differing in insulin resistance. METHODS The study group consisted of 40 men with type 1 diabetes. Tissue sensitivity to insulin was assessed on the basis of the glucose disposal rate (GDR) analyzed during hyperinsulinemic-euglycemic clamp. Patients were divided into groups with GDR <4.5 mg/kg/min (G1 group-lower insulin sensitivity) and GDR ≥4.5 mg/kg/min (G2 group-higher insulin sensitivity). During the exercise test, the heart rate, systolic volume, cardiac output, cardiac index were measured by the impedance meter (PhysioFlow). RESULTS Compared with the G2 group, the G1 group had a lower cardiac output (CO): during exercise 8.6 (IQR 7.7-10.0) versus 12.8 (IQR 10.8-13.7) L/min; P < 0.0001, at the maximal effort 13.1 (IQR 12.2-16.7) versus 18.6 (IQR 16.9-20.2) L/min; P = 0.001, and during observation after exercise 8.4 (IQR 6.3-9.6) versus 11.9 (IQR 10.1-13.1) L/min; P < 0.0001. We noticed a positive correlation of GDR and cardiac output: during the exercise test (r = 0.63, P = 0.0002), at the maximal effort (Rs 0.56, P = 0.001), and during observation after the exercise test (r = 0.72, P < 0.0001). In multivariate logistic regression, cardiac output during exercise and during observation was associated with high GDR, regardless of the age and duration of diabetes [OR: 1.98 (95% CI 1.10-3.56), P = 0.02 and OR: 1.91 (95% CI 1.05-3.48), P = 0.03; respectively]. CONCLUSION In nonobese subjects with type 1 diabetes, with good metabolic control, insulin resistance is associated with cardiac hemodynamic parameters assessed during and after exercise. The higher the insulin resistance the lower the cardiac output during maximal exercise in men with type 1 diabetes.
Collapse
Affiliation(s)
- Pawel Niedzwiecki
- Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences , Poznan, Poland
| | - Dariusz Naskret
- Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences , Poznan, Poland
| | - Stanislaw Pilacinski
- Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences , Poznan, Poland
| | - Maciej Pempera
- Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences , Poznan, Poland
| | - Aleksandra Uruska
- Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences , Poznan, Poland
| | - Anna Adamska
- Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences , Poznan, Poland
| | | |
Collapse
|
|
42
|
Zhou Q, Gu Y, Lang H, Wang X, Chen K, Gong X, Zhou M, Ran L, Zhu J, Mi M. Dihydromyricetin prevents obesity-induced slow-twitch-fiber reduction partially via FLCN/FNIP1/AMPK pathway. Biochim Biophys Acta Mol Basis Dis 2017; 1863:1282-1291. [PMID: 28363698 DOI: 10.1016/j.bbadis.2017.03.019] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 03/10/2017] [Accepted: 03/27/2017] [Indexed: 12/14/2022]
Abstract
Obesity is often accompanied by decreases in the proportion of skeletal muscle slow-twitch fibers and insulin sensitivity. Increased plasma non-esterified fatty acids (NEFA) levels are responsible for obesity-associated insulin resistance. Palmitate, one of the most elevated plasma NEFA in obesity, has been recognized as the principle inducer of insulin resistance. The present study showed that increased plasma NEFA levels were negatively linked to slow-twitch fiber proportion and insulin sensitivity, while slow-twitch fiber proportion was positively correlated to insulin sensitivity in high fat diet (HFD)-fed and ob/ob mice. Dihydromyricetin (DHM) intervention increased slow-twitch fiber proportion and improved insulin resistance. In cultured C2C12 myotubes, palmitate treatment resulted in decrease of slow-twitch fiber specific Myh7 expression and insulin resistance, concomitant with folliculin (FLCN) and folliculin-interacting protein 1 (FNIP1) expression increase, AMP-activated protein kinase (AMPK) inactivation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression decrease. Those palmitate-induced effects could be blocked by knock-down of FLCN expression or DHM intervention. Meanwhile, the protective effects of DHM were alleviated by over-expression of FLCN. In addition, the changes in AMPK activity and expression of FLCN and FNIP1 in vivo were consistent with those occurring in vitro. These findings suggest that DHM treatment prevents palmitate-induced slow-twitch fibers decrease partially via FLCN-FNIP1-AMPK pathway thereby improving insulin resistance in obesity.
