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Wang N, Li J, Tian E, Li S, Liu S, Cao F, Kong J, Yue B. Renin-angiotensin-aldosterone system variations in type 2 diabetes mellitus patients with different complications and treatments: Implications for glucose metabolism. PLoS One 2025; 20:e0316049. [PMID: 40106408 PMCID: PMC11922211 DOI: 10.1371/journal.pone.0316049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 12/04/2024] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND The presence of hypertension and various acute or chronic complications may affect the renin-angiotensin-aldosterone system (RAAS) in patients with type 2 diabetes mellitus (T2DM), which plays a crucial role in the regulation of glucose metabolism. However, the quantitative distribution of the RAAS components in relation to the progression of T2DM and the treatment of hyperglycemia and hypertension, as well as their association with different stages of complications and glucose metabolism, has not been well studied. METHODS We enrolled a total of 151 patients with T2DM and essential hypertension, 40 patients with T2DM and normotension, and 46 healthy controls in the study. They were categorized into subgroups based on criteria for diabetic complications. Statistical analyses, including Spearman rank correlation and multiple linear regression, were conducted to assess the relationship between RAAS components and glucose metabolism indexes such as HbA1c, FBG, CP, HOMA-β, HOMA-IR, and UACR. RESULTS The results revealed significant differences in AII, ALD, REN, and ARR levels across various complication subgroups. Notably, the concentrations of ALD and REN exhibited a consistent trend, while ARR showed an opposite trend to the REN concentration. More than 60% of hypertensive patients were treated with ACEI/ARBs and calcium channel blockers, while 29.8% of the patients were prescribed β-blockers, resulting in decreased REN and increased ARR levels. All T2DM patients received antidiabetic treatment, among which 95 (49.7%) took SGLT-2is, 40 (20.9%) took GLP-1RAs injection and 55(28.8%) took DPP-4is. The subsequent analysis revealed that SGLT-2is, GLP-1RAs, DPP-4is and other glucose-lowering agents had no statistically significant effect on the RAAS system (p > 0.05). The correlation matrix analysis indicated positive associations between ALD, REN, CP, and HOMA-IR. Furthermore, the REN levels were negatively correlated with UACR in the hypertensive group and positively correlated with HbA1c and FBG levels in the normotensive group. Multiple linear regression analysis demonstrated that ALD levels increased with higher levels of CP and HOMA-IR, independently of the RAAS system, anti-RAAS treatment and antidiabetic therapy. REN levels decreased with increasing UACR and β-blocker usage in the hypertensive group, while they increased with higher levels of HbA1c, FBG, and HOMA-IR in the normotensive group, independently of the RAAS system and antidiabetic therapy. CONCLUSIONS The activation status of the RAAS system varied among T2DM patients with different complications, highlighting the need for clinical differentiation. ALD was positively associated with insulin resistance and glucose metabolism impairment, while REN exhibited negative correlations with urinary microalbumin and β-blocker usage, and positive correlations with hyperglycemia and insulin resistance. Blocking the RAAS system holds promise for improving insulin sensitivity and β-cell function, and potentially reversing abnormal glucose tolerance or ameliorating glucose metabolism disorders.
