|
1
|
Huang C, Chang LY, Sheu JY, Huang YT, Chen JY, Lai CF, Wu VC. Exploring the high prevalence, comorbidities, and indicators of mild autonomous cortisol secretion in primary aldosteronism: a cohort study and systematic review. Hypertens Res 2025; 48:1716-1729. [PMID: 40069399 DOI: 10.1038/s41440-025-02172-5] [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: 11/03/2024] [Revised: 02/17/2025] [Accepted: 02/23/2025] [Indexed: 05/08/2025]
Abstract
Emerging evidence has suggested a significant prevalence of mild autonomous cortisol secretion (MACS) among patients diagnosed with primary aldosteronism (PA). However, MACS's clinical characteristics and implications in PA patients remain largely unexplored. To investigate the prevalence, comorbidities, and indicators of MACS in PA patients, we conducted a retrospective cohort study including 874 PA patients with dexamethasone suppression test results in the Taiwan Primary Aldosteronism Investigators (TAIPAI) cohort between February 2011 and February 2024. Additionally, we performed a systematic review and meta-analysis of 11 studies, encompassing a total of 2882 PA patients (CRD42023486755). After including the TAIPAI cohort data in the meta-analysis, the prevalence of MACS among PA patients was 21.9% (95% confidence interval [C.I.]: 18.1, 26.2), with a negative correlation with estimated glomerular filtration rate (eGFR) (r = -0.028, P < 0.01). The characteristics associated with MACS in PA patients included older age (mean difference [MD] = 5.51 year, P < 0.01), higher plasma aldosterone concentration (MD = 5.36 ng/dL, P < 0.01), lower plasma renin activity (MD = -0.15 ng/mL/h, P < 0.01), lower eGFR (MD = -4.91 mL/min/1.73 m2, P = 0.01), and larger adrenal tumor size (MD = 0.41 cm, P < 0.01). MACS was significantly associated with chronic kidney disease (odds ratio [OR] = 1.96, P < 0.01), diabetes mellitus (OR = 1.60, P = 0.04), and cardiovascular diseases (OR = 1.37, P = 0.02) among PA patients. The high prevalence and strong association of MACS with comorbidities underscore the importance of identifying it in PA patients. Clinical features such as advanced age, significant aldosterone-renin dysregulation, impaired kidney function, diabetes, cardiovascular disease, and large adrenal tumors are indicators for MACS screening in PA patients.
Collapse
Affiliation(s)
- Chieh Huang
- School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Li-Yang Chang
- School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jia-Yuh Sheu
- Department of Urology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Ta Huang
- Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Jui-Yi Chen
- Division of Nephrology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
- Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Chun-Fu Lai
- Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
| | - Vin-Cent Wu
- Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Primary Aldosteronism Center, National Taiwan University Hospital, Taipei, Taiwan
| |
Collapse
|
|
2
|
Ohira M, Kawagoe N, Kameyama C, Kondou Y, Igarashi M, Ueshiba H. Association of serum cortisol with insulin secretion and plasma aldosterone with insulin resistance in untreated type 2 diabetes: a cross-sectional study. Diabetol Metab Syndr 2025; 17:144. [PMID: 40296149 PMCID: PMC12036189 DOI: 10.1186/s13098-025-01706-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Accepted: 04/18/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND Insulin secretion and resistance are key pathophysiological factors in type 2 diabetes. However, only 55% of patients achieve long-term blood glucose treatment goals, highlighting the need to clarify the pathophysiology of type 2 diabetes. While cortisol and aldosterone levels have been linked to insulin secretion and resistance in participants without type 2 diabetes, their role in patients with type 2 diabetes remains unclear. In this study, we aimed to investigate the relationships among insulin secretion, insulin resistance, and cortisol or aldosterone levels in patients with untreated type 2 diabetes. METHODS We retrospectively reviewed 121 patients with untreated type 2 diabetes mellitus. We analyzed the relationships between various clinical parameters, including adrenal hormones, and insulin secretion (homeostatic model assessment [HOMA2-%B]) or insulin resistance (HOMA2-IR). Multiple regression analysis was performed to identify parameters associated with HOMA2-%B or HOMA2-IR. RESULTS Spearman's rank correlation coefficient revealed that body weight (BW); body mass index (BMI); estimated glomerular filtration rate; and serum creatinine, uric acid, total cholesterol, high-density lipoprotein cholesterol (HDL-C), sodium, potassium, chloride, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), serum C-peptide, and cortisol levels were significantly correlated with HOMA2-%B. Similarly, BW, BMI, aspartate transaminase levels, alanine transaminase (ALT) levels, triglyceride levels, HDL-C levels, FBG levels, serum C-peptide levels, renin activity, and plasma aldosterone concentration (PAC) were significantly correlated with HOMA2-IR. Multiple regression analysis revealed BMI, HbA1c levels, and cortisol levels as predictors of HOMA2-%B, whereas ALT levels and the PAC were predictors of HOMA2-IR. CONCLUSION Serum cortisol levels are associated with insulin secretion, and the PAC is associated with insulin resistance in patients with untreated type 2 diabetes. These findings suggest that aldosterone blockade may represent a potential therapeutic approach for reducing insulin resistance in patients with type 2 diabetes.
Collapse
Affiliation(s)
- Masahiro Ohira
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan.
| | - Naoyuki Kawagoe
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan
| | - Chisato Kameyama
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan
| | - Yuko Kondou
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan
| | - Madoka Igarashi
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan
| | - Hajime Ueshiba
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan
| |
Collapse
|
|
3
|
Mansour N, Bruedgam D, Heinrich D, Dischinger U, Reisch N, Völter F, Stüfchen I, Nowak E, Zopp S, Vasileva V, Öcal O, Wildgruber M, Seidensticker M, Ricke J, Bidlingmaier M, Reincke M, Ribeiro de Oliveira Longo Schweizer J. Mild autonomous cortisol secretion leads to reduced volumetric BMD at lumbar spine in patients with primary aldosteronism. Front Endocrinol (Lausanne) 2024; 15:1521680. [PMID: 39726840 PMCID: PMC11669511 DOI: 10.3389/fendo.2024.1521680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 11/26/2024] [Indexed: 12/28/2024] Open
Abstract
Objectives Glucocorticoid cosecretion is more common in primary aldosteronism (PA) than previously thought. Chronic subtle cortisol excess in patients with mild autonomous cortisol secretion (MACS) negatively affects bone health. This study aimed to evaluate the impact of MACS on bone density and turnover markers in PA patients. Methods Patients with PA and MACS (n = 50), confirmed by a 1-mg dexamethasone suppression test (DST) with a cortisol cutoff of ≥1.8 µg/dL without symptoms of overt Cushing, were compared to age- and sex-matched patients with PA without MACS (non-MACS, n = 50). Lumbar volumetric bone mineral density (vBMD) was extracted by a novel convolutional neural network (CNN)-based framework (SpineQ software v1.0) applied to routine CT data, incorporated into the diagnostic protocol for PA. Additionally, bone turnover markers-including osteocalcin, bone-specific alkaline phosphatase, N-terminal propeptide of type I collagen, and carboxy-terminal crosslinked telopeptide of type I collagen were evaluated between the groups. Results Median cortisol after DST was 1.1 µg/dL (30.3 nmol/L) [IQR: 0.5 µg/dL (13.8 nmol/L)] in the non-MACS group and 2.5 µg/dL (69.0 nmol/L) [IQR: 1.4 µg/dL (38.5 nmol/L)] in the MACS group (p < 0.001). Patients with MACS had significantly lower vBMD values compared to the non-MACS group (106.4 mg/cm³ vs. 116.6 mg/cm³, p = 0.038). Cortisol after DST negatively correlated with vBMD (Spearman's r=-0.33, p=0.00042). No significant differences in bone turnover markers were found, and classifications based on visible lesions on CT or PA-lateralization via adrenal venous sampling did not reveal any significant differences in these markers (p > 0.05 for all comparisons). Conclusion Despite non-significant differences in bone turnover markers between patients with PA with or without MACS, CT scans revealed significantly reduced vBMD in PA and MACS patients, indicating compromised bone health and vBMD significantly negatively correlated with cortisol post DST. Thus, opportunistic evaluation of vBMD in routine CT screenings could aid in the early detection of bone alterations in MACS and help mitigate potential long-term adverse effects on bone health.
Collapse
Affiliation(s)
- Nabeel Mansour
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Denise Bruedgam
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Daniel Heinrich
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Ulrich Dischinger
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany
| | - Nicole Reisch
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Friederike Völter
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Isabel Stüfchen
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Elisabeth Nowak
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Stephanie Zopp
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Victoriya Vasileva
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Osman Öcal
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Moritz Wildgruber
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Max Seidensticker
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Martin Bidlingmaier
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Martin Reincke
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | | |
Collapse
|
|
4
|
Hirsch A, Adolf C, Stüfchen I, Beuschlein F, Brüdgam D, Bidlingmaier M, Reincke M, Quinkler M. NT-proBNP levels in patients with primary hyperaldosteronism and autonomous cortisol cosecretion. Eur J Endocrinol 2024; 191:444-456. [PMID: 39343731 DOI: 10.1093/ejendo/lvae119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/24/2024] [Accepted: 09/26/2024] [Indexed: 10/01/2024]
Abstract
CONTEXT Patients with primary aldosteronism (PA) have higher cardiac comorbidities including more pronounced left ventricular hypertrophy than patients with essential hypertension. OBJECTIVE Autonomous cortisol cosecretion (ACS) is a common subtype in PA associated with a worse metabolic profile. HYPOTHESIS Autonomous cortisol cosecretion may affect myocardial parameters and result in a worse cardiac outcome compared to patients with PA and without ACS. METHODS Three hundred and sixty-seven patients with PA undergoing 1 mg dexamethasone suppression test (DST) and echocardiography at baseline from 2 centers of the German Conn's Registry were included. Follow-up for up to 3.8 years was available in 192 patients. RESULTS Patients with PA and ACS had higher NT-proBNP levels at baseline compared to patients with PA without ACS (114 vs 75.6 pg/mL, P = .02), but showed no difference in echocardiography values. NT-proBNP levels showed a significant positive correlation (r = 0.141, P = .011) with cortisol levels after DST at baseline. In response to therapy of PA, NT-proBNP levels decreased, but remained significantly higher in patients with ACS compared to patients without ACS. At follow-up, left ventricle end-diastolic dimension (LVEDD) decreased significantly only in patients without ACS. Left atrial diameter (LAD) decreased significantly in patients without ACS and in female patients with ACS but not in male patients. Left ventricular mass index (LVMI) significantly improved in female patients without ACS but remained unchanged in female patients with ACS as well as in male patients at follow-up. CONCLUSIONS In patients with PA, concomitant ACS is associated with a worse cardiac profile and only partial recovery even years after initiation of targeted PA therapy.
Collapse
Affiliation(s)
- Anna Hirsch
- Endocrinology in Charlottenburg, 10627 Berlin, Germany
- Clinical Endocrinology CCM, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Christian Adolf
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 Munich, Germany
| | - Isabel Stüfchen
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 Munich, Germany
| | - Felix Beuschlein
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 Munich, Germany
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich (USZ) und Universität Zürich (UZH), 8091 Zurich, Switzerland
- The LOOP Zurich - Medical Research Center, 8044 Zurich, Switzerland
| | - Denise Brüdgam
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 Munich, Germany
| | - Martin Bidlingmaier
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 Munich, Germany
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 Munich, Germany
| | | |
Collapse
|
|
5
|
Han M, Cao X, Zhang J, Yang X, Zhang Y, Liu Y. Association of Aldosterone, Renin, and Aldosterone to Renin Ratio with Metabolic Profile in Primary Aldosteronism. Diabetes Metab Syndr Obes 2024; 17:2065-2074. [PMID: 38778907 PMCID: PMC11110821 DOI: 10.2147/dmso.s457243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 04/23/2024] [Indexed: 05/25/2024] Open
Abstract
Purpose This study aimed to investigate the glycometabolism, fat mass, and lean mass in primary aldosteronism (PA) during disease progression. Patients and Methods Patients diagnosed with PA and healthy controls (HCs) were enrolled. A flash glucose monitoring system (FGMS) and dual-energy X-ray absorptiometry (DEXA) were used to measure glucose variability and glucose target rate along with fat mass and lean mass. Comparative analysis of FGMS- or DEXA-derived parameters along with correlation analyses between these parameters and PA progression were performed. Results Increased glucose variability and poor glucose target rate, along with an increased proportion of truncal fat mass, and decreased proportion of appendicular lean mass, were identified in PA group compared to those in HCs. Plasma aldosterone concentration was positively correlated with glucose variability and poor glucose target rate. Plasma renin concentration was positively correlated with the proportion of truncal fat mass and lean mass, and negatively correlated with the proportion of appendicular fat mass. Aldosterone-to-renin ratio was negatively correlated with the proportion of truncal fat mass and lean mass, and positively correlated with the proportion of appendicular fat mass. Conclusion Patients with PA presented significant differences in glycometabolism, fat mass, and lean mass compared with HCs, and these alterations correlated with PA progression.
Collapse
Affiliation(s)
- Minmin Han
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, 030000, People’s Republic of China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, 030000, People’s Republic of China
| | - Xiaoming Cao
- Department of Urology, First Hospital of Shanxi Medical University, Taiyuan, 030000, People’s Republic of China
| | - Jian Zhang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, 030000, People’s Republic of China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, 030000, People’s Republic of China
| | - Xifeng Yang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, 030000, People’s Republic of China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, 030000, People’s Republic of China
| | - Yi Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, 030000, People’s Republic of China
- Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan, 030000, People’s Republic of China
| | - Yunfeng Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, 030000, People’s Republic of China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, 030000, People’s Republic of China
| |
Collapse
|
|
6
|
Wang WT, Wu TH, Er LK, Huang CW, Tu KH, Fan KC, Tsai CH, Wang SY, Wu CY, Huang SH, Liu HW, Tseng FY, Wu WC, Chang CC, Cheng HM, Lin LY, Chueh JS, Lin YH, Hwu CM, Wu VC. Recent progress in unraveling cardiovascular complications associated with primary aldosteronism: a succinct review. Hypertens Res 2024; 47:1103-1119. [PMID: 38228750 DOI: 10.1038/s41440-023-01538-x] [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: 09/02/2023] [Revised: 11/13/2023] [Accepted: 11/14/2023] [Indexed: 01/18/2024]
Abstract
This comprehensive review offers a thorough exploration of recent advancements in our understanding of the intricate cardiovascular complications associated with Primary Aldosteronism (PA). PA encompasses a spectrum of conditions characterized by hypertension and excessive production of aldosterone operating independently of the renin-angiotensin system. Given its association with an elevated risk of cardiovascular and cerebrovascular complications, as well as a higher incidence of metabolic syndrome in comparison to individuals with essential hypertension (EH), an accurate diagnosis of PA is of paramount importance. This review delves into the intricate interplay between PA and cardiovascular health and focuses on the key pathophysiological mechanisms contributing to adverse cardiac outcomes. The impact of different treatment modalities on cardiovascular health is also examined, offering insights into potential therapeutic approaches. By highlighting the significance of recognizing PA as a significant contributor to cardiovascular morbidity, this review emphasizes the need for improved screening, early diagnosis, and tailored management strategies to both enhance patient care and mitigate the burden of cardiovascular diseases. The findings presented herein underscore the growing importance of PA in the context of cardiovascular medicine and emphasize the potential for translating these insights into targeted interventions to improve patient outcomes.
