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1
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Hua X, Liu Y, Xiao X. Association between lipid accumulation product and chronic obstructive pulmonary disease: a cross-sectional study based on U.S. adults. Front Nutr 2025; 11:1517108. [PMID: 39867561 PMCID: PMC11757112 DOI: 10.3389/fnut.2024.1517108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 12/23/2024] [Indexed: 01/28/2025] Open
Abstract
Background Lipid Accumulation Product (LAP), which is derived from measurements of waist circumference and triglyceride (TG) levels, serves as a comprehensive indicator of lipid accumulation. Emerging research indicates that lipid accumulation dysfunction might significantly contribute to the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Nevertheless, the investigation into the association between LAP and COPD risk is still insufficient, particularly in population-based research. This research intends to examine the possible correlation between LAP and the likelihood of developing COPD. Methods This study, designed as a cross-sectional analysis, made use of data gathered from the National Health and Nutrition Examination Survey (NHANES) spanning the years 2017 to 2020, encompassing a total of 7,113 eligible participants. LAP, the exposure variable, was calculated using waist circumference and triglyceride concentration. COPD diagnosis was determined using participants' self-reported information. To explore the association between LAP and COPD, multivariate logistic regression models were applied, and smoothing curve fitting was employed to examine any potential nonlinear patterns. Further analysis included stratified subgroup evaluations to assess how variables such as sex, smoking habits, and alcohol intake might impact the relationship between LAP and COPD. Results The findings indicated a significant increase in COPD risk with each one-unit rise in ln LAP, as evidenced by an Odds Ratio (OR) of 1.16 [95% Confidence Interval (CI): 1.04-1.30, p < 0.01]. Furthermore, a quartile-based analysis revealed that individuals in the highest ln LAP category had a considerably higher likelihood of developing COPD compared to those in the lowest category, with an OR of 1.35 (95% CI: 1.04-1.75, P for trend <0.01). Furthermore, the smoothing curve fitting identified a nonlinear and positive association between ln LAP and COPD, suggesting a steeper increase in risk as ln LAP values rise. Subgroup analysis suggested that this association remained fairly consistent across various demographic groups. Conclusion This study found a significant link between higher LAP levels and an elevated risk of COPD, with the association displaying a nonlinear pattern. As a marker of lipid accumulation abnormalities, LAP may serve as a valuable tool for assessing COPD risk and could inform strategies for early identification and targeted clinical management.
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Affiliation(s)
- Xingshi Hua
- Liaoning University of Traditional Chinese Medicine, Shenyang, China
- Liaoning University of Traditional Chinese Medicine Affiliated Second Hospital, Shenyang, China
| | - Ying Liu
- Liaoning University of Traditional Chinese Medicine, Shenyang, China
- Department of Pathology, The First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Xiaoyu Xiao
- Liaoning University of Traditional Chinese Medicine, Shenyang, China
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Piedepalumbo FV, Motos A, Blasi F, Torres A. Safety of steroids in severe community-acquired pneumonia. Eur Respir Rev 2025; 34:240131. [PMID: 39778921 PMCID: PMC11707601 DOI: 10.1183/16000617.0131-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 11/05/2024] [Indexed: 01/11/2025] Open
Abstract
The systemic use of corticosteroids for patients with severe community-acquired pneumonia (sCAP) remains controversial in clinical practice, particularly in terms of the safety profile of these drugs. This narrative review aims to analyse the available literature data concerning the safety of short-term steroid use in the treatment of sCAP, while also highlighting potential future research directions. Several trials and meta-analyses have evaluated corticosteroid therapy as an adjuvant treatment for sCAP, yielding heterogeneous results regarding its efficacy and safety. Despite the wide variability in results, it is generally accepted that steroids are not associated with a significant risk of healthcare-associated infections, gastrointestinal bleeding or acute kidney injury in patients with sCAP in the short term. Nevertheless, such drugs are linked to hyperglycaemia, necessitating regular monitoring and appropriate management. The influence of steroids on long-term outcomes and their potential risks in viral sCAP still needs to be investigated.
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Affiliation(s)
- Federica Viola Piedepalumbo
- Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli studi di Milano, Milan, Italy
- These authors contributed equally to this work
| | - Ana Motos
- Hospital Clínic, Cellex Laboratory, CIBERES (Center for Networked Biomedical Research Respiratory Diseases, 06/06/0028), FCRB-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), School of Medicine, University of Barcelona, Barcelona, Spain
- Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Université, Nantes, France
- These authors contributed equally to this work
| | - Francesco Blasi
- Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli studi di Milano, Milan, Italy
| | - Antoni Torres
- Hospital Clínic, Cellex Laboratory, CIBERES (Center for Networked Biomedical Research Respiratory Diseases, 06/06/0028), FCRB-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), School of Medicine, University of Barcelona, Barcelona, Spain
- Respiratory Intensive Care Unit, Pneumology Department, Hospital Clínic, Barcelona, Spain
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3
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Iliou A, Argyropoulou OD, Palamidas DA, Karagiannakou M, Benaki D, Tsezou KI, Vlachoyiannopoulos PG, Mikros E, Tzioufas AG. NMR-based metabolomics in giant cell arteritis and polymyalgia rheumatica sequential sera differentiates active and inactive disease. Rheumatology (Oxford) 2024; 63:3360-3369. [PMID: 37935429 DOI: 10.1093/rheumatology/kead590] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 09/28/2023] [Accepted: 10/24/2023] [Indexed: 11/09/2023] Open
Abstract
OBJECTIVES GCA is an inflammatory disease following a chronic, relapsing course. The metabolic alterations related to the intense inflammatory process during the active phase and the rapid impact of steroid treatment remain unknown. This study aims to investigate the serum metabolome in active and inactive disease states. METHODS A total of 110 serum samples from 50 patients (33 GCA and 17 PMR) at three time points-0 (V1: active disease), 1 and 6 months (V2 and V3: remission)-of treatment with glucocorticoids (GCs) were subjected to NMR-based metabolomic analysis. Multi- and univariate statistical analyses were utilized to unveil metabolome alterations following treatment. RESULTS Distinct metabolic profiles were identified between activity and remission, independent of disease type. N-acetylglycoproteins and cholines of bound phospholipids emerged as predictive markers of disease activity. Altered levels of 4 of the 21 small molecules were also observed, including increased levels of phenylalanine and decreased glutamine, alanine and creatinine in active disease. Metabolic fingerprinting discriminated GCA from PMR in remission. GCA and PMR patients exhibited characteristic lipid alterations as a response and/or adverse effect of GC treatment. Correlation analysis showed that several identified biomarkers were further associated with acute phase reactants, CRP and ESR. CONCLUSION The NMR profile of serum metabolome could identify and propose sensitive biomarkers of inflammation. Metabolome alterations, following GC treatment, could provide predictors for future steroid-induced side effects.
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Affiliation(s)
- Aikaterini Iliou
- Department of Pharmaceutical Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Ourania D Argyropoulou
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitris-Anastasios Palamidas
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Research Institute for Systemic Autoimmune Rheumatic Diseases (RISARD), Athens, Greece
| | - Marianna Karagiannakou
- Department of Pharmaceutical Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitra Benaki
- Department of Pharmaceutical Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantina-Ismini Tsezou
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Pharmagnose S.A., Inofyta, Greece
| | - Panayiotis G Vlachoyiannopoulos
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Research Institute for Systemic Autoimmune Rheumatic Diseases (RISARD), Athens, Greece
| | - Emmanuel Mikros
- Department of Pharmaceutical Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
- Pharmagnose S.A., Inofyta, Greece
- Pharma - Informatics Unit, Athena Research and Innovation Center in Information Communication & Knowledge Technologies, Marousi, Greece
| | - Athanasios G Tzioufas
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Research Institute for Systemic Autoimmune Rheumatic Diseases (RISARD), Athens, Greece
- Center of Stratified Medicine in Autoimmune and Rheumatic Diseases, Biomedical Research Foundation Academy of Athens, Athens, Greece
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Manning JE, Harris E, Mathieson H, Sorensen L, Luqmani R, McGettrick HM, Morgan AW, Young SP, Mackie SL. Polymyalgia rheumatica shows metabolomic alterations that are further altered by glucocorticoid treatment: Identification of metabolic correlates of fatigue. J Autoimmun 2024; 147:103260. [PMID: 38797046 DOI: 10.1016/j.jaut.2024.103260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 04/17/2024] [Accepted: 05/21/2024] [Indexed: 05/29/2024]
Abstract
OBJECTIVE In polymyalgia rheumatica (PMR), glucocorticoids (GCs) relieve pain and stiffness, but fatigue may persist. We aimed to explore the effect of disease, GCs and PMR symptoms in the metabolite signatures of peripheral blood from patients with PMR or the related disease, giant cell arteritis (GCA). METHODS Nuclear magnetic resonance spectroscopy was performed on serum from 40 patients with untreated PMR, 84 with new-onset confirmed GCA, and 53 with suspected GCA who later were clinically confirmed non-GCA, and 39 age-matched controls. Further samples from PMR patients were taken one and six months into glucocorticoid therapy to explore relationship of metabolites to persistent fatigue. 100 metabolites were identified using Chenomx and statistical analysis performed in SIMCA-P to examine the relationship between metabolic profiles and, disease, GC treatment or symptoms. RESULTS The metabolite signature of patients with PMR and GCA differed from that of age-matched non-inflammatory controls (R2 > 0.7). There was a smaller separation between patients with clinically confirmed GCA and those with suspected GCA who later were clinically confirmed non-GCA (R2 = 0.135). In PMR, metabolite signatures were further altered with glucocorticoid treatment (R2 = 0.42) but did not return to that seen in controls. Metabolites correlated with CRP, pain, stiffness, and fatigue (R2 ≥ 0.39). CRP, pain, and stiffness declined with treatment and were associated with 3-hydroxybutyrate and acetoacetate, but fatigue did not. Metabolites differentiated patients with high and low fatigue both before and after treatment (R2 > 0.9). Low serum glutamine was predictive of high fatigue at both time points (0.79-fold change). CONCLUSION PMR and GCA alter the metabolite signature. In PMR, this is further altered by glucocorticoid therapy. Treatment-induced metabolite changes were linked to measures of inflammation (CRP, pain and stiffness), but not to fatigue. Furthermore, metabolite signatures distinguished patients with high or low fatigue.
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Affiliation(s)
- Julia E Manning
- Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15-2TT, UK.
| | - Emma Harris
- School of Medicine, University of Leeds, Leeds, LS7 4SA, UK and School of Human and Health Sciences, University of Huddersfield, Huddersfield, UK.
| | - Hannah Mathieson
- School of Medicine, University of Leeds, Leeds, LS7 4SA, UK and Leeds NIHR Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
| | - Louise Sorensen
- School of Medicine, University of Leeds, Leeds, LS7 4SA, UK.
| | - Raashid Luqmani
- NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK.
| | - Helen M McGettrick
- Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15-2TT, UK.
| | - Ann W Morgan
- School of Medicine, University of Leeds, Leeds, School of Human and Health Sciences, University of Huddersfield, Huddersfield, And Leeds NIHR Medtech and in Vitro Diagnostics Co-operative, Leeds Teaching Hospitals NHS Trust, Leeds, LS7 4SA, UK.
| | - Stephen P Young
- Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15-2TT, UK.
| | - Sarah L Mackie
- School of Medicine, University of Leeds, Leeds, LS7 4SA, UK and School of Human and Health Sciences, University of Huddersfield, Huddersfield, UK.
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Cure O, Kizilkaya B, Ciftel S, Mercantepe F. The Effect of Anti-Tumor Necrosis Factor Therapy on The Plasma Atherogenic Index in Rheumatic Diseases. Metab Syndr Relat Disord 2024; 22:269-275. [PMID: 38252497 DOI: 10.1089/met.2023.0237] [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] [Indexed: 01/24/2024] Open
Abstract
Background: The risk of atherosclerosis is increased in individuals with rheumatological disease. The objective of this study is to examine the heightened susceptibility to atherosclerosis in persons afflicted with rheumatological disorders. This study aimed to assess the impact of anti-tumor necrosis factor (anti-TNF) medication on the plasma atherogenic index (PAI) in persons diagnosed with rheumatological disease. Methods: This study used a retrospective cross-sectional design to investigate a cohort of 136 patients with rheumatological disease who were undergoing anti-TNF therapy (Group 1), as well as a comparison group of 117 patients getting conventional therapy (Group 2). Measurements of PAI were conducted at the initial baseline and again at the sixth month of treatment. Results: Initially, there was no statistically significant disparity observed in PAI values between the two cohorts. After a period of 6 months, a notable reduction in PAI was identified in the group receiving anti-TNF medication (P = 0.01), while no significant alteration was detected in the group receiving conventional treatment. Conclusion: It provides findings showing that anti-TNF therapy can reduce the PAI in individuals with rheumatological disease. This may indicate a potential cardiovascular protective effect of anti-TNF therapy.
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Affiliation(s)
- Osman Cure
- Department of Rheumatology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
| | - Bayram Kizilkaya
- Department of Internal Medicine, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
| | - Serpil Ciftel
- Department of Endocrinology and Metabolism, Erzurum Regional Training and Research Hospital, Erzurum, Turkey
| | - Filiz Mercantepe
- Department of Endocrinology and Metabolism, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
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Pofi R, Caratti G, Ray DW, Tomlinson JW. Treating the Side Effects of Exogenous Glucocorticoids; Can We Separate the Good From the Bad? Endocr Rev 2023; 44:975-1011. [PMID: 37253115 PMCID: PMC10638606 DOI: 10.1210/endrev/bnad016] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/25/2023] [Accepted: 05/26/2023] [Indexed: 06/01/2023]
Abstract
It is estimated that 2% to 3% of the population are currently prescribed systemic or topical glucocorticoid treatment. The potent anti-inflammatory action of glucocorticoids to deliver therapeutic benefit is not in doubt. However, the side effects associated with their use, including central weight gain, hypertension, insulin resistance, type 2 diabetes (T2D), and osteoporosis, often collectively termed iatrogenic Cushing's syndrome, are associated with a significant health and economic burden. The precise cellular mechanisms underpinning the differential action of glucocorticoids to drive the desirable and undesirable effects are still not completely understood. Faced with the unmet clinical need to limit glucocorticoid-induced adverse effects alongside ensuring the preservation of anti-inflammatory actions, several strategies have been pursued. The coprescription of existing licensed drugs to treat incident adverse effects can be effective, but data examining the prevention of adverse effects are limited. Novel selective glucocorticoid receptor agonists and selective glucocorticoid receptor modulators have been designed that aim to specifically and selectively activate anti-inflammatory responses based upon their interaction with the glucocorticoid receptor. Several of these compounds are currently in clinical trials to evaluate their efficacy. More recently, strategies exploiting tissue-specific glucocorticoid metabolism through the isoforms of 11β-hydroxysteroid dehydrogenase has shown early potential, although data from clinical trials are limited. The aim of any treatment is to maximize benefit while minimizing risk, and within this review we define the adverse effect profile associated with glucocorticoid use and evaluate current and developing strategies that aim to limit side effects but preserve desirable therapeutic efficacy.