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Affiliation(s)
- Ningning Wang
- Department of Laboratory Medicine, The First People’s Hospital of Pingdingshan, Pingdingshan, Henan, China
| | - Junhui Li
- Department of Laboratory Medicine, The First People’s Hospital of Pingdingshan, Pingdingshan, Henan, China
| | - Erjun Tian
- Department of Laboratory Medicine, The First People’s Hospital of Pingdingshan, Pingdingshan, Henan, China
| | - Shutong Li
- Department of Laboratory Medicine, The First People’s Hospital of Pingdingshan, Pingdingshan, Henan, China
| | - Shuai Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Faculty of Laboratory Medicine, The First Clinical Medical College, Zhengzhou University, Zhengzhou, Henan, China
- Key Clinical Laboratory Medicine of Henan Province, Zhengzhou, Henan, China
| | - Fei Cao
- Department of Orthopedics, The First People’s Hospital of Pingdingshan, Pingdingshan, Henan, China
| | - Junfeng Kong
- Department of Laboratory Medicine, The First People’s Hospital of Pingdingshan, Pingdingshan, Henan, China
| | - Baohong Yue
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Faculty of Laboratory Medicine, The First Clinical Medical College, Zhengzhou University, Zhengzhou, Henan, China
- Key Clinical Laboratory Medicine of Henan Province, Zhengzhou, Henan, China
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Tian X, Chen S, Xia X, Xu Q, Zhang Y, Zheng C, Wu S, Wang A. Pathways from insulin resistance to incident cardiovascular disease: a Bayesian network analysis. Cardiovasc Diabetol 2024; 23:421. [PMID: 39574129 PMCID: PMC11583553 DOI: 10.1186/s12933-024-02510-w] [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: 09/13/2024] [Accepted: 11/13/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Insulin resistance coexist with many metabolic disorders, whether these disorders were promotors or pathway-factors for the association of insulin resistance and cardiovascular disease (CVD) remained unclear. We aimed to investigate the pathways related to elevated the triglyceride-glucose (TyG) index and pathways through elevated TyG index to the occurrence of CVD in Chinese adults. METHODS A total of 96,506 participants were enrolled from the Kailuan study. Bayesian network model with the max-min hill climbing algorithm and maximum likelihood estimation was applied to identify factors and pathways related to the TyG index, and quantitatively infer the impact of associated factors on elevated TyG index and the occurrence of CVD by computing conditional probabilities. RESULTS A final Bayesian network was constructed with 14 nodes and 25 arcs, creating 28 pathways related to elevated TyG index and 8 pathways from elevated TyG index to CVD. Elevated TyG index was causally associated with CVD, the condition probability was 11.9%. Pathways to elevated TyG index were mainly through unhealthy lifestyles and the subsequent increase in lipid profiles, especially smoking and low-density lipoprotein cholesterol. The most important pathway from elevated TyG index to CVD was through overweight/obesity, hypertension, and chronic kidney disease, with a condition probability of 18.5%. The maximum relative change rate related to elevated TyG index was observed for overweight/obesity (64.3%). CONCLUSIONS Elevated TyG index was causally associated with the risk of CVD, a combined control of lifestyles and metabolic factors may contribute to the reduction of TyG index and the prevention of CVD.
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Affiliation(s)
- Xue Tian
- Department of Epidemiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, No.119 South 4th Ring West Road, Fengtai District, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases,, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Department of Clinical Epidemiology and Clinical Trial, Capital Medical University, Beijing, China
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China
| | - Shuohua Chen
- Department of Cardiology, Kailuan Hospital, North China University of Science and Technology, 57 Xinhua East Rd, Tangshan, 063000, China
| | - Xue Xia
- Department of Epidemiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, No.119 South 4th Ring West Road, Fengtai District, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases,, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Department of Clinical Epidemiology and Clinical Trial, Capital Medical University, Beijing, China
| | - Qin Xu
- Department of Epidemiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, No.119 South 4th Ring West Road, Fengtai District, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases,, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Department of Clinical Epidemiology and Clinical Trial, Capital Medical University, Beijing, China
| | - Yijun Zhang
- Department of Epidemiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, No.119 South 4th Ring West Road, Fengtai District, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases,, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Department of Clinical Epidemiology and Clinical Trial, Capital Medical University, Beijing, China
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China
| | - Chenhao Zheng
- Statistics-Mathematics, Rutgers University, New Brunswick, New-Brunswick, NJ, USA
| | - Shouling Wu
- Department of Cardiology, Kailuan Hospital, North China University of Science and Technology, 57 Xinhua East Rd, Tangshan, 063000, China.
| | - Anxin Wang
- Department of Epidemiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, No.119 South 4th Ring West Road, Fengtai District, Beijing, 100070, China.
- China National Clinical Research Center for Neurological Diseases,, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
- Department of Clinical Epidemiology and Clinical Trial, Capital Medical University, Beijing, China.
