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Li HY, Wang Y, Ran M, Gao F, Zhu BY, Xiao HY, Xu C. Tacrolimus induces insulin receptor substrate 1 hyperphosphorylation and inhibits mTORc1/S6K1 cascade in HL7702 cells. World J Diabetes 2025; 16:97910. [PMID: 39959267 PMCID: PMC11718479 DOI: 10.4239/wjd.v16.i2.97910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/28/2024] [Accepted: 11/13/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Tacrolimus (FK506) is a key calcineurin inhibitor used to prevent organ transplant rejection and is effective in improving graft survival. However, it is linked to hyperglycemia and insulin resistance, contributing to new-onset diabetes after transplantation and negatively affecting islet function. AIM To study the effects of tacrolimus on the insulin signaling pathway of hepatocytes. METHODS HL7702 cells were treated with different concentrations of tacrolimus (0.1 mg/L, 1 mg/L, 5 mg/L) for 24 hours. The proteins involved in insulin signaling were detected by Western blotting. RESULTS Compared with the control group, phosphorylation of insulin receptor substrate (IRS) 1 at Ser 307 and Ser 323 were increased significantly when the tacrolimus concentration reached 1 and 5 mg/L. Phosphorylation of IRS1 at Ser 1101 was also increased, although not significantly. However, phosphorylation of Ribosomal protein S6 kinase beta-1 at Thr 389 was decreased significantly. The levels of phosphorylated glycogen synthase kinase 3α Ser 21 and Ser 9 were increased. Surprisingly, phosphorylation of glycogen synthase at Ser 641 was increased. There was no significant change in the activity of glycogen phosphorylase. CONCLUSION Tacrolimus has no direct effect on hepatic glucose metabolism, but inhibits IRS1-mediated insulin signaling. This may be one of the underlying mechanisms by which tacrolimus induces insulin resistance.
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Affiliation(s)
- Hao-Yan Li
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
| | - Yi Wang
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
| | - Min Ran
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
| | - Fei Gao
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
| | - Bo-Yu Zhu
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
| | - Hai-Ying Xiao
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
| | - Chun Xu
- Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
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Batista EK, de Lima LMA, Gomes DA, Crans DC, Silva WE, Belian MF, Lira EC. Dexamethasone-Induced Insulin Resistance Attenuation by Oral Sulfur-Oxidovanadium(IV) Complex Treatment in Mice. Pharmaceuticals (Basel) 2024; 17:760. [PMID: 38931427 PMCID: PMC11206843 DOI: 10.3390/ph17060760] [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: 05/09/2024] [Revised: 05/28/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024] Open
Abstract
Vanadium compounds are known to exert insulin-enhancing activity, normalize elevated blood glucose levels in diabetic subjects, and show significant activity in models of insulin resistance (IR). Faced with insulin resistance, the present work investigates the antidiabetic performance of a known oxidovanadium(IV)-based coordination compound-[VIVO(octd)]-and effects associated with glucocorticoid-induced insulin resistance in mice. The effects of [VIVO(octd)] were evaluated in a female Swiss mice model of insulin resistance induced by seven days of dexamethasone treatment in comparison with groups receiving metformin treatment. Biological assays such as hematological, TyG index, hepatic lipids, glycogen, oxidative stress in the liver, and oral glucose tolerance tests were evaluated. [VIVO(octd)] was characterized with 51V NMR, infrared spectroscopy (FTIR), electron paramagnetic resonance (EPR), electronic absorption spectroscopy, and mass spectrometry (ESI-FT-MS). The [VIVO(octd)] oral treatment (50 mg/kg) had an antioxidant effect, reducing 50% of fast blood glucose (p < 0.05) and 25% of the TyG index, which is used to estimate insulin resistance (p < 0.05), compared with the non-treated group. The oxidovanadium-sulfur compound is a promising antihyperglycemic therapeutic, including in cases aggravated by insulin resistance induced by glucocorticoid treatment.
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Affiliation(s)
- Eucilene K. Batista
- Departamento de Fisiologia e Farmacologia, Centro de Biociências, Universidade Federal de Pernambuco, Recife 50670-901, PE, Brazil; (E.K.B.); (D.A.G.); (E.C.L.)
| | - Lidiane M. A. de Lima
- Departamento de Química, Universidade Federal Rural de Pernambuco, Recife 52171-900, PE, Brazil; (L.M.A.d.L.); (W.E.S.)
| | - Dayane A. Gomes
- Departamento de Fisiologia e Farmacologia, Centro de Biociências, Universidade Federal de Pernambuco, Recife 50670-901, PE, Brazil; (E.K.B.); (D.A.G.); (E.C.L.)
| | - Debbie C. Crans
- Department of Chemistry, Colorado State University, Fort Collins, CO 80513, USA
- Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO 80513, USA
| | - Wagner E. Silva
- Departamento de Química, Universidade Federal Rural de Pernambuco, Recife 52171-900, PE, Brazil; (L.M.A.d.L.); (W.E.S.)
| | - Mônica F. Belian
- Departamento de Química, Universidade Federal Rural de Pernambuco, Recife 52171-900, PE, Brazil; (L.M.A.d.L.); (W.E.S.)
| | - Eduardo C. Lira
- Departamento de Fisiologia e Farmacologia, Centro de Biociências, Universidade Federal de Pernambuco, Recife 50670-901, PE, Brazil; (E.K.B.); (D.A.G.); (E.C.L.)
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Bavaresco A, Mazzeo P, Lazzara M, Barbot M. Adipose tissue in cortisol excess: What Cushing's syndrome can teach us? Biochem Pharmacol 2024; 223:116137. [PMID: 38494065 DOI: 10.1016/j.bcp.2024.116137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/14/2024] [Accepted: 03/14/2024] [Indexed: 03/19/2024]
Abstract
Endogenous Cushing's syndrome (CS) is a rare condition due to prolonged exposure to elevated circulating cortisol levels that features its typical phenotype characterised by moon face, proximal myopathy, easy bruising, hirsutism in females and a centripetal distribution of body fat. Given the direct and indirect effects of hypercortisolism, CS is a severe disease burdened by increased cardio-metabolic morbidity and mortality in which visceral adiposity plays a leading role. Although not commonly found in clinical setting, endogenous CS is definitely underestimated leading to delayed diagnosis with consequent increased rate of complications and reduced likelihood of their reversal after disease control. Most of all, CS is a unique model for systemic impairment induced by exogenous glucocorticoid therapy that is commonly prescribed for a number of chronic conditions in a relevant proportion of the worldwide population. In this review we aim to summarise on one side, the mechanisms behind visceral adiposity and lipid metabolism impairment in CS during active disease and after remission and on the other explore the potential role of cortisol in promoting adipose tissue accumulation.
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Affiliation(s)
- Alessandro Bavaresco
- Department of Medicine DIMED, University of Padua, Padua, Italy; Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padua, Padua, Italy
| | - Pierluigi Mazzeo
- Department of Medicine DIMED, University of Padua, Padua, Italy; Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padua, Padua, Italy
| | - Martina Lazzara
- Department of Medicine DIMED, University of Padua, Padua, Italy; Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padua, Padua, Italy
| | - Mattia Barbot
- Department of Medicine DIMED, University of Padua, Padua, Italy; Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padua, Padua, Italy.
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Delangre E, Pommier G, Tolu S, Uzan B, Bailbé D, Movassat J. Lithium treatment mitigates the diabetogenic effects of chronic cortico-therapy. Biomed Pharmacother 2023; 164:114895. [PMID: 37224758 DOI: 10.1016/j.biopha.2023.114895] [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: 03/23/2023] [Revised: 05/09/2023] [Accepted: 05/13/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND AND PURPOSE Glucocorticoids (GCs) are the main treatment for autoimmune and inflammatory disorders and are also used as immunosuppressive therapy for patients with organ transplantation. However, these treatments have several side effects, including metabolic disorders. Indeed, cortico-therapy may induce insulin resistance, glucose intolerance, disrupted insulin and glucagon secretion, excessive gluconeogenesis, leading to diabetes in susceptible individuals. Recently, lithium has been shown to alleviate deleterious effects of GCs in various diseased conditions. EXPERIMENTAL APPROACH In this study, using two rat models of GC-induced metabolic disorders, we investigated the effects of Lithium Chloride (LiCl) in the mitigation of deleterious effects of GCs. Rats were treated either with corticosterone or dexamethasone, and with or without LiCl. Animals were then assessed for glucose tolerance, insulin sensitivity, in vivo and ex vivo glucose-induced insulin secretion and hepatic gluconeogenesis. KEY RESULTS We showed that in rats chronically treated with corticosterone, lithium treatment markedly reduced insulin resistance. In addition, in rats treated with dexamethasone, lithium administration improved glucose tolerance, associated with enhanced insulin secretion in vivo. Moreover, liver gluconeogenesis was reduced upon LiCl treatment. The improvement of insulin secretion in vivo appeared to be due to an indirect regulation of β cell function, since the ex vivo assessment of insulin secretion and β cell mass in islets from animals treated with LiCl revealed no difference compared to untreated animals. CONCLUSION AND IMPLICATIONS Collectively, our data provide evidences for the beneficial effects of lithium to mitigate the adverse metabolic effects of chronic cortico-therapy.
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Affiliation(s)
- Etienne Delangre
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France
| | - Gaëlle Pommier
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France; Université Paris Cité, UFR Sciences du Vivant, F-75013 Paris, France
| | - Stefania Tolu
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France
| | - Benjamin Uzan
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France
| | - Danielle Bailbé
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France
| | - Jamileh Movassat
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France.
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Zhu JL, Hong L, Yuan SQ, Xu XM, Wei JR, Yin HY. Association between glucocorticoid use and all-cause mortality in critically ill patients with heart failure: A cohort study based on the MIMIC-III database. Front Pharmacol 2023; 14:1118551. [PMID: 36713831 PMCID: PMC9877223 DOI: 10.3389/fphar.2023.1118551] [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: 12/07/2022] [Accepted: 01/02/2023] [Indexed: 01/13/2023] Open
Abstract
Background: Heart failure (HF) is the terminal stage of various heart diseases. Conventional treatments have poor efficacy, and diuretic resistance can present. Previous studies have found that the use of glucocorticoids can enhance the diuretic effect of patients with heart failure and reduce heart failure symptoms. However, the relationship between glucocorticoid use and mortality in patients with heart failure in intensive care units is unclear. Objectives: The aim of this study was to determine the association between glucocorticoid use and all-cause mortality in critically ill patients with heart failure. Methods: The information on patients with heart failure in this study was extracted from the MIMIC-III (Medical Information Mart for Intensive Care-III) database. Patients in the glucocorticoid and non-glucocorticoid groups were matched using propensity scores. The Kaplan-Meier method was used to explore the difference in survival probability between the two groups. A Cox proportional-hazards regression model was used to analyze the hazard ratios (HRs) for the two patient groups. Subgroup analyses were performed with prespecified stratification variables to demonstrate the robustness of the results. Results: The study included 9,482 patients: 2,099 in the glucocorticoid group and 7,383 in the non-glucocorticoid group. There were 2,055 patients in each group after propensity-score matching. The results indicated that the non-glucocorticoid group was not significantly associated with reduced mortality in patients with heart failure during the 14-day follow-up period [HRs = .901, 95% confidence interval (CI) = .767-1.059]. During the follow-up periods of 15-30 and 15-90 days, the mortality risk was significantly lower in the non-glucocorticoid group than in the glucocorticoid group (HRs = .497 and 95% CI = .370-.668, and HRs = .400 and 95% CI = .310-.517, respectively). Subgroup analyses indicated no interaction among each stratification variable and glucocorticoid use. Conclusion: Glucocorticoid use was associated with an increased mortality risk in critically ill patients with heart failure.