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Affiliation(s)
- Riccardo Pofi
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
| | - Giorgio Caratti
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
| | - David W Ray
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK
- Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford OX37LE, UK
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
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Sikorski P, Li Y, Cheema M, Wolfe GI, Kusner LL, Aban I, Kaminski HJ. Serum metabolomics of treatment response in myasthenia gravis. PLoS One 2023; 18:e0287654. [PMID: 37816000 PMCID: PMC10564178 DOI: 10.1371/journal.pone.0287654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 06/09/2023] [Indexed: 10/12/2023] Open
Abstract
OBJECTIVE High-dose prednisone use, lasting several months or longer, is the primary initial therapy for myasthenia gravis (MG). Upwards of a third of patients do not respond to treatment. Currently no biomarkers can predict clinical responsiveness to corticosteroid treatment. We conducted a discovery-based study to identify treatment responsive biomarkers in MG using sera obtained at study entry to the thymectomy clinical trial (MGTX), an NIH-sponsored randomized, controlled study of thymectomy plus prednisone versus prednisone alone. METHODS We applied ultra-performance liquid chromatography coupled with electro-spray quadrupole time of flight mass spectrometry to obtain comparative serum metabolomic and lipidomic profiles at study entry to correlate with treatment response at 6 months. Treatment response was assessed using validated outcome measures of minimal manifestation status (MMS), MG-Activities of Daily Living (MG-ADL), Quantitative MG (QMG) score, or a strictly defined composite measure of response. RESULTS Increased serum levels of phospholipids were associated with treatment response as assessed by QMG, MMS, and the Responders classification, but all measures showed limited overlap in metabolomic profiles, in particular the MG-ADL. A panel including histidine, free fatty acid (13:0), γ-cholestenol and guanosine was highly predictive of the strictly defined treatment response measure. The AUC in Responders' prediction for these markers was 0.90 irrespective of gender, age, thymectomy or baseline prednisone use. Pathway analysis suggests that xenobiotic metabolism could play a major role in treatment resistance. There was no association with outcome and gender, age, thymectomy or baseline prednisone use. INTERPRETATION We have defined a metabolomic and lipidomic profile that can now undergo validation as a treatment predictive marker for MG patients undergoing corticosteroid therapy. Metabolomic profiles of outcome measures had limited overlap consistent with their assessing distinct aspects of treatment response and supporting unique biological underpinning for each outcome measure. Interindividual variation in prednisone metabolism may be a determinate of how well patients respond to treatment.
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Affiliation(s)
- Patricia Sikorski
- Department of Neurology & Rehabilitation Medicine, George Washington University, Washington, DC, United States of America
- Department of Pharmacology & Physiology, George Washington University, Washington, DC, United States of America
| | - Yaoxiang Li
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Mehar Cheema
- Department of Neurology & Rehabilitation Medicine, George Washington University, Washington, DC, United States of America
| | - Gil I. Wolfe
- Department of Neurology, University at Buffalo/SUNY, Buffalo, New York, United States of America
| | - Linda L. Kusner
- Department of Pharmacology & Physiology, George Washington University, Washington, DC, United States of America
| | - Inmaculada Aban
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Henry J. Kaminski
- Department of Neurology & Rehabilitation Medicine, George Washington University, Washington, DC, United States of America
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Hellmann PH, Bagger JI, Carlander KR, Hansen KB, Forman JL, Størling J, Chabanova E, Holst J, Vilsbøll T, Knop FK. No effect of the turmeric root phenol curcumin on prednisolone-induced glucometabolic perturbations in men with overweight or obesity. Endocr Connect 2023; 12:EC-22-0334. [PMID: 36800259 PMCID: PMC10083679 DOI: 10.1530/ec-22-0334] [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: 01/22/2023] [Accepted: 02/17/2023] [Indexed: 02/18/2023]
Abstract
OBJECTIVES Preclinically, curcumin has been shown to protect against glucocorticoid-induced insulin resistance. We evaluated the effect of curcumin administered with prednisolone in healthy overweight or obese men. METHODS In a double-blind, parallel-group trial, 24 overweight/obese non-diabetic men were randomised to one of three intervention groups (A) prednisolone placebo+curcumin placebo, (B) prednisolone (50 mg/day)+curcumin placebo or (C) prednisolone and curcumin (400 mg/day). Curcumin or curcumin placebo treatment started 1 day prior to 10-day prednisolone or prednisolone placebo treatment. The primary endpoint was change in prednisolone-induced insulin resistance assessed by homeostatic model assessment of insulin resistance (HOMA2-IR). Other endpoints included anthropometric measurements, magnetic resonance spectroscopy-assessed hepatic fat content, blood pressure, circulating metabolic markers and continuous glucose monitoring measures. RESULTS Baseline characteristics (mean ± s.d): age 44.2 ± 13.7 years, BMI 30.1 ± 3.5 kg/m2, HbAlc 33.3 ± 3.2 mmol/mol, HOMA2-IR 1.10 ± 0.45 and fasting plasma glucose 5.2 ± 0.4 mmol/L. Prednisolone significantly increased HOMA2-IR (estimated treatment difference 0.36 (95% CI 0.16; 0.57)). Co-treatment with curcumin had no effect on HOMA2-IR (estimated treatment difference 0.08 (95% CI -0.13; 0.39)). Prednisolone increased HbAlc, insulin, C-peptide, glucagon, blood pressure, mean interstitial glucose, time spent in hyperglycaemia and glucose variability, but no protective effect of curcumin on any of these measures was observed. CONCLUSIONS In this double-blind, placebo-controlled parallel-group study involving 24 overweight or obese men randomised to one of three treatment arms, curcumin treatment had no protective effect on prednisolone-induced insulin resistance or other glucometabolic perturbations.
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Affiliation(s)
- Pernille H Hellmann
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jonatan I Bagger
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Katrine R Carlander
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Katrine B Hansen
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Julie L Forman
- Section of Biostatistics, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Joachim Størling
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Elizaveta Chabanova
- Department of Radiology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Jens Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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9
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Fleeman L, Barrett R. Cushing Syndrome and Other Causes of Insulin Resistance in Dogs. Vet Clin North Am Small Anim Pract 2023; 53:711-730. [PMID: 36898861 DOI: 10.1016/j.cvsm.2023.01.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/10/2023]
Abstract
The most common causes of insulin resistance in diabetic dogs are Cushing syndrome, diestrus, and obesity. Cushing-associated effects include insulin resistance, excessive postprandial hyperglycemia, perceived short duration of insulin action, and/or substantial within-day and/or day-to-day glycemic variability. Successful strategies to manage excessive glycemic variability include basal insulin monotherapy and combined basal-bolus insulin treatment. Ovariohysterectomy and insulin treatment can achieve diabetic remission in about 10% of cases of diestrus diabetes. Different causes of insulin resistance have an additive effect on insulin requirements and the risk of progression to clinical diabetes in dogs.
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Affiliation(s)
- Linda Fleeman
- Animal Diabetes Australia, 5 Hood Street, Collingwood, Victoria 3066, Australia.
| | - Renea Barrett
- Animal Diabetes Australia, 5 Hood Street, Collingwood, Victoria 3066, Australia
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10
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Kulkarni S, Durham H, Glover L, Ather O, Phillips V, Nemes S, Cousens L, Blomgran P, Ambery P. Metabolic adverse events associated with systemic corticosteroid therapy-a systematic review and meta-analysis. BMJ Open 2022; 12:e061476. [PMID: 36549729 PMCID: PMC9772659 DOI: 10.1136/bmjopen-2022-061476] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES To assess the risk of new-onset or worsening hyperglycaemia, hypertension, weight gain and hyperlipidaemia with systemic corticosteroid therapy (CST) as reported in published randomised control trial (RCT) studies. DATA SOURCES Literature search using MEDLINE, EMBASE, Cochrane library, Web of Science and Scopus STUDY ELIGIBILITY CRITERIA: Published articles on results of RCT with a systemic CST arm with numerical data presented on adverse effect (AE). PARTICIPANTS AND INTERVENTIONS Reports of hyperglycaemia, hypertension, weight gain and hyperlipidaemia associated with systemic CST in patients or healthy volunteer's ≥17 years of age. STUDY APPRAISAL METHODS Risk of bias tool, assessment at the level of AE and key study characteristics. RESULTS A total of 5446 articles were screened to include 118 studies with 152 systemic CST arms (total participants=17 113 among which 8569 participants treated with CST). Pooled prevalence of hyperglycaemia in the CST arms within the studies was 10% (95% CI 7% to 14%), with the highest prevalence in respiratory illnesses at 22% (95% CI 9% to 35%). Pooled prevalence of severe hyperglycaemia, hypertension, weight gain and hyperlipidaemia within the corticosteroid arms was 5% (95% CI 2% to 9%), 6% (95% CI 4% to 8%), 13% (95% CI 8% to 18%), 8% (95% CI 4% to 17%), respectively. CST was significantly associated hyperglycaemia, hypertension and weight gain as noted in double-blinded placebo-controlled parallel-arms studies: OR of 2.13 (95% CI 1.66 to 2.72), 1.68 (95% CI 0.96 to 2.95) and 5.20 (95% CI 2.10 to 12.90), respectively. Intravenous therapy posed higher risk than oral therapy: OR of 2.39 (95% CI 1.16 to 4.91). LIMITATIONS There was significant heterogeneity in the AE definitions and quality of AE reporting in the primary studies and patient populations in the studies. The impact of cumulative dose effect on incidental AE could not be calculated. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS Systemic CST use is associated with increased risk of metabolic AEs, which differs for each disease group and route of administration. PROSPERO REGISTRATION NUMBER CRD42020161270.
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Affiliation(s)
- Spoorthy Kulkarni
- Clinical Pharmacology and Therapeutics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Hannah Durham
- Department of Urology, Imperial College Healthcare NHS Trust, London, UK
| | - Luke Glover
- Department of Medicine, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
| | - Osaid Ather
- Structural & Chemical Biology, The Francis Crick Institute, London, UK
| | - Veronica Phillips
- Medical Library, School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Szilard Nemes
- Data Science & AI, R&D BioPharmaceuticals, AstraZeneca, Gothenburg, Sweden
| | - Leslie Cousens
- Respiratory & Immunology, AstraZeneca R&D Boston, Waltham, Massachusetts, USA
| | - Parmis Blomgran
- Early Respiratory & Immunology, AstraZeneca R&D Gothenburg, Mölndal, Sweden
| | - Philip Ambery
- Late CVRM Research, AstraZeneca R&D Gothenburg, Mölndal, Sweden
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11
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Blonde L, Umpierrez GE, Reddy SS, McGill JB, Berga SL, Bush M, Chandrasekaran S, DeFronzo RA, Einhorn D, Galindo RJ, Gardner TW, Garg R, Garvey WT, Hirsch IB, Hurley DL, Izuora K, Kosiborod M, Olson D, Patel SB, Pop-Busui R, Sadhu AR, Samson SL, Stec C, Tamborlane WV, Tuttle KR, Twining C, Vella A, Vellanki P, Weber SL. American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. Endocr Pract 2022; 28:923-1049. [PMID: 35963508 PMCID: PMC10200071 DOI: 10.1016/j.eprac.2022.08.002] [Citation(s) in RCA: 221] [Impact Index Per Article: 73.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.
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Affiliation(s)
| | | | - S Sethu Reddy
- Central Michigan University, Mount Pleasant, Michigan
| | | | | | | | | | | | - Daniel Einhorn
- Scripps Whittier Diabetes Institute, La Jolla, California
| | | | | | - Rajesh Garg
- Lundquist Institute/Harbor-UCLA Medical Center, Torrance, California
| | | | | | | | | | | | - Darin Olson
- Colorado Mountain Medical, LLC, Avon, Colorado
| | | | | | - Archana R Sadhu
- Houston Methodist; Weill Cornell Medicine; Texas A&M College of Medicine; Houston, Texas
| | | | - Carla Stec
- American Association of Clinical Endocrinology, Jacksonville, Florida
| | | | - Katherine R Tuttle
- University of Washington and Providence Health Care, Seattle and Spokane, Washington
| | | | | | | | - Sandra L Weber
- University of South Carolina School of Medicine-Greenville, Prisma Health System, Greenville, South Carolina
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12
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dos Santos C, Karagiannopoulos A, Rafacho A, Perfilyev A, Eliasson L, Ling C, Bacos K. Glucocorticoids and glucolipotoxicity alter the DNA methylome and function of human EndoC-βH1 cells. Life Sci 2022; 307:120854. [DOI: 10.1016/j.lfs.2022.120854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/20/2022] [Accepted: 07/27/2022] [Indexed: 10/16/2022]
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13
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Wang CR, Tsai HW. Immediate-release tofacitinib reduces insulin resistance in non-diabetic active rheumatoid arthritis patients: A single-center retrospective study. World J Diabetes 2022; 13:454-465. [PMID: 35800413 PMCID: PMC9210542 DOI: 10.4239/wjd.v13.i6.454] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 04/18/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND An increased risk of insulin resistance (IR) has been identified in rheumatoid arthritis (RA), a chronic inflammatory disorder with elevated levels of pathogenic cytokines. Biologics targeting proinflammatory cytokines can control the disease and improve insulin sensitivity in RA. Although Janus kinase (JAK) signaling can regulate cytokine receptors and participate in RA pathogenesis, it remains to be elucidated whether there is a reduction of IR in such patients under JAK inhibitor (JAKi) therapy.
AIM To study the effect of JAKi treatment on the reduction of IR in RA patients with active disease.
METHODS A retrospective study was carried out from April 1, 2017 to March 31, 2021 in a population of non-diabetic patients with active RA who were undergoing tofacitinib (TOF) therapy with 5 mg twice-daily immediate-release formulation.