Collapse
Affiliation(s)
- Qicheng Zhou
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China
| | - Yeyun Gu
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China
| | - Hedong Lang
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China
| | - Xiaolan Wang
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China
| | - Ka Chen
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China
| | - Xinhua Gong
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China
| | - Min Zhou
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China
| | - Li Ran
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China
| | - Jundong Zhu
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China.
| | - Mantian Mi
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China.
| |
Collapse
|
|
43
|
Synergistic effects of metformin with liraglutide against endothelial dysfunction through GLP-1 receptor and PKA signalling pathway. Sci Rep 2017; 7:41085. [PMID: 28145471 PMCID: PMC5286534 DOI: 10.1038/srep41085] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 12/15/2016] [Indexed: 01/19/2023] Open
Abstract
Metformin or glucagon-like peptide-1 (GLP-1) analogue liraglutide has cardiovascular benefits. However, it is not clear whether their combined treatment have additive or synergistic effects on the vasculature. In this study, human umbilical vein endothelial cells (HUVECs), exposed to palmitic acid (PA) to induce endothelial dysfunction, were incubated with metformin, liraglutide or their combination. High fat diet (HFD)-fed ApoE−/− mice were randomized into control, metformin, liraglutide, and combination treatment groups. Results showed that in PA-treated HUVECs and HFD-fed ApoE−/− mice, combination of metformin and liraglutide at lower dose significantly improved endothelial dysfunction compared with the single treatment. Metformin upregulated GLP-1 receptor (GLP-1R) level and protein kinase A (PKA) phosphorylation. However, PKA inhibition but not GLP-1R blockade eliminated the protective effects of metformin on endothelial function. Furthermore, AMPK inhibitor compound C abolished the metformin-mediated upregulation of GLP-1R level and PKA phosphorylation. In conclusion, combination of metformin and liraglutide has synergistic protective effects on endothelial function. Moreover, metformin stimulates GLP-1R and PKA signalling via AMPK-dependent pathway, which may account for its synergistic protective effects with liraglutide. Our findings provide new insights on the interaction between metformin and GLP-1, and provide important information for designing new GLP-1-based therapy strategies in treating type 2 diabetes.
Collapse
|
|
44
|
Rodríguez-Carrio J, López P, Sánchez B, González S, Gueimonde M, Margolles A, de Los Reyes-Gavilán CG, Suárez A. Intestinal Dysbiosis Is Associated with Altered Short-Chain Fatty Acids and Serum-Free Fatty Acids in Systemic Lupus Erythematosus. Front Immunol 2017; 8:23. [PMID: 28167944 PMCID: PMC5253653 DOI: 10.3389/fimmu.2017.00023] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 01/05/2017] [Indexed: 12/21/2022] Open
Abstract
Metabolic impairments are a frequent hallmark of systemic lupus erythematosus (SLE). Increased serum levels of free fatty acids (FFA) are commonly found in these patients, although the underlying causes remain elusive. Recently, it has been suggested that factors other than inflammation or clinical features may be involved. The gut microbiota is known to influence the host metabolism, the production of short-chain fatty acids (SCFA) playing a potential role. Taking into account that lupus patients exhibit an intestinal dysbiosis, we wondered whether altered FFA levels may be associated with the intestinal microbial composition in lupus patients. To this aim, total and specific serum FFA levels, fecal SCFA levels, and gut microbiota composition were determined in 21 SLE patients and 25 healthy individuals. The Firmicutes to Bacteroidetes (F/B) ratio was strongly associated with serum FFA levels in healthy controls (HC), even after controlling for confounders. However, this association was not found in lupus patients, where a decreased F/B ratio and increased FFA serum levels were noted. An altered production of SCFA was related to the intestinal dysbiosis in lupus, while SCFA levels paralleled those of serum FFA in HC. Although a different serum FFA profile was not found in SLE, specific FFA showed distinct patterns on a principal component analysis. Immunomodulatory omega-3 FFA were positively correlated to the F/B ratio in HC, but not in SLE. Furthermore, divergent associations were observed for pro- and anti-inflammatory FFA with endothelial activation biomarkers in lupus patients. Overall, these findings support a link between the gut microbial ecology and the host metabolism in the pathological framework of SLE. A potential link between intestinal dysbiosis and surrogate markers of endothelial activation in lupus patients is supported, FFA species having a pivotal role.