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Cassandra Mkhize B, Mosili P, Sethu Ngubane P, Khathi A. The relationship between adipose tissue RAAS activity and the risk factors of prediabetes: a systematic review and meta-analysis. Adipocyte 2023; 12:2249763. [PMID: 37606270 PMCID: PMC10472858 DOI: 10.1080/21623945.2023.2249763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 07/29/2023] [Accepted: 08/11/2023] [Indexed: 08/23/2023] Open
Abstract
METHODS This systematic review was developed in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-2020) standards. This was accomplished by searching clinical MeSH categories in MEDLINE with full texts, EMBASE, Web of Science, PubMed, Cochrane Library, Academic Search Complete, ICTRP and ClinicalTrial.gov. Reviewers examined all the findings and selected the studies that satisfied the inclusion criteria. The Downs and Black Checklist was used to assess for bias, followed by a Review Manager v5. A Forrest plot was used for the meta-analysis and sensitivity analysis. The protocol for this review was registered with PROSPERO CRD42022320252. RESULTS The clinical studies (n = 2) comprised 1065 patients with prediabetes and 1103 normal controls. The RAAS measurements were completed in the adipose tissue. The RAAS components, renin and aldosterone were higher in the prediabetic (PD) compared to the control [mean difference (MD) = 0.16, 95% CI 0.16 (-0.13, 0.45), p = 0.25]. Furthermore, the PD group demonstrated higher triglycerides mean difference [MD = 7.84, 95% CI 7.84 (-9.84, 25.51), p = 0.38] and increased BMI [MD = 0.13, 95% CI 0.13 (-0.74, 0.99), p = 0.77] compared to the control. The overall quality of the studies was fair with a median score and range of 17 (16-18). CONCLUSION The current study highlights the relationship between increased BMI, RAAS and insulin resistance which is a predictor of prediabetes. The renin is slightly higher in the prediabetes group without any statistical significance, aldosterone is rather negatively associated with prediabetes which may be attributed to the use of anti-hypertensive treatment.
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Affiliation(s)
| | - Palesa Mosili
- Department of Human Physiology, University of KwaZulu-Natal, Westville, South Africa
| | | | - Andile Khathi
- Department of Human Physiology, University of KwaZulu-Natal, Westville, South Africa
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Huang X, Qin C, Guo X, Cao F, Tang C. Association of hemoglobin A1c with the incidence of hypertension: A large prospective study. Front Endocrinol (Lausanne) 2023; 13:1098012. [PMID: 36726461 PMCID: PMC9884972 DOI: 10.3389/fendo.2022.1098012] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 12/22/2022] [Indexed: 01/19/2023] Open
Abstract
Background Although hemoglobin A1c (HbA1c) is closely related to diabetes, its relationship with the incidence of hypertension is still unknown, so we aimed to evaluate the relationship between HbA1c and the incidence of hypertension in the general population. Method In this large prospective cohort study with a median follow-up of 2 years, we included 4,074 participants from the China Health and Nutrition Survey (CHNS). Multivariate COX regression, subgroup analysis, receiver operator characteristic (ROC) curve and restricted cubic spline (RCS) were used to evaluate the relationship between HbA1c and incidental hypertension. Results Compared with participants without incident hypertension, participants with incident hypertension had higher levels of HbA1c (P < 0.05). In univariate COX regression analysis, HbA1c was associated with the risk of hypertension (HR: 1.161, 95% CI: 1.105-1.221, P < 0.001). In multivariate COX regression analysis adjusted for confounding variables, HbA1c was still closely related to the risk of hypertension (HR: 1.102, 95% CI: 1.006-1.206, P = 0.037). And subgroup analysis showed that the relationship between HbA1c and hypertension remained significant in female, lower than high school and non-obese subgroups (P < 0.05). ROC curve also showed that HbA1c could predict the risk of hypertension (AUC = 0.583, 95% CI: 0.568-0.598, P < 0.001). Further RCS analysis showed that HbA1c was positively correlated with the risk of hypertension (P for nonlinearity = 0.642). Conclusion HbA1c was linearly and positively associated with the incidence of hypertension.