RESULTS Fifty-six RA patients, aged 30 years to 75 years (mean ± SD: 52.3 ± 11.1) with disease activity score 28 values ranging from 4.54 to 7.37 (5.82 ± 0.74), were classified into high-IR (> 2.0) and low-IR (≤ 2.0) groups based on their baseline homeostatic model assessment (HOMA)-IR levels. They had no previous exposure to JAKi, and received TOF therapy for no less than 6 mo. In 30 patients who were naïve to biologics, after a 24-week therapeutic period, the high-IR group showed reduced HOMA-IR levels (3.331 ± 1.036 vs 2.292 ± 0.707, P < 0.001). In another 26 patients who were exposed to tumor necrosis factor-α or interleukin-6 blockers, the high-IR group, despite having achieved a decrease but with lower magnitude than in naïve patients, showed reduced HOMA-IR levels (2.924 ± 0.790 vs 2.545 ± 1.080, P = 0.018).
CONCLUSION In this retrospective study, reduced IR was achieved in non-diabetic active RA patients following 24 wk of TOF therapy.
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Affiliation(s)
- Chrong-Reen Wang
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 70403, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan
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14
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Al-Beltagi M, Bediwy AS, Saeed NK. Insulin-resistance in paediatric age: Its magnitude and implications. World J Diabetes 2022; 13:282-307. [PMID: 35582667 PMCID: PMC9052009 DOI: 10.4239/wjd.v13.i4.282] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/12/2022] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
Insulin resistance (IR) is insulin failure in normal plasma levels to adequately stimulate glucose uptake by the peripheral tissues. IR is becoming more common in children and adolescents than before. There is a strong association between obesity in children and adolescents, IR, and the metabolic syndrome components. IR shows marked variation among different races, crucial to understanding the possible cardiovascular risk, specifically in high-risk races or ethnic groups. Genetic causes of IR include insulin receptor mutations, mutations that stimulate autoantibody production against insulin receptors, or mutations that induce the formation of abnormal glucose transporter 4 molecules or plasma cell membrane glycoprotein-1 molecules; all induce abnormal energy pathways and end with the development of IR. The parallel increase of IR syndrome with the dramatic increase in the rate of obesity among children in the last few decades indicates the importance of environmental factors in increasing the rate of IR. Most patients with IR do not develop diabetes mellitus (DM) type-II. However, IR is a crucial risk factor to develop DM type-II in children. Diagnostic standards for IR in children are not yet established due to various causes. Direct measures of insulin sensitivity include the hyperinsulinemia euglycemic glucose clamp and the insulin-suppression test. Minimal model analysis of frequently sampled intravenous glucose tolerance test and oral glucose tolerance test provide an indirect estimate of metabolic insulin sensitivity/resistance. The main aim of the treatment of IR in children is to prevent the progression of compensated IR to decompensated IR, enhance insulin sensitivity, and treat possible complications. There are three main lines for treatment: Lifestyle and behavior modification, pharmacotherapy, and surgery. This review will discuss the magnitude, implications, diagnosis, and treatment of IR in children.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta 31511, Egypt
- Department of Pediatrics, University Medical Center, Arabian Gulf University, Dr. Sulaiman Al Habib Medical Group, Manama 26671, Bahrain
| | - Adel Salah Bediwy
- Department of Chest Disease, Faculty of Medicine, Tanta University, Tanta 31527, Egypt
- Department of Pulmonology, University Medical Center, Arabian Gulf University, Dr. Sulaiman Al Habib Medical Group, Manama 26671, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Department of Pathology, Salmaniya Medical Complex, Ministry of Health, Manama 12, Bahrain
- Microbiology Section, Department of Pathology, Irish Royal College of Surgeon, Busaiteen 15503, Bahrain
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15
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Delai A, Gomes PM, Foss-Freitas MC, Elias J, Antonini SR, Castro M, Moreira AC, Mermejo LM. Hyperinsulinemic-Euglycemic Clamp Strengthens the Insulin Resistance in Nonclassical Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab 2022; 107:e1106-e1116. [PMID: 34693966 DOI: 10.1210/clinem/dgab767] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Insulin sensitivity evaluation by hyperinsulinemic-euglycemic clamp in nonclassical congenital adrenal hyperplasia (NC-CAH) due to 21-hydroxilase deficiency. DESIGN AND SETTING Cross-sectional study at university hospital outpatient clinics. PATIENTS AND METHODS NC-CAH patients (25 females, 6 males; 24 ± 10 years) subdivided into C/NC (compound heterozygous for 1 classical and 1 nonclassical allele) and NC/NC (2 nonclassical alleles) genotypes were compared to controls. RESULTS At diagnosis, C/NC patients presented higher basal and adrenocorticotropin-stimulated 17-hydroxyprogesterone and androstenedione levels than NC/NC genotype. Patients and controls presented similar weight, body mass index, abdominal circumference, and total fat body mass. NC-CAH patients showed higher waist-to-hip ratio, lower adiponectin and lower high-density lipoprotein cholesterol levels with no changes in fasting plasma glucose, glycated hemoglobin, homeostatic model assessment for insulin resistance, leptin, interleukin 6, tumor necrosis factor alpha, C-reactive protein, and carotid-intima-media thickness. All patients had used glucocorticoid (mean time of 73 months). Among the 22 patients with successful clamp, 13 were still receiving glucocorticoid-3 patients using cortisone acetate, 9 dexamethasone, and 1 prednisone (hydrocortisone equivalent dose of 5.5mg/m²/day), while 9 patients were off glucocorticoid but had previously used (hydrocortisone equivalent dose of 5.9mg/m2/day). The NC-CAH patients presented lower Mffm than controls (31 ± 20 vs 55 ± 23µmol/min-1/kg-1, P = 0.002). The Mffm values were inversely correlated with the duration of glucocorticoid treatment (r = -0.44, P = 0.04). There was association of insulin resistance and glucocorticoid type but not with androgen levels. CONCLUSION Using the gold standard method, the hyperinsulinemic-euglycemic clamp, insulin resistance was present in NC-CAH patients and related to prolonged use and long-acting glucocorticoid treatment. Glucocorticoid replacement and cardiometabolic risks should be monitored regularly in NC-CAH.
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Affiliation(s)
- Ariane Delai
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Patricia M Gomes
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Maria Cristina Foss-Freitas
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Jorge Elias
- Departments of Medical Imaging, Hematology, and Oncology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Sonir R Antonini
- Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Margaret Castro
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Ayrton C Moreira
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Livia M Mermejo
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
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16
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Heegaard B, Nelson LM, Gustafsson F. Steroid withdrawal after heart transplantation in adults. Transpl Int 2021; 34:2469-2482. [PMID: 34668614 DOI: 10.1111/tri.14142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 09/11/2021] [Accepted: 10/17/2021] [Indexed: 11/30/2022]
Abstract
Corticosteroids (CSs) are a key component of immunosuppressive treatment after heart transplantation (HTx). While effectively preventing acute rejection, several adverse effects including diabetes, hypertension, osteoporosis, and hyperlipidemia are associated with long-term use. As these complications may impair long-term outcome in HTx recipients, withdrawal of CSs is highly desirable, however, no uniform approach exists. Previous experience suggests that CS withdrawal can be accomplished without an increase in the incidence of acute rejection and even carrying a survival benefit. Also, common complications related to long-term CS use appear to be less frequent following CS discontinuation. Recipients who successfully discontinue CSs, however, likely belong to an immune-privileged subset of patients with low risk of post-transplant complications. Available studies evaluating CS withdrawal are highly heterogeneous and consensus on optimal timing and eligibility for withdrawal is lacking. Efforts to improve the understanding of optimal CS withdrawal strategy are of great importance in order to safely promote CS weaning in eligible patients and thereby alleviate the adverse effects of long-term CS use on post-transplant outcomes. The purpose of this review was to evaluate different protocols of CS withdrawal after HTx in terms of clinical outcomes and to explore criteria for successful CS withdrawal.
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Affiliation(s)
- Benedicte Heegaard
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Laerke Marie Nelson
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Finn Gustafsson
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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17
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Whyte MB, Vas PRJ, Umpleby AM. Could Exogenous Insulin Ameliorate the Metabolic Dysfunction Induced by Glucocorticoids and COVID-19? Front Endocrinol (Lausanne) 2021; 12:649405. [PMID: 34220705 PMCID: PMC8249851 DOI: 10.3389/fendo.2021.649405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 06/02/2021] [Indexed: 01/08/2023] Open
Abstract
The finding that high-dose dexamethasone improves survival in those requiring critical care due to COVID-19 will mean much greater usage of glucocorticoids in the subsequent waves of coronavirus infection. Furthermore, the consistent finding of adverse outcomes from COVID-19 in individuals with obesity, hypertension and diabetes has focussed attention on the metabolic dysfunction that may arise with critical illness. The SARS coronavirus itself may promote relative insulin deficiency, ketogenesis and hyperglycaemia in susceptible individuals. In conjunction with prolonged critical care, these components will promote a catabolic state. Insulin infusion is the mainstay of therapy for treatment of hyperglycaemia in acute illness but what is the effect of insulin on the admixture of glucocorticoids and COVID-19? This article reviews the evidence for the effect of insulin on clinical outcomes and intermediary metabolism in critical illness.
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Affiliation(s)
- Martin Brunel Whyte
- Faculty of Health Sciences, University of Surrey, Guildford, United Kingdom
- King’s College Hospital NHS Foundation Trust, London, United Kingdom
| | | | - Anne M. Umpleby
- Faculty of Health Sciences, University of Surrey, Guildford, United Kingdom
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18
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Andereggen L, Frey J, Andres RH, Luedi MM, Gralla J, Schubert GA, Beck J, Mariani L, Christ E. Impact of primary medical or surgical therapy on prolactinoma patients' BMI and metabolic profile over the long-term. JOURNAL OF CLINICAL AND TRANSLATIONAL ENDOCRINOLOGY 2021; 24:100258. [PMID: 34195008 PMCID: PMC8237353 DOI: 10.1016/j.jcte.2021.100258] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 06/09/2021] [Indexed: 11/23/2022]
Abstract
High prolactin (PRL) levels are associated with weight gain and impaired metabolic profiles. Long-term control of hyperprolactinemia can be attained by first-line surgery and medical therapy. Normalization of PRL improves patients’ BMI and fasting glucose levels. Marginal changes in patients’ metabolic profiles are noted regardless of the primary therapy. Not dopamine agonists per se, but rather the control of hyperprolactinemia plays a role in metabolic profile alterations. Objectives High prolactin levels have been associated with weight gain and impaired metabolic profiles. While treatment with dopamine agonists (DAs) has been shown to improve these parameters, there is a lack of surgical series on its comparative effect in prolactinoma patients. Methods In this retrospective, comparative study, consecutive patients with a prolactinoma were enrolled if treated with first-line transsphenoidal surgery (TSS) or with DAs. Patients with prolactinomas of Knosp grade >2 and those with a follow-up <24 months were excluded, as were patients with missing laboratory metabolic parameters at baseline and over the long-term. Effects of either treatment on BMI and the metabolic profile were analyzed, and independent risk factors for long-term obesity were calculated. Results Primary treatment was TSS for 12 patients (40%) and DAs for 18 patients (60%). At diagnosis, no significant differences between the two cohorts were observed with regard to adenoma size, Knosp grading, baseline prolactin (PRL) levels, prevalence of hypogonadism, or laboratory metabolic parameters. Mean follow-up was 51.9 months (range, 24–158). Over the long-term, both TSS and DAs led to the control of hyperprolactinemia (92% vs. 72%) and hypogonadism (78% vs. 83%) in the majority of patients. While a significant decrease in patients’ BMI and fasting glucose were observed, changes in the lipid profile were marginal and independent of the treatment modality. At baseline, increased BMI—but not the primary treatment strategy—was an independent predictor of long-term obesity. Conclusions Over the long-term, patients’ BMI and FG improve, but changes in the metabolic profile are marginal and independent of the primary treatment. It is presumable that not DAs per se, but rather the control of hyperprolactinemia plays a role in patients’ metabolic profile alterations.
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Affiliation(s)
- Lukas Andereggen
- Department of Neurosurgery, Kantonsspital Aarau, Aarau, Switzerland.,Faculty of Medicine, University of Bern, Bern, Switzerland
| | - Janine Frey
- Department of Gynecology and Obstetrics, Kantonsspital Lucerne, Lucerne, Switzerland
| | | | - Markus M Luedi
- Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Jan Gralla
- Department of Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | | | - Jürgen Beck
- Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany
| | - Luigi Mariani
- Department of Neurosurgery, University Hospital of Basel, Basel, Switzerland
| | - Emanuel Christ
- Department of Endocrinology, Diabetes and Metabolism, University Hospital of Basel, Basel, Switzerland
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19
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Ramos da Silva B, Rufato S, Mialich MS, Cruz LP, Gozzo T, Jordao AA. Metabolic syndrome and unfavorable outcomes on body composition and in visceral adiposities indexes among early breast cancer women post-chemotherapy. Clin Nutr ESPEN 2021; 44:306-315. [PMID: 34330483 DOI: 10.1016/j.clnesp.2021.06.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 12/30/2022]
Abstract
PURPOSE The study objected to investigate potential changes in metabolic, dietary, and nutritional status in women with stages I-III breast cancer exposed to chemotherapy. METHODS Women who were starting chemotherapy with no previous treatment were recruited. Anthropometrics, bioelectrical impedance analysis, handgrip strength, blood pressure and blood sample were collected. Visceral adiposity index and lipid accumulation product were calculated. Dietary intake was evaluated, and the multiple source methods program was applied. Metabolic syndrome (MetS) was assessed following the NCEP-ATP III criteria (defined as 3 of 5 components of MetS). All data were collected at 2-time points: diagnosis (T0) and after 1 month of completion of therapy (T1). Mean, standard deviation, percentage, and ANOVA in SAS Studio® were used to explore the results. RESULTS 61 women were included. We did not find any changes in anthropometrics and body composition. However, phase angle, extracellular water (EX) and ratio EX to total body water had expressive changes (p < 0.001). The results showed changes in lipid profile (p < 0.001), and greater unfavorable outcomes on adiposities index (p < 0.001). At the end of the study, 68,8% (N = 42) of the women developed MetS post-chemotherapy. CONCLUSION We have found supporting evidence for chemotherapy treatment resulting in worsening of nutritional markers, lipid profile and adiposity markers. After chemotherapy part of the sample developed MetS, even without changes in body weight, fat mass, and food intake. Breast cancer patients may benefit from targeted interventions before starting chemotherapy to prevent MetS post-treatment, and therefore reduce the risk of cardiovascular disease. Further investigation into this theme is needed.