Collapse
Affiliation(s)
- Javier Rodríguez-Carrio
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC) , Villaviciosa, Asturias , Spain
| | - Patricia López
- Area of Immunology, Department of Functional Biology, University of Oviedo , Oviedo, Asturias , Spain
| | - Borja Sánchez
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC) , Villaviciosa, Asturias , Spain
| | - Sonia González
- Area of Physiology, Department of Functional Biology, University of Oviedo , Oviedo, Asturias , Spain
| | - Miguel Gueimonde
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC) , Villaviciosa, Asturias , Spain
| | - Abelardo Margolles
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC) , Villaviciosa, Asturias , Spain
| | - Clara G de Los Reyes-Gavilán
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC) , Villaviciosa, Asturias , Spain
| | - Ana Suárez
- Area of Immunology, Department of Functional Biology, University of Oviedo , Oviedo, Asturias , Spain
| |
Collapse
|
|
45
|
Elfeky O, Longo S, Lai A, Rice GE, Salomon C. Influence of maternal BMI on the exosomal profile during gestation and their role on maternal systemic inflammation. Placenta 2016; 50:60-69. [PMID: 28161063 DOI: 10.1016/j.placenta.2016.12.020] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 12/15/2016] [Accepted: 12/18/2016] [Indexed: 12/23/2022]
Abstract
Recent studies report that 35% of women are either overweight or obese at reproductive age. The placenta continuously releases exosomes across gestation and their concentration is higher in pregnancy complications. While there is considerable interest in elucidating the role of exosomes during gestation, important questions remain to be answered: i) Does maternal BMI affect the exosomal profile across gestation? and ii) What is the contribution of placenta-derived exosomes to the total number of exosomes present in maternal plasma across gestation? Plasma samples were classified according to the maternal BMI into three groups (n = 15 per group): Lean, overweight, and obese. Total exosomes and specific placenta-derived exosomes were determined by Nanoparticle Tracking Analysis (NanoSight™) using quantum dots coupled with CD63 or PLAP antibodies. The effect of exosomes on cytokine (IL-6, IL-8, IL-10 and TNF-α) release from endothelial cells was established by cytokine array analysis (Bioplex-200). The total number of exosomes present in maternal circulation was strongly correlated with maternal BMI. Between ∼12% and ∼25% of circulating exosomes in maternal blood are of placental origin during gestation, and the contribution of placental exosomes to the total exosomal population decreases with higher maternal BMI across gestation. Exosomes increase IL-6, IL-8 and TNF-α release from endothelial cells, an effect even higher when exosomes were isolated from obese women compared to lean and overweight. This study established that maternal BMI is a factor that explains a significant component of the variation in the exosomes data. Exosomes may contribute to the maternal systemic inflammation during pregnancy.
Collapse
Affiliation(s)
- Omar Elfeky
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Australia
| | - Sherri Longo
- Department of Obstetrics and Gynecology, Ochsner Baptist Hospital, New Orleans, LA, USA
| | - Andrew Lai
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Australia
| | - Gregory E Rice
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Australia; Department of Obstetrics and Gynecology, Ochsner Baptist Hospital, New Orleans, LA, USA
| | - Carlos Salomon
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Australia; Department of Obstetrics and Gynecology, Ochsner Baptist Hospital, New Orleans, LA, USA.