Collapse
Affiliation(s)
- Wei-Ting Wang
- Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Tsung-Hui Wu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Leay-Kiaw Er
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei Tzu Chi Hospital, The Buddhist Medical Foundation, Hualien, Taiwan, ROC
- School of Medicine, Tzu-Chi University College of Medicine, Hualien, Taiwan, ROC
| | - Chien-Wei Huang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Nephrology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Kun-Hua Tu
- Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Kang-Chih Fan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan, ROC
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC
| | - Cheng-Hsuan Tsai
- Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan, ROC
| | - Shu-Yi Wang
- Division of Endocrinology & Metabolism, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan, ROC
| | - Chun-Yi Wu
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, ROC
| | - Shu-Heng Huang
- Division of Endocrinology & Metabolism, Department of Internal Medicine, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan, ROC
| | - Han-Wen Liu
- Division of Endocrinology & Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, ROC
| | - Fen-Yu Tseng
- Division of Endocrinology & Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, ROC
| | - Wan-Chen Wu
- Division of Endocrinology & Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, ROC
| | - Chin-Chen Chang
- Department of Medical Imaging, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, ROC
- Department and Graduate Institute of Forensic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, ROC
| | - Hao-Min Cheng
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC.
| | - Liang-Yu Lin
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Jeff S Chueh
- Primary Aldosteronism Center, National Taiwan University Hospital, (NTUH-PAC), Taipei, Taiwan, ROC
- TAIPAI, Taiwan Primary Aldosteronism Investigation (TAIPAI) Study Group, Taipei, Taiwan, ROC
- Department of Urology, National Taiwan University Hospital, Taipei, Taiwan, ROC
| | - Yen-Hung Lin
- Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan, ROC
- Primary Aldosteronism Center, National Taiwan University Hospital, (NTUH-PAC), Taipei, Taiwan, ROC
- TAIPAI, Taiwan Primary Aldosteronism Investigation (TAIPAI) Study Group, Taipei, Taiwan, ROC
| | - Chii-Min Hwu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC.
- Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
| | - Vin-Cent Wu
- Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
- School of Medicine, Tzu-Chi University College of Medicine, Hualien, Taiwan, ROC.
- Primary Aldosteronism Center, National Taiwan University Hospital, (NTUH-PAC), Taipei, Taiwan, ROC.
- TAIPAI, Taiwan Primary Aldosteronism Investigation (TAIPAI) Study Group, Taipei, Taiwan, ROC.
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, ROC.
| |
Collapse
|
|
7
|
Mansour N, Bruedgam D, Dischinger U, Kürzinger L, Adolf C, Walter R, Öcal O, Schmidt VF, Rudolph J, Ricke J, Reisch N, Reincke M, Wildgruber M, Heinrich D. Effect of mild cortisol cosecretion on body composition and metabolic parameters in patients with primary hyperaldosteronism. Clin Endocrinol (Oxf) 2024; 100:212-220. [PMID: 38164017 DOI: 10.1111/cen.15013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/08/2023] [Accepted: 12/15/2023] [Indexed: 01/03/2024]
Abstract
OBJECTIVE To investigate the effects of simultaneous cortisol cosecretion (CCS) on body composition in computed tomography (CT)-imaging and metabolic parameters in patients with primary aldosteronism (PA) with the objective of facilitating early detection. DESIGN Retrospective cohort study. PATIENTS Forty-seven patients with PA and CCS confirmed by 1-mg dexamethasone suppression test (DST) with a cutoff of ≥1.8 µg/dL were compared with PA patients with excluded CCS (non-CCS, n = 47) matched by age and sex. METHODS Segmentation of the fat compartments and muscle area at the third lumbar region was performed on non-contrast-enhanced CT images with dedicated segmentation software. Additionally, liver, spleen, pancreas and muscle attenuation were compared between the two groups. RESULTS Mean cortisol after DST was 1.2 µg/dL (33.1 nmol/L) in the non-CCS group and 3.2 µg/dL (88.3 nmol/L) in the CCS group with mild autonomous cortisol excess (MACE). No difference in total, visceral and subcutaneous fat volumes was observed between the CCS and non-CCS group (p = .7, .6 and .8, respectively). However, a multivariable regression analysis revealed a significant correlation between total serum cholesterol and results of serum cortisol after 1-mg DST (p = .026). Classification of the patients based on visible lesion on CT and PA-lateralization via adrenal venous sampling also did not show any significant differences in body composition. CONCLUSION MACE in PA patients does not translate into body composition changes on CT-imaging. Therefore, early detection of concurrent CCS in PA is currently only attainable through biochemical tests. Further investigation of the long-term clinical adverse effects of MACE in PA is necessary.
Collapse
Affiliation(s)
- Nabeel Mansour
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Denise Bruedgam
- Medizinische Klinik und Poliklinik IV, LMU Klinikum Innenstadt, Munich, Germany
| | - Ulrich Dischinger
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany
| | - Lydia Kürzinger
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany
| | - Christian Adolf
- Medizinische Klinik und Poliklinik IV, LMU Klinikum Innenstadt, Munich, Germany
| | - Roman Walter
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Osman Öcal
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Vanessa F Schmidt
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Jan Rudolph
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Nicole Reisch
- Medizinische Klinik und Poliklinik IV, LMU Klinikum Innenstadt, Munich, Germany
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, LMU Klinikum Innenstadt, Munich, Germany
| | - Moritz Wildgruber
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Daniel Heinrich
- Medizinische Klinik und Poliklinik IV, LMU Klinikum Innenstadt, Munich, Germany
| |
Collapse
|
|
8
|
Ebert T, Anker SD, Ruilope LM, Fioretto P, Fonseca V, Umpierrez GE, Birkenfeld AL, Lawatscheck R, Scott C, Rohwedder K, Rossing P. Outcomes With Finerenone in Patients With Chronic Kidney Disease and Type 2 Diabetes by Baseline Insulin Resistance. Diabetes Care 2024; 47:362-370. [PMID: 38151465 PMCID: PMC10909685 DOI: 10.2337/dc23-1420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/24/2023] [Indexed: 12/29/2023]
Abstract
OBJECTIVE To explore whether insulin resistance, assessed by estimated glucose disposal rate (eGDR), is associated with cardiorenal risk and whether it modifies finerenone efficacy. RESEARCH DESIGN AND METHODS In FIDELITY (N = 13,026), patients with type 2 diabetes, either 1) urine albumin-to-creatinine ratio (UACR) of ≥30 to <300 mg/g and estimated glomerular filtration rate (eGFR) of ≥25 to ≤90 mL/min/1.73 m2 or 2) UACR of ≥300 to ≤5,000 mg/g and eGFR of ≥25 mL/min/1.73 m2, who also received optimized renin-angiotensin system blockade, were randomized to finerenone or placebo. Outcomes included cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney (kidney failure, sustained decrease of ≥57% in eGFR from baseline, or renal death) composites. eGDR was calculated using waist circumference, hypertension status, and glycated hemoglobin for 12,964 patients. RESULTS Median eGDR was 4.1 mg/kg/min. eGDR CONCLUSIONS Insulin resistance was associated with increased cardiovascular (but not kidney) risk and did not modify finerenone efficacy.
Collapse
Affiliation(s)
- Thomas Ebert
- Medical Department III – Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
| | - Stefan D. Anker
- Department of Cardiology of German Heart Center Charité; Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research partner site Berlin, Charité Universitätsmedizin, Berlin, Germany
| | - Luis M. Ruilope
- Cardiorenal Translational Laboratory and Hypertension Unit, Institute of Research imas12, Madrid, Spain
- CIBER-CV, Hospital Universitario 12 de Octubre, Madrid, Spain
- Faculty of Sport Sciences, European University of Madrid, Madrid, Spain
| | | | - Vivian Fonseca
- Tulane University Health Sciences Center, New Orleans, LA
| | | | - Andreas L. Birkenfeld
- Department of Diabetology, Endocrinology and Nephrology, University Clinic, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
| | | | | | | | - Peter Rossing
- Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | | |
Collapse
|
|
9
|
Savarese G, Lindberg F, Filippatos G, Butler J, Anker SD. Mineralocorticoid receptor overactivation: targeting systemic impact with non-steroidal mineralocorticoid receptor antagonists. Diabetologia 2024; 67:246-262. [PMID: 38127122 PMCID: PMC10789668 DOI: 10.1007/s00125-023-06031-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 09/13/2023] [Indexed: 12/23/2023]
Abstract
The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart, vasculature, adipose tissue and kidneys. The inhibition of the MR with classical MR antagonists (MRA) has successfully improved outcomes most evidently in heart failure. However, real and perceived risk of side effects and limited tolerability associated with classical MRA have represented barriers to implementing MRA in settings where they have been already proven efficacious (heart failure with reduced ejection fraction) and studying their potential role in settings where they might be beneficial but where risk of safety events is perceived to be higher (renal disease). Novel non-steroidal MRA have distinct properties that might translate into favourable clinical effects and better safety profiles as compared with MRA currently used in clinical practice. Randomised trials have shown benefits of non-steroidal MRA in a range of clinical contexts, including diabetic kidney disease, hypertension and heart failure. This review provides an overview of the literature on the systemic impact of MR overactivation across organ systems. Moreover, we summarise the evidence from preclinical studies and clinical trials that have set the stage for a potential new paradigm of MR antagonism.
Collapse
Affiliation(s)
- Gianluigi Savarese
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
- Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden.
| | - Felix Lindberg
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Gerasimos Filippatos
- Department of Cardiology, University Hospital Attikon, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, TX, USA
- Department of Internal Medicine, University of Mississippi, Jackson, MS, USA
| | - Stefan D Anker
- Department of Cardiology (CVK) and Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin, Berlin, Germany.
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland.
| |
Collapse
|
|
10
|
The Effect of Aldosterone on Cardiorenal and Metabolic Systems. Int J Mol Sci 2023; 24:ijms24065370. [PMID: 36982445 PMCID: PMC10049192 DOI: 10.3390/ijms24065370] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/02/2023] [Accepted: 03/07/2023] [Indexed: 03/14/2023] Open
Abstract
Aldosterone, a vital hormone of the human body, has various pathophysiological roles. The excess of aldosterone, also known as primary aldosteronism, is the most common secondary cause of hypertension. Primary aldosteronism is associated with an increased risk of cardiovascular disease and kidney dysfunction compared to essential hypertension. Excess aldosterone can lead to harmful metabolic and other pathophysiological alterations, as well as cause inflammatory, oxidative, and fibrotic effects in the heart, kidney, and blood vessels. These alterations can result in coronary artery disease, including ischemia and myocardial infarction, left ventricular hypertrophy, heart failure, arterial fibrillation, intracarotid intima thickening, cerebrovascular disease, and chronic kidney disease. Thus, aldosterone affects several tissues, especially in the cardiovascular system, and the metabolic and pathophysiological alterations are related to severe diseases. Therefore, understanding the effects of aldosterone on the body is important for health maintenance in hypertensive patients. In this review, we focus on currently available evidence regarding the role of aldosterone in alterations of the cardiovascular and renal systems. We also describe the risk of cardiovascular events and renal dysfunction in hyperaldosteronism.
Collapse
|
|
11
|
Chen UL, Liao CW, Wang SM, Lai TS, Huang KH, Chang CC, Lee BC, Lu CC, Chang YR, Chang YY, Hung CS, Chueh JS, Wu VC, Tsai CH, Lin YH. Diabetes mellitus is associated with more adverse non-hemodynamic left ventricular remodeling and less recovery in patients with primary aldosteronism. J Investig Med 2023; 71:101-112. [PMID: 36647318 DOI: 10.1177/10815589221141840] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The elevated aldosterone in primary aldosteronism (PA) is associated with increased insulin resistance and prevalence of diabetes mellitus (DM). Both aldosterone excess and DM lead to left ventricular (LV) pathological remodeling. In this study, we investigated the impact of DM on LV non-hemodynamic remodeling in patients with PA. We enrolled 665 PA patients, of whom 112 had DM and 553 did not. Clinical, biochemical, and echocardiographic data were analyzed at baseline and 1 year after adrenalectomy. LV non-hemodynamic remodeling was represented by inappropriate excess left ventricular mass index (ieLVMI), which was defined as the difference between left ventricular mass index (LVMI) and predicted left ventricular mass index (pLVMI). Propensity score matching (PSM) was used with age, sex, systolic, and diastolic blood pressure to adjust for baseline variables. After PSM, the patient characteristics were balanced between the DM and non-DM groups, except for fasting glucose, HbA1c, and lipid profile. A total of 111 DM and 419 non-DM patients were selected for further analysis. Compared to the non-DM group, the DM group had significantly higher ieLVMI and LVMI. After multivariable linear regression analysis, the presence of DM remained a significant predictor of increased ieLVMI. After adrenalectomy, ieLVMI decreased significantly in the non-DM group but not in DM group. The presence of DM in PA patients was associated with more prominent non-hemodynamic LV remodeling and less recovery after adrenalectomy.