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Affiliation(s)
- Bruna Ramos da Silva
- Department of Health Sciences, Ribeirão Preto Medical School. University of Sao Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, São Paulo, Brazil.
| | - Sarah Rufato
- Department of Health Sciences, Ribeirão Preto Medical School. University of Sao Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, São Paulo, Brazil
| | - Mirele S Mialich
- Department of Health Sciences, Ribeirão Preto Medical School. University of Sao Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, São Paulo, Brazil
| | - Loris P Cruz
- Nursing School of Ribeirão Preto, University of Sao Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, São Paulo, Brazil
| | - Thais Gozzo
- Nursing School of Ribeirão Preto, University of Sao Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, São Paulo, Brazil
| | - Alceu A Jordao
- Department of Health Sciences, Ribeirão Preto Medical School. University of Sao Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, São Paulo, Brazil
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20
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Godinho-Mota JCM, Mota JF, Gonçalves LV, Soares LR, Schincaglia RM, Prado CM, Martins KA, Freitas-Junior R. Chemotherapy negatively impacts body composition, physical function and metabolic profile in patients with breast cancer. Clin Nutr 2020; 40:3421-3428. [PMID: 33309160 DOI: 10.1016/j.clnu.2020.11.020] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 10/22/2020] [Accepted: 11/15/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Evidence suggests that chemotherapy (CT) leads to unfavorable outcomes on nutritional and metabolic profile; however, this is poorly understood. OBJECTIVE To evaluate the impact of CT on body composition, bone mineral density (BMD), insulin resistance, lipid markers related to atherosclerotic cardiovascular diseases in women recently diagnosed with breast cancer according to menopausal status. METHODS This is a prospective study that enrolled women newly diagnosed with stage II-III breast cancer (2014-18). Body composition were measured by dual-energy x-ray absorptiometry. Blood samples were collected to assess lipid profile, insulin resistance and sensitivity, visceral adiposity index and lipid accumulation product were calculated. Dietary intake, physical activity and function were also evaluated at the time of breast cancer diagnosis and after CT completion. RESULTS Ninety-nine women (40.4% in the premenopausal stage) aged 51 ± 1 years took part in this study. CT duration was 197 ± 27 days and main regimen was anthracyclines with taxanes (88.9%). CT was associated with an increase in total and central adiposity, insulin resistance, and all lipid-related markers, and a decrease in appendicular lean mass index, BMD and HDL-c concentration. Premenopausal women experienced greater unfavorable outcomes on adiposity markers and BMD compared to postmenopausal women (p < 0.01). No changes were observed in dietary intake and physical activity after CT. CONCLUSIONS Breast cancer CT negatively impacted body composition and metabolic profile. Premenopausal women experienced greater unfavorable impact on adiposity markers and BMD.
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Affiliation(s)
| | - Joao Felipe Mota
- Clinical and Sports Nutrition Research Laboratory (Labince), School of Nutrition, Federal University of Goiás, Goiania, GO, Brazil.
| | - Larissa Vaz Gonçalves
- Centro Avançado de Diagnóstico da Mama, Hospital das Clínicas, Federal University of Goiás, Goiania, GO, Brazil
| | - Leonardo Ribeiro Soares
- Centro Avançado de Diagnóstico da Mama, Hospital das Clínicas, Federal University of Goiás, Goiania, GO, Brazil
| | - Raquel Machado Schincaglia
- Clinical and Sports Nutrition Research Laboratory (Labince), School of Nutrition, Federal University of Goiás, Goiania, GO, Brazil
| | - Carla M Prado
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada
| | - Karine Anuska Martins
- Centro Avançado de Diagnóstico da Mama, Hospital das Clínicas, Federal University of Goiás, Goiania, GO, Brazil
| | - Ruffo Freitas-Junior
- Centro Avançado de Diagnóstico da Mama, Hospital das Clínicas, Federal University of Goiás, Goiania, GO, Brazil
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21
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Othonos N, Marjot T, Woods C, Hazlehurst JM, Nikolaou N, Pofi R, White S, Bonaventura I, Webster C, Duffy J, Cornfield T, Moolla A, Isidori AM, Hodson L, Tomlinson JW. Co-administration of 5α-reductase Inhibitors Worsens the Adverse Metabolic Effects of Prescribed Glucocorticoids. J Clin Endocrinol Metab 2020; 105:5864156. [PMID: 32594135 PMCID: PMC7500580 DOI: 10.1210/clinem/dgaa408] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 06/28/2020] [Indexed: 12/20/2022]
Abstract
CONTEXT Glucocorticoids (GCs) are commonly prescribed, but their use is associated with adverse metabolic effects. 5α-reductase inhibitors (5α-RI) are also frequently prescribed, mainly to inhibit testosterone conversion to dihydrotestosterone. However, they also prevent the inactivation of GCs. OBJECTIVE We hypothesized that 5α-RI may worsen the adverse effects of GCs. DESIGN Prospective, randomized study. PATIENTS A total of 19 healthy male volunteers (age 45 ± 2 years; body mass index 27.1 ± 0.7kg/m2). INTERVENTIONS Participants underwent metabolic assessments; 2-step hyperinsulinemic, euglycemic clamp incorporating stable isotopes, adipose tissue microdialysis, and biopsy. Participants were then randomized to either prednisolone (10 mg daily) or prednisolone (10 mg daily) plus a 5α-RI (finasteride 5 mg daily or dutasteride 0.5 mg daily) for 7 days; metabolic assessments were then repeated. MAIN OUTCOME MEASURES Ra glucose, glucose utilization (M-value), glucose oxidation, and nonesterified fatty acids (NEFA) levels. RESULTS Co-administration of prednisolone with a 5α-RI increased circulating prednisolone levels (482 ± 96 vs 761 ± 57 nmol/L, P = 0.029). Prednisolone alone did not alter Ra glucose (2.55 ± 0.34 vs 2.62 ± 0.19 mg/kg/minute, P = 0.86), M-value (3.2 ± 0.5 vs 2.7 ± 0.7 mg/kg/minute, P = 0.37), or glucose oxidation (0.042 ± 0.007 vs 0.040 ± 0.004 mmol/hr/kg/minute, P = 0.79). However, co-administration with a 5α-RI increased Ra glucose (2.67 ± 0.16 vs 3.05 ± 0.18 mg/kg/minute, P < 0.05) and decreased M-value (4.0 ± 0.5 vs 2.6 ± 0.4 mg/kg/minute, P < 0.05), and oxidation (0.043 ± 0.003 vs 0.036 ± 0.002 mmol/hr/kg, P < 0.01). Similarly, prednisolone did not impair insulin-mediated suppression of circulating NEFA (43.1 ± 28.9 vs 36.8 ± 14.3 μmol/L, P = 0.81), unless co-administered with a 5α-RI (49.8 ± 8.6 vs 88.5 ± 13.5 μmol/L, P < 0.01). CONCLUSIONS We have demonstrated that 5α-RIs exacerbate the adverse effects of prednisolone. This study has significant translational implications, including the need to consider GC dose adjustments, but also the necessity for increased vigilance for the development of adverse effects.
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Affiliation(s)
- Nantia Othonos
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Thomas Marjot
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Conor Woods
- Department of Endocrinology, Naas General Hospital, Kildare and Tallaght Hospital, Dublin, Ireland
| | - Jonathan M Hazlehurst
- Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, UK
| | - Nikolaos Nikolaou
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Riccardo Pofi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, 00161, Italy
| | - Sarah White
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Ilaria Bonaventura
- Department of Experimental Medicine, Sapienza University of Rome, Rome, 00161, Italy
| | - Craig Webster
- Department of Pathology, University Hospitals Birmingham, NHS Foundation Trust, Birmingham, UK
| | - Joanne Duffy
- Department of Pathology, University Hospitals Birmingham, NHS Foundation Trust, Birmingham, UK
| | - Thomas Cornfield
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Ahmad Moolla
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, 00161, Italy
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
- Correspondence and Reprint Requests: Professor Jeremy Tomlinson, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK, E-mail:
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22
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Jacobsson M, van Raalte DH, Heijboer AC, den Heijer M, de Jongh RT. Short-Term Glucocorticoid Treatment Reduces Circulating Sclerostin Concentrations in Healthy Young Men: A Randomized, Placebo-Controlled, Double-Blind Study. JBMR Plus 2020; 4:e10341. [PMID: 32803106 PMCID: PMC7422706 DOI: 10.1002/jbm4.10341] [Citation(s) in RCA: 5] [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: 09/13/2019] [Revised: 12/09/2019] [Accepted: 12/25/2019] [Indexed: 11/08/2022] Open
Abstract
Glucocorticoid use is the most common cause of osteoporosis in young individuals. In the current study, we investigated the effects of glucocorticoid treatment on circulating sclerostin concentrations and serum bone turnover markers in healthy young men. We performed additional measurements in two combined randomized, placebo‐controlled, double‐blind, dose–response intervention studies: 64 healthy men (age: 22 ± 2 years; BMI: 22.1 ± 1.7 kg/m2) were allocated to receive placebo (n = 16), prednisolone 7.5 mg once daily (n = 24), or prednisolone 30 mg once daily (n = 24) for 2 weeks using block randomization. Primary outcome variables were serum sclerostin and serum bone turnover markers (CTx and P1NP), before and after the intervention. Baseline characteristics and variables did not differ between intervention groups. Compared with placebo, prednisolone high‐dose decreased serum sclerostin concentrations (−8.5 [−28.0 to 7.3] versus 1.5 [−6.5 to 20.0] pg/mL, p = 0.048), decreased P1NP concentrations (−28.0 [−39.3 to −18.3] versus –1.5 [−15.3 to 11.3] μg/L, p < 0.001) and increased CTx concentrations (108.0 [55.0 to 177.0] versus 64.0 [−24.3 to 120.0] ng/L, p = 0.038). Compared with placebo, prednisolone low‐dose did not alter sclerostin concentrations (p = 0.5) or CTx concentrations (p = 0.7), but tended to decrease P1NP concentrations (−9.0 [−24.0 to −1.3] versus –1.5 [−15.3 to 11.3] μg/L, p = 0.095). At baseline concentrations of sclerostin were positively correlated with concentrations of CTx (Spearman's rank correlation coefficient ρ = +0.409, p = 0.001), but not with P1NP. No significant correlations were observed between changes in outcome variables during the interventions. Short‐term high‐dose, but not low‐dose, prednisolone treatment reduces serum sclerostin concentrations in healthy young men. Whether this reflects a counter regulatory mechanism to compensate glucocorticoid‐induced negative effects through other mechanisms remains to be elucidated. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Merel Jacobsson
- Department of Internal Medicine, Division of Endocrinology, Amsterdam UMC Amsterdam The Netherlands
| | - Daniël H van Raalte
- Department of Internal Medicine, Division of Endocrinology, Amsterdam UMC Amsterdam The Netherlands
| | - Annemieke C Heijboer
- Endocrine Laboratory, Department of Clinical Chemistry, Amsterdam UMC University of Amsterdam Amsterdam The Netherlands
| | - Martin den Heijer
- Department of Internal Medicine, Division of Endocrinology, Amsterdam UMC Amsterdam The Netherlands
| | - Renate T de Jongh
- Department of Internal Medicine, Division of Endocrinology, Amsterdam UMC Amsterdam The Netherlands
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23
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Wang CR, Liu MF. Recombinant Soluble TNF-α Receptor Fusion Protein Therapy Reduces Insulin Resistance in Non-Diabetic Active Rheumatoid Arthritis Patients. ACR Open Rheumatol 2020; 2:401-406. [PMID: 32530139 PMCID: PMC7368139 DOI: 10.1002/acr2.11157] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 05/11/2020] [Indexed: 12/14/2022] Open
Abstract
Objective Current evidence highlights a link between insulin resistance (IR) and disease activity in rheumatoid arthritis (RA), suggesting that insulin sensitivity can be improved by treating patients with TNF‐α blockers. Although reduced IR has been shown in RA patients who receive monoclonal antibody treatment, the efficacy remains to be elucidated when using recombinant soluble receptor fusion proteins. In particular, etanercept (ETA) is capable of blocking lymphotoxin‐α, a cytokine‐related to IR‐associated disease status. Methods A prospective study was carried out in nondiabetic active RA patients receiving a 25‐mg subcutaneous ETA injection twice weekly. Results Thirty patients aged 31 to 73 years (50.9 ± 10.6), naïve to biological and targeted synthetic disease‐modifying antirheumatic drugs with DAS28 scores of 5.17 to 7.49 (6.11 ± 0.66), were classified into high‐IR and low‐IR groups based on their baseline homeostatic model assessment (HOMA)‐IR levels. No differences were found between the two groups in terms of age, sex, weight, body mass index, seropositivity, and medication profiles before the injection. After a 24‐week therapeutic period, there were reduced HOMA‐IR levels in all patients in the high‐IR group (3.390 ± 0.636 to 2.234 ± 0.870, P < 0.001). A greater decrease in DAS28 values was found in patients with reduced IR than those without a reduction (2.54 ± 0.67 versus 1.46 ± 0.46, P = 0.006) in the low‐IR group. Conclusion We observed an improvement in insulin sensitivity in nondiabetic active RA patients following 24‐week recombinant soluble TNF‐α receptor fusion protein therapy.