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Affiliation(s)
- Jia-Liang Zhu
- Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China,Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Liang Hong
- Department of Intensive Care Unit, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Shi-Qi Yuan
- Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Xiao-Mei Xu
- Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China,Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jian-Rui Wei
- Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China,*Correspondence: Jian-Rui Wei, ; Hai-Yan Yin,
| | - Hai-Yan Yin
- Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China,*Correspondence: Jian-Rui Wei, ; Hai-Yan Yin,
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Mehlich A, Bolanowski M, Mehlich D, Witek P. Medical treatment of Cushing's disease with concurrent diabetes mellitus. Front Endocrinol (Lausanne) 2023; 14:1174119. [PMID: 37139336 PMCID: PMC10150952 DOI: 10.3389/fendo.2023.1174119] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
Abstract
Cushing's disease (CD) is a severe endocrine disorder characterized by chronic hypercortisolaemia secondary to an overproduction of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. Cortisol excess impairs normal glucose homeostasis through many pathophysiological mechanisms. The varying degrees of glucose intolerance, including impaired fasting glucose, impaired glucose tolerance, and Diabetes Mellitus (DM) are commonly observed in patients with CD and contribute to significant morbidity and mortality. Although definitive surgical treatment of ACTH-secreting tumors remains the most effective therapy to control both cortisol levels and glucose metabolism, nearly one-third of patients present with persistent or recurrent disease and require additional treatments. In recent years, several medical therapies demonstrated prominent clinical efficacy in the management of patients with CD for whom surgery was non-curative or for those who are ineligible to undergo surgical treatment. Cortisol-lowering medications may have different effects on glucose metabolism, partially independent of their role in normalizing hypercortisolaemia. The expanding therapeutic landscape offers new opportunities for the tailored therapy of patients with CD who present with glucose intolerance or DM, however, additional clinical studies are needed to determine the optimal management strategies. In this article, we discuss the pathophysiology of impaired glucose metabolism caused by cortisol excess and review the clinical efficacy of medical therapies of CD, with particular emphasis on their effects on glucose homeostasis.
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Affiliation(s)
- Anna Mehlich
- Department of Internal Medicine, Endocrinology and Diabetes, Medical University of Warsaw, Warsaw, Poland
| | - Marek Bolanowski
- Chair and Department of Endocrinology, Diabetes, and Isotope Treatment, Wroclaw Medical University, Wroclaw, Poland
| | - Dawid Mehlich
- Laboratory of Molecular OncoSignalling, International Institute of Molecular Mechanisms and Machines (IMol) Polish Academy of Sciences, Warsaw, Poland
- Doctoral School of Medical University of Warsaw, Medical University of Warsaw, Warsaw, Poland
- Laboratory of Experimental Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Przemysław Witek
- Department of Internal Medicine, Endocrinology and Diabetes, Medical University of Warsaw, Warsaw, Poland
- *Correspondence: Przemysław Witek,
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Sultana N, Islam R, Das RR, Haque Z, Rafiq K, Khan MAHNA. Steroid growth promoter modified glucose profile and liver morphology in broiler by altering the localization and expression pattern of hepatic glucocorticoid receptors. Res Vet Sci 2022; 152:277-288. [DOI: 10.1016/j.rvsc.2022.08.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 08/21/2022] [Accepted: 08/23/2022] [Indexed: 01/08/2023]
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Nishiyama M, Iwasaki Y, Makino S. Animal Models of Cushing's Syndrome. Endocrinology 2022; 163:6761324. [PMID: 36240318 DOI: 10.1210/endocr/bqac173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Indexed: 11/19/2022]
Abstract
Endogenous Cushing's syndrome is characterized by unique clinical features and comorbidities, and progress in the analysis of its genetic pathogenesis has been achieved. Moreover, prescribed glucocorticoids are also associated with exogenous Cushing's syndrome. Several animal models have been established to explore the pathophysiology and develop treatments for Cushing's syndrome. Here, we review recent studies reporting animal models of Cushing's syndrome with different features and complications induced by glucocorticoid excess. Exogenous corticosterone (CORT) administration in drinking water is widely utilized, and we found that CORT pellet implantation in mice successfully leads to a Cushing's phenotype. Corticotropin-releasing hormone overexpression mice and adrenal-specific Prkar1a-deficient mice have been developed, and AtT20 transplantation methods have been designed to examine the medical treatments for adrenocorticotropic hormone-producing pituitary neuroendocrine tumors. We also review recent advances in the molecular pathogenesis of glucocorticoid-induced complications using animal models.
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Affiliation(s)
- Mitsuru Nishiyama
- Health Care Center, Kochi University, Kochi city, Kochi 780-8520, Japan
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku city, Kochi 783-8505, Japan
| | - Yasumasa Iwasaki
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku city, Kochi 783-8505, Japan
- Department of Clinical Nutrition, Faculty of Health Science, Suzuka University of Medical Science, Suzuka city, Mie 510-0293Japan
| | - Shinya Makino
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku city, Kochi 783-8505, Japan
- Department of Internal Medicine, Osaka Gyomeikan Hospital, Osaka city, Osaka 554-0012Japan
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Salehidoost R, Korbonits M. Glucose and lipid metabolism abnormalities in Cushing's syndrome. J Neuroendocrinol 2022; 34:e13143. [PMID: 35980242 DOI: 10.1111/jne.13143] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 04/15/2022] [Indexed: 11/30/2022]
Abstract
Prolonged excess of glucocorticoids (GCs) has adverse systemic effects leading to significant morbidities and an increase in mortality. Metabolic alterations associated with the high level of the GCs are key risk factors for the poor outcome. These include GCs causing excess gluconeogenesis via upregulation of key enzymes in the liver, a reduction of insulin sensitivity in skeletal muscle, liver and adipose tissue by inhibiting the insulin receptor signalling pathway, and inhibition of insulin secretion in beta cells leading to dysregulated glucose metabolism. In addition, chronic GC exposure leads to an increase in visceral adipose tissue, as well as an increase in lipolysis resulting in higher circulating free fatty acid levels and in ectopic fat deposition. Remission of hypercortisolism improves these metabolic changes, but very often does not result in full resolution of the abnormalities. Therefore, long-term monitoring of metabolic variables is needed even after the resolution of the excess GC levels.
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Affiliation(s)
- Rezvan Salehidoost
- Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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10
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Speelman T, Dale L, Louw A, Verhoog NJD. The Association of Acute Phase Proteins in Stress and Inflammation-Induced T2D. Cells 2022; 11:2163. [PMID: 35883605 PMCID: PMC9321356 DOI: 10.3390/cells11142163] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/02/2022] [Accepted: 07/04/2022] [Indexed: 02/06/2023] Open
Abstract
Acute phase proteins (APPs), such as plasminogen activator inhibitor-1 (PAI-1), serum amyloid A (SAA), and C-reactive protein (CRP), are elevated in type-2 diabetes (T2D) and are routinely used as biomarkers for this disease. These APPs are regulated by the peripheral mediators of stress (i.e., endogenous glucocorticoids (GCs)) and inflammation (i.e., pro-inflammatory cytokines), with both implicated in the development of insulin resistance, the main risk factor for the development of T2D. In this review we propose that APPs, PAI-1, SAA, and CRP, could be the causative rather than only a correlative link between the physiological elements of risk (stress and inflammation) and the development of insulin resistance.
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Affiliation(s)
| | | | | | - Nicolette J. D. Verhoog
- Biochemistry Department, Stellenbosch University, Van der Byl Street, Stellenbosch 7200, South Africa; (T.S.); (L.D.); (A.L.)
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11
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Saleh SR, Manaa A, Sheta E, Ghareeb DA, Abd-Elmonem NM. The Synergetic Effect of Egyptian Portulaca oleracea L. (Purslane) and Cichorium intybus L. (Chicory) Extracts against Glucocorticoid-Induced Testicular Toxicity in Rats through Attenuation of Oxidative Reactions and Autophagy. Antioxidants (Basel) 2022; 11:antiox11071272. [PMID: 35883763 PMCID: PMC9311541 DOI: 10.3390/antiox11071272] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 12/10/2022] Open
Abstract
Long-term glucocorticoids can alter sperm motility, vitality, or morphology, disrupting male reproductive function. This study scrutinized the synergistic benefits of two Egyptian plants against dexamethasone (Dexa)-induced testicular and autophagy dysfunction in male rats. Phytochemical ingredients and the combination index were estimated for Purslane ethanolic extract (PEE) and Chicory water extract (CWE). Four control groups received saline and 100 mg/kg of each PEE, CWE, and PEE/CWE, daily for 8 weeks. Dexa (1 mg/kg daily for 6 weeks) induced infertility where PEE, CWE, and PEE/CWE were given. Seminal analysis, male hormones, glycemic and oxidative stress markers, endoplasmic reticulum (ER) stress markers (Sigma 1R and GRP78), and autophagy regulators (Phospho-mTOR, LC3I/II, PI3KC3, and Beclin-1, P62, ATG5, and ATG7) were measured. The in vitro study illustrated the synergistic (CI < 1) antioxidant capacity of the PEE/CWE combination. Dexa exerts testicular damage by inducing oxidative reactions, a marked reduction in serum testosterone, TSH and LH levels, insulin resistance, ER stress, and autophagy. In contrast, the PEE and CWE extracts improve fertility hormones, sperm motility, and testicular histological alterations through attenuating oxidative stress and autophagy, with a synergistic effect upon combination. In conclusion, the administration of PEE/CWE has promised ameliorative impacts on male infertility and can delay disease progression.
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Affiliation(s)
- Samar R. Saleh
- Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21515, Egypt; (A.M.); (D.A.G.); (N.M.A.-E.)
- Correspondence: or ; Tel.: +20-122-573-2849; Fax: +2-(03)-391-1794
| | - Ashraf Manaa
- Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21515, Egypt; (A.M.); (D.A.G.); (N.M.A.-E.)
| | - Eman Sheta
- Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria 21131, Egypt;
| | - Doaa A. Ghareeb
- Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21515, Egypt; (A.M.); (D.A.G.); (N.M.A.-E.)
| | - Nihad M. Abd-Elmonem
- Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21515, Egypt; (A.M.); (D.A.G.); (N.M.A.-E.)
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Flis DJ, Bialobrodzka EG, Rodziewicz-Flis EA, Jost Z, Borkowska A, Ziolkowski W, Kaczor JJ. The Effect of Long-Lasting Swimming on Rats Skeletal Muscles Energy Metabolism after Nine Days of Dexamethasone Treatment. Int J Mol Sci 2022; 23:748. [PMID: 35054933 PMCID: PMC8775511 DOI: 10.3390/ijms23020748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/04/2022] [Accepted: 01/08/2022] [Indexed: 12/04/2022] Open
Abstract
This study investigates the effect of Dexamethasone (Dex) treatment on blood and skeletal muscle metabolites level and skeletal muscle activity of enzymes related to energy metabolism after long-duration swimming. To evaluate whether Dex treatment, swimming, and combining these factors act on analyzed data, rats were randomly divided into four groups: saline treatment non-exercise and exercise and Dex treatment non-exercised and exercised. Animals in both exercised groups underwent long-lasting swimming. The concentration of lipids metabolites, glucose, and lactate were measured in skeletal muscles and blood according to standard colorimetric and fluorimetric methods. Also, activities of enzymes related to aerobic and anaerobic metabolism were measured in skeletal muscles. The results indicated that Dex treatment induced body mass loss and increased lipid metabolites in the rats' blood but did not alter these changes in skeletal muscles. Interestingly, prolonged swimming applied after 9 days of Dex treatment significantly intensified changes induced by Dex; however, there was no difference in skeletal muscle enzymatic activities. This study shows for the first time the cumulative effect of exercise and Dex on selected elements of lipid metabolism, which seems to be essential for the patient's health due to the common use of glucocorticoids like Dex.