Collapse
Affiliation(s)
- Uei-Lin Chen
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.,Cardiovascular Center, National Taiwan University Hospital, Taipei
| | - Che-Wei Liao
- Department of Medicine, National Taiwan University Cancer Center, Taipei
| | - Shuo-Meng Wang
- Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei
| | - Tai-Shuan Lai
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei
| | - Kuo-How Huang
- Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei
| | - Chin-Chen Chang
- Department of Medical Imaging, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei
| | - Bo-Ching Lee
- Department of Medical Imaging, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei
| | - Ching-Chu Lu
- Department of Nuclear Medicine, National Taiwan University Hospital, Taipei
| | - Yi-Ru Chang
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.,Cardiovascular Center, National Taiwan University Hospital, Taipei
| | - Yi-Yao Chang
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.,Cardiology Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City.,Center of General Education, Chihlee University of Technology, New Taipei City
| | - Chi-Sheng Hung
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.,Cardiovascular Center, National Taiwan University Hospital, Taipei
| | - Jeff S Chueh
- Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei
| | - Vin-Cent Wu
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei
| | - Cheng-Hsuan Tsai
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.,Cardiovascular Center, National Taiwan University Hospital, Taipei.,National Taiwan University College of Medicine Graduate Institute of Clinical Medicine
| | - Yen-Hung Lin
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.,Cardiovascular Center, National Taiwan University Hospital, Taipei
| | | |
Collapse
|
|
12
|
Moustaki M, Paschou SA, Vakali EC, Vryonidou A. Secondary diabetes mellitus due to primary aldosteronism. Endocrine 2023; 79:17-30. [PMID: 36001240 DOI: 10.1007/s12020-022-03168-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/07/2022] [Indexed: 01/07/2023]
Abstract
Primary aldosteronism (PA) and diabetes mellitus (DM) are clinical conditions that increase cardiovascular risk. Approximately one in five patients with PA have DM. Nevertheless, the pathophysiology linking these two entities is not entirely understood. In addition, the majority of patients with PA have glucocorticoid co-secretion, which is associated with increased risk of impaired glucose homeostasis. In the present review, we aim to comprehensively discuss all the available research data concerning the interplay between mineralocorticoid excess and glucose metabolism, with separate analysis of the sequalae in muscle, adipose tissue, liver and pancreas. Aldosterone binds both mineralocorticoid and glucocorticoid receptors and amplifies tissue glucocorticoid activity, via 11-β-hydroxysteroid dehydrogenase type 1 stimulation. A clear classification of the molecular events as per specific receptor in insulin-sensitive tissues is impossible, while their synergistic interaction is plausible. Furthermore, aldosterone induces oxidative stress and inflammation, perturbs adipokine expression, thermogenesis and lipogenesis in adipose tissue, and increases hepatic steatosis. In pancreas, enhanced oxidative stress and inflammation of beta cells, predominantly upon glucocorticoid receptor activation, impair insulin secretion. No causality between hypokalemia and impaired insulin response is yet proven; in contrast, hypokalemia appears to be implicated with insulin resistance and hepatic steatosis. The superior efficacy of adrenalectomy in ameliorating glucose metabolism vs. mineralocorticoid receptor antagonists in clinical studies highlights the contribution of non-mineralocorticoid receptor-mediated mechanisms in the pathophysiologic process. The exact role of hypokalemia, the mechanisms linking mineralocorticoid excess with hepatic steatosis, and possible disease-modifying role of pioglitazone warrant further studies.
Collapse
Affiliation(s)
- Melpomeni Moustaki
- Department of Endocrinology and Diabetes Centre, Hellenic Red Cross Hospital, Athens, Greece
| | - Stavroula A Paschou
- Endocrine Unit and Diabetes Centre, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
| | - Eleni C Vakali
- Department of Endocrinology and Diabetes Centre, Hellenic Red Cross Hospital, Athens, Greece
| | - Andromachi Vryonidou
- Department of Endocrinology and Diabetes Centre, Hellenic Red Cross Hospital, Athens, Greece
| |
Collapse
|
|
13
|
Zhang C, Jiang Y, Su T, Jiang L, Zhou W, Zhong X, Wu L, Wang W. Newly diagnosed diabetes mellitus is a risk factor for cardiocerebrovascular events in primary aldosteronism. Endocrine 2022; 77:519-526. [PMID: 35904746 PMCID: PMC9385765 DOI: 10.1007/s12020-022-03095-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 05/23/2022] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To explore the prevalence and clinical significance of newly diagnosed diabetes mellitus (DM) in patients with primary aldosteronism (PA). Investigating the risk factors for cardiocerebrovascular disease (CCVD) will guide strategies for reducing CCVD in patients with PA. METHODS We retrospectively included 729 PA patients without DM and conducted oral glucose tolerance tests. RESULTS We found that 15.0% of PA patients had newly diagnosed DM. The DM prevalence increased with elevated aldosterone levels [OR = 3.20 (1.77, 5.78), P value < 0.001]. The rate of CCVD in newly diagnosed diabetic PA patients was higher than that in nondiabetic PA patients at diagnosis (11.9% vs. 5.0%, P = 0.005). Furthermore, multivariate logistic analysis revealed that HT duration [1.055 (1.002,1.111), P = 0.041] and newly diagnosed DM [2.600 (1.072,6.303), P = 0.034] were significantly associated with CCVD in PA patients. CONCLUSION The prevalence of newly diagnosed DM in PA patients was higher than that in the general population. Aldosterone level was an independent risk factor for DM not for CCVD. CCVD was correlated with longer HT duration and newly diagnosed DM. Therefore, it is crucial to screen DM at the diagnosis in PA patients.
Collapse
Affiliation(s)
- Cui Zhang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiran Jiang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tingwei Su
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Jiang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiwei Zhou
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xu Zhong
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Luming Wu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiqing Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
14
|
El-Domiaty HF, Sweed E, Kora MA, Zaki NG, Khodir SA. Activation of angiotensin-converting enzyme 2 ameliorates metabolic syndrome-induced renal damage in rats by renal TLR4 and nuclear transcription factor κB downregulation. Front Med (Lausanne) 2022; 9:904756. [PMID: 36035416 PMCID: PMC9411523 DOI: 10.3389/fmed.2022.904756] [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: 03/25/2022] [Accepted: 06/27/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Metabolic syndrome (MetS) is an independent risk factor for chronic kidney disease (CKD) through many mechanisms, including activation of the renin-angiotensin system. The deleterious effects of angiotensin II (Ang II) can be counterbalanced by angiotensin-converting enzyme 2 (ACE2). Diminazene aceturate (DIZE), an anti-trypanosomal drug, can activate ACE2. OBJECTIVE This study aimed to investigate the possible reno-protective effects of DIZE in MetS rats with elucidation of related mechanisms. MATERIALS AND METHODS Thirty adult male Wistar albino rats were divided equally into control, MetS, and MetS + DIZE groups. Body weight, systolic blood pressure (SBP), and urinary albumin levels were measured. Serum levels of fasting blood glucose (FBG), insulin, uric acid, lipid profile, urea, and creatinine were measured. Homeostasis Model Assessment Index (HOMA-IR) was estimated. Subsequently, renal levels of ACE2, Ang II, malondialdehyde (MDA), reduced glutathione (GSH), and tumor necrosis factor-α (TNF-α) were measured with histopathological and immunohistochemical assessment of TLR4 and NF-κB in renal tissues. RESULTS MetS caused dyslipidemia with significant increases in body weight, SBP, FBG, serum insulin, HOMA-IR, uric acid, urea, creatinine, urinary albumin, and renal levels of Ang II, MDA, and TNF-α, whereas renal ACE2 and GSH were significantly decreased. Renal TLR4 and NF-κB immunoreactivity in MetS rats was upregulated. DIZE supplementation of MetS rats induced significant improvements in renal function parameters; this could be explained by the ability of DIZE to activate renal ACE2 and decrease renal Ang II levels with downregulation of renal TLR4 and NF-κB expression. CONCLUSION DIZE exerts a reno-protective effect in MetS, mainly by downregulating renal TLR4 and NF-κB levels.
Collapse
Affiliation(s)
- Heba F. El-Domiaty
- Department of Medical Physiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Eman Sweed
- Department of Clinical Pharmacology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Mona A. Kora
- Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Nader G. Zaki
- Department of Anatomy and Embryology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Suzan A. Khodir
- Department of Medical Physiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| |
Collapse
|
|
15
|
Tsai CH, Wu XM, Liao CW, Chen ZW, Pan CT, Chang YY, Lee BC, Chiu YW, Lai TS, Wu VC, Hung CS, Lin YH. Diabetes mellitus is associated with worse baseline and less post-treatment recovery of arterial stiffness in patients with primary aldosteronism. Ther Adv Chronic Dis 2022; 13:20406223211066727. [PMID: 35070251 PMCID: PMC8771743 DOI: 10.1177/20406223211066727] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 11/24/2021] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Aldosterone excess in primary aldosteronism (PA) has been linked to insulin resistance, and diabetes mellitus has been associated with increased arterial stiffness and worse cardiovascular outcomes. However, the impact of diabetes on baseline and post-treatment arterial stiffness in patients with PA is unknown. METHODS This study prospectively enrolled 1071 PA patients, of whom 177 had diabetes and 894 did not. Clinical, biochemical, and brachial-ankle pulse wave velocity (baPWV) data were analyzed at baseline and 1 year after PA-specific treatment. After propensity score matching of age, sex, body mass index, systolic and diastolic blood pressure, hypertension duration, and number of antihypertensive medications, 144 patients with diabetes and 320 without diabetes were included for further analysis. RESULTS After propensity score matching, the baseline characteristics were balanced between the diabetes and nondiabetes groups except for fasting glucose, HbA1c, and lipid profiles. The patients with diabetes had significantly worse baseline baPWV compared with those without diabetes. After multivariable linear regression, the presence of diabetes mellitus remained a significant predictor of worse baseline mean baPWV (β: 46.3, 95% confidence interval: 2.9-89.7, p = 0.037). After 1 year of PA-specific treatment, only the nondiabetes group had significant recovery of mean baPWV (1661.8 ± 332.3 to 1565.0 ± 329.2 cm/s, p < 0.001; Δ = -96.8 ± 254.6 cm/s). In contrast, the diabetes group had less improvement (1771.2 ± 353.8 cm/s to 1742.0 ± 377.2 cm/s, p = 0.259; Δ = -29.2 ± 263.2 cm/s) even though the systolic and diastolic blood pressure significantly improved in both groups. CONCLUSION The presence of diabetes mellitus in PA patients was associated with worse baseline and less post-treatment recovery of arterial stiffness.
Collapse
Affiliation(s)
- Cheng-Hsuan Tsai
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei
| | - Xue-Ming Wu
- Department of Internal Medicine, Taoyuan General Hospital, Taoyuan
| | - Che-Wei Liao
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei; Cancer Center, Department of Medicine, National Taiwan University, Taipei
| | - Zheng-Wei Chen
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei; Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin
| | - Chien-Ting Pan
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei; Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin
| | - Yi-Yao Chang
- Cardiovascular Medical Center, Cardiology Division, Far Eastern Memorial Hospital, New Taipei City
| | - Bo-Ching Lee
- Department of Medical Imaging, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei
| | - Yu-Wei Chiu
- Cardiovascular Medical Center, Cardiology Division, Far Eastern Memorial Hospital, New Taipei City; Department of Computer Science and Engineering, Yuan Ze University, Taoyuan City
| | - Tai-Shuan Lai
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei
| | - Vin-Cent Wu
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei
| | - Chi-Shen Hung
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, No. 7, Chung-Shan South Road, Taipei 100 Cardiovascular Center, National Taiwan University Hospital, Taipei
| | - Yen-Hung Lin
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, No. 7, Chung-Shan South Road, Taipei 100 Cardiovascular Center, National Taiwan University Hospital, Taipei
| |
Collapse
|
|
16
|
Bu X, Sun F, Zhang H, Liu X, Zhao Z, He H, Li Y, Yan Z, Zhu Z. Clinical Characteristics of Target Organ Damage in Primary Aldosteronism with or without Metabolic Syndrome. J Diabetes Res 2022; 2022:8932133. [PMID: 36117521 PMCID: PMC9473883 DOI: 10.1155/2022/8932133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 08/08/2022] [Indexed: 11/18/2022] Open
Abstract
The aim of this study is to investigate the prevalence of metabolic disorders in patients with primary aldosteronism (PA) and target organ damage (TOD) in different subtypes of patients with PA with or without metabolic syndrome (MS). Patients with PA were screened out from those with secondary hypertension and then subtyped via adrenal venous sampling (AVS). Baseline clinical characteristics (blood pressure, blood glucose, abdominal circumference, and lipid profile) were collected for the diagnosis of MS. Organ damage was evaluated according to cardiac and carotid ultrasound and urine microalbumin measurements. In all 261 patients with PA, 113 patients had concomitant MS and experienced more severe cardiac hypertrophy and increased intima-media thickness (IMT). The incidence of MS and diabetes mellitus (DM) had no statistic difference between the two groups, moreover, the rates of TOD were not different except microalbuminuria. However, metabolic disorders caused more remarkable TOD in PA patients with unilateral hypersecretion. It showed that cardiac hypertrophy was associated with obesity while microalbuminuria was related to plasma aldosterone concentration (PAC) in PA patients. In this retrospective study, our findings suggest that the effect of metabolic disorders on organ damage is more remarkable in patients with unilateral PA.
Collapse
Affiliation(s)
- Xiaona Bu
- Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Army Medical University of PLA, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Fang Sun
- Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Army Medical University of PLA, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Hexuan Zhang
- Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Army Medical University of PLA, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Xiaoli Liu
- Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Army Medical University of PLA, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Zhigang Zhao
- Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Army Medical University of PLA, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Hongbo He
- Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Army Medical University of PLA, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Yingsha Li
- Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Army Medical University of PLA, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Zhencheng Yan
- Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Army Medical University of PLA, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Zhiming Zhu
- Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Army Medical University of PLA, Chongqing Institute of Hypertension, Chongqing 400042, China
| |
Collapse
|
|
17
|
Zhao D, Wu NN, Zhang YY. Eplerenone–A novel Mineralocorticoid receptor antagonist for the clinical application. ENVIRONMENTAL DISEASE 2022. [DOI: 10.4103/ed.ed_7_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
|
18
|
The Expression of RAAS Key Receptors, Agtr2 and Bdkrb1, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome. Genes (Basel) 2021; 12:genes12111717. [PMID: 34828323 PMCID: PMC8621801 DOI: 10.3390/genes12111717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/22/2021] [Accepted: 10/27/2021] [Indexed: 11/25/2022] Open
Abstract
Wolfram syndrome (WS) 1 is a rare monogenic neurodegenerative disorder caused by mutations in the gene encoding WFS1. Knowledge of the pathophysiology of WS is incomplete and to date, there is no treatment available. Here, we describe early deviations in the renin-angiotensin-aldosterone system (RAAS) and bradykinin pathway (kallikrein kinin system, KKS) observed in a rat model of WS (Wfs1 KO) and the modulative effect of glucagon-like peptide-1 receptor agonist liraglutide (LIR) and anti-epileptic drug valproate (VPA), which have been proven effective in delaying WS progression in WS animal models. We found that the expression of key receptors of the RAAS and KKS, Agtr2 and Bdkrb1, were drastically downregulated both in vitro and in vivo at an early stage in a rat model of WS. Moreover, in Wfs1, KO serum aldosterone levels were substantially decreased and bradykinin levels increased compared to WT animals. Neither treatment nor their combination affected the gene expression levels seen in the Wfs1 KO animals. However, all the treatments elevated serum aldosterone and decreased bradykinin in the Wfs1 KO rats, as well as increasing angiotensin II levels independent of genotype. Altogether, our results indicate that Wfs1 deficiency might disturb the normal functioning of RAAS and KKS and that LIR and VPA have the ability to modulate these systems.