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Affiliation(s)
- Xu Huang
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Cheng Qin
- Department of Geriatric Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xiaoxu Guo
- Department of Digestive Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Feng Cao
- Department of Geriatric Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Chengchun Tang
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
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Comprehensive Network Analysis Reveals the Targets and Potential Multitarget Drugs of Type 2 Diabetes Mellitus. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8255550. [PMID: 35936218 PMCID: PMC9352488 DOI: 10.1155/2022/8255550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/29/2022] [Accepted: 07/06/2022] [Indexed: 11/18/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disease with increasing prevalence and mortality year by year. The purpose of this study was to explore new therapeutic targets and candidate drugs for multitargets by single-cell RNA expression profile analysis, network pharmacology, and molecular docking. Single-cell RNA expression profiling of islet β cell samples between T2DM patients and nondiabetic controls was conducted to identify important subpopulations and the marker genes. The potential therapeutic targets of T2DM were identified by the overlap analysis of insulin-related genes and diabetes-related genes, the construction of protein-protein interaction network, and the molecular complex detection (MCODE) algorithm. The network distance method was employed to determine the potential drugs of the target. Molecular docking and molecular dynamic simulations were carried out using AutoDock Vina and Gromacs2019, respectively. Eleven cell clusters were identified by single-cell RNA sequencing (scRNA-seq) data, and three of them (C2, C8, and C10) showed significant differences between T2DM samples and normal samples. Eight genes from differential cell clusters were found from differential cell clusters to be associated with insulin activity and T2DM. The MCODE algorithm built six key subnetworks, with five of them correlating with inflammatory pathways and immune cell infiltration. Importantly, CCR5 was a gene within the key subnetworks and was differentially expressed between normal samples and T2DM samples, with the highest area under the ROC curve (AUC) of 82.5% for the diagnosis model. A total of 49 CCR5-related genes were screened, and DB05494 was identified as the most potential drug with the shortest distance to CCR5-related genes. Molecular docking illustrated that DB05494 stably bound with CCR5 (-8.0 kcal/mol) through multiple hydrogen bonds (LYS26, TYR37, TYR89, CYS178, and GLN280) and hydrophobic bonds (TRP86, PHE112, ILE198, TRP248, and TYR251). This study identified CCR5 as a potential therapeutic target and screened DB05494 as a potential drug for T2DM treatment.
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Jiang SJ. Roles of transient receptor potential channel 6 in glucose-induced cardiomyocyte injury. World J Diabetes 2022; 13:338-357. [PMID: 35582666 PMCID: PMC9052005 DOI: 10.4239/wjd.v13.i4.338] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 01/18/2022] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diabetic cardiomyopathy (DCM) is a serious complication of end-stage diabetes that presents symptoms such as cardiac hypertrophy and heart failure. The transient receptor potential channel 6 (TRPC6) protein is a very important selective calcium channel that is closely related to the development of various cardiomyopathies.
AIM To explore whether TRPC6 affects cardiomyocyte apoptosis and proliferation inhibition in DCM.
METHODS We compared cardiac function and myocardial pathological changes in wild-type mice and mice injected with streptozotocin (STZ), in addition to comparing the expression of TRPC6 and P-calmodulin-dependent protein kinase II (P-CaMKII) in them. At the same time, we treated H9C2 cardiomyocytes with high glucose and then evaluated the effects of addition of SAR, a TRPC6 inhibitor, and KN-93, a CaMKII inhibitor, to such H9C2 cells in a high-glucose environment.
RESULTS We found that STZ-treated mice had DCM, decreased cardiac function, necrotic cardiomyocytes, and limited proliferation. Western blot and immunofluorescence were used to detect the expression levels of various appropriate proteins in the myocardial tissue of mice and H9C2 cells. Compared to those in the control group, the expression levels of the apoptosis-related proteins cleaved caspase 3 and Bax were significantly higher in the experimental group, while the expression of the proliferation-related proteins proliferating cell nuclear antigen (PCNA) and CyclinD1 was significantly lower. In vivo and in vitro, the expression of TRPC6 and P-CaMKII increased in a high-glucose environment. However, addition of inhibitors to H9C2 cells in a high-glucose environment resulted in alleviation of both apoptosis and proliferation inhibition.
CONCLUSION The inhibition of apoptosis and proliferation of cardiomyocytes in a high-glucose environment may be closely related to activation of the TRPC6/P-CaMKII pathway.