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Affiliation(s)
- Damian Jozef Flis
- Department of Pharmaceutical Pathophysiology, Faculty of Pharmacy, Medical University of Gdansk, Dębinki 7 Street, 80-211 Gdansk, Poland
| | | | - Ewa Aleksandra Rodziewicz-Flis
- Department of Basic Physiotherapy, Gdansk University of Physical Education and Sport, K. Gorkiego 1 Street, 80-336 Gdansk, Poland;
| | - Zbigniew Jost
- Department of Biochemistry, Gdansk University of Physical Education and Sport, K. Gorkiego 1 Street, 80-336 Gdansk, Poland;
| | - Andzelika Borkowska
- Department of Bioenergetics and Physiology of Exercise, Faculty of Health Sciences, Medical University of Gdansk, Dębinki 1 Street, 80-211 Gdansk, Poland;
| | - Wieslaw Ziolkowski
- Department of Rehabilitation Medicine, Faculty of Health Sciences, Medical University of Gdansk, Al. Zwycięstwa 30, 80-219 Gdansk, Poland;
| | - Jan Jacek Kaczor
- Department of Animal and Human Physiology, University of Gdansk, J. Bazynskiego 8 Street, 80-308 Gdansk, Poland;
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13
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Distinct mechanisms involving diacylglycerol, ceramides, and inflammation underlie insulin resistance in oxidative and glycolytic muscles from high fat-fed rats. Sci Rep 2021; 11:19160. [PMID: 34580412 PMCID: PMC8476522 DOI: 10.1038/s41598-021-98819-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 09/07/2021] [Indexed: 12/16/2022] Open
Abstract
This study investigated whether oxidative and glycolytic rat skeletal muscles respond differently to a high-fat (HF) sucrose-enriched diet with respect to diacylglycerol (DAG) and ceramides accumulation, protein kinase C (PKC) activation, glucose metabolism, and the expression of inflammatory genes. HF diet (8 weeks) suppressed insulin-stimulated glycogen synthesis and glucose oxidation in soleus (Sol), extensor digitorum longus (EDL) and epitrochlearis (Epit) muscles. However, DAG and ceramides levels increased in Sol and EDL, but not in Epit muscles of HF-fed rats. Additionally, membrane-bound PKC-delta and PKC-theta increased in Sol and EDL, whereas in Epit muscles both PKC isoforms were reduced by HF diet. In Epit muscles, HF diet also increased the expression of tumor necrosis factor-α (TNF-α) receptors (CD40 and FAS), toll-like receptor 4 (TLR4), and nuclear factor kappa light polypeptide gene enhancer in B cells (NF-kB), whereas in Sol and EDL muscles the expression of these inflammatory genes remained unchanged upon HF feeding. In conclusion, HF diet caused DAG and ceramides accumulation, PKC activation, and the induction of inflammatory pathways in a fiber type-specific manner. These findings help explain why oxidative and glycolytic muscles similarly develop insulin resistance, despite major differences in their metabolic characteristics and responsiveness to dietary lipid abundance.
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14
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Song MK, Kim YJ, Kim SH, Yeo SG, Kim YJ. Environmental enrichment modulates silent information regulator 1 (SIRT1) activity to attenuate central presbycusis in a rat model of normal aging. Exp Gerontol 2021; 155:111552. [PMID: 34530105 DOI: 10.1016/j.exger.2021.111552] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/21/2021] [Accepted: 08/31/2021] [Indexed: 11/15/2022]
Abstract
Age-related hearing loss (ARHL) is sensory impairment in the elderly. This study aimed to identify a critical molecular mechanism that can maintain young phenotypes. We focused on the effect of exposure to environmental enrichment (EE) for 12 weeks in the central auditory pathway and limbic system of aged rats. The effects of EE were compared with the effects of dexamethasone administration. We found that in 74-week-old rats hearing function was significantly reduced and the number of neuronal specific nuclear protein (NeuN)-positive cells was decreased by 10-15% in the auditory cortex, amygdala, and hippocampus. EE exposure did not significantly affect the number of neurons, but DX administration significantly decreased their numbers in the amygdala compared with untreated aged rats. Both treatments reduced inducible nitric oxide synthase (iNOS) expression in the auditory pathway and limbic system. Exposure to EE significantly increased silent information regulator 1 (SIRT1) expression and activity, and nicotinamide phosphoribosyltransferase (NAMPT) concentration. In this study, the exposure to EE resulted in attenuated age-related hearing loss accompanied by reduction of iNOS expression and increase SIRT1 activity and NAMPT level. These data showed that EE may be a potential therapeutic to prevent ARHL.
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Affiliation(s)
- Min Kyung Song
- Department of Nursing, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Yoon Ju Kim
- Department of Nursing, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Sang Hoon Kim
- Department of Otorhinolaryngology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Seung Geun Yeo
- Department of Otorhinolaryngology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
| | - Youn-Jung Kim
- College of Nursing Science, Kyung Hee University·East-West Nursing Research Institute, Seoul, Republic of Korea.
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15
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Chen F, Hao L, Zhu S, Yang X, Shi W, Zheng K, Wang T, Chen H. Potential Adverse Effects of Dexamethasone Therapy on COVID-19 Patients: Review and Recommendations. Infect Dis Ther 2021; 10:1907-1931. [PMID: 34296386 PMCID: PMC8298044 DOI: 10.1007/s40121-021-00500-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022] Open
Abstract
In the context of the coronavirus disease 2019 (COVID-19) pandemic, the global healthcare community has raced to find effective therapeutic agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, dexamethasone is the first and an important therapeutic to significantly reduce the risk of death in COVID-19 patients with severe disease. Due to powerful anti-inflammatory and immunosuppressive effects, dexamethasone could attenuate SARS-CoV-2-induced uncontrolled cytokine storm, severe acute respiratory distress syndrome and lung injury. Nevertheless, dexamethasone treatment is a double-edged sword, as numerous studies have revealed that it has significant adverse impacts later in life. In this article, we reviewed the literature regarding the adverse effects of dexamethasone administration on different organ systems as well as related disease pathogenesis in an attempt to clarify the potential harms that may arise in COVID-19 patients receiving dexamethasone treatment. Overall, taking the threat of COVID19 pandemic into account, we think it is necessary to apply dexamethasone as a pharmaceutical therapy in critical patients. However, its adverse side effects cannot be ignored. Our review will help medical professionals in the prognosis and follow-up of patients treated with dexamethasone. In addition, given that a considerable amount of uncertainty, confusion and even controversy still exist, further studies and more clinical trials are urgently needed to improve our understanding of the parameters and the effects of dexamethasone on patients with SARS-CoV-2 infection.
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Affiliation(s)
- Fei Chen
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China.
| | - Lanting Hao
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
| | - Shiheng Zhu
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
| | - Xinyuan Yang
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
| | - Wenhao Shi
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
| | - Kai Zheng
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
| | - Tenger Wang
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
| | - Huiran Chen
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
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16
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Chronic glucocorticoid treatment induces hepatic lipid accumulation and hyperinsulinaemia in part through actions on AgRP neurons. Sci Rep 2021; 11:13776. [PMID: 34215821 PMCID: PMC8253818 DOI: 10.1038/s41598-021-93378-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 06/04/2021] [Indexed: 11/08/2022] Open
Abstract
Glucocorticoids (GCs) are widely prescribed anti-inflammatory medicines, but their use can lead to metabolic side-effects. These may occur through direct actions of GCs on peripheral organs, but could also be mediated by the hypothalamic AgRP neurons, which can increase food intake and modify peripheral metabolism. Therefore, the aim of this study was to examine the metabolic effects of chronic treatment with the GC corticosterone (Cort, 75 μg/ml in drinking water) in mice lacking the glucocorticoid receptor (GR) on AgRP neurons. Female AgRP-GR KO mice had delayed onset of Cort-induced hyperphagia. However, AgRP-GR KO had little impact on the increased body weight or adiposity seen with 3 weeks Cort treatment. Cort caused hepatic steatosis in control mice, but in Cort treated female AgRP-GR KO mice there was a 25% reduction in liver lipid content and lower plasma triglycerides. Additionally, Cort treatment led to hyperinsulinaemia, but compared to controls, Cort-treated AgRP-GR KO mice had both lower fasting insulin levels and lower insulin levels during a glucose tolerance test. In conclusion, these data indicate that GCs do act through AgRP neurons to contribute, at least in part, to the adverse metabolic consequences of chronic GC treatment.
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17
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Zhang F, Karam JG. Glycemic Profile of Intravenous Dexamethasone-Induced Hyperglycemia Using Continuous Glucose Monitoring. AMERICAN JOURNAL OF CASE REPORTS 2021; 22:e930733. [PMID: 33907174 PMCID: PMC8088783 DOI: 10.12659/ajcr.930733] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Patient: Female, 70-year-old Final Diagnosis: Diabetes mellitus type 2 • pancreatic adenocarcinoma Symptoms: Hyperglycemia Medication: Insulin • Dexamethasone Clinical Procedure: Continuous glucose monitoring (CGM) Specialty: Endocrinology • Diabetes and Metabolism
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Affiliation(s)
- Fan Zhang
- Division of Endocrinology, Diabetes and Metabolism, State University of New York, Downstate Medical Center, Brooklyn, NY, USA.,Division of Endocrinology, Diabetes and Metabolism, Brookdale University Hospital Medical Center, Brooklyn, NY, USA
| | - Jocelyne G Karam
- Division of Endocrinology, Diabetes and Metabolism, State University of New York, Downstate Medical Center, Brooklyn, NY, USA.,Division of Endocrinology, Diabetes and Metabolism, Maimonides Medical Center, Brooklyn, NY, USA
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18
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The 'Jekyll and Hyde' of Gluconeogenesis: Early Life Adversity, Later Life Stress, and Metabolic Disturbances. Int J Mol Sci 2021; 22:ijms22073344. [PMID: 33805856 PMCID: PMC8037741 DOI: 10.3390/ijms22073344] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/18/2021] [Accepted: 03/23/2021] [Indexed: 01/06/2023] Open
Abstract
The physiological response to a psychological stressor broadly impacts energy metabolism. Inversely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal axis (HPA), and sympathetic nervous system activation. Glucocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of energy homeostasis and have been linked to metabolic diseases including obesity, insulin resistance, and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of genes associated with glucose and lipid regulatory pathways and thereby control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism. There are elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, and the most prominent are early life adversity, or exposure to traumatic stress. We hypothesise that when the HPA axis is so disturbed after early life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a “Jekyll and Hyde” role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.
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19
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Molecular Mechanisms of Glucocorticoid-Induced Insulin Resistance. Int J Mol Sci 2021; 22:ijms22020623. [PMID: 33435513 PMCID: PMC7827500 DOI: 10.3390/ijms22020623] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/29/2020] [Accepted: 01/02/2021] [Indexed: 12/12/2022] Open
Abstract
Glucocorticoids (GCs) are steroids secreted by the adrenal cortex under the hypothalamic-pituitary-adrenal axis control, one of the major neuro-endocrine systems of the organism. These hormones are involved in tissue repair, immune stability, and metabolic processes, such as the regulation of carbohydrate, lipid, and protein metabolism. Globally, GCs are presented as ‘flight and fight’ hormones and, in that purpose, they are catabolic hormones required to mobilize storage to provide energy for the organism. If acute GC secretion allows fast metabolic adaptations to respond to danger, stress, or metabolic imbalance, long-term GC exposure arising from treatment or Cushing’s syndrome, progressively leads to insulin resistance and, in fine, cardiometabolic disorders. In this review, we briefly summarize the pharmacological actions of GC and metabolic dysregulations observed in patients exposed to an excess of GCs. Next, we describe in detail the molecular mechanisms underlying GC-induced insulin resistance in adipose tissue, liver, muscle, and to a lesser extent in gut, bone, and brain, mainly identified by numerous studies performed in animal models. Finally, we present the paradoxical effects of GCs on beta cell mass and insulin secretion by the pancreas with a specific focus on the direct and indirect (through insulin-sensitive organs) effects of GCs. Overall, a better knowledge of the specific action of GCs on several organs and their molecular targets may help foster the understanding of GCs’ side effects and design new drugs that possess therapeutic benefits without metabolic adverse effects.