Collapse
|
|
19
|
Ferreira JP, Lamiral Z, McMurray JJV, Swedberg K, van Veldhuisen DJ, Vincent J, Rossignol P, Pocock SJ, Pitt B, Zannad F. Impact of Insulin Treatment on the Effect of Eplerenone: Insights From the EMPHASIS-HF Trial. Circ Heart Fail 2021; 14:e008075. [PMID: 34129365 DOI: 10.1161/circheartfailure.120.008075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Patients with heart failure with reduced ejection fraction (HFrEF) and insulin-treated diabetes have a high risk of cardiovascular complications. Mineralocorticoid receptor antagonists may mitigate this risk. We aim to explore the effect of eplerenone on cardiovascular outcomes and all-cause mortality in HFrEF patients with diabetes, including those treated with insulin in the EMPHASIS-HF trial (Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms). METHODS The primary outcome was the composite of heart failure hospitalization or cardiovascular death. Cox models with treatment-by-diabetes subgroup interaction terms were used. RESULTS The median follow-up was 21 (10-33) months. Of the 2737 patients included, 623 (23%) had non-insulin-treated diabetes, 236 (9%) had insulin-treated diabetes and 1878 did not have diabetes. Patients with insulin-treated diabetes were younger, more often women, with higher body mass index, waist circumference, more frequent ischemic heart failure cause, impaired kidney function, and longer diabetes duration. Compared with patients without diabetes, those with insulin-treated diabetes had a 2-fold higher risk of having a primary outcome event. The hazard ratio (95% CI) for the effect of eplerenone, compared with placebo, on the primary outcome was 0.31 (0.19-0.50) in insulin-treated diabetes, 0.69 (0.50-0.93) in non-insulin-treated diabetes, and 0.72 (0.58-0.88) in patients without diabetes; interaction P=0.007. The annualized number needed-to-treat-to-benefit with regards to the primary outcome was 3 (95% CI, 3-4) in patients with insulin-treated diabetes, 16 (13-19) in patients with diabetes not receiving insulin, and 26 (24-28) in patients without diabetes. CONCLUSIONS Patients with insulin-treated diabetes experienced a greater benefit from eplerenone than those with diabetes not treated with insulin and people without diabetes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00232180.
Collapse
Affiliation(s)
- João Pedro Ferreira
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques, - Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F., Z.L., P.R., F.Z.)
| | - Zohra Lamiral
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques, - Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F., Z.L., P.R., F.Z.)
| | - John J V McMurray
- BHF Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.V.M.)
| | - Karl Swedberg
- Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.)
| | - Dirk J van Veldhuisen
- Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands (D.J.v.V.)
| | | | - Patrick Rossignol
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques, - Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F., Z.L., P.R., F.Z.)
| | - Stuart J Pocock
- Department of Biostatistics, London School of Hygiene and Tropical Medicine, London, United Kingdom (S.J.P.)
| | - Bertram Pitt
- Division of Cardiology, University of Michigan, Ann Arbor (B.P.)
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques, - Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F., Z.L., P.R., F.Z.)
| |
Collapse
|
|
20
|
Gendreitzig P, Künzel HE, Adolf C, Handgriff L, Müller L, Holler F, Sturm L, Heinrich DA, Reincke M, Quinkler M. Autonomous Cortisol Secretion Influences Psychopathological Symptoms in Patients With Primary Aldosteronism. J Clin Endocrinol Metab 2021; 106:e2423-e2433. [PMID: 33596311 DOI: 10.1210/clinem/dgab099] [Citation(s) in RCA: 7] [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: 01/09/2021] [Indexed: 01/18/2023]
Abstract
CONTEXT Primary aldosteronism (PA) is associated with impaired quality of life (QoL). Autonomous cortisol cosecretion (ACS) is a relevant phenotype of PA, which could contribute to depression and anxiety disorders. This has not been investigated so far. OBJECTIVE To evaluate the prevalence of depression and anxiety in PA patients according to ACS. METHODS We performed testing for hypercortisolism and evaluated anxiety, depression and QoL by self-rating questionnaires in newly diagnosed PA patients of the German Conn's Registry; 298 patients were reevaluated at follow-up. RESULTS In the overall cohort, scores for anxiety (P < .001), depression (P < .001), and QoL (mental P = .021; physical P = .015) improved significantly at follow-up. This improvement was seen in both subgroups of patients with and without ACS, with the exception of the mental subscore in no-ACS patients. Analysis for sex differences showed that anxiety decreased significantly in females with ACS and no-ACS, whereas males with no-ACS failed to improve. Depression improved significantly in males and females with ACS (P = .004, P = 0.011 respectively), but not in those with no-ACS. Physical subscore of QoL improved significantly (P = .023) in females with ACS and mental subscore (P = .027) in males with ACS, whereas no differences were seen for the no-ACS groups. CONCLUSION Improvement in depression and anxiety scores in response to treatment of PA is more pronounced in patients with ACS in contrast to no-ACS suggesting a role of ACS in the psychopathological symptoms of patients with PA. Furthermore, we observed significant differences in depression and anxiety scores between the sexes.
Collapse
Affiliation(s)
- Pauline Gendreitzig
- Endokrinologie in Charlottenburg, Endokrinologie Praxis am Stuttgarter Platz, Berlin, Germany
| | - Heike E Künzel
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, München, Germany
| | - Christian Adolf
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, München, Germany
| | - Laura Handgriff
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, München, Germany
| | - Lisa Müller
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, München, Germany
| | - Finn Holler
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, München, Germany
| | - Lisa Sturm
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, München, Germany
| | - Daniel A Heinrich
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, München, Germany
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, München, Germany
| | - Marcus Quinkler
- Endokrinologie in Charlottenburg, Endokrinologie Praxis am Stuttgarter Platz, Berlin, Germany
| |
Collapse
|
|
21
|
Grewal S, Fosam A, Chalk L, Deven A, Suzuki M, Correa RR, Blau JE, Demidowich AP, Stratakis CA, Muniyappa R. Insulin sensitivity and pancreatic β-cell function in patients with primary aldosteronism. Endocrine 2021; 72:96-103. [PMID: 33462741 PMCID: PMC8087621 DOI: 10.1007/s12020-020-02576-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 11/26/2020] [Indexed: 10/22/2022]
Abstract
BACKGROUND Primary aldosteronism (PA) is associated with an increased risk for dysglycemia. However, the effects of hyperaldosteronism on insulin sensitivity and β-cell function are unclear. METHODS Using a cross-sectional study design, we assessed insulin sensitivity and pancreatic β-cell function from an oral glucose tolerance test (OGTT) in patients from two cohorts: subjects with PA (n = 21) and essential hypertension control (EHC) subjects (n = 22). Age, sex, BMI, and mean arterial pressure adjusted measures of insulin sensitivity and β-cell function were compared between the groups. RESULTS PA individuals were less insulin sensitive compared to EHC subjects (Quantitative insulin sensitivity check index [QUICKI]: 0.340 ± 0.006 vs. 0.374 ± 0.013, p < 0.001; Matsuda index: 4.14 ± 0.49 vs. 7.87 ± 1.42, p < 0.001; SI: 11.45 ± 4.85 vs. 21.23 ± 6.11 dL/kg/min per μU/mL, p = 0.02). The hepatic insulin resistance index (HIRI) was higher in PA subjects (PA: 5.61 ± 1.01 vs. EHC: 4.13 ± 0.61, p = 0.002). The insulinogenic index (IGI), an index of β-cell function was higher in the PA cohort (PA: 1.49 ± 0.27 vs. 1.11 ± 0.21 μU/mL/mg/dL, p = 0.03). However, the oral disposition index (DI) was similar between the groups (PA: 4.77 ± 0.73 vs. EHC: 5.46 ± 0.85, p = 0.42), which likely accounts for the similar glucose tolerance between the two cohorts, despite lower sensitivity. CONCLUSIONS In summary, insulin sensitivity is significantly lower in PA with an appropriately compensated β-cell function. These results suggest that excess aldosterone and/or other steroids in the context of PA may negatively affect insulin action without adversely impacting β-cell function.
Collapse
Affiliation(s)
- Shivraj Grewal
- Clinical Endocrine Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Andin Fosam
- Clinical Endocrine Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Liam Chalk
- Clinical Endocrine Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Arjun Deven
- Clinical Endocrine Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Mari Suzuki
- Clinical Endocrine Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Ricardo Rafael Correa
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Jenny E Blau
- Clinical Endocrine Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Andrew Paul Demidowich
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Constantine A Stratakis
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Ranganath Muniyappa
- Clinical Endocrine Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
| |
Collapse
|
|
22
|
Katsuragawa S, Tsurutani Y, Takiguchi T, Saito J, Nishikawa T. Impact of primary aldosteronism on renal function in patients with type 2 diabetes. J Diabetes Investig 2021; 12:217-225. [PMID: 32583599 PMCID: PMC7858111 DOI: 10.1111/jdi.13332] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/15/2020] [Accepted: 06/16/2020] [Indexed: 01/13/2023] Open
Abstract
AIMS/INTRODUCTION Renal dysfunction might quickly progress in patients with type 2 diabetes mellitus, when accompanied by hypertension. However, whether primary aldosteronism (PA), which autonomously over-secretes aldosterone, causes additional renal damage in patients with type 2 diabetes mellitus is unclear. We evaluated the impact of PA on renal function in patients with type 2 diabetes mellitus. MATERIALS AND METHODS A retrospective review of all patients with type 2 diabetes mellitus who visited Yokohama Rosai Hospital's (Yokohama Japan) outpatient department between April 2017 and March 2018 was carried out. Records of patients with PA who underwent PA treatment by adrenalectomy or mineralocorticoid receptor antagonists (PA group) and those without PA (non-PA group) were extracted, and renal function was compared between the two groups. Untreated PA patients were excluded, as their renal function might be overestimated as a result of glomerular hyperfiltration. RESULTS There were 83 patients in the PA group and 1,580 patients in the non-PA group. The PA group had significantly lower estimated glomerular filtration rates than the non-PA group (66.3 [52.4-78.2] vs 70.5 [56.0-85.6] mL/min/1.73 m2 , P = 0.047). Multiple regression analysis showed that PA was a factor for decreased estimated glomerular filtration rate, independent of age, sex, glycated hemoglobin, diuretic use and hypertension (P = 0.025). PA induced a 3.7-mL/min/1.73 m2 (95% confidence interval 0.47-6.9) decrease in estimated glomerular filtration rate, equivalent to that induced by 4.4 years of aging. CONCLUSIONS Our results show that in patients with type 2 diabetes mellitus, PA is an independent risk factor for renal dysfunction. To prevent the progression of renal failure, PA should not be overlooked.
Collapse
Affiliation(s)
- Sho Katsuragawa
- Endocrinology and Diabetes CenterYokohama Rosai HospitalYokohamaJapan
| | - Yuya Tsurutani
- Endocrinology and Diabetes CenterYokohama Rosai HospitalYokohamaJapan
| | - Tomoko Takiguchi
- Endocrinology and Diabetes CenterYokohama Rosai HospitalYokohamaJapan
| | - Jun Saito
- Endocrinology and Diabetes CenterYokohama Rosai HospitalYokohamaJapan
| | - Tetsuo Nishikawa
- Endocrinology and Diabetes CenterYokohama Rosai HospitalYokohamaJapan
| |
Collapse
|
|
23
|
Inoue K, Kitamoto T, Tsurutani Y, Saito J, Omura M, Nishikawa T. Cortisol Co-Secretion and Clinical Usefulness of ACTH Stimulation Test in Primary Aldosteronism: A Systematic Review and Biases in Epidemiological Studies. Front Endocrinol (Lausanne) 2021; 12:645488. [PMID: 33796078 PMCID: PMC8008473 DOI: 10.3389/fendo.2021.645488] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/15/2021] [Indexed: 02/03/2023] Open
Abstract
The hypothalamus-pituitary-adrenal (HPA) axis plays an important role in primary aldosteronism. Aldosterone biosynthesis is regulated not only by angiotensin II in the renin-angiotensin-aldosterone system, but also by adrenocorticotropic hormone (ACTH), one of the key components of the HPA axis. Although previous studies have reported cortisol cosecretion in primary aldosteronism, particularly aldosterone-producing adenoma (APA), the clinical relevance of such aldosterone and cortisol cosecretion from APA and hypertension or other metabolic disorders has not been fully established. Several somatic mutations including KCNJ5 and CACNA1D are known to induce autonomous production of aldosterone in APA, and the aldosterone responsiveness to ACTH may vary according to each mutation. The ACTH stimulation test has been reported to be a useful tool to distinguish the subtypes of primary aldosteronism (e.g., unilateral vs bilateral) in some studies, but it has not been commonly applied in clinical practice due to limited evidence. Given the recent advancement of imaging, omics research, and computational approach, it is important to summarize the most updated evidence to disentangle the potential impact of cortisol excess in primary aldosteronism and whether the ACTH stimulation test needs to be considered during the diagnostic process of primary aldosteronism. In this article, we conducted a systematic review of epidemiological studies about (i) cortisol cosecretion in primary aldosteronism and (ii) the ACTH stimulation test for the diagnosis of primary aldosteronism (including subtype diagnosis). Then, we discussed potential biases (e.g., confounding bias, overadjustment, information bias, selection bias, and sampling bias) in the previous studies and introduced some advanced epidemiological/statistical methods to minimize these limitations. A better understanding of biases and epidemiological perspective on this topic would allow us to produce further robust evidence and balanced discussion about the causal mechanisms involving the HPA axis and clinical usefulness of the ACTH stimulation test among patients with primary aldosteronism.