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Affiliation(s)
- Shi-Jun Jiang
- School of Basic Medicine, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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Zeng W, Chu TTW, Ho CS, Lo CWS, Chan ASL, Kong APS, Tomlinson B, Chan SW. Lack of Effects of Renin-Angiotensin-Aldosterone System Activity and Beta-Adrenoceptor Pathway Polymorphisms on the Response to Bisoprolol in Hypertension. Front Cardiovasc Med 2022; 9:842875. [PMID: 35433877 PMCID: PMC9010557 DOI: 10.3389/fcvm.2022.842875] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 02/10/2022] [Indexed: 01/02/2023] Open
Abstract
PURPOSE This study examined the effects of plasma renin activity (PRA), angiotensin II (Ang II) and aldosterone (PAC) concentrations as well as common polymorphisms in the β1-Adrenoceptor gene (ADRB1) and the G-protein α-Subunit (Gαs) protein gene the G protein α-Subunit 1 gene (GNAS) on the blood pressure (BP) and heart rate (HR) response to bisoprolol in Chinese patients with hypertension. METHODS Patients with sitting clinic systolic BP (SBP) 140-169 mmHg and/or diastolic BP (DBP) 90-109 mmHg after placebo run-in were treated with open-label bisoprolol 2.5 mg daily for 6 weeks. Patients diagnosed as having primary aldosteronism or renal artery stenosis were excluded. PRA, Ang II and PAC concentrations were measured after the placebo run-in and after 6 weeks of treatment. The Ser49Gly and Arg389Gly polymorphisms in ADRB1 and the c.393C > T polymorphism in GNAS were genotyped by the TaqMan® assay. RESULTS In 99 patients who completed the study, baseline PAC levels were significantly associated with baseline DBP and plasma potassium on univariate but not on multivariate linear regression analysis. PRA, Ang II, and PAC concentrations at baseline were not associated with changes in BP with bisoprolol treatment, but the values were all significantly reduced (PRA -0.141 ± 0.595 ng/mL/h, Ang II -2.390 ± 5.171 pmol/L and aldosterone -51.86 ± 119.1 pg/mL; all P < 0.05) following 6 weeks of bisoprolol treatment. There were no significant differences in BP or HR responses in patients with baseline PRA above or below the PRA cut-point of 0.65 ng/mL/h or the median value of 0.9 ng/ml/hour. There were no significant associations of the ADRB1 and GNAS polymorphisms with the clinic and ambulatory BP and HR responses to bisoprolol. CONCLUSION Baseline PRA, PAC and Ang II concentrations showed no significant association with the BP response to bisoprolol treatment, but all these parameters were reduced after 6 weeks of treatment with bisoprolol. The two common polymorphisms in ADRB1 and the c.393C > T polymorphism in GNAS had no significant association with the BP and HR response to bisoprolol in these patients.
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Affiliation(s)
- Weiwei Zeng
- Shenzhen Baoan Women’s and Children’s Hospital, Jinan University, Shenzhen, China
| | - Tanya T. W. Chu
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Chung Shun Ho
- Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Clara W. S. Lo
- Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Alan S. L. Chan
- Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Alice P. S. Kong
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Brian Tomlinson
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- Faculty of Medicine, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Sze Wa Chan
- School of Health Sciences, Caritas Institute of Higher Education, Hong Kong, Hong Kong SAR, China
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Finsen SH, Hansen MR, Hoffmann‐Petersen J, Højgaard HF, Mortensen SP. Eight weeks of mineralocorticoid blockade does not improve insulin sensitivity in type 2 diabetes. Physiol Rep 2021; 9:e14971. [PMID: 34350730 PMCID: PMC8339527 DOI: 10.14814/phy2.14971] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 06/25/2021] [Accepted: 06/25/2021] [Indexed: 11/24/2022] Open
Abstract
Individuals with type 2 diabetes have an increased risk of cardiovascular disease. A correlation between plasma aldosterone and hyperinsulinemia has been demonstrated in vivo, and hyperinsulinemia and insulin resistance are independently associated with the development of cardiovascular complications. We investigated if mineralocorticoid blockade (Eplerenone) improves insulin sensitivity in individuals with type 2 diabetes compared to healthy controls. We included 13 participants with type 2 diabetes (<5 years; male/female, Caucasians) and 10 healthy control participants (male/female, Caucasians). On 2 experimental days, before and at the end of the 8 weeks of treatment with mineralocorticoid blockade, a two-stage hyperinsulinemic-isoglycemic clamp (20 and 50 mU∙m-2 min-1 ) was performed for the determination of insulin sensitivity. No change in insulin sensitivity was detected at the end of the mineralocorticoid blockade in the individuals with type 2 diabetes or the healthy controls. Both before and at the end of the treatment with mineralocorticoid blockade, the individuals with type 2 diabetes had a lower insulin sensitivity compared to healthy controls. In conclusion, mineralocorticoid receptor blockade does not appear to improve insulin sensitivity in individuals with type 2 diabetes. CLINICAL TRIAL REGISTRATION: NCT03017703. https://clinicaltrials.gov/ct2/show/NCT03017703.