| |
Collapse
|
|
46
|
Wang K, Wang E, Qin Z, Zhou Z, Geng Y, Chen D. Effects of dietary vitamin E deficiency on systematic pathological changes and oxidative stress in fish. Oncotarget 2016; 7:83869-83879. [PMID: 27911874 PMCID: PMC5356631 DOI: 10.18632/oncotarget.13729] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 11/15/2016] [Indexed: 11/25/2022] Open
Abstract
The aim of this study was to investigate the effects of dietary vitamin E deficiency on systematic pathological changes and oxidative stress in fish. A total of 320 healthy common carp (Cyprinus carpio) were randomized into four groups; the control group was fed a basal diet supplemented with 100 IUkg-1 of vitamin E, while the three experimental groups were fed the same basal diet with reduced vitamin E content (0, 25, or 50 IUkg-1). Findings showed that fish in the experimental groups mainly presented with sekoke disease, exophthalmia, leprnorthsis, and ascites. Histopathological and ultrastructural changes comprised nutritional myopathy with muscle fiber denaturation and necrosis, and multi-tissue organ swelling, degeneration, and necrosis. Compared with the control group, RBC count, hemoglobin content, vitamin E concentration, and superoxide dismutase activity were significantly lower in all three experimental groups. However, malondialdehyde content was considerably higher in experimental groups than in the control group. However, there was no difference in glutathione peroxidase activity among groups. In conclusion, dietary vitamin E deficiency (<100 IUkg-1) can cause severe injury and, in particular, oxidative damage in common carp. The oxidative damage might be a main influence caused by vitamin E deficiency in fish. These findings reveal the complete systematic pathological effect of vitamin E deficiency in common carp, which may be applicable to other fish and animals.
Collapse
Affiliation(s)
- Kaiyu Wang
- Department of Basic Veterinary, Sichuan Agricultural University, Chengdu, Sichuan, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Erlong Wang
- Department of Basic Veterinary, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Zhenyang Qin
- Department of Basic Veterinary, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Zhen Zhou
- Department of Basic Veterinary, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Yi Geng
- Department of Basic Veterinary, Sichuan Agricultural University, Chengdu, Sichuan, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Defang Chen
- Department of Aquaculture, Sichuan Agricultural University, Chengdu, Sichuan, China
| |
Collapse
|
|
47
|
Ke J, Wei R, Yu F, Zhang J, Hong T. Liraglutide restores angiogenesis in palmitate-impaired human endothelial cells through PI3K/Akt-Foxo1-GTPCH1 pathway. Peptides 2016; 86:95-101. [PMID: 27777063 DOI: 10.1016/j.peptides.2016.10.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 10/21/2016] [Accepted: 10/21/2016] [Indexed: 12/20/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) and its analogues have a beneficial role in cardiovascular system. Here, we aimed to investigate whether liraglutide, a GLP-1 analogue, modulated angiogenesis impaired by palmitic acid (PA) in cultured human umbilical vein endothelial cells (HUVECs). Cells were incubated with liraglutide (3-100 nmol/L) in the presence of PA (0.5mmol/L), and endothelial tube formation was observed and quantified. The protein levels of signaling molecules were analyzed and the specific inhibitors were used to identify the signaling pathways through which liraglutide affected angiogenesis. Results showed that liraglutide ameliorated endothelial tube formation impaired by PA in HUVECs in a dose-dependent manner. Meanwhile, liraglutide increased the phosphorylation of Akt and forkhead box O1 (Foxo1), and upregulated the levels of guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1) and endothelial nitric oxide synthase (eNOS) in PA-impaired HUVECs. Notably, addition of the PI3K inhibitor LY294002, Foxo1 nuclear export inhibitor trifluoperazine dihydrochloride (TFP), GTPCH1 inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP) or NOS inhibitor N-nitro-l-arginine-methyl ester (L-NAME) eliminated the angiogenic effect of liraglutide. Moreover, either LY294002 or TFP abolished the liraglutide-induced upregulation of GTPCH1 and eNOS protein levels. In conclusion, liraglutide restores angiogenesis in PA-impaired HUVECs. The effect is mediated via upregulation of GTPCH1 and eNOS levels in a PI3K/Akt-Foxo1-dependent mechanism.