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Affiliation(s)
| | - Ming-Fei Liu
- National Cheng Kung University Hospital, Tainan, Taiwan
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24
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Bouter KEC, van Bommel EJM, Jansen H, van Harskamp D, Schierbeek H, Ackermans MT, Serlie MJ, Schimmel AWM, Nieuwdorp M, Dallinga‐Thie GM, van Raalte DH. The effect of dapagliflozin on apolipoprotein B and glucose fluxes in patients with type 2 diabetes and well-controlled plasma LDL cholesterol. Diabetes Obes Metab 2020; 22:988-996. [PMID: 32026592 PMCID: PMC7318266 DOI: 10.1111/dom.13990] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/10/2020] [Accepted: 01/31/2020] [Indexed: 02/06/2023]
Abstract
AIM To dissect the effects of the sodium-glucose linked transporter 2 inhibitor dapagliflozin on lipid metabolism and assess whether these effects could potentially offset cardiovascular benefit with this drug-class. MATERIALS AND METHODS We assessed the effect of dapagliflozin on lipid metabolism in 11 adults with uncomplicated type 2 diabetes. After 4 weeks of statin wash-out and 4 weeks of rosuvastatin 10 mg treatment, participants were treated with dapagliflozin 10 mg once-daily for 5 weeks. Before and after dapagliflozin, plasma lipids were measured and very low-density lipoprotein (VLDL)-1 and VLDL-2 apolipoprotein (Apo)B fluxes were assessed using (5.5.5-2 H3 )-leucine tracer infusion. In addition, hepatic and peripheral insulin sensitivity as well as insulin-mediated inhibition of peripheral lipolysis were measured during a two-step hyperinsulinemic-euglycaemic clamp using (6,6-2 H2 )-glucose and (1,1,2,3,3-2 H5 )-glycerol tracers. RESULTS Rosuvastatin decreased all plasma lipids significantly: total cholesterol from 4.5 (3.2-6.2) to 3.1 (2.5-3.8) mmol/L, LDL cholesterol from 2.6 (1.7-3.4) to 1.5 (1.1-2.2) mmol/L, HDL cholesterol from 1.34 (0.80-2.02) to 1.19 (0.74-1.89) mmol/L and triglycerides from 0.92 (0.31-3.91) to 0.79 (0.32-2.10) mmol/L. The addition of dapaglifozin to rosuvastatin did not raise either LDL cholesterol or total cholesterol, and only increased HDL cholesterol by 0.08 (-0.03-0.13) mmol/L (P = 0.03). In line with this, dapagliflozin did not affect VLDL-1 or VLDL-2 ApoB fluxes. Fasting endogenous glucose production tended to increase by 0.9 (-3.4-3.1) μmol kg-1 min-1 (P = 0.06), but no effect on hepatic and peripheral insulin sensitivity or on peripheral lipolysis was observed. CONCLUSIONS Dapagliflozin has no effect on plasma LDL-cholesterol levels or VLDL-apoB fluxes in the context of optimal lipid-lowering treatment, which will thus not limit cardiovascular benefit when lipids are adequately controlled.
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Affiliation(s)
- Kristien E. C. Bouter
- Department of Vascular Medicine and Experimental Vascular MedicineAmsterdam University Medical Centersthe Netherlands
| | - Erik J. M. van Bommel
- Diabetes Center, Department of Internal MedicineAmsterdam University Medical Centersthe Netherlands
| | - Hans Jansen
- Department of Vascular Medicine and Experimental Vascular MedicineAmsterdam University Medical Centersthe Netherlands
| | - Dewi van Harskamp
- Department of Clinical Chemistry, Laboratory of EndocrinologyAmsterdam University Medical Centersthe Netherlands
| | - Henk Schierbeek
- Department of Clinical Chemistry, Laboratory of EndocrinologyAmsterdam University Medical Centersthe Netherlands
| | - Mariëtte T. Ackermans
- Department of Clinical Chemistry, Laboratory of EndocrinologyAmsterdam University Medical Centersthe Netherlands
| | - Mireille J. Serlie
- Department of Endocrinology and MetabolismAmsterdam University Medical Centersthe Netherlands
| | - Alinda W. M. Schimmel
- Department of Vascular Medicine and Experimental Vascular MedicineAmsterdam University Medical Centersthe Netherlands
| | - Max Nieuwdorp
- Department of Vascular Medicine and Experimental Vascular MedicineAmsterdam University Medical Centersthe Netherlands
| | - Geesje M. Dallinga‐Thie
- Department of Vascular Medicine and Experimental Vascular MedicineAmsterdam University Medical Centersthe Netherlands
| | - Daniël H. van Raalte
- Department of Vascular Medicine and Experimental Vascular MedicineAmsterdam University Medical Centersthe Netherlands
- Diabetes Center, Department of Internal MedicineAmsterdam University Medical Centersthe Netherlands
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25
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Aldibbiat AM, Al-Sharefi A. Do Benefits Outweigh Risks for Corticosteroid Therapy in Acute Exacerbation of Chronic Obstructive Pulmonary Disease in People with Diabetes Mellitus? Int J Chron Obstruct Pulmon Dis 2020; 15:567-574. [PMID: 32214806 PMCID: PMC7084124 DOI: 10.2147/copd.s236305] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 02/21/2020] [Indexed: 12/22/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) and diabetes mellitus (DM) are chronic health conditions with significant impacts on quality and extent of life. People with COPD and DM appear to have worse outcomes in each of the comorbid conditions. Treatment with corticosteroids in acute exacerbation of COPD (AECOPD) has been shown to reduce treatment failure and exacerbation relapse, and to shorten length of hospital stay, but not to affect the inexorable gradual worsening of lung function. Treatment with corticosteroids can lead to a wide spectrum of side effects and complications, including worsening hyperglycemia and deterioration of diabetes control in those with pre-existing DM. The relationship between COPD and DM is rather complex and accumulating evidence indicates a distinct phenotype of the comorbid state. Several randomized controlled trials on corticosteroid treatment in AECOPD excluded people with DM or did not report on outcomes in this subgroup. As such, the perceived benefits of corticosteroids in AECOPD in people with DM have not been validated. In people with COPD and DM, the detrimental side effects of corticosteroids are guaranteed, while the benefits are not confirmed and only presumed based on extrapolation from the general COPD population. Therefore, the potential for harm when prescribing corticosteroids for AECOPD in people with DM cannot be excluded.
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Affiliation(s)
- Ali M Aldibbiat
- Dasman Diabetes Institute, Kuwait City, Kuwait
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Ahmed Al-Sharefi
- Metabolic and Diabetes Unit, Sunderland Royal Hospital, South Tyneside and Sunderland NHS Foundation Trust, Sunderland, UK
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Abstract
Idiopathic shoulder stiffness (i.e. frozen shoulder, FS) is a common pathology of the glenohumeral joint characterized by a sudden onset of pain syndrome and progressive restriction of the range of motion. While the histological changes of FS are accompanied by synovial inflammation and increasing capsular fibrosis, the underlying cause of FS is still unknown. The treatment options for FS are multifarious and include medication, local steroid injection, physiotherapy, hydrodistension, manipulation under anesthesia, arthroscopic and open capsular release. As the disease is usually self-limiting and the symptoms resolve after 2-3 years, especially conservative treatment measures are often clinically applied; however, in this context there is still no scientifically based consensus on which treatment measures are most likely to contribute to symptom relief in which phase of the disease. For this reason, this article focuses on the description of the scientifically investigated conservative treatment methods in FS and their temporal classification into the classical three-phase course of the disease.
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27
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Predictive factors for the development of diabetes in cancer patients treated with phosphatidylinositol 3-kinase inhibitors. Cancer Chemother Pharmacol 2019; 84:405-414. [PMID: 31250153 DOI: 10.1007/s00280-019-03889-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 06/08/2019] [Indexed: 01/26/2023]
Abstract
PURPOSE Targeted therapy using phosphatidylinositol 3-kinase (PI3K) inhibitors is used to treat cancer such as lymphoma. In animal studies, its use raised concern about alteration of glucose metabolism. To date, clinical data are inconclusive; therefore, we investigated the incidence and clinical manifestations of diabetes in cancer patients treated with PI3K inhibitors. METHODS In a retrospective review of diabetes-free patients with advanced solid tumors treated with PI3K inhibitor, we performed Cox regression to identify independent predictors for the development of diabetes. RESULTS Of 38 patients (mean age: 54.5 years, 23.7% female) having a mean duration of follow-up of 238.5 days who initiated PI3K inhibitors, 55.3% developed diabetes during treatment (mean 29.1 days); among these, 28.6% experienced remission of diabetes after discontinuing PI3K inhibitors (mean 72.1 days). Patients with incident diabetes had higher anti-hypertensive medication use, higher HbA1c levels and fasting glucose at baseline, and longer duration of PI3K inhibitor use (P = 0.024, P = 0.005, P = 0.008, and P = 0.023, respectively). Previous steroid use and lower baseline HbA1c level were significantly associated with development of diabetes (HR = 8.41, 95% CI 1.89-37.33; HR = 2.16, 95% CI 1.09-4.25, respectively). Patients whose diabetes remitted after discontinuing PI3K inhibitors were younger (P = 0.035) and had lower fasting glucose levels during PI3K inhibitor treatment (P = 0.001) compared to those non-remitters. CONCLUSIONS Previous steroid use and lower baseline HbA1c level may be important predictors for developing diabetes in patients with advanced solid tumors treated with PI3K inhibitors, warranting close observation and careful intervention.
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Tatalovic M, Lehmann R, Cheetham M, Nowak A, Battegay E, Rampini SK. Management of hyperglycaemia in persons with non-insulin-dependent type 2 diabetes mellitus who are started on systemic glucocorticoid therapy: a systematic review. BMJ Open 2019; 9:e028914. [PMID: 31154314 PMCID: PMC6549610 DOI: 10.1136/bmjopen-2019-028914] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVES What is the most effective pharmacological intervention for glycaemic control in known type 2 diabetes mellitus (DM) without prior insulin treatment and newly started on systemic glucocorticoid therapy? DESIGN We conducted a systematic literature review. DATA SOURCES We searched MEDLINE, Embase and Cochrane Library databases and Google for articles from 2002 to July 2018. ELIGIBILITY CRITERIA We combined search terms relating to DM (patients, >16 years of age), systemic glucocorticoids, glycaemic control, randomised controlled trials (RCTs) and observational studies. DATA EXTRACTION AND SYNTHESIS We screened and evaluated articles, extracted data and assessed risk of bias and quality of evidence according to Grading of Recommendations Assessment, Development and Evaluation guidelines. RESULTS Eight of 2365 articles met full eligibility criteria. Basal-bolus insulin (BBI) strategy for patients under systemic glucocorticoid therapy was comparatively effective but provided insufficient glucose control, depending on time of day. BBI strategy with long-acting insulin and neutral protamin Hagedorn as basal insulin provided similar overall glycaemic control. Addition of various insulin strategies to standard BBI delivered mixed results. Intermediate-acting insulin (IMI) as additional insulin conferred no clear benefits, and glycaemic control with sliding scale insulin was inferior to BBI or IMI. No studies addressed whether anticipatory or compensatory insulin adjustments are better for glycaemic control. CONCLUSION The lack of suitably designed RCTs and observational studies, heterogeneity of interventions, target glucose levels and glucose monitoring, poor control of DM subgroups and low to moderate quality of evidence render identification of optimal pharmacological interventions for glycaemic control and insulin management difficult. Even findings on the widely recommended BBI regimen as intensive insulin therapy for patients with DM on glucocorticoids are inconclusive. High-quality evidence from studies with well-defined DM phenotypes, settings and treatment approaches is needed to determine optimal pharmacological intervention for glycaemic control. PROSPERO REGISTRATION NUMBER CRD42015024739.
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Affiliation(s)
- Milos Tatalovic
- Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Roger Lehmann
- Department of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland
| | - Marcus Cheetham
- Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland
- Center of Competence Multimorbidity, University of Zurich, Zurich, Switzerland
| | - Albina Nowak
- Department of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland
| | - Edouard Battegay
- Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland
- Center of Competence Multimorbidity, University of Zurich, Zurich, Switzerland
| | - Silvana K Rampini
- Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland
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Mohammed MA, Mahmoud MO, Awaad AS, Gamal GM, Abdelfatah D. Alpha lipoic acid protects against dexamethasone-induced metabolic abnormalities via APPL1 and PGC-1 α up regulation. Steroids 2019; 144:1-7. [PMID: 30684496 DOI: 10.1016/j.steroids.2019.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 01/08/2019] [Accepted: 01/17/2019] [Indexed: 11/24/2022]
Abstract
BACKGROUND Glucocorticoids (GCs) have various uses in the medicine in different specialties. However, GCs administration is usually accompanying with multiple side effects such as hyperglycemia and hyperlipidemia. Alpha lipoic acid (ALA) has been documented to posse anti-diabetic properties. AIM OF THE STUDY this study highlights the role of ALA in avoiding dexamethasone induced metabolic disturbance. MATERIALS & METHODS 30 rats were randomly divided into 5 groups: Group (1): Control group; Groups 3, 4, and 5: rats received dexamethasone 1 mg/kg/day for 10 days; Groups 2, 4, and 5: Rats received ALA 100 mg/kg/day all the duration of the study, 2 weeks before dexamethasone, or concomitant with dexamethasone respectively. For each rat, we collected blood samples for measurement of glucose, lipid profiles, adiponectin, irisin, and Phosphoinositide 3-kinase (PI3K). We also isolated gastrocnemius muscles for measurement of insulin receptor substrate-1(IRS-1), peroxisome proliferator-activated receptor γ coactivator 1 α(PGC1-α), and adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1(APPL) gene expression. RESULTS Dexamethasone administration caused hyperglycemia, hyperlipemia, decrease the level of adiponectin, irisin, and PI3K besides decreasing the gene expression of IRS-1, PGC-1 α, and APPL1. ALA administration pre or concomitant to dexamethasone avoided these results. CONCLUSION ALA can prevent metabolic abnormalities induced by dexamethasone via PGC1α and APPL1 upregulation.
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Affiliation(s)
| | - Mohamed O Mahmoud
- Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Egypt
| | - Ashraf Sayed Awaad
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Beni-Suef University, Egypt
| | | | - Dina Abdelfatah
- Department of Biochemistry, Faculty of Medicine, Cairo University, Egypt
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Combination Therapy with Empagliflozin and Insulin Results in Successful Glycemic Control: A Case Report of Uncontrolled Diabetes Caused by Autoimmune Pancreatitis and Subsequent Steroid Treatment. Case Rep Endocrinol 2019; 2019:9415347. [PMID: 30895163 PMCID: PMC6393920 DOI: 10.1155/2019/9415347] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 02/01/2019] [Indexed: 12/24/2022] Open
Abstract
A 66-year-old Japanese male presented with thirst, polyuria, and hemoglobin A1c and postprandial glucose levels (13.1% and 529 mg/dL, respectively) that indicated severe hyperglycemia. Based on his high immunoglobulin G4 level and the results of magnetic resonance imaging and magnetic resonance cholangiopancreatography, we diagnosed him with autoimmune pancreatitis. Insulin was initiated to control his diabetes. One month later, the patient commenced on prednisolone therapy for the treatment of autoimmune pancreatitis, after which his total insulin dosage increased to a maximum of 52 units/day. When the prednisolone dosage was later tapered, the patient's total dosage of insulin was reduced to 42 units/day. However, he had gained 3.6 kg from the start of prednisolone therapy, and 42 units/day was insufficient for maintaining glycemic control. Thus, empagliflozin, a sodium-dependent glucose transporter 2 (SGLT2) inhibitor, was added. Thereafter, we were able to reduce the patient's total dosage of insulin; it was eventually discontinued with good glycemic control and weight loss. Such results suggest that the combination of insulin with an SGLT2 inhibitor may be a viable option for the treatment of diabetic patients on prednisolone therapy.