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Affiliation(s)
- Stine H. Finsen
- Department of Cardiovascular and Renal ResearchUniversity of Southern DenmarkOdenseDenmark
| | - Mie R. Hansen
- Department of Cardiovascular and Renal ResearchUniversity of Southern DenmarkOdenseDenmark
| | | | | | - Stefan P. Mortensen
- Department of Cardiovascular and Renal ResearchUniversity of Southern DenmarkOdenseDenmark
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Otaki Y, Watanabe T, Konta T, Watanabe M, Asahi K, Yamagata K, Fujimoto S, Tsuruya K, Narita I, Kasahara M, Shibagaki Y, Iseki K, Moriyama T, Kondo M, Watanabe T. One-year change in plasma volume and mortality in the Japanese general population: An observational cohort study. PLoS One 2021; 16:e0254665. [PMID: 34255808 PMCID: PMC8277070 DOI: 10.1371/journal.pone.0254665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 06/30/2021] [Indexed: 02/05/2023] Open
Abstract
Background Changes in plasma volume, a marker of plasma volume expansion and contraction, are gaining attention in the field of cardiovascular disease because of its role in the prevention and management of heart failure. However, it remains unknown whether a 1-year change in plasma volume is a risk factor for all-cause, cardiovascular, and non-cardiovascular mortality in the general population. Methods and results We used a nationwide database of 134,291 subjects (age 40–75 years) who participated in the annual “Specific Health Check and Guidance in Japan” check-up for 2 consecutive years between 2008 and 2011. A 1-year change in plasm volume was calculated using the Strauss–Davis-Rosenbaum formula. There were 220 cardiovascular deaths, 1,001 non-cardiovascular deaths including 718 cancer deaths, and 1,221 all-cause deaths during the follow-up period of 3.9 years. All subjects were divided into quintiles based on the 1-year change in plasma volume. Kaplan–Meier analysis demonstrated that the highest 5th quintile had the greatest risk among the five groups. Multivariate Cox proportional hazard regression analysis demonstrated that a 1-year change in plasma volume was an independent risk factor for all-cause, cardiovascular, non-cardiovascular, and cancer deaths. The addition of a 1-year change in plasma volume to cardiovascular risk factors significantly improved the C-statistic, net reclassification, and integrated discrimination indexes. Conclusions Here, we have demonstrated for the first time that a 1-year change in plasma volume could be an additional risk factor for all-cause, cardiovascular, and non-cardiovascular (mainly cancer) mortality in the general population.