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20
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Mosili P, Mkhize BC, Ngubane P, Sibiya N, Khathi A. The dysregulation of the hypothalamic-pituitary-adrenal axis in diet-induced prediabetic male Sprague Dawley rats. Nutr Metab (Lond) 2020; 17:104. [PMID: 33308255 PMCID: PMC7731754 DOI: 10.1186/s12986-020-00532-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Altered function of the hypothalamic-pituitary-adrenal (HPA) axis in type 2 diabetic patients, a condition preceded by pre-diabetes, has been shown to increase the risk of depression as well as cause downstream effects resulting in upregulation of gluconeogenesis and dyslipidemia. In addition, stress, either psychological from managing diabetes or lifestyle related, further activates the HPA axis causing an exaggerated stress response. This study investigated the activity of the HPA axis in selected markers of glucose handling, and the stress response relative to components of the HPA axis in a diet-induced pre-diabetic rat model. METHODS Sprague Dawley Rats were randomly divided into non-pre-diabetic group (NPD) and pre-diabetic group (PD) (n = 6, per group) over a 20-week induction period and a further 12-week experimental period to get 32 weeks. At the end of the 20 and 32-week periods, glucose handling using the Homeostasis Model Assessment indices, adrenocorticotropic (ACTH) and corticosterone (CORT) concentrations were measured. Stress was induced and the forced swim test were performed in the 12-week experimental week. At the end of 32 weeks glucocorticoid and mineralocorticoid hippocampal receptors were also measured. RESULTS Impaired glucose handling in the PD group as well as increase in corticosterone was observed at the end of both 20 and 32-week periods by comparison to NPD groups. No changes were observed in ACTH concentration at week 20 while, at week 32, a decrease in plasma ACTH concentration was observed in the PD group by comparison to the NPD group. The stressed-induced animals were stressed using the forced swim test: the behaviour observed showed an increase in immobility time in the PD stressed group by comparison to the NPD group. This was followed by the observation of a decrease in ACTH and CORT concentration in the PD stressed group by comparison to the NPD stressed group. Mineralocorticoid and glucocorticoid receptors gene expression were elevated in the stressed PD group relative to the stressed NPD group. CONCLUSION These observations, together, suggest that diet-induced pre-diabetes is associated with impaired HPA axis activity and deteriorating response to stress.
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Affiliation(s)
- Palesa Mosili
- Department of Human Physiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Room E2-401, Westville, 4000, South Africa.
| | - Bongeka Cassandra Mkhize
- Department of Human Physiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Room E2-401, Westville, 4000, South Africa
| | - Phikelelani Ngubane
- Department of Human Physiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Room E2-401, Westville, 4000, South Africa
| | - Ntethelelo Sibiya
- Pharmacology Division, Faculty of Pharmacy, Rhodes University, Grahamstown, 6140, South Africa
| | - Andile Khathi
- Department of Human Physiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Room E2-401, Westville, 4000, South Africa
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21
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Zhao Q, Zhou J, Pan Y, Ju H, Zhu L, Liu Y, Zhang Y. The difference between steroid diabetes mellitus and type 2 diabetes mellitus: a whole-body 18F-FDG PET/CT study. Acta Diabetol 2020; 57:1383-1393. [PMID: 32647998 PMCID: PMC7547981 DOI: 10.1007/s00592-020-01566-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 06/26/2020] [Indexed: 12/22/2022]
Abstract
AIMS Steroid diabetes mellitus (SDM) is a metabolic syndrome caused by an increase in glucocorticoids, and its pathogenesis is unclear. 18F-FDG PET/CT can reflect the glucose metabolism of tissues and organs under living conditions. Here, PET/CT imaging of SDM and type 2 diabetes mellitus (T2DM) rats was used to visualize changes in glucose metabolism in the main glucose metabolizing organs and investigate the pathogenesis of SDM. METHODS SDM and T2DM rat models were established. During this time, PET/CT imaging was used to measure the %ID/g value of skeletal muscle and liver to evaluate glucose uptake. The pancreatic, skeletal muscle and liver were analyzed by immunohistochemistry. RESULTS SDM rats showed increased fasting blood glucose and insulin levels, hyperplasia of islet α and β cells, increased FDG uptake in skeletal muscle accompanied by an up-regulation of PI3Kp85α, IRS-1, and GLUT4, no significant changes in liver uptake, and that glycogen storage in the liver and skeletal muscle increased. T2DM rats showed atrophy of pancreatic islet β cells and decreased insulin levels, significantly reduced FDG uptake and glycogen storage in skeletal muscle and liver. CONCLUSIONS The pathogenesis of SDM is different from that of T2DM. The increased glucose metabolism of skeletal muscle may be related to the increased compensatory secretion of insulin. Glucocorticoids promote the proliferation of islet α cells and cause an increase in gluconeogenesis in the liver, which may cause increased blood glucose.
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Affiliation(s)
- Qingqing Zhao
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Jinxin Zhou
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Yu Pan
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Huijun Ju
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Liying Zhu
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Yang Liu
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Yifan Zhang
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China.
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22
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Huang P, Chen K, Ma T, Cao N, Weng D, Xu C, Xu L. The effects of short-term treatment of microcystin-LR on the insulin pathway in both the HL7702 cell line and livers of mice. ENVIRONMENTAL TOXICOLOGY 2020; 35:727-737. [PMID: 32073747 DOI: 10.1002/tox.22907] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 12/07/2019] [Accepted: 01/17/2020] [Indexed: 06/10/2023]
Abstract
Our previous work indicated exposure of Human liver cell 7702 (HL7702) cells to Microcystin-leucine-arginine (MC-LR) for 24 hours can disrupt insulin (INS) signaling by the hyperphosphorylation of specific proteins. For further exploring the time-dependent effect posed by MC-LR on this pathway, in the current study, HL7702 cells together with mice were exposed to the MC-LR with different concentrations under short-term treatment, and then, protein phosphatase 2A (PP2A) activity and expression of proteins related to INS signaling, as well as the characteristics of their action in the liver, were investigated. The results indicated, in HL7702 cells with 0.5, 1, and 6 hours of treatment by MC-LR, PP2A activity showed an obvious decrease in a time and concentration-dependent manner. While the total protein level of Akt, glycogen synthase kinase 3 (GSK-3), and glycogen synthase remained unchanged, GSK-3 and Akt phosphorylation increased significantly. In livers of mice with 1 hour of intraperitoneal injection with MC-LR, a similar change in these proteins was observed. In addition, the levels of total IRS1 and p-IRS1 at serine sites showed decreasing and increasing trends,respectively, and the hematoxylin and eosin staining showed that liver tissues of mice in the maximum-dose group exhibited obvious hepatocyte degeneration and hemorrhage. Our results further proved that short-term treatment with MC-LR can inhibit PP2A activity and disrupt INS signaling proteins' phosphorylation level, thereby interfering with the INS pathway. Our findings provide a helpful understanding of the toxic effects posed by MC-LR on the glucose metabolism of liver via interference with the INS signaling pathway.
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Affiliation(s)
- Pu Huang
- Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou, China
| | - Kele Chen
- Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tianfeng Ma
- Department I of Clinical Medicine, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Naifang Cao
- Department I of Clinical Medicine, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Dengpo Weng
- Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chun Xu
- Department of Endocrinology, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Lihong Xu
- Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou, China
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Abstract
PURPOSE OF REVIEW Impairment of glucose metabolism is commonly encountered in Cushing's syndrome. It is the source of significant morbidity and mortality even after successful treatment of Cushing's. This review is to understand the recent advances in understanding the pathophysiology of diabetes mellitus from excess cortisol. RECENT FINDINGS In-vitro studies have led to significant advancement in understanding the molecular effects of cortisol on glucose metabolism. Some of these findings have been translated with human data. There is marked reduction in insulin action and glucose disposal with a concomitant, insufficient increase in insulin secretion. Cortisol has a varied effect on adipose tissue, with increased lipolysis in subcutaneous adipose tissue in the extremities, and increased lipogenesis in visceral and subcutaneous truncal adipose tissue. SUMMARY Cushing's syndrome results in marked impairment in insulin action and glucose disposal resulting in hyperglycemia. Further studies are required to understand the effect on incretin secretion and action, gastric emptying, and its varied effect on adipose tissue.
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Affiliation(s)
- Anu Sharma
- Division of Diabetes and Endocrinology, University of Utah School of Medicine, Salt Lake City, UT
| | - Adrian Vella
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo College of Medicine, Rochester, MN
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24
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Rahimi L, Rajpal A, Ismail-Beigi F. Glucocorticoid-Induced Fatty Liver Disease. Diabetes Metab Syndr Obes 2020; 13:1133-1145. [PMID: 32368109 PMCID: PMC7171875 DOI: 10.2147/dmso.s247379] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 03/27/2020] [Indexed: 01/08/2023] Open
Abstract
Glucocorticoids (GCs) are commonly used at high doses and for prolonged periods (weeks to months) in the treatment of a variety of diseases. Among the many side effects are increased insulin resistance with disturbances in glucose/insulin homeostasis and increased deposition of lipids (mostly triglycerides) in the liver. Here, we review the metabolic pathways of lipid deposition and removal from the liver that become altered by excess glucocorticoids. Pathways of lipid deposition stimulated by excess glucocorticoids include 1) increase in appetite and high caloric intake; 2) increased blood glucose levels due to GC-induced stimulation of gluconeogenesis; 3) stimulation of de novo lipogenesis that is augmented by the high glucose and insulin levels and by GC itself; and 4) increased release of free fatty acids from adipose stores and stimulation of their uptake by the liver. Pathways that decrease hepatic lipids affected by glucocorticoids include a modest stimulation of very-low-density lipoprotein synthesis and secretion into the circulation and inhibition of β-oxidation of fatty acids. Role of 11β-hydroxysteroid dehydrogenases-1 and -2 and the reversible conversion of cortisol to cortisone on intracellular levels of cortisol is examined. In addition, GC control of osteocalcin expression and the effect of this bone-derived hormone in increasing insulin sensitivity are discussed. Finally, research focused on gaining a better understanding of the dose and duration of treatment with glucocorticoids, which leads to increased triglyceride deposition in the liver, and the reversibility of the condition is highlighted.
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Affiliation(s)
- Leili Rahimi
- Department of Medicine, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Aman Rajpal
- Department of Medicine, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
- Cleveland VA Medical Center, Cleveland, OH, USA
| | - Faramarz Ismail-Beigi
- Department of Medicine, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
- Cleveland VA Medical Center, Cleveland, OH, USA
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25
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Araujo JEDS, Miguel-dos-Santos R, Macedo FN, Cunha PS, Fontes MT, Murata GM, Lauton-Santos S, Santana-Filho VJ, Silva AMDO, Antoniolli AR, Curi R, Quintans JDSS, Barreto RDSS, Santos MRV, Quintans-Junior LJ, Barreto AS. Effects of high doses of glucocorticoids on insulin-mediated vasodilation in the mesenteric artery of rats. PLoS One 2020; 15:e0230514. [PMID: 32187237 PMCID: PMC7080254 DOI: 10.1371/journal.pone.0230514] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 03/02/2020] [Indexed: 01/11/2023] Open
Abstract
Several pathological conditions predict the use of glucocorticoids for the management of the inflammatory response; however, chronic or high dose glucocorticoid treatment is associated with hyperglycemia, hyperlipidemia, and insulin resistance and can be considered a risk factor for cardiovascular disease. Therefore, we investigated the mechanisms involved in the vascular responsiveness and inflammatory profile of mesenteric arteries of rats treated with high doses of glucocorticoids. Wistar rats were divided into a control (CO) group and a dexamethasone (DEX) group, that received dexamethasone for 7 days (2mg/kg/day, i.p.). Blood samples were used to assess the lipid profile and insulin tolerance. Vascular reactivity to Phenylephrine (Phe) and insulin, and O2•-production were evaluated. The intracellular insulin signaling pathway PI3K/AKT/eNOS and MAPK/ET-1 were investigated. Regarding the vascular inflammatory profile, TNF-α, IL-6, IL-1β and IL-18 were assessed. Dexamethasone-treated rats had decreased insulin tolerance test and endothelium-dependent vasodilation induced by insulin. eNOS inhibition caused vasoconstriction in the DEX group, which was abolished by the ET-A antagonist. Insulin-mediated relaxation in the DEX group was restored in the presence of the O2.- scavenger TIRON. Nevertheless, in the DEX group there was an increase in Phe-induced vasoconstriction. In addition, the intracellular insulin signaling pathway PI3K/AKT/eNOS was impaired, decreasing NO bioavailability. Regarding superoxide anion generation, there was an increase in the DEX group, and all measured proinflammatory cytokines were also augmented in the DEX group. In addition, the DEX-group presented an increase in low-density lipoprotein cholesterol (LDL-c) and total cholesterol (TC) and reduced high-density lipoprotein cholesterol (HDL-c) levels. In summary, treatment with high doses of dexamethasone promoted changes in insulin-induced vasodilation, through the reduction of NO bioavailability and an increase in vasoconstriction via ET-1 associated with generation of O2•- and proinflammatory cytokines.