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Emanuel AL, de Clercq NC, Koopen AM, van Poelgeest E, Serlie MJM, van Raalte DH, Kramer MHH, Nieuwdorp M, Eringa EC, Serné EH. Iloprost infusion prevents the insulin-induced reduction in skeletal muscle microvascular blood volume but does not enhance peripheral glucose uptake in type 2 diabetic patients. Diabetes Obes Metab 2018; 20:2523-2531. [PMID: 29885045 DOI: 10.1111/dom.13410] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 05/22/2018] [Accepted: 06/05/2018] [Indexed: 01/26/2023]
Abstract
AIMS In type 2 diabetes impaired insulin-induced muscle perfusion is thought to contribute to reduced whole-body glucose uptake. In this study, we examined the effects of iloprost, a stable prostacyclin analogue, on insulin-induced muscle capillary recruitment and whole-body glucose uptake. MATERIALS AND METHODS In a randomized cross-over design, 12 type 2 diabetes patients (age, 55 [46-69] years; BMI, 33.1 [31.0-39] kg/m2 ) underwent two hyperinsulinaemic-euglycaemic clamps, one with and one without simultaneous low-dose iloprost infusion. Contrast-enhanced ultrasonography of the vastus lateralis muscle was performed before and during the clamp. Muscle capillary recruitment was calculated as percentage change in microvascular blood volume (MBV) before and during the clamp. RESULTS Insulin infusion reduced skeletal muscle MBV by ~50% compared to the fasting state (fasting, 1.77·10-4 [1.54·10-5 -2.44·10-3 ] arbitrary units (AU); hyperinsulinaemia, 6.69·10-5 [2.68·10-6 -5.72·10-4 ] AU; P = 0.050). Infusion of iloprost prevented this insulin-induced skeletal muscle capillary derecruitment, from (-49.5 [-89.5 to 55.3] %) to (8.0 [-68.8 to 306.6] %), for conditions without and with iloprost, respectively. The rate of glucose disappearance (Rd ) did not change significantly during iloprost infusion (17.3 [10.0-40.8] μmol/kg/min) compared with insulin infusion alone (17.6 [9.9-68.7] μmol/kg/min). CONCLUSIONS Our data suggest that acute improvement in insulin-stimulated muscle perfusion is not an attractive therapeutic approach to bypass cellular resistance to glucose uptake in type 2 diabetes. Whether long-term improvements in insulin-induced muscle perfusion may prove beneficial for glucose disposal remains to be determined.
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Affiliation(s)
- Anna L Emanuel
- Department of Internal Medicine, VU University Medical Centre, Diabetes Centre, Amsterdam, Netherlands
| | - Nicolien C de Clercq
- Department of Internal Medicine, Academic Medical Centre, Amsterdam, Netherlands
| | - Annefleur M Koopen
- Department of Internal Medicine, Academic Medical Centre, Amsterdam, Netherlands
| | - Erik van Poelgeest
- Department of Internal Medicine, VU University Medical Centre, Diabetes Centre, Amsterdam, Netherlands
| | - Mireille J M Serlie
- Department of Internal Medicine, Academic Medical Centre, Amsterdam, Netherlands
| | - Daniel H van Raalte
- Department of Internal Medicine, VU University Medical Centre, Diabetes Centre, Amsterdam, Netherlands
| | - Mark H H Kramer
- Department of Internal Medicine, VU University Medical Centre, Diabetes Centre, Amsterdam, Netherlands
| | - Max Nieuwdorp
- Department of Internal Medicine, VU University Medical Centre, Diabetes Centre, Amsterdam, Netherlands
- Department of Internal Medicine, Academic Medical Centre, Amsterdam, Netherlands
| | - Etto C Eringa
- Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| | - Erik H Serné
- Department of Internal Medicine, VU University Medical Centre, Diabetes Centre, Amsterdam, Netherlands
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Radhakutty A, Burt MG. MANAGEMENT OF ENDOCRINE DISEASE: Critical review of the evidence underlying management of glucocorticoid-induced hyperglycaemia. Eur J Endocrinol 2018; 179:R207-R218. [PMID: 30299889 DOI: 10.1530/eje-18-0315] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Glucocorticoids are frequently prescribed to patients with a wide range of inflammatory and autoimmune diseases. The semi-synthetic glucocorticoid prednisolone is most commonly prescribed and in two main patterns. Prednisolone is prescribed short term at medium-high doses to treat an acute inflammatory illness or long term at lower doses to attenuate chronic inflammatory disease progression. In hospitalized patients with acute prednisolone-induced hyperglycaemia, there is a distinct circadian pattern of glucose elevation, which occurs predominantly in the afternoon and evening. As a morning dose of isophane insulin has a pharmacokinetic pattern that matches this pattern of glucose elevation, treatment comprising a basal dose of morning isophane insulin in combination with short-acting insulin boluses is generally recommended. However, evidence is lacking that isophane-based basal bolus insulin is more efficacious than other insulin regimens. In outpatients, low-dose prednisolone causes a small increase in post glucose-load glucose concentration but no change in overall glycaemic control as measured by glycosylated haemoglobin. If treatment is indicated, metformin has been shown to be effective and may attenuate other adverse effects of long-term prednisolone therapy. Further studies are necessary in order to identify factors underlying the variability in response to insulin therapy and clinical benefits of treatment in hospitalized patients with prednisolone-induced hyperglycaemia. In outpatients prescribed low-dose prednisolone, the cardiovascular risk associated with postprandial hyperglycaemia and efficacy of hypoglycaemic therapies should be evaluated in future randomized clinical trials.
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Affiliation(s)
- Anjana Radhakutty
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
- Southern Adelaide Diabetes and Endocrine Services, Flinders Medical Centre, Adelaide, South Australia, Australia
- Department of Diabetes and Endocrinology, Lyell Mc Ewin Hospital, Adelaide, South Australia, Australia
| | - Morton G Burt
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
- Southern Adelaide Diabetes and Endocrine Services, Flinders Medical Centre, Adelaide, South Australia, Australia
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Qin C, Li J, Tang K. The Paraventricular Nucleus of the Hypothalamus: Development, Function, and Human Diseases. Endocrinology 2018; 159:3458-3472. [PMID: 30052854 DOI: 10.1210/en.2018-00453] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 07/16/2018] [Indexed: 02/08/2023]
Abstract
The paraventricular nucleus of the hypothalamus (PVH), located in the ventral diencephalon adjacent to the third ventricle, is a highly conserved brain region present in species from zebrafish to humans. The PVH is composed of three main types of neurons, magnocellular, parvocellular, and long-projecting neurons, which play imperative roles in the regulation of energy balance and various endocrinological activities. In this review, we focus mainly on recent findings about the early development of the hypothalamus and the PVH, the functions of the PVH in the modulation of energy homeostasis and in the hypothalamus-pituitary system, and human diseases associated with the PVH, such as obesity, short stature, hypertension, and diabetes insipidus. Thus, the investigations of the PVH will benefit not only understanding of the development of the central nervous system but also the etiology of and therapy for human diseases.
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Affiliation(s)
- Cheng Qin
- Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi, China
- Institute of Life Science, Nanchang University, Nanchang, Jiangxi, China
| | - Jiaheng Li
- Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi, China
- Institute of Life Science, Nanchang University, Nanchang, Jiangxi, China
| | - Ke Tang
- Institute of Life Science, Nanchang University, Nanchang, Jiangxi, China
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, Guangdong, China
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van Bommel EJM, de Jongh RT, Brands M, Heijboer AC, den Heijer M, Serlie MJ, van Raalte DH. The osteoblast: Linking glucocorticoid-induced osteoporosis and hyperglycaemia? A post-hoc analysis of a randomised clinical trial. Bone 2018; 112:173-176. [PMID: 29729427 DOI: 10.1016/j.bone.2018.04.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 04/25/2018] [Accepted: 04/28/2018] [Indexed: 10/17/2022]
Abstract
HYPOTHESIS Glucocorticoids (GCs) induce osteoporosis predominantly by inhibiting osteoblast activity. We hypothesised that osteoblastic factors could also be linked to GC-induced adverse metabolic effects. METHODS We performed a post-hoc analysis of a randomised, placebo-controlled, double blind, dose-response intervention study involving 32 healthy males (age: 22 ± 3 years; BMI 22.4 ± 1.7 kg/m2) who were allocated to prednisolone (PRED) 7.5 mg once daily (n = 12), PRED 30 mg once daily (n = 12), or placebo (n = 8) for two weeks using block randomisation. Mean outcomes measures included osteocalcin, N-terminal propeptide of type 1 procollagen (P1NP) and their relation to glucose and lipid metabolism, measured by stable isotopes, before and at 2 weeks of treatment, in the fasted state and during a two-step hyperinsulinaemic clamp. RESULTS Osteocalcin and P1NP concentrations were dose-dependently decreased by PRED treatment (p < 0.001 both). PRED dosages dose-dependently reduced sensitivity of the liver and skeletal muscle for insulin (p < 0.001 both) and impaired suppression of lipolysis mediated by insulin (p < 0.01). In multivariate analyses, GC-induced changes in osteocalcin concentrations related to reduces hepatic insulin sensitivity (β = -0.315; p = 0.044). In addition, GC-induced changes in P1NP were negatively related to changes in insulin-mediated suppression of hepatic glucose production (r = -0.582; p = 0.001), and were positively related to insulin-stimulated glucose uptake (r = 0.638; p < 0.001). Finally, changes in PN1P were negatively related to changes in fasting hypertriglyceridemia (r = -0.499; p = 0.004) and insulin-induced suppression of lipolysis rates (r = -0.494; p = 0.006). CONCLUSION GC treatment alters osteoblastic function which is associated with several adverse metabolic effects of GC treatment. Future causal studies are needed to assess the specific mediator(s) by which the osteoblast alters intermediary metabolism. CLINICAL TRIAL REGISTRATION NUMBER ISRCTN83991850.
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Affiliation(s)
- Erik J M van Bommel
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Renate T de Jongh
- Department of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands
| | - Myrte Brands
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands
| | - Annemieke C Heijboer
- Department of Clinical Chemistry, Endocrine Laboratory, VU University Medical Center, Amsterdam, The Netherlands
| | - Martin den Heijer
- Department of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands
| | - Mireille J Serlie
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands
| | - Daniel H van Raalte
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
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Pranger IG, van Raalte DH, Brands M, Muskiet MHA, Kema IP, Serlie MJ, Diamant M, Bakker SJL, Muskiet FAJ. Influence of prednisolone on parameters of de novo lipogenesis and indices for stearoyl-CoA- and Δ6- desaturase activity in healthy males: A Post-hoc analysis of a randomized, placebo-controlled, double-blind trial. Prostaglandins Leukot Essent Fatty Acids 2018; 132:8-15. [PMID: 29735021 DOI: 10.1016/j.plefa.2018.03.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 03/26/2018] [Accepted: 03/29/2018] [Indexed: 01/28/2023]
Abstract
Glucocorticoid treatment decreases liver insulin sensitivity and may modify fatty acid metabolism. We investigated the influence of oral prednisolone on indices for de novo lipogenesis (DNLi), stearoyl-CoA desaturase (SCDi) and Δ6-desaturase (D6Di) activity in healthy males. In addition, we explored whether the changes may be associated with prednisolone-induced changes in glucose and lipid metabolism and insulin sensitivity. Thirty-two healthy young males (mean ± SD age 22 ± 3 years, BMI 22.4 ± 1.7 kg/m2) were allocated to receive prednisolone 7.5 mg/day (PRED7.5; n = 12), prednisolone 30 mg/day (PRED30; n = 12), or placebo (n = 8) in a randomized double-blind fashion for 2 weeks. Fatty acid compositions of plasma cholesteryl esters (CE), phospholipids (PL) and triglycerides (TG) were measured at baseline and on day 14. DNLi, SCDi and D6Di were estimated from product/precursor ratios in CE, with DNLi primary deriving from 16:1ω7/18:2ω6, SCDi from 16:1ω7/16:0 and D6Di from 22:6ω3/20:5ω3. Ratios were also assessed in PL and TG. In CE, PRED30 increased DNLi by 51.2 [95%CI 14.8; 87.6]%, increased SCDi by 48.6 [18.7; 78.5]%, and decreased D6Di by 57.7 [-91.8; -23.5]% (p ≤ 0.01 for all, compared to placebo). The prednisolone-induced increases in DNLi and SCDi were positively correlated with insulin sensitivity (r = 0.35 and 0.50, respectively). Similar results were found in PL and TG. Prednisolone dose-dependently increases DNLi and SCDi and decreases D6Di in plasma CE, PL and TG in healthy males after 2 weeks. The observed unfavorable effects on fatty acid metabolism were related to the induction of glucocorticoid-induced insulin resistance.
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Affiliation(s)
- I G Pranger
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
| | - D H van Raalte
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - M Brands
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands
| | - M H A Muskiet
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - I P Kema
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - M J Serlie
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands
| | - M Diamant
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - S J L Bakker
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - F A J Muskiet
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Lai LYH, Harris E, West RM, Mackie SL. Association between glucocorticoid therapy and incidence of diabetes mellitus in polymyalgia rheumatica and giant cell arteritis: a systematic review and meta-analysis. RMD Open 2018. [PMID: 29531778 PMCID: PMC5845432 DOI: 10.1136/rmdopen-2017-000521] [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] [Indexed: 12/15/2022] Open
Abstract
Background Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are almost always treated with glucocorticoids (GCs), but long-term GC use is associated with diabetes mellitus (DM). The absolute incidence of this complication in this patient group remains unclear. Objective To quantify the absolute risk of GC-induced DM in PMR and GCA from published literature. Methods We identified literature from inception to February 2017 reporting diabetes following exposure to oral GC in patients with PMR and/or GCA without pre-existing diabetes. A random-effects meta-analysis was performed to summarise the findings. Results 25 eligible publications were identified. In studies of patients with GCA, mean cumulative GC dose was almost 1.5 times higher than in studies of PMR (8.2 g vs 5.6 g), with slightly longer treatment duration and longer duration of follow-up (6.4 years vs 4.4 years). The incidence proportion (cumulative incidence) of patients who developed new-onset DM was 6% (95% CI 3% to 9%) for PMR and 13% (95% CI 9% to 17%) for GCA. Based on UK data on incidence rate of DM in the general population, the expected background incidence rate of DM over 4.4 years in patients with PMR and 6.4 years in patients with GCA (follow-up duration) would be 4.8% and 7.0%, respectively. Heterogeneity between studies was high (I2=79.1%), as there were differences in study designs, patient population, geographical locations and treatment. Little information on predictors of DM was found. Conclusion Our meta-analysis produced plausible estimates of DM incidence in patients with PMR and GCA, but there is insufficient published data to allow precise quantification of DM risk.