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Affiliation(s)
- Yoichiro Otaki
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Tetsu Watanabe
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
- * E-mail:
| | - Tsuneo Konta
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Masafumi Watanabe
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Koichi Asahi
- Steering Committee of Research on Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment by Specific Health Check, Fukushima, Japan
| | - Kunihiro Yamagata
- Steering Committee of Research on Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment by Specific Health Check, Fukushima, Japan
| | - Shouichi Fujimoto
- Steering Committee of Research on Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment by Specific Health Check, Fukushima, Japan
| | - Kazuhiko Tsuruya
- Steering Committee of Research on Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment by Specific Health Check, Fukushima, Japan
| | - Ichiei Narita
- Steering Committee of Research on Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment by Specific Health Check, Fukushima, Japan
| | - Masato Kasahara
- Steering Committee of Research on Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment by Specific Health Check, Fukushima, Japan
| | - Yugo Shibagaki
- Steering Committee of Research on Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment by Specific Health Check, Fukushima, Japan
| | - Kunitoshi Iseki
- Steering Committee of Research on Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment by Specific Health Check, Fukushima, Japan
| | - Toshiki Moriyama
- Steering Committee of Research on Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment by Specific Health Check, Fukushima, Japan
| | - Masahide Kondo
- Steering Committee of Research on Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment by Specific Health Check, Fukushima, Japan
| | - Tsuyoshi Watanabe
- Steering Committee of Research on Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment by Specific Health Check, Fukushima, Japan
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Abstract
PURPOSE OF REVIEW Diabetic kidney disease is a growing problem leading to end-stage kidney disease but also atherosclerotic cardiovascular disease and heart failure. Aldosterone is a key risk factor promoting inflammation and fibrosis causing cardio-renal failure. Current options and challenges with mitigating the risk of aldosterone are reviewed. RECENT FINDINGS More aggressive renin-angiotensin-aldosterone system (RAAS) blockade can be maintained in individuals with hyperkalemia if new potassium binders are added. Aldosterone synthase inhibitors may lower aldosterone without causing hyperkalemia. Novel nonsteroidal mineralocorticoid receptor antagonists (MRA) are able to lower proteinuria and markers of heart failure, with limited potassium problems and without renal impairment. Ongoing clinical trials are evaluating the safety and potential benefits of nonsteroidal MRAs on progression of renal disease and development of cardiovascular outcomes in type 2 diabetes and kidney disease. SUMMARY Aldosterone is an important driver of inflammation and fibrosis leading to renal and cardiovascular complications. MRA lower albuminuria but data showing prevention of end-stage kidney disease are lacking. Side effects including hyperkalemia have previously prevented long-term studies in diabetic kidney disease but new treatment strategies with potassium binders, aldosterone synthase inhibitors and nonsteroidal MRA have been developed for clinical testing.
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Song J, Wei N, Zhao Y, Jiang Y, Wu X, Gao H. Elevated glycosylated hemoglobin levels and their interactive effects on hypertension risk in nondiabetic Chinese population: a cross-sectional survey. BMC Cardiovasc Disord 2020; 20:218. [PMID: 32398007 PMCID: PMC7216652 DOI: 10.1186/s12872-020-01501-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 04/30/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Abnormal glucose metabolism has been suggested to be involved in the development of hypertension. This study investigated the effect of the association and potential interaction of glycosylated hemoglobin (HbA1c) and other factors on the risk of hypertension among Chinese nondiabetic adults. METHODS As a cross-sectional survey, the current work deployed a questionnaire survey, anthropometric tests, and biochemical measures for each of the eligible participants. The HbA1c levels were quantified and grouped by quartiles. Correlations between HbA1c and hypertension, isolated systolic hypertension (ISH), and isolated diastolic hypertension (IDH) risk were investigated by logistic analyses. For evaluating the interactive effects, the parameters of relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (SI) were calculated, respectively. RESULTS In the current study, 1462 nondiabetic subjects were enrolled. In total, the prevalence rates of hypertension, ISH and IDH were 22.4, 9.6 and 4.5%, respectively. When HbA1c levels were grouped by quartile, it was revealed that the prevalence rates of hypertension and ISH were substantially elevated across groups (Pfor trend < 0.001). In the multivariable logistic regression analyses, in comparison with the first quartile of HbA1c, the normalized OR for hypertension risk was 1.90 (95% CI: 1.28-2.80) for the highest quartile. Also, the risk of ISH was significantly increased with HbA1c level in the highest quartile relative to in the bottom quartile (OR: 2.23,95% CI:1.47-3.71). However, no significant relationship between the HbA1c level and IDH risk was observed (OR: 1.78, 95% CI: 0.82-3.84). Eventually, it was demonstrated from the interactive effect analysis that HbA1c significantly interacted with abdominal obesity (RERI: 1.48, 95% CI: 0.38-2.58; AP: 0.37, 95% CI: 0.14-0.60 and SI: 1.96, 95% CI: 1.06-3.62) and family history of hypertension (AP: 0.37, 95% CI: 0.05-0.70) in influencing the risk of hypertension in nondiabetic participants. CONCLUSION Higher HbA1c levels significantly enhanced the risk of hypertension and ISH, but not IDH among Chinese nondiabetic adults. Moreover, the risk of hypertension was also aggravated by the upregulated HbA1c in a synergistic manner alongside abdominal obesity and family history of hypertension.