Collapse
Affiliation(s)
- Kosuke Inoue
- Department of Epidemiology, University of California, Los Angeles (UCLA) Fielding School of Public Health, Los Angeles, CA, United States
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Yokohama, Japan
| | - Takumi Kitamoto
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Yokohama, Japan
- Division of Endocrinology, Department of Medicine, Columbia University, New York, NY, United States
| | - Yuya Tsurutani
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Yokohama, Japan
| | - Jun Saito
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Yokohama, Japan
| | - Masao Omura
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Yokohama, Japan
| | - Tetsuo Nishikawa
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Yokohama, Japan
- *Correspondence: Tetsuo Nishikawa,
| |
Collapse
|
|
24
|
Wang C, Jing H, Sun Z, Yao J, Zhang X, Liu T, Wu Y. A Bibliometric Analysis of Primary Aldosteronism Research From 2000 to 2020. Front Endocrinol (Lausanne) 2021; 12:665912. [PMID: 33986730 PMCID: PMC8111213 DOI: 10.3389/fendo.2021.665912] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/06/2021] [Indexed: 11/18/2022] Open
Abstract
Thousands of papers on primary aldosteronism (PA) have been published in the last two decades. This study aimed to evaluate the research hotspots and future trends in PA research using bibliometric analysis. A total of 2,365 PA research papers between 2000 and 2020 were included. The dominant position of the United States in global PA research throughout this 20-year period was evident, and it was also the country most frequently involved in international cooperation. The University of Padua was the most productive institution and a leader in research collaboration. The Journal of Clinical Endocrinology & Metabolism was the most productive journal in terms of the number of publications on PA. Further, Mulatero P, Reincke M, Beuschlein F and Wu VC all made significant contributions to PA research. Five hotspots have been identified: (1) metabolic syndrome associated with PA; (2) molecular mechanisms of PA; (3) adrenal adenoma and adrenal cortex; (4) hypertension associated with PA; and (5) clinical monitoring parameters and diagnosis in patients with PA. Our results suggest that the molecular mechanisms of PA will remain research hotspots in the future. International collaboration is also expected to widen and deepen in the field of PA research.
Collapse
Affiliation(s)
- Chengyuan Wang
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Hongwei Jing
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Zuyu Sun
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Jiaxi Yao
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Xinyu Zhang
- Department of Pulmonary Critical Care Medicine, The First Hospital of China Medical University, Shenyang, China
| | - Tao Liu
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
- *Correspondence: Ying Wu, ; Tao Liu,
| | - Ying Wu
- Phase I Clinical Trails Center, The First Hospital of China Medical University, Shenyang, China
- *Correspondence: Ying Wu, ; Tao Liu,
| |
Collapse
|
|
25
|
Chen KM, Lee BC, Chen PT, Liu KL, Lin KH, Chang CC, Wu TH, Hong JS, Lin YH. Evaluation of Abdominal Computed Tomography Scans for Differentiating the Discrepancies in Abdominal Adipose Tissue Between Two Major Subtypes of Primary Aldosteronism. Front Endocrinol (Lausanne) 2021; 12:647184. [PMID: 34335463 PMCID: PMC8323492 DOI: 10.3389/fendo.2021.647184] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 05/14/2021] [Indexed: 11/26/2022] Open
Abstract
The aim of this study was to analyze the differences in the distribution of abdominal adipose tissue between the two subtypes of primary aldosteronism (PA) using abdominal computed tomography. We retrospectively analyzed patients diagnosed as having essential hypertension (EH) or PA from the prospectively collected Taiwan Primary Aldosteronism Investigation (TAIPAI) database. Patients with PA were divided into the subgroups of idiopathic hyperaldosteronism (IHA) and unilateral aldosterone-producing adenoma (APA). Patients' basic clinicodemographic data were collected, and a self-developed CT-based software program was used to quantify the abdominal adiposity indexes, including visceral adipose tissue (VAT) area, VAT ratio, waist circumference (WC), subcutaneous adipose tissue (SAT) area, and SAT ratio. We included 190 patients with EH and 436 patients with PA (238 with IHA and 198 with APA). The APA group had significantly lower abdominal adiposity indexes than the other groups. We also found negative correlations of aldosterone-to-renin ratio (ARR) with VAT area, VAT ratio, WC, and body mass index (BMI) in the APA group. After propensity score matching (which left 184 patients each in the IHA and APA groups), patients in the APA group still had significantly lower WC, SAT area, SAT ratio, and VAT ratio than those in the IHA group. Furthermore, logistic regression analysis indicated that lower probability of abdominal obesity was significantly related to patients with APA. Our data revealed that the distribution of abdominal adipose tissue was similar in patients with IHA and those with EH, but the abdominal adiposity indexes were significantly lower in patients with APA than in those with IHA and EH.
Collapse
Affiliation(s)
- Kuan-Ming Chen
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Industrial Ph.D. Program of Biomedical Science and Engineering, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan
- Industrial Ph.D. Program of Biomedical Science and Engineering, School of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Bo-Ching Lee
- Department of Medical Imaging, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Po-Ting Chen
- Department of Medical Imaging, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Kao-Lang Liu
- Department of Medical Imaging, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Kuan-Heng Lin
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Industrial Ph.D. Program of Biomedical Science and Engineering, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan
- Industrial Ph.D. Program of Biomedical Science and Engineering, School of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Chin-Chen Chang
- Department of Medical Imaging, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
- Department and Graduate Institute of Forensic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- *Correspondence: Chin-Chen Chang, ; Tung-Hsin Wu,
| | - Tung-Hsin Wu
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- *Correspondence: Chin-Chen Chang, ; Tung-Hsin Wu,
| | - Jia-Sheng Hong
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Yen-Hung Lin
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| |
Collapse
|
|
26
|
Lin YF, Peng KY, Chang CH, Hu YH, Wu VC, Chung SD. Changes in Glucose Metabolism after Adrenalectomy or Treatment with a Mineralocorticoid Receptor Antagonist for Primary Aldosteronism. Endocrinol Metab (Seoul) 2020; 35:838-846. [PMID: 33261310 PMCID: PMC7803597 DOI: 10.3803/enm.2020.797] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 09/23/2020] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Data on the effects of excess aldosterone on glucose metabolism are inconsistent. This study compared the changes in glucose metabolism in patients with primary aldosteronism (PA) after adrenalectomy or treatment with a mineralocorticoid receptor antagonist (MRA). METHODS Overall, 241 patients were enrolled; 153 underwent adrenalectomy and 88 received an MRA. Fasting glucose, homeostatic model assessment of insulin resistance (HOMA-IR), and homeostatic model assessment of β-cell function (HOMA-β) were compared between the treatment groups after 1 year. Plasma aldosterone concentration (PAC) and factors determining HOMA-IR and PAC were evaluated. RESULTS No baseline differences were observed between the groups. Fasting insulin, HOMA-IR, and HOMA-β increased in both groups and there were no significant differences in fasting glucose following treatment. Multiple regression analysis showed associations between PAC and HOMA-IR (β=0.172, P=0.017) after treatment. Treatment with spironolactone was the only risk factor associated with PAC >30 ng/dL (odds ratio, 5.2; 95% confidence interval [CI], 2.7 to 10; P<0.001) and conferred a 2.48-fold risk of insulin resistance after 1 year compared with surgery (95% CI, 1.3 to 4.8; P=0.007). CONCLUSION Spironolactone treatment might increase insulin resistance in patients with PA. This strengthened the current recommendation that adrenalectomy is the preferred strategy for patient with positive lateralization test. Achieving a post-treatment PAC of <30 ng/dL for improved insulin sensitivity may be appropriate.
Collapse
Affiliation(s)
- Yu-Fang Lin
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei,
Taiwan
| | - Kang-Yung Peng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei,
Taiwan
| | - Chia-Hui Chang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei Tzu Chi Hospital, The Buddhist Medical Foundation, New Taipei,
Taiwan
| | - Ya-Hui Hu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei Tzu Chi Hospital, The Buddhist Medical Foundation, New Taipei,
Taiwan
| | - Vin-Cent Wu
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei,
Taiwan
| | - Shiu-Dong Chung
- Division of Urology, Department of Surgery, Far-Eastern Memorial Hospital, New Taipei,
Taiwan
- Graduate Program in Biomedical Informatics, College of Informatics, Yuan-Ze University, Chung-Li,
Taiwan
| | | |
Collapse
|
|
27
|
Handgriff L, Adolf C, Heinrich DA, Braun L, Nirschl N, Sturm L, Ladurner R, Ricke J, Seidensticker M, Bidlingmaier M, Reincke M. The Impact of Glucocorticoid Co-Secretion in Primary Aldosteronism on Thyroid Autoantibody Titers During the Course of Disease. Horm Metab Res 2020; 52:404-411. [PMID: 32403151 PMCID: PMC7746512 DOI: 10.1055/a-1164-1944] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Excess aldosterone is associated with the increased risk of cardio-/cerebrovascular events as well as metabolic comorbidities not only due to its hypertensive effect but also due to its proinflammatory action. Autonomous cortisol secretion (ACS) in the setting of primary aldosteronism (PA) is known to worsen cardiovascular outcome and potentially exhibit immunosuppressive effects. The aim of this study was to determine the impact of ACS status in patients with PA on kinetics of thyroid autoantibodies (anti-TPO, anti-TG) pre and post therapy initiation. Ninety-seven PA patients (43 unilateral, 54 with bilateral PA) from the database of the German Conn's Registry were included. Anti-TPO and anti-TG levels were measured pre and 6-12 months post therapeutic intervention. Patients were assessed for ACS according to their 24- hour urinary cortisol excretion, late night salivary cortisol and low-dose dexamethasone suppression test. Abnormal test results in line with ACS were identified in 74.2% of patients with PA. Following adrenalectomy, significant increases in anti-TPO levels were observed in patients with at least one abnormal test (p = 0.049), adrenalectomized patients with at least two pathological ACS tests (p = 0.015) and adrenalectomized patients with pathologic dexamethasone suppression tests (p = 0.018). No antibody increases were observed in unilateral PA patients without ACS and in patients with bilateral PA receiving mineralocorticoid antagonist therapy (MRA). Our data are in line with an immunosuppressive effect of mild glucocorticoid excess in PA on thyroid autoantibody titers. This effect is uncovered by adrenalectomy, but not by MRA treatment.
Collapse
Affiliation(s)
- Laura Handgriff
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität
München, Munich, Germany
| | - Christian Adolf
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität
München, Munich, Germany
| | - Daniel A. Heinrich
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität
München, Munich, Germany
| | - Leah Braun
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität
München, Munich, Germany
| | - Nina Nirschl
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität
München, Munich, Germany
| | - Lisa Sturm
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität
München, Munich, Germany
| | - Roland Ladurner
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie,
Klinikum der Universität München, Munich, Germany
| | - Jens Ricke
- Klinik und Poliklinik für Radiologie, Klinikum der
Universität München, Munich, Germany
| | - Max Seidensticker
- Klinik und Poliklinik für Radiologie, Klinikum der
Universität München, Munich, Germany
| | - Martin Bidlingmaier
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität
München, Munich, Germany
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität
München, Munich, Germany
- Correspondence Prof. Martin Reincke Medizinische Klinik und Poliklinik IV, Klinikum derUniversität MünchenZiemssenstraße 180336 MünchenGermany+49 89 4400 52411+49 89 4400 52194
| |
Collapse
|
|
28
|
Han M, Cao X, Zhao C, Yang L, Yin N, Shen P, Zhang J, Gao F, Ren Y, Liang D, Yang J, Zhang Y, Liu Y. Assessment of Glycometabolism Impairment and Glucose Variability Using Flash Glucose Monitoring System in Patients With Adrenal Diseases. Front Endocrinol (Lausanne) 2020; 11:544752. [PMID: 33101192 PMCID: PMC7546367 DOI: 10.3389/fendo.2020.544752] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 09/08/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND This study aimed to investigate the characteristics and extent of glycometabolism impairment in patients with adrenal diseases, including Cushing syndrome, primary aldosteronism, pheochromocytoma, and nonfunctional adrenal incidentaloma. METHODS This study enrolled thirty-two patients with adrenal diseases as adrenal disease groups and eight healthy individuals as healthy controls. Blood glucose levels were indicated by glucose concentration in interstitial fluid, which was documented using flash glucose monitoring system. According to flash glucose monitoring system data, parameters representing general blood glucose alterations, within-day and day-to-day glucose variability, and glucose-target-rate were calculated. Furthermore, blood glucose levels at nocturnal, fasting, and postprandial periods were analyzed. Besides, islet β-cell function and insulin resistance were assessed. RESULTS Analysis of flash glucose monitoring system-related parameters indicated impaired glycometabolism in patients with adrenal diseases compared with that of healthy controls at general blood glucose, within-day and day-to-day glucose variability, and glucose-target-rate levels. Furthermore, the dynamic glucose monitoring data revealed that significantly affected blood glucose levels compared with that of healthy controls were observed at postprandial periods in the Cushing syndrome and primary aldosteronism groups; at nocturnal, fasting and postprandial periods in the pheochromocytoma group. Significant insulin resistance and abnormal β-cell function were observed in the Cushing syndrome group compared with that in healthy controls. CONCLUSION Adrenal diseases can negatively affect glucose metabolism. Patients diagnosed with adrenal diseases should receive timely and appropriate treatment to avoid adverse cardiovascular events linked to hyperglycemia and insulin resistance.