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Affiliation(s)
- Lana Yin Hui Lai
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Emma Harris
- Centre for Applied Research in Health, School of Human and Health Sciences, University of Huddersfield, Huddersfield, UK
| | - Robert M West
- Leeds Institute of Health Sciences, University of Leeds, Leeds, UK
| | - Sarah Louise Mackie
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
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Scaroni C, Zilio M, Foti M, Boscaro M. Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management. Endocr Rev 2017; 38:189-219. [PMID: 28368467 DOI: 10.1210/er.2016-1105] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 03/15/2017] [Indexed: 12/13/2022]
Abstract
An impaired glucose metabolism, which often leads to the onset of diabetes mellitus (DM), is a common complication of chronic exposure to exogenous and endogenous glucocorticoid (GC) excess and plays an important part in contributing to morbidity and mortality in patients with Cushing syndrome (CS). This article reviews the pathogenesis, epidemiology, diagnosis, and management of changes in glucose metabolism associated with hypercortisolism, addressing both the pathophysiological aspects and the clinical and therapeutic implications. Chronic hypercortisolism may have pleiotropic effects on all major peripheral tissues governing glucose homeostasis. Adding further complexity, both genomic and nongenomic mechanisms are directly induced by GCs in a context-specific and cell-/organ-dependent manner. In this paper, the discussion focuses on established and potential pathologic molecular mechanisms that are induced by chronically excessive circulating levels of GCs and affect glucose homeostasis in various tissues. The management of patients with CS and DM includes treating their hyperglycemia and correcting their GC excess. The effects on glycemic control of various medical therapies for CS are reviewed in this paper. The association between DM and subclinical CS and the role of screening for CS in diabetic patients are also discussed.
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Affiliation(s)
- Carla Scaroni
- Endocrinology Unit, Department of Medicine, DIMED, University of Padova, Via Ospedale 105, 35128 Padua, Italy
| | - Marialuisa Zilio
- Endocrinology Unit, Department of Medicine, DIMED, University of Padova, Via Ospedale 105, 35128 Padua, Italy
| | - Michelangelo Foti
- Department of Cell Physiology & Metabolism, Centre Médical Universitaire, 1 Rue Michel Servet, 1211 Genèva, Switzerland
| | - Marco Boscaro
- Endocrinology Unit, Department of Medicine, DIMED, University of Padova, Via Ospedale 105, 35128 Padua, Italy
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Jørgensen MB, Hornum M, van Hall G, Bistrup C, Hansen JM, Mathiesen ER, Feldt-Rasmussen B. The impact of kidney transplantation on insulin sensitivity. Transpl Int 2017; 30:295-304. [DOI: 10.1111/tri.12907] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 10/03/2016] [Accepted: 12/12/2016] [Indexed: 01/04/2023]
Affiliation(s)
- Morten B. Jørgensen
- Department of Nephrology; Rigshospitalet, University of Copenhagen; Copenhagen Denmark
| | - Mads Hornum
- Department of Nephrology; Rigshospitalet, University of Copenhagen; Copenhagen Denmark
| | - Gerrit van Hall
- Clinical Metabolomics Core Facility; Clinical Biochemistry, Rigshospitalet; University of Copenhagen; Copenhagen Denmark
| | - Claus Bistrup
- Department of Nephrology; Odense University Hospital; Odense Denmark
| | - Jesper M. Hansen
- Department of Nephrology; Herlev Hospital; University of Copenhagen; Copenhagen Denmark
| | - Elisabeth R. Mathiesen
- Department of Endocrinology; Rigshospitalet, University of Copenhagen; Copenhagen Denmark
| | - Bo Feldt-Rasmussen
- Department of Nephrology; Rigshospitalet, University of Copenhagen; Copenhagen Denmark
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Abstract
Glucocorticoid hormones (GC) regulate essential physiological functions including energy homeostasis, embryonic and postembryonic development, and the stress response. From the biomedical perspective, GC have garnered a tremendous amount of attention as highly potent anti-inflammatory and immunosuppressive medications indispensable in the clinic. GC signal through the GC receptor (GR), a ligand-dependent transcription factor whose structure, DNA binding, and the molecular partners that it employs to regulate transcription have been under intense investigation for decades. In particular, next-generation sequencing-based approaches have revolutionized the field by introducing a unified platform for a simultaneous genome-wide analysis of cellular activities at the level of RNA production, binding of transcription factors to DNA and RNA, and chromatin landscape and topology. Here we describe fundamental concepts of GC/GR function as established through traditional molecular and in vivo approaches and focus on the novel insights of GC biology that have emerged over the last 10 years from the rapidly expanding arsenal of system-wide genomic methodologies.
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Affiliation(s)
- Maria A Sacta
- Hospital for Special Surgery, The David Rosensweig Genomics Center, New York, NY 10021; .,Weill Cornell/Rockefeller/Sloan Kettering MD/PhD program, New York, NY 10021
| | - Yurii Chinenov
- Hospital for Special Surgery, The David Rosensweig Genomics Center, New York, NY 10021;
| | - Inez Rogatsky
- Hospital for Special Surgery, The David Rosensweig Genomics Center, New York, NY 10021; .,Weill Cornell/Rockefeller/Sloan Kettering MD/PhD program, New York, NY 10021
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Nicolau J, Lequerré T, Bacquet H, Vittecoq O. Rheumatoid arthritis, insulin resistance, and diabetes. Joint Bone Spine 2016; 84:411-416. [PMID: 27777170 DOI: 10.1016/j.jbspin.2016.09.001] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/14/2016] [Indexed: 12/16/2022]
Abstract
Recent progress in the management of rheumatoid arthritis (RA) is turning attention toward comorbidities, such as diabetes. The objectives of this review are to clarify the links between RA and diabetes and to assess potential effects of disease-modifying antirheumatic drugs (DMARDs) on diabetes. The increased insulin resistance seen in RA is closely linked to the systemic inflammation induced by certain proinflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin-6. The prevalence of type 2 diabetes is increased in patients with RA. Furthermore, certain DMARDs including hydroxychloroquine, methotrexate, TNFα antagonist, and interleukin-1β antagonists seem to improve the markers of glucose metabolism. In contrast, glucocorticoids tend to adversely affect glycemic control, particularly when taken chronically. Consequently, a crucial yet insufficiently applied rule is that cardiovascular risk factors must be sought and treated routinely, particularly as the choice of the DMARD may affect glucose metabolism.
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Affiliation(s)
- Julia Nicolau
- Service de rhumatologie, hôpital Charles-Nicolle, hôpitaux de Rouen, CHU, 76031 Rouen cedex, France
| | - Thierry Lequerré
- Service de rhumatologie, Inserm 905, institut de recherche et d'innovation biomédicales, CIC/CRB1404, université de Rouen, hôpitaux de Rouen, CHU, 76031 Rouen cedex, France.
| | - Hélène Bacquet
- Service de médecine interne, hôpital de Dieppe, 76200 Dieppe, France
| | - Olivier Vittecoq
- Service de rhumatologie, Inserm 905, institut de recherche et d'innovation biomédicales, CIC/CRB1404, université de Rouen, hôpitaux de Rouen, CHU, 76031 Rouen cedex, France
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Impact of Glucocorticoid Excess on Glucose Tolerance: Clinical and Preclinical Evidence. Metabolites 2016; 6:metabo6030024. [PMID: 27527232 PMCID: PMC5041123 DOI: 10.3390/metabo6030024] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 07/28/2016] [Accepted: 07/29/2016] [Indexed: 12/28/2022] Open
Abstract
Glucocorticoids (GCs) are steroid hormones that exert important physiological actions on metabolism. Given that GCs also exert potent immunosuppressive and anti-inflammatory actions, synthetic GCs such as prednisolone and dexamethasone were developed for the treatment of autoimmune- and inflammatory-related diseases. The synthetic GCs are undoubtedly efficient in terms of their therapeutic effects, but are accompanied by significant adverse effects on metabolism, specifically glucose metabolism. Glucose intolerance and reductions in insulin sensitivity are among the major concerns related to GC metabolic side effects, which may ultimately progress to type 2 diabetes mellitus. A number of pre-clinical and clinical studies have aimed to understand the repercussions of GCs on glucose metabolism and the possible mechanisms of GC action. This review intends to summarize the main alterations that occur in liver, skeletal muscle, adipose tissue, and pancreatic islets in the context of GC-induced glucose intolerance. For this, both experimental (animals) and clinical studies were selected and, whenever possible, the main cellular mechanisms involved in such GC-side effects were discussed.
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The hypertension of Cushing's syndrome: controversies in the pathophysiology and focus on cardiovascular complications. J Hypertens 2016; 33:44-60. [PMID: 25415766 PMCID: PMC4342316 DOI: 10.1097/hjh.0000000000000415] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cushing's syndrome is associated with increased mortality, mainly due to cardiovascular complications, which are sustained by the common development of systemic arterial hypertension and metabolic syndrome, which partially persist after the disease remission. Cardiovascular diseases and hypertension associated with endogenous hypercortisolism reveal underexplored peculiarities. The use of exogenous corticosteroids also impacts on hypertension and cardiovascular system, especially after prolonged treatment. The mechanisms involved in the development of hypertension differ, whether glucocorticoid excess is acute or chronic, and the source endogenous or exogenous, introducing inconsistencies among published studies. The pleiotropic effects of glucocorticoids and the overlap of the several regulatory mechanisms controlling blood pressure suggest that a rigorous comparison of in-vivo and in-vitro studies is necessary to draw reliable conclusions. This review, developed during the first ‘Altogether to Beat Cushing's syndrome’ workshop held in Capri in 2012, evaluates the most important peculiarities of hypertension associated with CS, with a particular focus on its pathophysiology. A critical appraisal of most significant animal and human studies is compared with a systematic review of the few available clinical trials. A special attention is dedicated to the description of the clinical features and cardiovascular damage secondary to glucocorticoid excess. On the basis of the consensus reached during the workshop, a pathophysiology-oriented therapeutic algorithm has been developed and it could serve as a first attempt to rationalize the treatment of hypertension in Cushing's syndrome.
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Nijhoff MF, Engelse MA, Dubbeld J, Braat AE, Ringers J, Roelen DL, van Erkel AR, Spijker HS, Bouwsma H, van der Boog PJM, de Fijter JW, Rabelink TJ, de Koning EJP. Glycemic Stability Through Islet-After-Kidney Transplantation Using an Alemtuzumab-Based Induction Regimen and Long-Term Triple-Maintenance Immunosuppression. Am J Transplant 2016; 16:246-53. [PMID: 26288226 DOI: 10.1111/ajt.13425] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 06/01/2015] [Accepted: 06/21/2015] [Indexed: 01/25/2023]
Abstract
Pancreatic islet transplantation is performed in a select group of patients with type 1 diabetes mellitus. Immunosuppressive regimens play an important role in long-term islet function. We aimed to investigate the efficacy of islet transplantation in patients with type 1 diabetes and a previous kidney transplantation using an alemtuzumab-based induction regimen and triple maintenance immunosuppression. Patients with type 1 diabetes, who had received a kidney transplant previously, were treated with alemtuzumab as induction therapy for their first islet transplantation and basiliximab induction therapy for subsequent islet transplantations. Maintenance immunosuppression consisted of triple immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone). Thirteen patients (age 50.9 ± 9.2 years, duration of diabetes 35 ± 9 years) received a total of 22 islet transplantations. One- and 2-year insulin independence was 62% and 42%, respectively; graft function was 100% and 92%, respectively. HbA1c dropped from 57.2 ± 13.1 (7.4 ± 1.2%) to 44.5 ± 11.8 mmol/molHb (6.2 ± 0.9%) (p = 0.003) after 2 years. Six of 13 patients suffered from severe hypoglycemia before islet transplantation. After transplantation, severe hypoglycemia was restricted to the only patient who lost graft function. Creatinine clearance was unchanged. Islet-after-kidney transplantation in patients with type 1 diabetes using an alemtuzumab-based induction regimen leads to considerable islet allograft function and improvement in glycemic control.