Collapse
Affiliation(s)
- Jing Ke
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Rui Wei
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Fei Yu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Jingjing Zhang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Tianpei Hong
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.
| |
Collapse
|
|
48
|
Heidarianpour A, Hajizadeh S, Khoshbaten A, Niaki AG, Bigdili MR, Pourkhalili K. Effects of chronic exercise on endothelial dysfunction and insulin signaling of cutaneous microvascular in streptozotocin-induced diabetic rats. ACTA ACUST UNITED AC 2016; 14:746-52. [DOI: 10.1097/hjr.0b013e32817ed02f] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- Ali Heidarianpour
- Department of Physiology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Sohrab Hajizadeh
- Department of Physiology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Ali Khoshbaten
- Department of Physiology, Baghiyatallah Medical Sciences University, Tehran, Iran
| | - Abbas Ghanbari Niaki
- Department of Physical Education and Sport Science, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Reza Bigdili
- Department of Physiology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Khalil Pourkhalili
- Department of Physiology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| |
Collapse
|
|
49
|
Abstract
Although considerable research has addressed the potential role of inflammatory mediators in the pathogenesis of coronary heart disease, the relevance of this pathway to the pathogenesis of type 2 diabetes has only recently attracted interest. Circulating levels of inflammatory mediators correlate with insulin resistance and are significantly elevated in groups at risk of type 2 diabetes. Several prospective studies indicate that C-reactive protein and white cell count, together with other acute phase markers, predict incident diabetes independently of established predictors. Measures known to prevent diabetes (weight loss, exercise and metformin) and those more recently suggested (statins, ACE inhibitors and thiazolidinediones) have all been shown to exhibit anti-inflammatory actions. Mechanisms linking inflammation to diabetes development are beginning to be unravelled. Emerging knowledge of inflammatory mediators may help to predict those at risk of type 2 diabetes, and further work in this area may lead to novel means of prevention and treatment.
Collapse
Affiliation(s)
- Naveed Sattar
- Department of Pathological Biochemistry, Glasgow Royal Infirmary, Glasgow, G31 2ER, Scotland, UK,
| | | | | |
Collapse
|
|
50
|
Liu Z, Jiang C, Zhang J, Liu B, Du Q. Resveratrol inhibits inflammation and ameliorates insulin resistant endothelial dysfunction via regulation of AMP-activated protein kinase and sirtuin 1 activities. J Diabetes 2016; 8:324-35. [PMID: 25850408 DOI: 10.1111/1753-0407.12296] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 02/24/2015] [Accepted: 03/25/2015] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Resveratrol is a phytoalexin with beneficial effects on human health. The aim of the present study was to investigate the effects of resveratrol on endothelial dysfunction involved in insulin signaling and inflammation. METHODS Endothelial cells were stimulated with palmitate (PA) to induce insulin resistance characterized by a loss of insulin-mediated nitric oxide (NO) production. Diabetes was induced in rats by fructose feeding. The effects of resveratrol and the mechanisms involved were investigated using an aortic relaxation assay and Western blot analysis. RESULTS In endothelial cells, 0.1-10 μmol/L resveratrol suppressed IκB kinase β (IKKβ)/nuclear factor-κB phosphorylation, as well as tumor necrosis factor-α and interleukin-6 production, and restored the insulin receptor substrate-1 (Irs-1)/Akt/endothelial NO synthase signaling pathway. Furthermore, resveratrol effectively inhibited the mitogenic actions of insulin by decreasing the secretion of endothelin-1 and plasminogen activator inhibitor-1. It also positively regulated AMP-activated kinase (AMPK) and sirtuin 1 (SIRT1) activation, which contributed to the inhibition of inflammation implicated in endothelial insulin resistance. Stimulation with PA and long term-fructose feeding impaired insulin-mediated vessel dilation in rat aorta, whereas pretreatment of aortic rings with resveratrol (0.1-10 μmol/L) or treatment of rats with 5 or 20 mg/kg resveratrol counteracted these changes. CONCLUSION The results indicate that resveratrol inhibits inflammation and facilitates insulin phosphatidylinositol 3-kinase signaling by beneficial modulation of IRS-1 function partly via regulation of AMPK and SIRT1 activity in the endothelium.
Collapse
Affiliation(s)
- Zifeng Liu
- PI-WEI Institute, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Cuihua Jiang
- State Key Laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicines, Nanjing, China
| | - Jinghua Zhang
- State Key Laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicines, Nanjing, China
| | - Baolin Liu
- State Key Laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicines, Nanjing, China
| | - Qun Du
- PI-WEI Institute, Guangzhou University of Chinese Medicine, Guangzhou, China
| |
Collapse
|