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Affiliation(s)
- João Eliakim dos S. Araujo
- Laboratory of Cardiovascular Pharmacology, Department of Physiology, Federal University of Sergipe, Sao Cristovao, Sergipe, Brazil
| | - Rodrigo Miguel-dos-Santos
- Laboratory of Cardiovascular Biology and Oxidative Stress, Department of Physiology, Federal University of Sergipe, Sao Cristovao, Sergipe, Brazil
| | | | - Patrícia S. Cunha
- Laboratory of Cardiovascular Pharmacology, Department of Physiology, Federal University of Sergipe, Sao Cristovao, Sergipe, Brazil
| | - Milene Tavares Fontes
- Vascular Physiology Laboratory, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Gilson Masahiro Murata
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Sandra Lauton-Santos
- Laboratory of Cardiovascular Biology and Oxidative Stress, Department of Physiology, Federal University of Sergipe, Sao Cristovao, Sergipe, Brazil
| | - Valter J. Santana-Filho
- Laboratory of Cardiovascular Pharmacology, Department of Physiology, Federal University of Sergipe, Sao Cristovao, Sergipe, Brazil
| | - Ana Mara de O. Silva
- Laboratory of Cardiovascular Pharmacology, Department of Physiology, Federal University of Sergipe, Sao Cristovao, Sergipe, Brazil
| | - Angelo Roberto Antoniolli
- Laboratory of Cardiovascular Pharmacology, Department of Physiology, Federal University of Sergipe, Sao Cristovao, Sergipe, Brazil
| | - Rui Curi
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Jullyana de S. S. Quintans
- Laboratory of Cardiovascular Pharmacology, Department of Physiology, Federal University of Sergipe, Sao Cristovao, Sergipe, Brazil
| | - Rosana de S. S. Barreto
- Laboratory of Cardiovascular Pharmacology, Department of Physiology, Federal University of Sergipe, Sao Cristovao, Sergipe, Brazil
| | - Marcio R. V. Santos
- Laboratory of Cardiovascular Pharmacology, Department of Physiology, Federal University of Sergipe, Sao Cristovao, Sergipe, Brazil
| | - Lucindo J. Quintans-Junior
- Laboratory of Cardiovascular Pharmacology, Department of Physiology, Federal University of Sergipe, Sao Cristovao, Sergipe, Brazil
| | - André S. Barreto
- Laboratory of Cardiovascular Pharmacology, Department of Physiology, Federal University of Sergipe, Sao Cristovao, Sergipe, Brazil
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ARAUJO JOÃOE, MACEDO FABRÍCION, OLIVEIRA DAVIP, BRITTO RAQUELM, QUINTANS JULLYANAS, BARRETO ROSANAS, SANTOS MARCIOR, QUINTANS-JUNIOR LUCINDOJ, BARRETO ANDRÉS. Resistance training prevents the reduction of insulin-mediated vasodilation in the mesenteric artery of dexamethasone-treated rats. AN ACAD BRAS CIENC 2020; 92:e20200316. [DOI: 10.1590/0001-3765202020200316] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 07/22/2020] [Indexed: 12/30/2022] Open
Affiliation(s)
- JOÃO E.S. ARAUJO
- Universidade Federal de Sergipe, Brazil; Programa de Pós-Graduação em Ciências da Saúde, Brazil; Universidade Tiradentes, Brazil
| | | | | | | | - JULLYANA S.S. QUINTANS
- Universidade Federal de Sergipe, Brazil; Programa de Pós-Graduação em Ciências da Saúde, Brazil
| | - ROSANA S.S. BARRETO
- Universidade Federal de Sergipe, Brazil; Programa de Pós-Graduação em Ciências da Saúde, Brazil
| | - MARCIO R.V. SANTOS
- Universidade Federal de Sergipe, Brazil; Programa de Pós-Graduação em Ciências da Saúde, Brazil
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He Z, Kong X, Shao T, Zhang Y, Wen C. Alterations of the Gut Microbiota Associated With Promoting Efficacy of Prednisone by Bromofuranone in MRL/lpr Mice. Front Microbiol 2019; 10:978. [PMID: 31118928 PMCID: PMC6504707 DOI: 10.3389/fmicb.2019.00978] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 04/18/2019] [Indexed: 12/16/2022] Open
Abstract
Gut microbiota played an important role in systemic lupus erythematosus (SLE) and glucocorticoids were prone to cause alterations in gut microbiota. This study addressed the effect of bromofuranone on the treatment of SLE with prednisone, since bromofuranone could regulate gut microbiota by inhibiting the AI-2/LuxS quorum-sensing. Remarkably, bromofuranone did not alleviate lupus but promoted the efficacy of prednisone in the treatment of lupus. The alterations in the gut microbiota, including decreased Mucispirillum, Oscillospira, Bilophila and Rikenella, and increased Anaerostipes, were associated with prednisone treatment for SLE. In addition, the increase of Lactobacillus, Allobaculum, Sutterella, and Adlercreutzia was positively associated with the bromofuranone-mediated promotion for the treatment of lupus. This was the first study demonstrating that the efficacy of glucocorticoids could be affected by the interventions in gut microbiota.
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Affiliation(s)
| | | | | | - Yun Zhang
- Institute of Basic Research in Clinical Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Chengping Wen
- Institute of Basic Research in Clinical Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
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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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Mousovich‐Neto F, Matos MS, Costa ACR, Melo Reis RA, Atella GC, Miranda‐Alves L, Carvalho DP, Ketzer LA, Corrêa da Costa VM. Brown adipose tissue remodelling induced by corticosterone in male Wistar rats. Exp Physiol 2019; 104:514-528. [DOI: 10.1113/ep087332] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 01/15/2019] [Indexed: 12/16/2022]
Affiliation(s)
- Felippe Mousovich‐Neto
- Laboratório de Fisiologia Endócrina Doris Rosenthal Universidade Federal do Rio de Janeiro Rio de Janeiro Brasil
| | - Marina Souza Matos
- Laboratório de Fisiologia Endócrina Doris Rosenthal Universidade Federal do Rio de Janeiro Rio de Janeiro Brasil
| | - Anna Carolina Rego Costa
- Laboratório de Neuroquímica Instituto de Biofísica Carlos Chagas Filho Universidade Federal do Rio de Janeiro Rio de Janeiro Brasil
| | - Ricardo Augusto Melo Reis
- Laboratório de Neuroquímica Instituto de Biofísica Carlos Chagas Filho Universidade Federal do Rio de Janeiro Rio de Janeiro Brasil
| | - Georgia Correa Atella
- Laboratório de Bioquímica de Lipídeos e Lipoproteínas Instituto de Bioquímica Médica Leopoldo de Meis Universidade Federal do Rio de Janeiro Rio de Janeiro Brasil
| | - Leandro Miranda‐Alves
- Instituto de Ciências Biomédicas Universidade Federal do Rio de Janeiro Rio de Janeiro Brasil
| | - Denise P. Carvalho
- Laboratório de Fisiologia Endócrina Doris Rosenthal Universidade Federal do Rio de Janeiro Rio de Janeiro Brasil
| | - Luisa Andrea Ketzer
- Núcleo Multidisciplinar de Pesquisa UFRJ‐Xerém em Biologia Campus Duque de Caxias Universidade Federal do Rio de Janeiro Rio de Janeiro Brasil
| | - Vânia Maria Corrêa da Costa
- Laboratório de Fisiologia Endócrina Doris Rosenthal Universidade Federal do Rio de Janeiro Rio de Janeiro Brasil
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Chemical denervation using botulinum toxin increases Akt expression and reduces submaximal insulin-stimulated glucose transport in mouse muscle. Cell Signal 2019; 53:224-233. [DOI: 10.1016/j.cellsig.2018.10.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 10/17/2018] [Accepted: 10/19/2018] [Indexed: 12/31/2022]
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de França IR, Meneses-Santos D, Moreira GV, Lima FB, Carvalho CRDO, Marçal AC. Insulin signaling pathway in the masseter muscle of dexamethasone-treated rats. Interv Med Appl Sci 2018; 10:226-232. [PMID: 30792919 PMCID: PMC6376360 DOI: 10.1556/1646.10.2018.44] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background and aims The treatment with glucocorticoids may induce molecular changes in the level and/or degree of phosphorylation of proteins located downstream of the insulin receptor/insulin-like growth factor receptor (IR/IGF1R) in many tissues. However, few studies have investigated the intracellular insulin pathway in the masseter muscle. Therefore, this study aimed to analyze the IR/IGF1R signaling pathway in the masseter muscle of rats treated with dexamethasone. Materials and methods Male Wistar rats were divided into two groups: control group (intraperitoneally injected with 0.9% NaCl solution) and dexamethasone group [intraperitoneally injected with 1 mg/kg (bw) dexamethasone solution] for 10 consecutive days. Sections of the masseter muscle were removed at time zero and after the infusion of regular insulin into the portal vein. Results Dexamethasone administration induces body weight loss without changing masseter muscle weight and reduces the expression of total IR and PI3K proteins; total levels of IRS1, Akt, and ERK1 remain unchanged between groups. The degree of phosphorylation/activity of IRS1 after insulin stimulus increased only in the control group; degree of phosphorylation of Akt increased in both groups, but this increase was attenuated in the dexamethasone group. Discussion and conclusion The degree of phosphorylation/activity in the masseter muscle is different from that in other muscle territories.
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Affiliation(s)
- Igor Rabelo de França
- Department of Medicine, Center of Biological Sciences and Health, Federal University of Sergipe, Aracaju, Brazil
| | - Daniela Meneses-Santos
- Department of Morphology, Center of Biological Sciences and Health, Federal University of Sergipe, São Cristóvão, Brazil
| | - Gabriela Virginia Moreira
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Fábio Bessa Lima
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | | | - Anderson Carlos Marçal
- Department of Morphology, Center of Biological Sciences and Health, Federal University of Sergipe, São Cristóvão, Brazil
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Abstract
Glucocorticoids are steroid hormones that play a key role in metabolic adaptations during stress, such as fasting and starvation, in order to maintain plasma glucose levels. Excess and chronic glucocorticoid exposure, however, causes metabolic syndrome including insulin resistance, dyslipidemia, and hyperglycemia. Studies in animal models of metabolic disorders frequently demonstrate that suppressing glucocorticoid signaling improves insulin sensitivity and metabolic profiles. Glucocorticoids convey their signals through an intracellular glucocorticoid receptor (GR), which is a transcriptional regulator. The adipocyte is one cell type that contributes to whole body metabolic homeostasis under the influence of GR. Glucocorticoids' functions on adipose tissues are complex. Depending on various physiological or pathophysiological states as well as distinct fat depots, glucocorticoids can either increase or decrease lipid storage in adipose tissues. In rodents, glucocorticoids have been shown to reduce the thermogenic activity of brown adipocytes. However, in human acute glucocorticoid exposure, glucocorticoids act to promote thermogenesis. In this article, we will review the recent studies on the mechanisms underlying the complex metabolic functions of GR in adipocytes. These include studies of the metabolic outcomes of adipocyte specific GR knockout mice and identification of novel GR primary target genes that mediate glucocorticoid action in adipocytes.