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Affiliation(s)
- M F Nijhoff
- Department of Medicine, Division of Endocrinology and Metabolism, Leiden University Medical Centre, Leiden, the Netherlands.,Division of Nephrology and Transplantation, Leiden University Medical Centre, Leiden, the Netherlands
| | - M A Engelse
- Division of Nephrology and Transplantation, Leiden University Medical Centre, Leiden, the Netherlands
| | - J Dubbeld
- Departments of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
| | - A E Braat
- Departments of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
| | - J Ringers
- Departments of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
| | - D L Roelen
- Immunohematology, Leiden University Medical Centre, Leiden, the Netherlands
| | - A R van Erkel
- Radiology, Leiden University Medical Centre, Leiden, the Netherlands
| | - H S Spijker
- Division of Nephrology and Transplantation, Leiden University Medical Centre, Leiden, the Netherlands
| | - H Bouwsma
- Division of Nephrology and Transplantation, Leiden University Medical Centre, Leiden, the Netherlands
| | - P J M van der Boog
- Division of Nephrology and Transplantation, Leiden University Medical Centre, Leiden, the Netherlands
| | - J W de Fijter
- Division of Nephrology and Transplantation, Leiden University Medical Centre, Leiden, the Netherlands
| | - T J Rabelink
- Division of Nephrology and Transplantation, Leiden University Medical Centre, Leiden, the Netherlands
| | - E J P de Koning
- Department of Medicine, Division of Endocrinology and Metabolism, Leiden University Medical Centre, Leiden, the Netherlands.,Division of Nephrology and Transplantation, Leiden University Medical Centre, Leiden, the Netherlands
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44
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Burt MG, Drake SM, Aguilar-Loza NR, Esterman A, Stranks SN, Roberts GW. Efficacy of a basal bolus insulin protocol to treat prednisolone-induced hyperglycaemia in hospitalised patients. Intern Med J 2015; 45:261-6. [PMID: 25565560 DOI: 10.1111/imj.12680] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 01/03/2015] [Indexed: 01/08/2023]
Abstract
BACKGROUND/AIM Few studies have specifically investigated treatment of prednisolone-induced hyperglycaemia. AIM To determine if a basal bolus insulin (BBI) protocol for inpatient hyperglycaemia is effective in patients prescribed acute prednisolone for an inflammatory disease. METHODS In a cross-sectional study, 66 patients with type 2 diabetes admitted to a general medical ward and treated with BBI for up to 5 days were studied. Twenty-four patients were taking prednisolone ≥10 mg/day to treat an acute inflammatory disease. The remaining 42 patients were a control group. The primary outcome was mean daily blood glucose level. RESULTS There were no significant differences in glycosylated haemoglobin (8.1 ± 1.0 vs 8.1 ± 1.6%, P = 0.88), age (77 ± 11 vs 75 ± 14 years, P = 0.57), male sex (63 vs 60%, P = 0.81) or body mass index (30.0 ± 5.3 vs 30.2 ± 11.5 kg/m(2) , P = 0.90) between patients taking prednisolone and controls. Mean daily glucose concentration was higher in patients taking prednisolone than in controls (12.2 ± 0.3 vs 10.0 ± 0.1 mmol/L, P < 0.001). Blood glucose level was higher in patients on prednisolone at 1700 h (14.6 ± 0.6 vs 10.3 ± 0.3 mmol/L, P < 0.001) and 2100 h (14.5 ± 0.6 vs 10.5 ± 0.3 mmol/L, P < 0.001), with no significant differences at 0700 h and 1200 h. These findings occurred despite patients taking prednisolone receiving a higher daily insulin dose than controls (0.67-0.70 vs 0.61-0.65 U/kg, P = 0.001) because of higher doses of ultra-rapid-acting insulin at 1200 h and 1700 h. CONCLUSIONS Hospitalised patients taking prednisolone had substantial afternoon and evening hyperglycaemia despite receiving BBI via a protocol for inpatient hyperglycaemia. Specific insulin regimens for prednisolone-induced hyperglycaemia are needed that recommend more insulin during this time period.
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Affiliation(s)
- M G Burt
- Southern Adelaide Diabetes and Endocrine Services, Repatriation General Hospital, Adelaide, South Australia, Australia; Faculty of Health Sciences, Flinders University, Adelaide, South Australia, Australia
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45
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Dube S, Slama MQ, Basu A, Rizza RA, Basu R. Glucocorticoid Excess Increases Hepatic 11β-HSD-1 Activity in Humans: Implications in Steroid-Induced Diabetes. J Clin Endocrinol Metab 2015; 100:4155-62. [PMID: 26308294 PMCID: PMC4702452 DOI: 10.1210/jc.2015-2673] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
CONTEXT Animal studies indicate that glucocorticoids increase hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) expression and activity. OBJECTIVE Our goal was to determine whether glucocorticoid excess increases cortisol production in the liver via 11β-HSD-1 enzyme pathway in humans. DESIGN A total of 1 mg each [4-(13)C] cortisone and [9,12,12-(2)H3] cortisol were ingested, and [1,2,6,7-(3)H] cortisol was infused to measure C13 cortisol (derived from ingested [4-(13)C] cortisone) turnover using the triple tracer technique, whereas glucose turnover was measured using isotope dilution technique following [6-6(2)H2] glucose infusion during a saline clamp. SETTING This study took place at the Mayo Clinic Clinical Research Unit. PARTICIPANTS Thirty nondiabetic healthy subjects participated. INTERVENTION Subjects were randomized to hydrocortisone (n = 15) or placebo 50 mg twice daily (n = 15) for 1 week. OUTCOME MEASURES Hepatic cortisol production and endogenous glucose production were measured. RESULTS Plasma cortisol concentrations were higher throughout the study period in hydrocortisone group. Rates of appearance of C13 cortisol and hepatic C13 cortisol production were higher in hydrocortisone vs placebo group, indicating increased hepatic 11β-HSD-1 activity. Higher plasma cortisol and presumably higher intrahepatic cortisol was associated with impaired suppression of endogenous glucose production in hydrocortisone vs placebo group. CONCLUSION Chronic glucocorticoid excess increases intrahepatic cortisone to cortisol conversion via the 11β-HSD-1 pathway. The extent to which this causes or exacerbates steroid induced hepatic insulin resistance remains to be determined.
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Affiliation(s)
- Simmi Dube
- Endocrine Research Unit (S.D., M.Q.S., A.B., R.A.R., R.B.), Division of Endocrinology, Diabetes, Nutrition; Mayo Clinic, Rochester, MN 55905
| | - Michael Q Slama
- Endocrine Research Unit (S.D., M.Q.S., A.B., R.A.R., R.B.), Division of Endocrinology, Diabetes, Nutrition; Mayo Clinic, Rochester, MN 55905
| | - Ananda Basu
- Endocrine Research Unit (S.D., M.Q.S., A.B., R.A.R., R.B.), Division of Endocrinology, Diabetes, Nutrition; Mayo Clinic, Rochester, MN 55905
| | - Robert A Rizza
- Endocrine Research Unit (S.D., M.Q.S., A.B., R.A.R., R.B.), Division of Endocrinology, Diabetes, Nutrition; Mayo Clinic, Rochester, MN 55905
| | - Rita Basu
- Endocrine Research Unit (S.D., M.Q.S., A.B., R.A.R., R.B.), Division of Endocrinology, Diabetes, Nutrition; Mayo Clinic, Rochester, MN 55905
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Langsford D, Dwyer K. Dysglycemia after renal transplantation: Definition, pathogenesis, outcomes and implications for management. World J Diabetes 2015; 6:1132-51. [PMID: 26322159 PMCID: PMC4549664 DOI: 10.4239/wjd.v6.i10.1132] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Revised: 07/06/2015] [Accepted: 08/16/2015] [Indexed: 02/05/2023] Open
Abstract
New-onset diabetes after transplantation (NODAT) is major complication following renal transplantation. It commonly develops within 3-6 mo post-transplantation. The development of NODAT is associated with significant increase in risk of major cardiovascular events and cardiovascular death. Other dysglycemic states, such as impaired glucose tolerance are also associated with increasing risk of cardiovascular events. The pathogenesis of these dysglycemic states is complex. Older recipient age is a consistent major risk factor and the impact of calcineurin inhibitors and glucocorticoids has been well described. Glucocorticoids likely cause insulin resistance and calcineurin inhibitors likely cause β-cell toxicity. The impact of transplantation in incretin hormones remains to be clarified. The oral glucose tolerance test remains the best diagnostic test but other tests may be validated as screening tests. Possibly, NODAT can be prevented by administering insulin early in patients identified as high risk for NODAT. Once NODAT has been diagnosed altering immunosuppression may be acceptable, but creates the difficulty of balancing immunological with metabolic risk. With regard to hypoglycemic use, metformin may be the best option. Further research is needed to better understand the pathogenesis, identify high risk patients and to improve management options given the significant increased risk of major cardiovascular events and death.
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Sato S, Saisho Y, Inaishi J, Kou K, Murakami R, Yamada T, Itoh H. Effects of Glucocorticoid Treatment on β- and α-Cell Mass in Japanese Adults With and Without Diabetes. Diabetes 2015; 64:2915-27. [PMID: 25883114 DOI: 10.2337/db15-0151] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 04/11/2015] [Indexed: 11/13/2022]
Abstract
The aim of this study was 1) to clarify β-cell regenerative capacity in the face of glucocorticoid (GC)-induced insulin resistance and 2) to clarify the change in β- and α-cell mass in GC-induced diabetes in humans. We obtained the pancreases from 100 Japanese autopsy case subjects. The case subjects were classified according to whether or not they had received GC therapy before death and the presence or absence of diabetes. Fractional β-cell area (%BCA) and α-cell area (%ACA) were quantified, and the relationship with GC therapy was evaluated. As a result, in case subjects without diabetes, there was no significant difference in %BCA between case subjects with and without GC therapy (1.66 ± 1.05% vs. 1.21 ± 0.59%, P = 0.13). %ACA was also not significantly different between the two groups. In case subjects with type 2 diabetes, %BCA and %ACA were both significantly reduced compared with control subjects without diabetes; however, neither %BCA nor %ACA was significantly decreased in case subjects with GC-induced diabetes. There was a significant negative correlation between %BCA and HbA1c measured before death; however, this relationship was attenuated in case subjects with GC therapy. In conclusion, the current study suggests that β- and α-cell mass remain largely unchanged in the face of GC-induced insulin resistance in Japanese individuals, implying limited capacity of β-cell regeneration in adult humans. The absence of apparent β-cell deficit in case subjects with GC-induced diabetes suggests that GC-induced diabetes is mainly caused by insulin resistance and/or β-cell dysfunction, but not necessarily a deficit of β-cell mass.
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Affiliation(s)
- Seiji Sato
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yoshifumi Saisho
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Jun Inaishi
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Kinsei Kou
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Rie Murakami
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Taketo Yamada
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hiroshi Itoh
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Katsuyama H, Sako A, Adachi H, Hamasaki H, Yanai H. Effects of 6-month sitagliptin treatment on metabolic parameters in diabetic patients taking oral glucocorticoids: a retrospective cohort study. J Clin Med Res 2015; 7:479-84. [PMID: 25883713 PMCID: PMC4394923 DOI: 10.14740/jocmr2153w] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2015] [Indexed: 12/20/2022] Open
Abstract
Background There are no guidelines for the treatment of diabetes in patients taking glucocorticoids. We studied to understand the effects of 6-month treatment with sitagliptin on metabolic parameters in diabetic patients taking glucocorticoids. Methods We retrospectively picked up patients who had been prescribed sitagliptin for 6 months during the continuous prescription of oral glucocorticoids between October 2010 and October 2013 by a chart-based analysis, and compared the data before the sitagliptin treatment with the data at 6 months after the sitagliptin treatment started. Results Fifteen patients were eligible for the analyses in our study. The plasma glucose and HbA1c levels were significantly reduced by the sitagliptin treatment. Furthermore, body weight significantly decreased. We found a significant and inverse correlation between the change in HbA1c levels and HbA1c levels at baseline. However, there was no significant correlation between the change in HbA1c levels and the daily glucocorticoid dose at baseline. Conclusions The present study demonstrated that sitagliptin significantly reduced plasma glucose, HbA1c and body weight. Further, sitagliptin was more effective to improve glycemic control in patients taking glucocorticoids with higher HbA1c levels, independently of the daily glucocorticoid dose.
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Affiliation(s)
- Hisayuki Katsuyama
- Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba 272-8516, Japan
| | - Akahito Sako
- Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba 272-8516, Japan ; Clinical Research Center, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba 272-8516, Japan
| | - Hiroki Adachi
- Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba 272-8516, Japan
| | - Hidetaka Hamasaki
- Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba 272-8516, Japan
| | - Hidekatsu Yanai
- Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba 272-8516, Japan ; Clinical Research Center, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba 272-8516, Japan
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Rao MN, Neylan TC, Grunfeld C, Mulligan K, Schambelan M, Schwarz JM. Subchronic sleep restriction causes tissue-specific insulin resistance. J Clin Endocrinol Metab 2015; 100:1664-71. [PMID: 25658017 PMCID: PMC4399283 DOI: 10.1210/jc.2014-3911] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
CONTEXT Short sleep duration is associated with an increased risk of type 2 diabetes. Subchronic sleep restriction (SR) causes insulin resistance, but the mechanisms and roles of specific tissues are unclear. OBJECTIVE The purpose of this article was to determine whether subchronic SR altered (1) hepatic insulin sensitivity, (2) peripheral insulin sensitivity, and (3) substrate utilization. DESIGN This was a randomized crossover study in which 14 subjects underwent 2 admissions separated by a washout period. Each admission had 2 acclimatization nights followed by 5 nights of either SR (4 hours time in bed) or normal sleep (8 hours time in bed). MAIN OUTCOME MEASURE/METHODS: Insulin sensitivity (measured by hyperinsulinemic-euglycemic clamp) and hepatic insulin sensitivity (measured by stable isotope techniques) were measured. In addition, we assayed stress hormone (24-hour urine free cortisol, metanephrine, and normetanephrine), nonesterified fatty acid (NEFA), and β-hydroxybutyrate (β-OH butyrate) levels. Resting energy expenditure (REE) and respiratory quotient (RQ) were measured by indirect calorimetry. RESULTS Compared to normal sleep, whole-body insulin sensitivity decreased by 25% (P = .008) with SR and peripheral insulin sensitivity decreased by 29% (P = .003). Whereas hepatic insulin sensitivity (endogenous glucose production) did not change significantly, percent gluconeogenesis increased (P = .03). Stress hormones increased modestly (cortisol by 21%, P = .04; metanephrine by 8%, P = .014; normetanephrine by 18%, P = .002). Fasting NEFA and β-OH butyrate levels increased substantially (62% and 55%, respectively). REE did not change (P = 0.98), but RQ decreased (0.81 ± .02 vs 0.75 ± 0.02, P = .045). CONCLUSION Subchronic SR causes unique metabolic disturbances characterized by peripheral, but not hepatic, insulin resistance; this was associated with a robust increase in fasting NEFA levels (indicative of increased lipolysis), decreased RQ, and increased β-OH butyrate levels (indicative of whole-body and hepatic fat oxidation, respectively). We postulate that elevated NEFA levels are partially responsible for the decrease in peripheral sensitivity and modulation of hepatic metabolism (ie, increase in gluconeogenesis without increase in endogenous glucose production). Elevated cortisol and metanephrine levels may contribute to insulin resistance by increasing lipolysis and NEFA levels.
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Affiliation(s)
- Madhu N Rao
- San Francisco Veterans Affairs Medical Center (M.N.R., T.C.N., C.G.), San Francisco, California 94121; Department of Medicine (M.N.R., C.G., K.M., M.S., J.-M.S.), Division of Endocrinology and Metabolism and Department of Psychiatry (T.C.N.), University of California, San Francisco, San Francisco, California 94143; and Touro University (J.-M.S.), Vallejo, California 94592
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Shaharir SS, Gafor AHA, Said MSM, Kong NCT. Steroid-induced diabetes mellitus in systemic lupus erythematosus patients: analysis from a Malaysian multi-ethnic lupus cohort. Int J Rheum Dis 2014; 18:541-7. [DOI: 10.1111/1756-185x.12474] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
| | | | | | - Norella C. T. Kong
- Nephrology; Universiti Kebangsaan Malaysia Medical Centre; Kuala Lumpur Malaysia
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