Collapse
Affiliation(s)
- Minmin Han
- First Clinical Medical College, Shanxi Medical University, Taiyuan, China
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiaoming Cao
- Department of Urology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Changjian Zhao
- Department of Urology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Luyang Yang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Nan Yin
- Department of Urology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Pengliang Shen
- Department of Urology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Jin Zhang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Fei Gao
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yi Ren
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Dong Liang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Jing Yang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yi Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
- *Correspondence: Yi Zhang, ; Yunfeng Liu,
| | - Yunfeng Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- *Correspondence: Yi Zhang, ; Yunfeng Liu,
| |
Collapse
|
|
29
|
Kwak MK, Lee JY, Kim BJ, Lee SH, Koh JM. Effects of Primary Aldosteronism and Different Therapeutic Modalities on Glucose Metabolism. J Clin Med 2019; 8:E2194. [PMID: 31842354 PMCID: PMC6947343 DOI: 10.3390/jcm8122194] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 12/09/2019] [Indexed: 01/09/2023] Open
Abstract
Despite findings that aldosterone impairs glucose metabolism, studies concerning the effect of primary aldosteronism (PA) and its treatment on glucose metabolism are controversial. We aimed to determine glucose metabolism in PA and the effect of the treatment modality. We compared glucose metabolism between PA patients (N = 286) and age-, sex-, and body mass index-matched controls (N = 816), and the changes in glucose metabolism depending on the treatment modality (adrenalectomy vs. spironolactone treatment). Hyperglycemia including diabetes mellitus (DM; 19.6% vs. 13.1%, p = 0.011) was more frequent in PA patients. Hyperglycemia was also more frequent in PA patients without subclinical hypercortisolism (SH: p < 0.001) and in those regardless of hypokalemia (p < 0.001-0.001). PA patients and PA patients without SH had higher DM risk (odds ratio (OR); 95% confidence interval (CI): 1.63; 1.11-2.39 and 1.65; 1.08-2.51, respectively) after adjusting confounders. In PA patients, there was significant decrease in the DM prevalence (21.3% to 16.7%, p = 0.004) and fasting plasma glucose (p = 0.006) after adrenalectomy. However, there was no significant change in them after spironolactone treatment. Adrenalectomy was associated with more improved glucose status than spironolactone treatment (OR; 95% CI: 2.07; 1.10-3.90). Glucose metabolism was impaired in PA, regardless of hypokalemia and SH status, and was improved by adrenalectomy, but not spironolactone treatment.
Collapse
Affiliation(s)
- Mi Kyung Kwak
- Division of Endocrinology and Metabolism, Hallym University Dongtan Sacred Heart Hospital, Dongtan, 7, Keunjaebong-gil, Hwaseong 18450, Gyeonggi-do, Korea;
| | - Jee Yang Lee
- Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea; (J.Y.L.); (B.-J.K.)
| | - Beom-Jun Kim
- Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea; (J.Y.L.); (B.-J.K.)
| | - Seung Hun Lee
- Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea; (J.Y.L.); (B.-J.K.)
| | - Jung-Min Koh
- Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea; (J.Y.L.); (B.-J.K.)
| |
Collapse
|
|
30
|
Kumar A, Patel DR, Brennan DM, Wolski KE, Lincoff AM, Ruotolo G, McErlean E, Weerakkody G, Riesmeyer JS, Nicholls SJ, Nissen SE, Menon V. Plasma Aldosterone Levels Are Not Associated With Cardiovascular Events Among Patients With High-Risk Vascular Disease: Insights From the ACCELERATE Trial. J Am Heart Assoc 2019; 8:e013790. [PMID: 31752637 PMCID: PMC6912956 DOI: 10.1161/jaha.119.013790] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Background The failure of cholesteryl ester transfer protein inhibitor torcetrapib was associated with an off‐target increase in plasma aldosterone. We sought to evaluate the impact of evacetrapib on plasma aldosterone level and determine the association between plasma aldosterone level and major adverse cardiovascular events among patients with stable high‐risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. Methods and Results We included all patients with a plasma aldosterone level (N=1624) and determined the impact of evacetrapib exposure compared with placebo on plasma aldosterone levels after 12 months of treatment. Using baseline and postexposure aldosterone levels, hazard ratios for major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, cerebrovascular accident, hospitalization for unstable angina, and revascularization) with increasing quartile of baseline and percentage change in plasma aldosterone level at follow‐up were calculated. The average age was 65.2 years, 75.7% were men, 93.7% were hypertensive, 73.3% were diabetic, and 57.6% had a prior myocardial infarction. Baseline plasma aldosterone level (85.2 [43, 150] versus 86.8 [43, 155] pmol/L; P=0.81) and follow‐up percentage change (13.6% [−29, 88] versus 17.9% [−24, 87]; P=0.23) were similar between those who received evacetrapib and placebo. During median follow‐up of 28 months, major adverse cardiovascular events occurred in 263 patients (16.2%). The hazard ratios for increasing quartile of baseline or percentage change in plasma aldosterone level at follow‐up were not significant for major adverse cardiovascular events. These findings remained consistent when adjusting for significant characteristics. Conclusions Exposure to evacetrapib did not result in significant change in plasma aldosterone levels compared with placebo. Among patients with stable high‐risk vascular disease, plasma aldosterone levels were not a predictor for future cardiovascular events. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01687998.
Collapse
Affiliation(s)
- Anirudh Kumar
- Heart and Vascular Institute Cleveland Clinic Foundation Cleveland OH
| | - Divyang R Patel
- Heart and Vascular Institute Cleveland Clinic Foundation Cleveland OH
| | | | - Kathy E Wolski
- Heart and Vascular Institute Cleveland Clinic Foundation Cleveland OH
| | - A Michael Lincoff
- Heart and Vascular Institute Cleveland Clinic Foundation Cleveland OH
| | | | - Ellen McErlean
- Heart and Vascular Institute Cleveland Clinic Foundation Cleveland OH
| | | | | | - Stephen J Nicholls
- Monash Cardiovascular Research Centre Monash University Melbourne Australia
| | - Steven E Nissen
- Heart and Vascular Institute Cleveland Clinic Foundation Cleveland OH
| | - Venu Menon
- Heart and Vascular Institute Cleveland Clinic Foundation Cleveland OH
| |
Collapse
|
|
31
|
Gerards J, Heinrich DA, Adolf C, Meisinger C, Rathmann W, Sturm L, Nirschl N, Bidlingmaier M, Beuschlein F, Thorand B, Peters A, Reincke M, Roden M, Quinkler M. Impaired Glucose Metabolism in Primary Aldosteronism Is Associated With Cortisol Cosecretion. J Clin Endocrinol Metab 2019; 104:3192-3202. [PMID: 30865224 DOI: 10.1210/jc.2019-00299] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 03/07/2019] [Indexed: 01/05/2023]
Abstract
CONTEXT Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and metabolic risks. Recent studies report glucocorticoid cosecretion as a relevant phenotype of PA, which could contribute to associated risks, including type 2 diabetes mellitus (T2DM). The relationship between autonomous cortisol secretion (ACS) and glucose metabolism in PA has not been investigated. OBJECTIVE To evaluate the prevalence of impaired glucose homeostasis in patients with PA according to cortisol cosecretion. DESIGN We performed oral glucose tolerance tests (OGTTs) and complete testing for hypercortisolism [1-mg dexamethasone suppression test (DST), late-night salivary cortisol, 24-hour urinary free cortisol] in 161 newly diagnosed patients with PA of the German Conn Registry. Seventy-six of 161 patients were reevaluated at follow-up. We compared our results to a population-based sample from the Cooperative Health Research in the Region of Augsburg (KORA)-F4 study matched to the participants with PA (3:1) by sex, age, and body mass index. RESULTS At the time of diagnosis, 125 patients (77.6%) had a pathological response in at least one of the Cushing screening tests; T2DM was diagnosed in 6.4% of these 125 cases. Patients with a pathological DST exhibited significantly higher 2-hour plasma glucose in OGTTs and were significantly more often diagnosed with T2DM than were patients with a normal DST (20% vs 0.8%, P < 0.0001) and matched controls from the KORA study (20.6% vs 5.9%, P = 0.022). Patients with PA without ACS tended to have higher homeostatic model assessment of insulin resistance levels than did KORA control subjects (P = 0.05). CONCLUSION ACS appears frequently in patients with PA and is associated with impaired glucose metabolism, which could increase the risk of T2DM. PA itself seems to enhance insulin resistance.
Collapse
Affiliation(s)
| | - Daniel A Heinrich
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Christian Adolf
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Christa Meisinger
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center of Environmental Health, Neuherberg, Germany
| | - Wolfgang Rathmann
- Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Duesseldorf, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Lisa Sturm
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Nina Nirschl
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Martin Bidlingmaier
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Felix Beuschlein
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zurich, Switzerland
| | - Barbara Thorand
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center of Environmental Health, Neuherberg, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center of Environmental Health, Neuherberg, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Michael Roden
- German Center for Diabetes Research, Munich-Neuherberg, Germany
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Duesseldorf, Germany
| | | |
Collapse
|
|
32
|
Dietary Approaches to Stop Hypertension (DASH): potential mechanisms of action against risk factors of the metabolic syndrome. Nutr Res Rev 2019; 33:1-18. [PMID: 31358075 DOI: 10.1017/s0954422419000155] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The metabolic syndrome is a cluster of disorders dominated by abdominal obesity, hypertriacylglycerolaemia, low HDL-cholesterol, high blood pressure and high fasting glucose. Diet modification is a safe and effective way to treat the metabolic syndrome. Dietary Approaches to Stop Hypertension (DASH) is a dietary pattern rich in fruits, vegetables and low-fat dairy products, and low in meats and sweets. DASH provides good amounts of fibre, K, Ca and Mg, and limited quantities of total fat, saturated fat, cholesterol and Na. Although DASH was initially designed for the prevention or control of hypertension, using a DASH diet has other metabolic benefits. In the present review, the effect of each dietary component of DASH on the risk factors of the metabolic syndrome is discussed. Due to limited fat and high fibre and Ca content, individuals on the DASH diet are less prone to overweight and obesity and possess lower concentrations of total and LDL-cholesterol although changes in TAG and HDL-cholesterol have been less significant and available evidence in this regard is still inconclusive. Moreover, high amounts of fruit and vegetables in DASH provide great quantities of K, Mg and fibre, all of which have been shown to reduce blood pressure. K, Mg, fibre and antioxidants have also been effective in correcting glucose and insulin abnormalities. Evidence is provided from cross-sectional investigations, cohort studies and randomised controlled trials, and, where available, from published meta-analyses. Mechanisms are described according to human studies and, in the case of a lack of evidence, from animal and cell culture investigations.
Collapse
|
|
33
|
Bothou C, Beuschlein F, Spyroglou A. Links between aldosterone excess and metabolic complications: A comprehensive review. DIABETES & METABOLISM 2019; 46:1-7. [PMID: 30825519 DOI: 10.1016/j.diabet.2019.02.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 02/13/2019] [Accepted: 02/17/2019] [Indexed: 02/04/2023]
Abstract
Shortly after the first description of primary aldosteronism (PA) appeared in the 1950s by Jerome Conn, an association of the condition with diabetes mellitus was documented. However, a clear pathophysiological interrelationship linking the two entities has yet to be established. Nevertheless, so far, many mechanisms contributing to insulin resistance and dysregulation of glucose uptake have been described. At the same time, many observational studies have reported an increased prevalence of the metabolic syndrome (MetS) among patients with PA. Regarding the relationship between aldosterone levels and obesity, a vicious cycle of adipokine-induced aldosterone production and aldosterone adipogenic action may be further contributing to MetS manifestations in PA patients. However, whether aldosterone excess affects lipid metabolism is still under investigation. Also, recent findings of the coexistence of glucocorticoid excess in many cases of PA highlight the need for further studies to examine the presumed link between high aldosterone levels and various metabolic parameters. In the present review, our focus is to comprehensively present the spectrum of available research findings concerning the possible associations between aldosterone excess and metabolic alterations, including impaired glucose metabolism, insulin resistance and, consequently, diabetes, altered lipid metabolism and the development of fatty liver. In addition, the complex relationship between obesity and aldosterone is discussed in detail.
Collapse
Affiliation(s)
- C Bothou
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich, Zürich, Switzerland; Competence Centre of Personalized Medicine, Molecular and Translational Biomedicine PhD Program, University of Zurich, Zurich, Switzerland
| | - F Beuschlein
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich, Zürich, Switzerland; Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU, Munich, Germany.
| | - A Spyroglou
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich, Zürich, Switzerland
| |
Collapse
|
|
34
|
Hermidorff MM, de Assis LVM, Isoldi MC. Genomic and rapid effects of aldosterone: what we know and do not know thus far. Heart Fail Rev 2018; 22:65-89. [PMID: 27942913 DOI: 10.1007/s10741-016-9591-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Aldosterone is the most known mineralocorticoid hormone synthesized by the adrenal cortex. The genomic pathway displayed by aldosterone is attributed to the mineralocorticoid receptor (MR) signaling. Even though the rapid effects displayed by aldosterone are long known, our knowledge regarding the receptor responsible for such event is still poor. It is intense that the debate whether the MR or another receptor-the "unknown receptor"-is the receptor responsible for the rapid effects of aldosterone. Recently, G protein-coupled estrogen receptor-1 (GPER-1) was elegantly shown to mediate some aldosterone-induced rapid effects in several tissues, a fact that strongly places GPER-1 as the unknown receptor. It has also been suggested that angiotensin receptor type 1 (AT1) also participates in the aldosterone-induced rapid effects. Despite this open question, the relevance of the beneficial effects of aldosterone is clear in the kidneys, colon, and CNS as aldosterone controls the important water reabsorption process; on the other hand, detrimental effects displayed by aldosterone have been reported in the cardiovascular system and in the kidneys. In this line, the MR antagonists are well-known drugs that display beneficial effects in patients with heart failure and hypertension; it has been proposed that MR antagonists could also play an important role in vascular disease, obesity, obesity-related hypertension, and metabolic syndrome. Taken altogether, our goal here was to (1) bring a historical perspective of both genomic and rapid effects of aldosterone in several tissues, and the receptors and signaling pathways involved in such processes; and (2) critically address the controversial points within the literature as regarding which receptor participates in the rapid pathway display by aldosterone.