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Affiliation(s)
- Rebecca A Lee
- Endocrinology Graduate Program and Department of Nutritional Science & Toxicology, University of California Berkeley, Berkeley, CA 94720-3104, USA
| | - Charles A Harris
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA
| | - Jen-Chywan Wang
- Endocrinology Graduate Program and Department of Nutritional Science & Toxicology, University of California Berkeley, Berkeley, CA 94720-3104, USA
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Xie Y, Perry BD, Espinoza D, Zhang P, Price SR. Glucocorticoid-induced CREB activation and myostatin expression in C2C12 myotubes involves phosphodiesterase-3/4 signaling. Biochem Biophys Res Commun 2018; 503:1409-1414. [PMID: 30025893 PMCID: PMC6173943 DOI: 10.1016/j.bbrc.2018.07.056] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Accepted: 07/10/2018] [Indexed: 11/02/2022]
Abstract
Muscle atrophy in metabolic conditions like chronic kidney disease (CKD) and diabetes are associated with glucocorticoid production, dysfunctional insulin/Akt/FoxO3 signaling and increased myostatin expression. We recently found that CREB, a transcription factor proposed to regulate myostatin expression, is highly phosphorylated in some wasting conditions. Based on a novel Akt-PDE3/4 signaling paradigm, we hypothesized that reduced Akt signaling contributes to CREB activation and myostatin expression. C2C12 myotubes were incubated with dexamethasone (Dex), an atrophy-inducing synthetic glucocorticoid. Akt/CREB signaling and myostatin expression were evaluated by immunoblot and qPCR analyses. Inhibitors of Akt, phosphodiesterase (PDE)-3/4, and protein kinase A (PKA) signaling were used to test our hypothesis. Incubating myotubes with Dex for 3-24 h inhibited Akt phosphorylation and enhanced CREB phosphorylation as well as myostatin mRNA and protein. Inhibition of PI3K/Akt signaling with LY294002 similarly increased CREB phosphorylation. Isobutyl-methylxanthine (IBMX, a pan PDE inhibitor), milrinone (PDE3 inhibitor) and rolipram (PDE4 inhibitor) augmented CREB phosphorylation and myostatin expression. Inhibition of protein kinase A by PKI reverted Dex- or IBMX-induced CREB phosphorylation and myostatin expression. Our study provides evidence supporting a newly identified mechanism by which a glucocorticoid-related reduction in Akt signaling contributes to myostatin expression via CREB activation.
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Affiliation(s)
- Yang Xie
- Department of Medicine, Renal Division, Emory University, Atlanta, GA 30322, USA; Department of Nephrology, Xiangya Hospital and Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China; Department of Nephrology, Beijing Hospital, Beijing 100730, PR China
| | - Ben D Perry
- Department of Medicine, Renal Division, Emory University, Atlanta, GA 30322, USA; Research Service Line, Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA; School of Science and Health, Western Sydney University, Campbelltown NSW 2560, Australia
| | - Daniel Espinoza
- Research Service Line, Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Peng Zhang
- Department of Medicine, Renal Division, Emory University, Atlanta, GA 30322, USA; Research Service Line, Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - S Russ Price
- Department of Medicine, Renal Division, Emory University, Atlanta, GA 30322, USA; Research Service Line, Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA; Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
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Inácio MD, Rafacho A, de Paula Camaforte NA, Teixeira P, Vareda PMP, Violato NM, Bosqueiro JR. Prevention of Elevation in Plasma Triacylglycerol with High-Dose Bezafibrate Treatment Abolishes Insulin Resistance and Attenuates Glucose Intolerance Induced by Short-Term Treatment with Dexamethasone in Rats. Int J Endocrinol 2018; 2018:3257812. [PMID: 30532777 PMCID: PMC6250034 DOI: 10.1155/2018/3257812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 08/07/2018] [Accepted: 08/27/2018] [Indexed: 12/04/2022] Open
Abstract
OBJECTIVE Fibrates are used as lipid-lowering drugs and are well tolerated as cotreatments when glucose metabolism disturbances are also present. Synthetic glucocorticoids (GCs) are diabetogenic drugs that cause dyslipidemia, dysglycemia, glucose intolerance, and insulin resistance when in excess. Thus, we aimed to describe the potential of bezafibrate in preventing or attenuating the adverse effects of GCs on glucose and lipid homeostasis. METHODS Male Wistar rats were treated with high-dose bezafibrate (300 mg/kg, body mass (b.m.)) daily for 28 consecutive days. In the last five days, the rats were also treated with dexamethasone (1 mg/kg, b.m.). RESULTS Dexamethasone treatment reduced the body mass gain and food intake, and bezafibrate treatment exerted no impact on these parameters. GC treatment caused an augmentation in fasting and fed glycemia, plasma triacylglycerol and nonesterified fatty acids, and insulinemia, and bezafibrate treatment completely prevented the elevation in plasma triacylglycerol and attenuated all other parameters. Insulin resistance and glucose intolerance induced by GC treatment were abolished and attenuated, respectively, by bezafibrate treatment. CONCLUSION High-dose bezafibrate treatment prevents the increase in plasma triacylglycerol and the development of insulin resistance and attenuates glucose intolerance in rats caused by GC treatment, indicating the involvement of dyslipidemia in the GC-induced insulin resistance.
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Affiliation(s)
- Maiara Destro Inácio
- Institute of Biosciences, São Paulo State University–UNESP, Botucatu, SP, Brazil
| | - Alex Rafacho
- Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina–UFSC, Florianópolis, SC, Brazil
| | | | - Poliana Teixeira
- Institute of Biosciences, São Paulo State University–UNESP, Botucatu, SP, Brazil
| | | | | | - José Roberto Bosqueiro
- Department of Physical Education, Faculty of Sciences, São Paulo State University–UNESP, Bauru, SP, Brazil
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Krupková M, Liška F, Kazdová L, Šedová L, Kábelová A, Křenová D, Křen V, Šeda O. Single-Gene Congenic Strain Reveals the Effect of Zbtb16 on Dexamethasone-Induced Insulin Resistance. Front Endocrinol (Lausanne) 2018; 9:185. [PMID: 29731739 PMCID: PMC5919955 DOI: 10.3389/fendo.2018.00185] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 04/05/2018] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Glucocorticoids (GCs) are potent therapeutic agents frequently used for treatment of number of conditions, including hematologic, inflammatory, and allergic diseases. Both their therapeutic and adverse effects display significant interindividual variation, partially attributable to genetic factors. We have previously isolated a seven-gene region of rat chromosome 8 sensitizing to dexamethasone (DEX)-induced dyslipidemia and insulin resistance (IR) of skeletal muscle. Using two newly derived congenic strains, we aimed to investigate the effect of one of the prime candidates for this pharmacogenetic interaction, the Zbtb16 gene. METHODS Adult male rats of SHR-Lx.PD5PD-Zbtb16 (n = 9) and SHR-Lx.PD5SHR-Zbtb16 (n = 8) were fed standard diet (STD) and subsequently treated with DEX in drinking water (2.6 µg/ml) for 3 days. The morphometric and metabolic profiles of both strains including oral glucose tolerance test, triacylglycerols (TGs), free fatty acids, insulin, and C-reactive protein levels were assessed before and after the DEX treatment. Insulin sensitivity of skeletal muscle and visceral adipose tissue was determined by incorporation of radioactively labeled glucose. RESULTS The differential segment of SHR-Lx.PD5SHR-Zbtb16 rat strain spans 563 kb and contains six genes: Htr3a, Htr3b, Usp28, Zw10, Tmprss5, and part of Drd2. The SHR-Lx.PD5PD-Zbtb16 minimal congenic strain contains only Zbtb16 gene on SHR genomic background and its differential segment spans 254 kb. Total body weight was significantly increased in SHR-Lx.PD5PD-Zbtb16 strain compared with SHR-Lx.PD5SHR-Zbtb16 , however, no differences in the weights of adipose tissue depots were observed. While STD-fed rats of both strains did not show major differences in their metabolic profiles, after DEX treatment the SHR-Lx.PD5PD-Zbtb16 congenic strain showed increased levels of TGs, glucose, and blunted inhibition of lipolysis by insulin. Both basal and insulin-stimulated incorporation of radioactively labeled glucose into skeletal muscle glycogen were significantly reduced in SHR-Lx.PD5PD-Zbtb16 strain, but the insulin sensitivity of adipose tissue was comparable between the two strains. CONCLUSION The metabolic disturbances including impaired glucose tolerance, dyslipidemia, and IR of skeletal muscle observed after DEX treatment in the congenic SHR-Lx.PD5PD-Zbtb16 reveal the Zbtb16 locus as a possible sensitizing factor for side effects of GC therapy.
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Affiliation(s)
- Michaela Krupková
- The First Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University, The General Teaching Hospital, Prague, Czechia
| | - František Liška
- The First Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University, The General Teaching Hospital, Prague, Czechia
| | - Ludmila Kazdová
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Lucie Šedová
- The First Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University, The General Teaching Hospital, Prague, Czechia
- Laboratory of Transgenic Models of Diseases, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Vestec, Prague, Czechia
| | - Adéla Kábelová
- The First Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University, The General Teaching Hospital, Prague, Czechia
| | - Drahomíra Křenová
- The First Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University, The General Teaching Hospital, Prague, Czechia
| | - Vladimír Křen
- The First Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University, The General Teaching Hospital, Prague, Czechia
| | - Ondřej Šeda
- The First Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University, The General Teaching Hospital, Prague, Czechia
- *Correspondence: Ondřej Šeda,
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Liu J, Xu C, Zhang S, Li H, Chen K, Huang P, Guo Z, Xu L. Microcystin-LR disrupts insulin signaling by hyperphosphorylating insulin receptor substrate 1 and glycogen synthase. ENVIRONMENTAL TOXICOLOGY 2018; 33:16-22. [PMID: 28984034 DOI: 10.1002/tox.22456] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 07/21/2017] [Accepted: 07/27/2017] [Indexed: 06/07/2023]
Abstract
Microcystin-LR (MC-LR) is a cyanobacteria-derived heptapeptide that has been commonly characterized as a hepatotoxin. Although the liver is a primary organ in glucose homeostasis, the effect of MC-LR on glucose metabolism remains unclear. In this study, the human liver cell line HL7702 and ICR mice were exposed to various concentrations of MC-LR for 24 h, and the proteins involved in insulin signaling were investigated. The results showed that MC-LR treatment induced the hyperphosphorylation of insulin receptor substrate 1 (IRS1) at several serine sites, S307, S323, S636/639, and S1101 in HL7702 cells, and S302, S318, S632/635, and S1097 in mice livers. In addition, the activation of S6K1 was demonstrated to play an important role in MC-LR-induced IRS1 hyperphosphorylation at several serine sites. Decreased levels of total IRS1 were observed in the mice livers, but there was no significant change in HL7702 cells. MC-LR also induced glycogen synthase (GS) hyperphosphorylation at S641 (inactivating GS) both in vitro and in vivo, even glycogen synthase kinase 3, a well-known GS kinase, was inactivated after MC-LR treatment. Moreover, MC-LR could block insulin-induced GS activation. In addition, glucose transport in liver cells was not impacted by MC-LR either with or without insulin stimulation. Our study implies that MC-LR can interfere with the actions of IRS1 and GS in insulin signaling and may have a toxic effect on glucose metabolism in the liver.