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Affiliation(s)
- Jian Song
- School of public health, Bengbu medical college, Bengbu, 233000, Anhui Province, China
| | - Nana Wei
- Department of general medicine, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui Province, China
| | - Yingying Zhao
- Bengbu health board, 568 Nanhu road, Bengbu, 233000, Anhui Province, China
| | - Yuhong Jiang
- School of public health, Bengbu medical college, Bengbu, 233000, Anhui Province, China
| | - Xuesen Wu
- School of public health, Bengbu medical college, Bengbu, 233000, Anhui Province, China
| | - Huaiquan Gao
- School of public health, Bengbu medical college, Bengbu, 233000, Anhui Province, China.
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12
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Hamon SM, Griffin TP, Islam MN, Wall D, Griffin MD, O'Shea PM. Defining reference intervals for a serum growth differentiation factor-15 (GDF-15) assay in a Caucasian population and its potential utility in diabetic kidney disease (DKD). Clin Chem Lab Med 2019; 57:510-520. [PMID: 30218600 DOI: 10.1515/cclm-2018-0534] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Accepted: 08/09/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND Growth differentiation factor-15 (GDF-15), a stress responsive cytokine, is a promising biomarker of renal functional decline in diabetic kidney disease (DKD). This study aimed primarily to establish normative data and secondarily to evaluate the potential utility of GDF-15 in DKD using Roche Diagnostics electrochemiluminescence immunoassay (ECLIA) in an Irish Caucasian population. METHODS Following informed consent, 188 healthy volunteers and 128 participants with diabetes (72 with and 56 without DKD) were recruited to a cross-sectional study. Baseline demographics, anthropometric measurements and laboratory measurements were recorded. Blood for GDF-15 measurement was collected into plain specimen tubes kept at room temperature and processed (centrifugation, separation of serum, freezing at -80 °C) within 1 h of phlebotomy pending batch analyses. Reference intervals were determined using the 2.5th and 97.5th percentiles for serum GDF-15 concentration. RESULTS Of 188 healthy participants, 63 failed to meet study inclusion criteria. The reference interval for serum GDF-15 was 399 ng/L (90% confidence interval [CI]: 399-399) - 1335 ng/L (90% CI: 1152-1445). Receiver operator characteristics (ROC) curve analysis for DKD determined the area under the ROC curve to be 0.931 (95% CI: 0.893-0.959; p<0.001). The optimum GDF-15 cutoff for predicting DKD was >1136 ng/L providing a diagnostic sensitivity and specificity of 94.4% and 79%, respectively, and positive likelihood ratio of 4.5:1 (95% CI: 3.4-6.0). CONCLUSIONS The reference interval for serum GDF-15 in a healthy Irish Caucasian population using Roche Diagnostics ECLIA was established and a preliminary determination of the potential of GDF-15 as a screening test for DKD was made. Further prospective validation with a larger DKD cohort will be required before the cutoff presented here is recommended for clinical use.
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Affiliation(s)
- Siobhan M Hamon
- Department of Clinical Biochemistry, Saolta University Health Care Group (SUHCG), Galway University Hospitals, Galway, Ireland
| | - Tomás P Griffin
- Centre for Diabetes, Endocrinology and Metabolism, Saolta University Health Care Group (SUHCG), Galway University Hospitals, Galway, Ireland.,Regenerative Medicine Institute at CÚRAM SFI Research Centre, School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
| | - Md Nahidul Islam
- Department of Clinical Biochemistry, Saolta University Health Care Group (SUHCG), Galway University Hospitals, Galway, Ireland.,Regenerative Medicine Institute at CÚRAM SFI Research Centre, School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
| | - Deirdre Wall
- School of Mathematics, Statistics and Applied Mathematics, National University of Ireland Galway (NUIG), Galway, Ireland
| | - Matthew D Griffin
- Regenerative Medicine Institute at CÚRAM SFI Research Centre, School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland.,Department of Nephrology, Saolta University Health Care Group (SUHCG), Galway University Hospitals, Galway, Ireland
| | - Paula M O'Shea
- Department of Clinical Biochemistry, Saolta University Health Care Group (SUHCG), Galway University Hospitals, Galway, Ireland
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