Collapse
Affiliation(s)
- Milla Marques Hermidorff
- Laboratory of Hypertension, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Campus Morro do Cruzeiro, Ouro Preto, MG, 35400-000, Brazil
| | - Leonardo Vinícius Monteiro de Assis
- Laboratory of Comparative Physiology of Pigmentation, Department of Physiology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
| | - Mauro César Isoldi
- Laboratory of Hypertension, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Campus Morro do Cruzeiro, Ouro Preto, MG, 35400-000, Brazil.
| |
Collapse
|
|
35
|
Wang L, Niu YM, Wu SS, Zhang C, Zhou L, Zuo HX, Wang P. A Study on the Association Between Polymorphisms in the Cytochrome P450 Family 17 Subfamily A Member 1 Gene Region and Type 2 Diabetes Mellitus in Han Chinese. Front Endocrinol (Lausanne) 2018; 9:323. [PMID: 29942286 PMCID: PMC6004380 DOI: 10.3389/fendo.2018.00323] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 05/28/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Cytochrome P450 family 17 subfamily A member 1 (CYP17A1) gene encodes a key enzyme in the synthesis and metabolism of steroid hormones and has been associated with various factors, such as hypertension, insulin resistance, and polycystic ovary syndrome. However, whether the gene was associated with type 2 diabetes mellitus (T2DM) has not been reported yet. Therefore, we sought to investigate whether CYP17A1 was associated with T2DM and related traits among Han Chinese. METHODS Three tagging single nucleotide polymorphisms (rs1004467, rs17115149, and rs12413409), in the CYP17A1 gene region were selected and genotyped in a case-control study that included 440 diabetes and 1,320 control subjects. Effects of genetic loci were studied using univariate unconditional logistic regression and multivariate logistic regression analysis adjusted for age, sex, family history, body mass index, smoking, and drinking. Bioinformatics analysis was also conducted using the GEO DataSets and PROMO database to gain hints of possible mechanism. RESULTS Rs17115149 and rs12413409 polymorphisms were significantly associated with the risk of T2DM, even after adjusting for age, sex, family history, body mass index, smoking, and drinking. In stratified analyses, rs1004467 and rs12413409 showed significant association with T2DM in the older age group (≥65 years) and, in the case of rs12413409, the risk of T2DM was significant in men but not in women. Rs17115149 had significant association with T2DM in the hypertension subgroup, and rs12413409 in the non-hypertension subgroup. Moreover, rs12413409 showed significant association with plasma glucose levels in the recessive model (P = 0.020) among subjects not taking hypoglycemic measures. Bioinformatics analysis revealed significantly higher CYP17A1 gene expression in T2DM patients compared to healthy controls. Finally, the mutant T allele of the rs17115149 polymorphism allowed binding to the RBP-Jkappa transcription factor. CONCLUSION This is the first report to identify that variants rs1004467, rs17115149, and rs12413409 of CYP17A1, are related to plasma glucose levels and T2DM among Han Chinese. Our results suggest that CYP17A1 might constitute a risk gene for progression to T2DM.
Collapse
Affiliation(s)
- Long Wang
- Department of Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yu-Ming Niu
- Department of Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
- *Correspondence: Yu-Ming Niu, ; Shi-Shi Wu,
| | - Shi-Shi Wu
- Department of Histology and Embryology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
- *Correspondence: Yu-Ming Niu, ; Shi-Shi Wu,
| | - Chao Zhang
- Department of Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Li Zhou
- Research Center for Medicine and Social Development, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Hong-Xia Zuo
- Department of Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Peng Wang
- Department of Clinical Laboratory, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| |
Collapse
|
|
36
|
Min SH, Kim SH, Jeong IK, Cho HC, Jeong JO, Lee JH, Kang HJ, Kim HS, Park KS, Lim S. Independent Association of Serum Aldosterone Level with Metabolic Syndrome and Insulin Resistance in Korean Adults. Korean Circ J 2018; 48:198-208. [PMID: 29557106 PMCID: PMC5861312 DOI: 10.4070/kcj.2017.0200] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 11/13/2017] [Accepted: 11/21/2017] [Indexed: 12/21/2022] Open
Abstract
Background and Objectives A relationship between renin-angiotensin system (RAS) components and metabolic syndrome (MetS) has been suggested, but not elucidated clearly. We examined the levels of RAS components in patients with and without MetS and their association with MetS in Korean population. Methods This study was approved by the review boards of the participating institutions and endorsed by the Korean Society of Lipid and Atherosclerosis. We screened 892 Koreans aged ≥20 years who underwent evaluation of hypertension, diabetes, or dyslipidemia at 6 tertiary hospitals in 2015–2016. After excluding patients who were taking diuretics, β-blockers, or RAS blockers, or suspected of primary aldosteronism, 829 individuals were enrolled. Anthropometric and biochemical parameters including aldosterone, plasma renin activity (PRA), and aldosterone-to-PRA ratio were evaluated. The homeostasis model assessment for insulin resistance (HOMA-IR) were used for evaluating insulin resistance. Results The mean age of the participants was 52.8±12.8 years, 56.3% were male, and their mean systolic and diastolic blood pressures were 133.9±20.0 and 81.2±14.6 mmHg, respectively. The levels of serum aldosterone, but not PRA, were significantly higher in subjects with MetS than in those without (20.6±33.6 vs. 15.3±12.2 ng/dL, p<0.05), and positively correlated with waist circumference, blood pressure, triglycerides, and glycated hemoglobin. The levels of aldosterone were independently associated with the number of MetS components and HOMA-IR after adjusting for conventional risk factors. Conclusions Serum aldosterone levels were higher in Korean adults with MetS than in those without. This finding suggests that increased aldosterone level might be closely associated with insulin resistance.
Collapse
Affiliation(s)
- Se Hee Min
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Se Hong Kim
- Department of Family Medicine, St. Vincent's Hospital, The Catholic University of Korea College of Medicine, Suwon, Korea
| | - In Kyung Jeong
- Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University College of Medicine, Seoul, Korea
| | - Ho Chan Cho
- Department of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, Korea
| | - Jin Ok Jeong
- Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea
| | - Ju Hee Lee
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Hyun Jae Kang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo Soo Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kyong Soo Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Soo Lim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
| |
Collapse
|
|
37
|
Chung YC, Tzeng CY, Chen YI, Chang SW, Hsu TH, Ho WJ, Kuo YH, Hung PH, Chang SL. Improving insulin resistance with Antrodia cinnamomea mycelium powder to induce a hypoglycemic effect in dexamethasone‑induced insulin‑resistant rats. Mol Med Rep 2017; 17:3260-3266. [PMID: 29257321 DOI: 10.3892/mmr.2017.8259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 09/21/2017] [Indexed: 11/06/2022] Open
Abstract
Insulin resistance is a major factor in type II diabetes development, occurring when insulin levels are normal, but do not have normal interactions with adipose, muscle or liver tissue. The present study aimed to explore the hypoglycemic effect of Antrodia cinnamomea (AC) mycelium powder by evaluating its impact on insulin resistance and plasma free fatty acid (FFA) levels in steroid‑induced insulin‑resistant (SIIR) rats. Male Wistar rats were administered dexamethasone for 5 days to induce insulin resistance. The SIIR rats were subsequently randomly assigned into three experimental groups (EGs) and a control group (CG), where saline was orally administered. The EGs were orally administered different doses of AC (100, 200 or 500 mg/kg) and an optimal dose for further study was determined. Changes in plasma insulin and glucose levels were calculated to investigate the hypoglycemic effect of AC. To evaluate insulin resistance, the homeostasis model assessment‑estimated insulin resistance of the SIIR rats was determined. Changes in plasma FFA levels were detected and levels of insulin signal proteins (IRS‑1, GLUT‑4 and PI3K) were analyzed by western blot to elucidate AC's mechanism of action. The SIIR rats exhibited significantly decreased plasma glucose levels in the first 30 min, with plasma FFA levels displaying a marked downward trend (P<0.05) when they were administered the optimal dose of AC (200 mg/kg). The decrease in plasma glucose and FFA levels was significantly larger in the EG compared to the CG, and insulin signal protein levels were also significantly increased (P<0.05). The hypoglycemic effect observed may be due to decreased plasma FFA levels and increased expression of intracellular insulin signal proteins. Furthermore, insulin sensitivity was enhanced, indicating that AC acts as an insulin sensitizer in insulin resistant animal models.
Collapse
Affiliation(s)
- Yuan-Chiang Chung
- Department of Surgery Chung-Kang Branch, Cheng‑Ching Hospital, Taichung 40764, Taiwan, R.O.C
| | - Chung-Yuh Tzeng
- Department of Medicinal Botanicals and Health Applications, Da‑Yeh University, Changhua 51591, Taiwan, R.O.C
| | - Ying-I Chen
- Department of Medicinal Botanicals and Health Applications, Da‑Yeh University, Changhua 51591, Taiwan, R.O.C
| | - Shu-Wei Chang
- Department of Medicinal Botanicals and Health Applications, Da‑Yeh University, Changhua 51591, Taiwan, R.O.C
| | - Tai-Hao Hsu
- Department of Bioindustry Technology, Da‑Yeh University, Changhua 51591, Taiwan, R.O.C
| | - Wai-Jane Ho
- Department of Medicinal Botanicals and Health Applications, Da‑Yeh University, Changhua 51591, Taiwan, R.O.C
| | - Yueh-Hsiung Kuo
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 41354, Taiwan, R.O.C
| | - Pei-Hsiu Hung
- Division of Traditional Chinese, Ditmanson Medical Foundation Chia‑Yi Christian Hospital, Chiayi 60002, Taiwan, R.O.C
| | - Shih-Liang Chang
- Department of Medicinal Botanicals and Health Applications, Da‑Yeh University, Changhua 51591, Taiwan, R.O.C
| |
Collapse
|
|
38
|
Zavatta G, Casadio E, Rinaldi E, Pagotto U, Pasquali R, Vicennati V. Aldosterone and type 2 diabetes mellitus. Horm Mol Biol Clin Investig 2016; 26:53-9. [PMID: 26876814 DOI: 10.1515/hmbci-2015-0065] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 01/18/2016] [Indexed: 12/25/2022]
Abstract
Primary hyperaldosteronism (PA) has recently been demonstrated to be strictly associated to metabolic syndrome as compared with essential hypertension (EH). Besides, the characteristics of metabolic syndrome are different in PA compared to EH, as high fasting glucose is more frequent in the former condition. The adverse effect of excess aldosterone on insulin metabolic signaling has generated increasing interest in the role of hyperaldosteronism in the pathogenesis of insulin resistance and resistant hypertension. Moreover, aldosterone receptor antagonist therapy in diabetic and cardiopathic patients improved coronary flow. The aim of this review is to present recent knowledge about the relationship between aldosterone, insulin resistance and diabetes.
Collapse
|
|
39
|
Abstract
Abdominal obesity and elevated blood pressure commonly occur in the same patient and are key components of the metabolic syndrome. However, the association between obesity and increased blood pressure is variable. We review mechanisms linking cardiovascular and metabolic disease in such patients including altered systemic and regional hemodynamic control, neurohumoral activation, and relative natriuretic peptide deficiency. Moreover, we discuss recent results using omics techniques providing insight in molecular pathways linking adiposity, metabolic disease, and arterial hypertension. Recognition of the mechanisms orchestrating the crosstalk between cardiovascular and metabolic regulation in individual patients may lead to better and more precise treatments. It is reassuring that recently developed cardiovascular and metabolic medications may in fact ameliorate, both, cardiovascular and metabolic risks.
Collapse
Affiliation(s)
- Jens Jordan
- Institute for Clinical Pharmacology, Medical School Hannover, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
| | - Andreas L Birkenfeld
- Section of Metabolic Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Dresden, TU, Germany
- Center for Clinical Studies, GWT-TUD GmbH, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID), A Member of the German Center for Diabetes Research (DZD e.V.), Dresden, Germany
| |
Collapse
|
|
40
|
Roles of Aldosterone Receptor Antagonists in Heart Failure, Hypertension, and Chronic Kidney Disease. J Nurse Pract 2016. [DOI: 10.1016/j.nurpra.2015.10.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
|
|
41
|
The impacts of obesity on the cardiovascular and renal systems: cascade of events and therapeutic approaches. Curr Hypertens Rep 2016; 17:7. [PMID: 25620635 DOI: 10.1007/s11906-014-0520-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
There is a neglected epidemic of both obesity and metabolic syndrome in industrialized and unindustrialized countries all over the globe. Both conditions are associated with a high incidence of other serious pathologies, such as cardiovascular and renal diseases. In this article, we review the potential underlying mechanisms by which obesity and metabolic syndrome promote hypertension, including changes in cardiovascular-renal physiology induced by leptin, the sympathetic nervous system, the renin-angiotensin-aldosterone system, insulin resistance, free fatty acids, natriuretic peptides, and proinflammatory cytokines. We also discuss the potential underlying mechanisms by which obesity promotes other cardiovascular and renal conditions, as well as available nonpharmacologic and pharmacologic approaches for treating obesity-induced hypertension. The findings presented herein suggest that adipocytes may be a key regulator of cardiovascular and renal function.
Collapse
|
|
42
|
Abstract
In recent years, an increasing number of studies have revealed deleterious effects of aldosterone via the mineralocorticoid receptor (MR). Especially in patients with primary aldosteronism (PA) a significant higher estimated risk of developing cardiovascular comorbidities and comortalities compared to essential hypertensives was reported. As diabetes mellitus and the metabolic syndrome are one of the major contributors to cardiovascular morbidity and mortality their connection to aldosterone excess became a focus of research in PA patients. Several studies assessed the effect of PA on glucose metabolism, the prevalence of diabetes mellitus, and the effect of PA treatment on both revealing different results. Therefore, we performed an extensive literature research. This review focuses on the current knowledge of the connection between aldosterone excess, glucose homeostasis, and diabetes mellitus in patients with PA. We have highlighted this topic from a pro and contra perspective followed by a summarizing concluding remark. Additionally, we have briefly reviewed the data on possible underlying mechanisms and indicated future considerations on the possible impact of cortisol co-secretion in PA.
Collapse
Affiliation(s)
- H Remde
- Clinical Endocrinology, Charité Campus Mitte, Berlin, Germany
| | - G Hanslik
- Clinical Endocrinology, Charité Campus Mitte, Berlin, Germany
| | - N Rayes
- Clinic for Surgery, Campus Virchow, Charité University Medicine Berlin, Berlin, Germany
| | - M Quinkler
- Endocrinology in Charlottenburg, Berlin, Germany
| |
Collapse
|
|
43
|
Hanslik G, Wallaschofski H, Dietz A, Riester A, Reincke M, Allolio B, Lang K, Quack I, Rump LC, Willenberg HS, Beuschlein F, Quinkler M, Hannemann A. Increased prevalence of diabetes mellitus and the metabolic syndrome in patients with primary aldosteronism of the German Conn's Registry. Eur J Endocrinol 2015; 173:665-75. [PMID: 26311088 DOI: 10.1530/eje-15-0450] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 08/26/2015] [Indexed: 12/30/2022]
Abstract
DESIGN Abnormalities in glucose homeostasis have been described in patients with primary aldosteronism (PA) but most studies show inconsistent results. Therefore, we aimed to compare the prevalence of type 2 diabetes mellitus and metabolic syndrome (MetS) in newly diagnosed PA patients to a matched control cohort of the background population. METHODS In total, 305 PA patients of the prospective German Conn's Registry were compared to the population-based Study of Health In Pomerania (SHIP1; n=2454). A 1:1 match regarding sex, age, and BMI resulted in 269 matched pairs regarding type 2 diabetes and 183 matched pairs regarding MetS. Of the total, 153 PA patients underwent oral glucose tolerance testing (OGTT) at diagnosis and 38 PA patients were reevaluated at follow-up. RESULTS Type 2 diabetes and MetS were significantly more frequent in PA patients than in the control population (17.2% vs 10.4%, P=0.03; 56.8% vs 44.8%, P=0.02 respectively). Also, HbA1c levels were higher in PA patients than in controls (P<0.01). Of the total, 35.3% of non-diabetic PA patients showed an abnormal OGTT (¼ newly diagnosed type 2 diabetes and ¾ impaired glucose tolerance). PA patients with an abnormal OGTT at baseline presented with significantly improved 2 h OGTT glucose (P=0.01) at follow-up. We detected a negative correlation between 2 h OGTT glucose levels and serum potassium (P<0.01). CONCLUSIONS Type 2 diabetes and MetS are more prevalent in patients with PA than in controls matched for sex, age, BMI, and blood pressure. This may explain in part the increased cardiovascular disease morbidity and mortality in PA patients.