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Affiliation(s)
- Jinghui Liu
- Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Chun Xu
- Department of Endocrinology, General Hospital of the Chinese People's Armed Police Forces, Beijing, 100039, China
| | - Shaofeng Zhang
- Department of Endocrinology, General Hospital of the Chinese People's Armed Police Forces, Beijing, 100039, China
| | - Haoyan Li
- Department of Endocrinology, General Hospital of the Chinese People's Armed Police Forces, Beijing, 100039, China
| | - Kele Chen
- Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Pu Huang
- Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Zonglou Guo
- Department of Biosystem Engineering, College of Biosystem Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China
| | - Lihong Xu
- Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou, 310058, China
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Wu T, Yang L, Jiang J, Ni Y, Zhu J, Zheng X, Wang Q, Lu X, Fu Z. Chronic glucocorticoid treatment induced circadian clock disorder leads to lipid metabolism and gut microbiota alterations in rats. Life Sci 2017; 192:173-182. [PMID: 29196049 DOI: 10.1016/j.lfs.2017.11.049] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 11/22/2017] [Accepted: 11/28/2017] [Indexed: 12/11/2022]
Abstract
AIM Glucocorticoids (GCs), steroid hormones synthetized by the adrenal gland, are regulated by circadian cycles, and dysregulation of GC signaling can lead to the development of metabolic syndrome. The effects and potential mechanism of GCs in physiology were investigated in the present study. MAIN METHODS Male Wistar rats were orally administered dexamethasone sodium phosphate (DEX, 0.01 and 0.05mg/kg body weight per day) for 7weeks. KEY FINDING DEX treatment attenuated body weight gain and reduced food intake, whereas it induced the accumulation of fat. Administration of DEX induced dysregulation of the expression of lipogenic genes in both fat and liver. Moreover, the mRNA levels of genes related to mitochondrial biogenesis and function were significantly downregulated in the liver and fat of DEX-treated rats. Furthermore, DEX treatment caused a significant reduction in the richness and diversity of the microbiota in the colon, as assessed using high-throughput sequencing of the 16s rRNA gene V3-V4 region, an increase in inflammatory cell infiltration, and a decrease in mucus secretion in the colon. Additionally, DEX administration induced phase shift or loss of circadian rhythmicity of clock-related genes in peripheral tissues. These results were associated with higher serum corticosterone levels and upregulation of GC receptor (GR) expression in peripheral tissues. SIGNIFICANCE Our findings indicate that long-term administration of GC caused lipid accumulation, changes in the structure of the intestinal flora, and reduced colonic mucus secretion in vivo. The mechanism of these physiological changes may involve a circadian rhythm disorder and dysregulation of GR expression.
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Affiliation(s)
- Tao Wu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, China
| | - Luna Yang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, China
| | - Jianguo Jiang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, China
| | - Yinhua Ni
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, China
| | - Jiawei Zhu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, China
| | - Xiaojun Zheng
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, China
| | - Qi Wang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, China
| | - Xin Lu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, China
| | - Zhengwei Fu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, China.
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Teich T, Pivovarov JA, Porras DP, Dunford EC, Riddell MC. Curcumin limits weight gain, adipose tissue growth, and glucose intolerance following the cessation of exercise and caloric restriction in rats. J Appl Physiol (1985) 2017; 123:1625-1634. [PMID: 28839007 DOI: 10.1152/japplphysiol.01115.2016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Weight regain, adipose tissue growth, and insulin resistance can occur within days after the cessation of regular dieting and exercise. This phenomenon has been attributed, in part, to the actions of stress hormones as well as local and systemic inflammation. We investigated the effect of curcumin, a naturally occurring polyphenol known for its anti-inflammatory properties and inhibitory action on 11β-HSD1 activity, on preserving metabolic health and limiting adipose tissue growth following the cessation of daily exercise and caloric restriction (CR). Sprague-Dawley rats (6-7 wk old) underwent a "training" protocol of 24-h voluntary running wheel access and CR (15-20 g/day; ~50-65% of ad libitum intake) for 3 wk ("All Trained") or were sedentary and fed ad libitum ("Sed"). After 3 wk, All Trained were randomly divided into one group which was terminated immediately ("Trained"), and two detrained groups which had their wheels locked and were reintroduced to ad libitum feeding for 1 wk. The wheel locked groups received either a daily gavage of a placebo ("Detrained + Placebo") or curcumin (200 mg/kg) ("Detrained + Curcumin"). Cessation of daily CR and exercise caused an increase in body mass, as well as a 9- to 14-fold increase in epididymal, perirenal, and inguinal adipose tissue mass, all of which were attenuated by curcumin ( P < 0.05). Insulin area under the curve (AUC) during an oral glucose tolerance test, HOMA-IR, and C-reactive protein (CRP) were elevated 6-, 9-, and 2-fold, respectively, in the Detrained + Placebo group vs. the Trained group (all P < 0.05). Curcumin reduced insulin AUC, HOMA-IR, and CRP vs. the placebo group (all P < 0.05). Our results indicate that curcumin has a protective effect against weight regain and impaired metabolic control following a successful period of weight loss through diet and exercise, perhaps via inhibition of glucocorticoid action and inflammation. NEW & NOTEWORTHY Weight regain after dieting and exercise is a common phenomenon plaguing many individuals. The biological mechanisms underlying weight regain are incompletely understood and are likely multifactorial. In this paper, we examined the metabolic implications of curcumin, a compound known for its anti-inflammatory properties and inhibitory action on the enzyme 11β-HSD1, in a rodent model of adiposity rebound after the cessation of diet and exercise.
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Affiliation(s)
- Trevor Teich
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University , Toronto, Ontario , Canada
| | - Jacklyn A Pivovarov
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University , Toronto, Ontario , Canada
| | - Deanna P Porras
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University , Toronto, Ontario , Canada
| | - Emily C Dunford
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University , Toronto, Ontario , Canada
| | - Michael C Riddell
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University , Toronto, Ontario , Canada
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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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Kuo T, Chen TC, Lee RA, Nguyen NHT, Broughton AE, Zhang D, Wang JC. Pik3r1 Is Required for Glucocorticoid-Induced Perilipin 1 Phosphorylation in Lipid Droplet for Adipocyte Lipolysis. Diabetes 2017; 66:1601-1610. [PMID: 28292967 PMCID: PMC5440017 DOI: 10.2337/db16-0831] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 03/09/2017] [Indexed: 12/26/2022]
Abstract
Glucocorticoids promote lipolysis in white adipose tissue (WAT) to adapt to energy demands under stress, whereas superfluous lipolysis causes metabolic disorders, including dyslipidemia and hepatic steatosis. Glucocorticoid-induced lipolysis requires the phosphorylation of cytosolic hormone-sensitive lipase (HSL) and perilipin 1 (Plin1) in the lipid droplet by protein kinase A (PKA). We previously identified Pik3r1 (also called p85α) as a glucocorticoid receptor target gene. Here, we found that glucocorticoids increased HSL phosphorylation, but not Plin1 phosphorylation, in adipose tissue-specific Pik3r1-null (AKO) mice. Furthermore, in lipid droplets, the phosphorylation of HSL and Plin1 and the levels of catalytic and regulatory subunits of PKA were increased by glucocorticoids in wild-type mice. However, these effects were attenuated in AKO mice. In agreement with reduced WAT lipolysis, glucocorticoid- initiated hepatic steatosis and hypertriglyceridemia were improved in AKO mice. Our data demonstrated a novel role of Pik3r1 that was independent of the regulatory function of phosphoinositide 3-kinase in mediating the metabolic action of glucocorticoids. Thus, the inhibition of Pik3r1 in adipocytes could alleviate lipid disorders caused by excess glucocorticoid exposure.
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Affiliation(s)
- Taiyi Kuo
- Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA
| | - Tzu-Chieh Chen
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA
- Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA
| | - Rebecca A Lee
- Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA
| | - Nguyen Huynh Thao Nguyen
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA
| | - Augusta E Broughton
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA
| | - Danyun Zhang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA
| | - Jen-Chywan Wang
- Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA
- Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA
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Khelfi A, Azzouz M, Abtroun R, Reggabi M, Alamir B. [Direct mechanism of action in toxic myopathies]. ANNALES PHARMACEUTIQUES FRANÇAISES 2017; 75:323-343. [PMID: 28526123 DOI: 10.1016/j.pharma.2017.04.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 04/02/2017] [Accepted: 04/03/2017] [Indexed: 01/04/2023]
Abstract
Toxic myopathies are a large group of disorders generated by surrounding agents and characterized by structural and/or functional disturbances of muscles. The most recurrent are those induced by commonly used medications. Illicit drugs, environmental toxins from animals, vegetables, or produced by micro-organisms as well as chemical products commonly used are significant causes of such disorders. The muscle toxicity results from multiple mechanisms at different biological levels. Many agents can induce myotoxicity through a direct mechanism in which statins, glucocorticoids and ethyl alcohol are the most representative. Diverse mechanisms were highlighted as interaction with macromolecules and induction of metabolic and cellular dysfunctions. Muscle damage can be related to amphiphilic properties of some drugs (chloroquine, hydroxychloroquine, etc.) leading to specific lysosomal disruptions and autophagic dysfunctions. Some agents affect the whole muscle fiber by inducing oxidative stress (ethyl alcohol and some statins) or triggering cell death pathways (apoptosis or necrosis) resulting in extensive alterations. More studies on these mechanisms are needed. They would allow a better knowledge of the intracellular mediators involved in these pathologies in order to develop targeted therapies of high efficiency.
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Affiliation(s)
- A Khelfi
- Service de toxicologie, CHU Bab-El-Oued, rue Mohamed-Lamine-Debaghine, 16009 Alger, Algérie; Centre national de toxicologie, route du Petit-Staouali-Delly-Brahim, 16062 Alger, Algérie.
| | - M Azzouz
- Laboratoire central de biologie et de toxicologie, EHS Ait-Idir, rue Abderrezak-Hahad-Casbah, 16017 Alger, Algérie
| | - R Abtroun
- Service de toxicologie, CHU Bab-El-Oued, rue Mohamed-Lamine-Debaghine, 16009 Alger, Algérie
| | - M Reggabi
- Laboratoire central de biologie et de toxicologie, EHS Ait-Idir, rue Abderrezak-Hahad-Casbah, 16017 Alger, Algérie
| | - B Alamir
- Service de toxicologie, CHU Bab-El-Oued, rue Mohamed-Lamine-Debaghine, 16009 Alger, Algérie; Centre national de toxicologie, route du Petit-Staouali-Delly-Brahim, 16062 Alger, Algérie
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Bergqvist N, Nyman E, Cedersund G, Stenkula KG. A systems biology analysis connects insulin receptor signaling with glucose transporter translocation in rat adipocytes. J Biol Chem 2017; 292:11206-11217. [PMID: 28495883 DOI: 10.1074/jbc.m117.787515] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 05/03/2017] [Indexed: 12/26/2022] Open
Abstract
Type 2 diabetes is characterized by insulin resistance, which arises from malfunctions in the intracellular insulin signaling network. Knowledge of the insulin signaling network is fragmented, and because of the complexity of this network, little consensus has emerged for the structure and importance of the different branches of the network. To help overcome this complexity, systems biology mathematical models have been generated for predicting both the activation of the insulin receptor (IR) and the redistribution of glucose transporter 4 (GLUT4) to the plasma membrane. Although the insulin signal transduction between IR and GLUT4 has been thoroughly studied with modeling and time-resolved data in human cells, comparable analyses in cells from commonly used model organisms such as rats and mice are lacking. Here, we combined existing data and models for rat adipocytes with new data collected for the signaling network between IR and GLUT4 to create a model also for their interconnections. To describe all data (>140 data points), the model needed three distinct pathways from IR to GLUT4: (i) via protein kinase B (PKB) and Akt substrate of 160 kDa (AS160), (ii) via an AS160-independent pathway from PKB, and (iii) via an additional pathway from IR, e.g. affecting the membrane constitution. The developed combined model could describe data not used for training the model and was used to generate predictions of the relative contributions of the pathways from IR to translocation of GLUT4. The combined model provides a systems-level understanding of insulin signaling in rat adipocytes, which, when combined with corresponding models for human adipocytes, may contribute to model-based drug development for diabetes.