Collapse
Affiliation(s)
- Gregor Hanslik
- Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany
| | - Henri Wallaschofski
- Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany
| | - Anna Dietz
- Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany
| | - Anna Riester
- Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany
| | - Martin Reincke
- Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany
| | - Bruno Allolio
- Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany
| | - Katharina Lang
- Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany
| | - Ivo Quack
- Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany
| | - Lars C Rump
- Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany
| | - Holger S Willenberg
- Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany
| | - Felix Beuschlein
- Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany
| | - Marcus Quinkler
- Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany
| | - Anke Hannemann
- Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, GermanyInstitute of Clinical Chemistry and Laboratory MedicineUniversity Medicine Greifswald, Greifswald, GermanyMedizinische Klinik und Poliklinik IVEndocrinology and Metabolism, University Hospital Munich, Munich, GermanyEndocrinology and Diabetes UnitDepartment of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, GermanyDepartment of NephrologyMedical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, GermanyDivision of Endocrinology and MetabolismRostock University Medical Center, Rostock, GermanyEndocrinology in CharlottenburgStuttgarter Platz 1, 10627 Berlin, Germany
| |
Collapse
|
|
44
|
Association of Angiotensin Converting Enzyme Insertion-Deletion Polymorphism with Hypertension in Emiratis with Type 2 Diabetes Mellitus and Its Interaction with Obesity Status. DISEASE MARKERS 2015; 2015:536041. [PMID: 26491214 PMCID: PMC4603605 DOI: 10.1155/2015/536041] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 08/12/2015] [Indexed: 01/06/2023]
Abstract
The association of Angiotensin Converting Enzyme (ACE) insertion-deletion (I/D) polymorphism with Type 2 Diabetes Mellitus (T2DM) and hypertension has been extensively studied throughout various ethnic populations but largely with inconsistent findings. We investigated these associations in Emirati population and their interaction with obesity status. Saliva samples were collected from a total of 564 Emiratis (277 T2DM and 297 healthy). DNA was extracted and the samples were genotyped for ACE I/D polymorphism by a PCR based method followed by gel electrophoresis. Upon evaluation of the ACE I/D polymorphism amongst all T2DM, hypertensive patients, and respective controls regardless of obesity status, ACE DD genotype was not found to be associated with either T2DM [odds ratio (OR) = 1.34, p = 0.086] or hypertension [odd ratio (OR) = 1.02, p = 0.93]. When the genetic variants amongst the nonobese and obese population were analyzed separately, the risk genotype ACE DD conferred significantly increased risk of hypertension in nonobese population [odds ratio (OR) = 1.80, p = 0.02] but was found to be protective against the hypertension in the obese group ((OR) = 0.54, p = 0.01). However, there was no effect of obesity status on the association of ACE genotypes with T2DM. The risk of hypertension associated with ACE DD is modulated by obesity status and hence future genetic association studies should take obesity into account for the interpretation of data. We also confirmed that ACE I/D polymorphism is not associated with T2DM risk in Emirati population.
Collapse
|
|
45
|
Aldosterone induces clonal β-cell failure through glucocorticoid receptor. Sci Rep 2015; 5:13215. [PMID: 26287126 PMCID: PMC4541150 DOI: 10.1038/srep13215] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 07/20/2015] [Indexed: 12/21/2022] Open
Abstract
Aldosterone excess causes insulin resistance in peripheral tissues and directly impairs the function of clonal β-cell. The aim of this study was to investigate the molecular mechanisms involved in the aldosterone-induced impairment of clonal β-cells. As expected, aldosterone induced apoptosis and β-cell dysfunction, including impairment of insulin synthesis and secretion, which were reversed by Glucocorticoid receptor (GR) antagonists or GR-specific siRNA. However, mineralocorticoid receptor (MR) antagonists or MR-specific siRNA had no effect on impairment of clonal β-cells induced by aldosterone. Besides, aldosterone significantly decreased expression and activity of MafA, while activated JNK and p38 MAPK in a GR-dependent manner. In addition, JNK inhibitors (SP600125) and/or p38 inhibitors (SB203580) could abolish the effect of aldosterone on MafA expression and activity. Importantly, overexpression of JNK1 or p38 reversed the protective effect of a GR antagonist on the decrease of MafA expression and activity. Furthermore, aldosterone inhibits MafA expression at the transcriptional and post-transcriptional level through activation of JNK and p38, respectively. Consequently, overexpression of MafA increased synthesis and secretion of insulin, and decreased apoptosis in clonal β-cells exposed to aldosterone. These findings identified aldosterone as an inducer of clonal β-cell failure that operates through the GR-MAPK-MafA signaling pathway.
Collapse
|
|
46
|
Lasheen NN. Pancreatic functions in high salt fed female rats. Physiol Rep 2015; 3:e12443. [PMID: 26216433 PMCID: PMC4552525 DOI: 10.14814/phy2.12443] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 05/22/2015] [Accepted: 05/28/2015] [Indexed: 02/07/2023] Open
Abstract
Salt consumption has been increased worldwide and the association of high salt diets with enhanced inflammation and target organ damage was reported. Little data were available about the effect of high salt diet on exocrine function of pancreas, while the relation between high salt intake and insulin sensitivity was controversial. This study was designed to investigate the effect of high salt diet on exocrine and endocrine pancreatic functions, and to elucidate the possible underlying mechanism(s). Twenty adult female Wistar rats were randomly divided into two groups; control group; fed standard rodent diet containing 0.3% NaCl, and high salt fed group; fed 8% NaCl for 8 weeks. On the day of sacrifice, rats were anesthized by i.p. pentobarbitone (40 μg/kg B.W.). Nasoanal length was measured and fasting blood glucose was determined from rat tail. Blood samples were obtained from abdominal aorta for determination of plasma sodium, potassium, amylase, lipase, aldosterone, insulin, transforming growth factor-β (TGF-β1), and interleukin 6 (IL6). Pancreata of both groups were histologically studied. Compared to control group, 8-week high salt fed group showed: significant elevation in body weight, body mass index, Lee index, plasma sodium, TGF-β1 and IL6, however, plasma aldosterone, amylase, lipase, and insulin levels were significantly decreased. A nonsignificant increase in plasma potassium and nonsignificant changes in fasting blood glucose and HOMA-IR were detected between groups. Pancreatic fibrosis was observed in test group. High salt diet for 8 weeks caused pancreatic fibrosis evidenced by decline of both exocrine and endocrine functions of pancreas in Wistar rats.
Collapse
Affiliation(s)
- Noha N Lasheen
- Physiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| |
Collapse
|
|
47
|
Even SEL, Dulak-Lis MG, Touyz RM, Nguyen Dinh Cat A. Crosstalk between adipose tissue and blood vessels in cardiometabolic syndrome: implication of steroid hormone receptors (MR/GR). Horm Mol Biol Clin Investig 2015; 19:89-101. [PMID: 25390018 DOI: 10.1515/hmbci-2014-0013] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 08/06/2014] [Indexed: 11/15/2022]
Abstract
Crosstalk between adipose tissue and blood vessels is vital to vascular homeostasis and is disturbed in cardiovascular and metabolic diseases such as hypertension, diabetes and obesity. Cardiometabolic syndrome (CMS) refers to the clustering of obesity-related metabolic disorders such as insulin resistance, glucose and lipid profile alterations, hypertension and cardiovascular diseases. Mechanisms underlying these associations remain unclear. Adipose tissue associated with the vasculature [known as perivascular adipose tissue (PVAT)] has been shown to produce myriads of adipose tissue-derived substances called adipokines, including hormones, cytokines and reactive oxygen species (ROS), which actively participate in the regulation of vascular function and local inflammation by endocrine and/or paracrine mechanisms. As a result, the signaling from PVAT to the vasculature is emerging as a potential therapeutic target for obesity and diabetes-related vascular dysfunction. Accumulating evidence supports a shift in our understanding of the crucial role of elevated plasma levels of aldosterone in obesity, promoting insulin resistance and hypertension. In obesity, aldosterone/mineralocorticoid receptor (MR) signaling induces an abnormal secretion of adipokines, ROS production and systemic inflammation, which in turn contribute to impaired insulin signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular abnormalities. Thus, aldosterone excess exerts detrimental metabolic and vascular effects that participate to the development of the CMS and its associated cardiovascular abnormalities. In this review, we focus on the physiopathological roles of corticosteroid receptors in the interplay between PVAT and the vasculature, which underlies their potential as key regulators of vascular function.
Collapse
|
|
48
|
Kim HW, Lee DH, Lee SA, Koh G. A relationship between serum potassium concentration and insulin resistance in patients with type 2 diabetes mellitus. Int Urol Nephrol 2015; 47:991-9. [PMID: 25966806 DOI: 10.1007/s11255-015-1001-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Accepted: 04/26/2015] [Indexed: 02/06/2023]
Abstract
PURPOSE In patients with type 2 diabetes mellitus (DM), insulin-stimulated glucose uptake is impaired. However, the relationship between serum potassium concentration and insulin resistance is poorly defined. This study aimed to investigate the association between serum potassium concentration and insulin resistance in these patients. METHODS Between April 2009 and October 2012, 180 patients with type 2 DM were analyzed. Insulin resistance was estimated using the homeostasis model and assessment (HOMA) index; resistance was defined as an index value of >2. The association between serum potassium concentration and insulin resistance was analyzed using linear regression methods. The incidence of hyperkalemia was also evaluated during follow-up. RESULTS Mean serum potassium concentration was 4.12 ± 0.47 mEq/l. The median HOMA index score was 2.1 (interquartile range 1.1-3.4). When the patients were compared based on insulin resistance, serum potassium concentration was higher in the patients with insulin resistance compared with the patients without (4.25 ± 0.48 vs. 4.09 ± 0.44 mEq/l, p = 0.015). The variables found to be the determinants of serum potassium concentration included female, renal function, serum sodium level, log aldosterone-to-plasma renin activity ratio, glycosylated hemoglobin, and log HOMA index. Over a mean follow-up period of 2.6 ± 1.1 years, 37 of 180 patients (21 %) experienced episodic hyperkalemia. Patients with insulin resistance experienced episodic hyperkalemia more frequently than those without. CONCLUSIONS Serum potassium concentration is likely to be increased in the patients with poorly controlled type 2 DM with insulin resistance than in those without insulin resistance.
Collapse
Affiliation(s)
- Hyun Woo Kim
- Department of Internal Medicine, Jeju National University School of Medicine, 102 Jejudaehakno, Jeju City, Jeju, 690-756, Republic of Korea,
| | | | | | | |
Collapse
|
|
49
|
The necessity and effectiveness of mineralocorticoid receptor antagonist in the treatment of diabetic nephropathy. Hypertens Res 2015; 38:367-74. [PMID: 25762415 DOI: 10.1038/hr.2015.19] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 12/06/2014] [Accepted: 12/31/2014] [Indexed: 02/06/2023]
Abstract
Diabetes mellitus is a major cause of chronic kidney disease (CKD), and diabetic nephropathy is the most common primary disease necessitating dialysis treatment in the world including Japan. Major guidelines for treatment of hypertension in Japan, the United States and Europe recommend the use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, which suppress the renin-angiotensin system (RAS), as the antihypertensive drugs of first choice in patients with coexisting diabetes. However, even with the administration of RAS inhibitors, failure to achieve adequate anti-albuminuric, renoprotective effects and a reduction in cardiovascular events has also been reported. Inadequate blockade of aldosterone may be one of the reasons why long-term administration of RAS inhibitors may not be sufficiently effective in patients with diabetic nephropathy. This review focuses on treatment in diabetic nephropathy and discusses the significance of aldosterone blockade. In pre-nephropathy without overt nephropathy, a mineralocorticoid receptor antagonist can be used to enhance the blood pressure-lowering effects of RAS inhibitors, improve insulin resistance and prevent clinical progression of nephropathy. In CKD categories A2 and A3, the addition of a mineralocorticoid receptor antagonist to an RAS inhibitor can help to maintain 'long-term' antiproteinuric and anti-albuminuric effects. However, in category G3a and higher, sufficient attention must be paid to hyperkalemia. Mineralocorticoid receptor antagonists are not currently recommended as standard treatment in diabetic nephropathy. However, many studies have shown promise of better renoprotective effects if mineralocorticoid receptor antagonists are appropriately used.
Collapse
|
|
50
|
Heer M, Egert S. Nutrients other than carbohydrates: their effects on glucose homeostasis in humans. Diabetes Metab Res Rev 2015; 31:14-35. [PMID: 24510463 DOI: 10.1002/dmrr.2533] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Revised: 01/30/2014] [Accepted: 02/02/2014] [Indexed: 02/06/2023]
Abstract
Besides carbohydrates, other nutrients, such as dietary protein and amino acids; the supply of fat, vitamin D, and vitamin K; and sodium intake seem to affect glucose homeostasis. Although their effect is less pronounced than that of the amount and composition of carbohydrates, it seems reasonable to consider how nutrient intake habits may be modified to support an improved glucose homeostasis. For instance, taking into account the effect of some nutrients to lower blood glucose concentration on a day-by-day basis might support improvement of glucose homeostasis in the long run. On the other hand, lowering sodium intake too much, as recommended to avoid the development of hypertension, particularly in sodium-sensitive people, might lead to insulin resistance and thereby might risk increasing fasting as well as postprandial blood glucose concentrations. This review summarizes the state of our knowledge of how several nutrients other than carbohydrates, such as protein, fatty acids, vitamin D, vitamin K, magnesium, zinc, chromium, and sodium, affect blood glucose concentrations. Sufficient evidence exists to show that, in prospective studies based on randomized controlled trials, these selected nutrients affect blood glucose regulation. The review describes potential mechanisms leading to the observed effect. As much as is possible from the available data, the extent of the effect, is considered.
Collapse
|