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Affiliation(s)
| | - Elin Nyman
- From the Departments of Biomedical Engineering and.,Cardiovascular and Metabolic Diseases Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D, SE431 83 Gothenburg, Sweden, and
| | - Gunnar Cedersund
- From the Departments of Biomedical Engineering and .,Clinical and Experimental Medicine and Biomedical Engineering, Linköping University, SE581 85 Linköping, Sweden
| | - Karin G Stenkula
- Glucose Transport and Protein Trafficking, Department of Experimental Medical Sciences, Biomedical Centre, Lund University, SE221 84 Lund, Sweden
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Battiston FG, Dos Santos C, Barbosa AM, Sehnem S, Leonel ECR, Taboga SR, Anselmo-Franci JA, Lima FB, Rafacho A. Glucose homeostasis in rats treated with 4-vinylcyclohexene diepoxide is not worsened by dexamethasone treatment. J Steroid Biochem Mol Biol 2017; 165:170-181. [PMID: 27264932 DOI: 10.1016/j.jsbmb.2016.06.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 05/31/2016] [Accepted: 06/01/2016] [Indexed: 12/19/2022]
Abstract
4-vinilcyclohexene diepoxide (4-VCD) causes premature ovarian failure and may result in estrogen deficiency, characterizing the transition to estropause in rodents (equivalent to menopause in women). Estropause/menopause is associated with metabolic derangements such as glucose intolerance and insulin resistance. Glucocorticoids (GCs) are known to exert diabetogenic effects. Thus, we aimed to investigate whether rats with premature ovarian failure are more prone to the diabetogenic effects of GC. For this, immature female rats received daily injections of 4-VCD [160mg/kg body weight (b.w.), intraperitoneally (i.p.)] for 15 consecutive days, whereas control rats received vehicle. After 168days of the completion of 4-VCD administration, rats were divided into 4 groups: CTL-received daily injections of saline (1mL/kg, b.w., i.p.) for 5days; DEX-received daily injections of dexamethasone (1mg/kg, b.w., i.p.) for 5days; VCD-treated as CTL group; VCD+DEX-treated as DEX group. Experiments and euthanasia occurred one day after the last dexamethasone injection. 4-VCD-treated rats exhibited ovary hypotrophy and reduced number of preantral follicles (p<0.05). Premature ovarian failure had no impact on the body weight gain or food intake, but both were reduced by the effects of dexamethasone. The increase in blood glucose, plasma insulin and triacylglycerol levels as well as the reduction in insulin sensitivity caused by dexamethasone treatment was not exacerbated in the VCD+DEX group of rats. Premature ovarian failure did change neither the hepatic content of glycogen and triacylglycerol nor the glycerol release from perigonadal adipose tissue. Glucose intolerance was observed in the VCD group after an ipGTT (p<0.05), but not after an oral glucose challenge. Glucose intolerance and compensatory pancreatic β-cell mass caused by GC were not modified by ovarian failure in the VCD+DEX group. We conclude that reduced ovarian function has no major implications on the diabetogenic effects promoted by GC treatment, indicating that other factors related to aging may make rats more vulnerable to GC side effects on glucose metabolism.
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Affiliation(s)
- Francielle Garghetti Battiston
- Department of Physiological Sciences and Multicenter Graduate Program in Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina-UFSC, Florianópolis, Brazil
| | - Cristiane Dos Santos
- Department of Physiological Sciences and Multicenter Graduate Program in Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina-UFSC, Florianópolis, Brazil
| | - Amanda Marreiro Barbosa
- Department of Physiological Sciences and Multicenter Graduate Program in Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina-UFSC, Florianópolis, Brazil
| | - Sibele Sehnem
- Department of Physiological Sciences and Multicenter Graduate Program in Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina-UFSC, Florianópolis, Brazil
| | - Ellen Cristina Rivas Leonel
- Department of Biology, Institute of Biosciences, Letters and Exact Sciences, Univ. Estadual Paulista-IBILCE/UNESP, São José do Rio Preto, SP, Brazil
| | - Sebastião Roberto Taboga
- Department of Biology, Institute of Biosciences, Letters and Exact Sciences, Univ. Estadual Paulista-IBILCE/UNESP, São José do Rio Preto, SP, Brazil
| | - Janete A Anselmo-Franci
- Department of Morphology, Center of Biological Sciences, School of Dentistry of Ribeirão Preto, São Paulo University-USP, Ribeirão Preto, SP, Brazil
| | - Fernanda Barbosa Lima
- Department of Physiological Sciences and Multicenter Graduate Program in Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina-UFSC, Florianópolis, Brazil
| | - Alex Rafacho
- Department of Physiological Sciences and Multicenter Graduate Program in Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina-UFSC, Florianópolis, Brazil.
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Aluri VM, Julius BR, Langstengel JO, Fronteras ML, Sivitz WI. Glucocorticoids And Cornstarch Therapy For Non–Islet Cell Tumor Hypoglycemia: A Case Report. AACE Clin Case Rep 2017. [DOI: 10.4158/ep161317.cr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Dunford EC, Mandel ER, Mohajeri S, Haas TL, Riddell MC. Metabolic effects of prazosin on skeletal muscle insulin resistance in glucocorticoid-treated male rats. Am J Physiol Regul Integr Comp Physiol 2017; 312:R62-R73. [PMID: 27834289 DOI: 10.1152/ajpregu.00146.2016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Revised: 11/07/2016] [Accepted: 11/07/2016] [Indexed: 02/06/2023]
Abstract
High-dose glucocorticoids (GC) induce skeletal muscle atrophy, insulin resistance, and reduced muscle capillarization. Identification of treatments to prevent or reverse capillary rarefaction and metabolic deterioration caused by prolonged elevations in GCs would be therapeutically beneficial. Chronic administration of prazosin, an α1-adrenergic antagonist, increases skeletal muscle capillarization in healthy rodents and, recently, in a rodent model of elevated GCs and hyperglycemia. The purpose of this study was to determine whether prazosin administration would improve glucose tolerance and insulin sensitivity, through prazosin-mediated sparing of capillary rarefaction, in this rodent model of increased GC exposure. Prazosin was provided in drinking water (50 mg/l) to GC-treated or control rats (400 mg implants of either corticosterone or a wax pellet) for 7 or 14 days (n = 5-14/group). Whole body measures of glucose metabolism were correlated with skeletal muscle capillarization (C:F) at 7 and 14 days in the four groups of rats. Individual C:F was found to be predictive of insulin sensitivity (r2 = 0.4781), but not of glucose tolerance (r2 = 0.1601) and compared with water only, prazosin treatment decreased insulin values during oral glucose challenge by approximately one-third in corticosterone (Cort)-treated animals. Cort treatment, regardless of duration, induced significant glycolytic skeletal muscle atrophy (P < 0.05), decreased IRS-1 protein content (P < 0.05), and caused elevations in FOXO1 protein expression (P < 0.05), which were unaffected with prazosin administration. In summary, it appears that α1-adrenergic antagonism improves Cort-induced skeletal muscle vascular impairments and reduces insulin secretion during an oral glucose tolerance test, but is unable to improve the negative alterations directly affecting the myocyte, including muscle size and muscle signaling protein expression.
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Affiliation(s)
- Emily C Dunford
- School of Kinesiology and Health Science, Faculty of Health, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, York University, Toronto, Ontario, Canada
| | - Erin R Mandel
- School of Kinesiology and Health Science, Faculty of Health, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, York University, Toronto, Ontario, Canada
| | - Sepideh Mohajeri
- School of Kinesiology and Health Science, Faculty of Health, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, York University, Toronto, Ontario, Canada
| | - Tara L Haas
- School of Kinesiology and Health Science, Faculty of Health, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, York University, Toronto, Ontario, Canada
| | - Michael C Riddell
- School of Kinesiology and Health Science, Faculty of Health, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, York University, Toronto, Ontario, Canada
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Kishimoto M, Noda M. Verification of glycemic profiles using continuous glucose monitoring: cases with steroid use, liver cirrhosis, enteral nutrition, or late dumping syndrome. THE JOURNAL OF MEDICAL INVESTIGATION 2016; 62:1-10. [PMID: 25817276 DOI: 10.2152/jmi.62.1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Glycemic control is often difficult to achieve in patients with diabetes, especially in the presence of comorbid diseases or conditions such as steroid-use or liver cirrhosis, or in patients receiving enteral nutrition. Moreover, reactive hypoglycemia due to late dumping syndrome in people having undergone gastrectomy is also a matter of concern. Empirically and theoretically, the typical glycemic profiles associated with these conditions have been determined; however, what actually happens during a 24-h span is still somewhat obscure. In order to verify and provide information about the 24-h glycemic profiles associated with these conditions, 8 patients with the 4 above-mentioned conditions were monitored using a continuous glucose monitoring system (CGMS). For all 8 patients, CGMS provided detailed information regarding the 24-h glycemic profiles. The CGM results showed typical glycemic patterns for each condition, and we were moreover able to observe the effects of various practical treatments. Based on these cases, we conclude that the CGMS is highly useful for determining the glycemic patterns of patients with the aforementioned conditions in a practical setting; and this system may be used to monitor the treatment success of such cases.
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Affiliation(s)
- Miyako Kishimoto
- Department of Diabetes, Endocrinology, and Metabolism Center Hospital; 2.Diabetes and Metabolism Information Center, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine
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Dunford EC, Riddell MC. The Metabolic Implications of Glucocorticoids in a High-Fat Diet Setting and the Counter-Effects of Exercise. Metabolites 2016; 6:metabo6040044. [PMID: 27929385 PMCID: PMC5192450 DOI: 10.3390/metabo6040044] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 11/25/2016] [Accepted: 11/30/2016] [Indexed: 02/06/2023] Open
Abstract
Glucocorticoids (GCs) are steroid hormones, naturally produced by activation of the hypothalamic-pituitary-adrenal (HPA) axis, that mediate the immune and metabolic systems. Synthetic GCs are used to treat a number of inflammatory conditions and diseases including lupus and rheumatoid arthritis. Generally, chronic or high dose GC administration is associated with side effects such as steroid-induced skeletal muscle loss, visceral adiposity, and diabetes development. Patients who are taking exogenous GCs could also be more susceptible to poor food choices, but the effect that increasing fat consumption in combination with elevated exogenous GCs has only recently been investigated. Overall, these studies show that the damaging metabolic effects initiated through exogenous GC treatment are significantly amplified when combined with a high fat diet (HFD). Rodent studies of a HFD and elevated GCs demonstrate more glucose intolerance, hyperinsulinemia, visceral adiposity, and skeletal muscle lipid deposition when compared to rodents subjected to either treatment on its own. Exercise has recently been shown to be a viable therapeutic option for GC-treated, high-fat fed rodents, with the potential mechanisms still being examined. Clinically, these mechanistic studies underscore the importance of a low fat diet and increased physical activity levels when individuals are given a course of GC treatment.
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Affiliation(s)
- Emily C Dunford
- School of Kinesiology and Health Science, Faculty of Health, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, York University, 4700 Keele Street, Toronto, ON M3J 1P3, Canada.
| | - Michael C Riddell
- School of Kinesiology and Health Science, Faculty of Health, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, York University, 4700 Keele Street, Toronto, ON M3J 1P3, Canada.
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Wu T, Jiang J, Yang L, Li H, Zhang W, Chen Y, Zhao B, Kong B, Lu P, Zhao Z, Zhu J, Fu Z. Timing of glucocorticoid administration determines severity of lipid metabolism and behavioral effects in rats. Chronobiol Int 2016; 34:78-92. [PMID: 27791398 DOI: 10.1080/07420528.2016.1238831] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Glucocorticoids (GCs) are a group of steroid hormones secreted by the adrenal glands in circadian cycles, and the dysregulation of GC signaling has been suggested to cause metabolic syndrome. Even though prolonged GC exposure is associated with serious side effects such as metabolic syndrome and central nervous system disorders, the use of GCs in anti-inflammatory and immunosuppressive therapies has been continuously rising. Meanwhile, the exact mechanisms by which GCs can influence the lipid metabolism as well as behavior and how they are affected by time remain unknown. In this study, the effects of two different long-term GC dosing regimens on lipid metabolism and behavior were investigated. Male Wistar rats received daily administrations of the GC dexamethasone sodium phosphate (DEX, 0.5 mg/kg body weight) at either ZT0 (Dex0) or ZT12 (Dex12). After 6 weeks of treatment, DEX-treated rats, especially those treated at ZT0, had higher hepatic lipid accumulation and serum triglyceride levels and less locomotor activity than did control rats. In addition, serum levels of corticosterone, 5-hydroxy tryptamine and norepinephrine were decreased in the Dex0 group but not in the Dex12 group compared to the control group. Furthermore, quantitative real-time polymerase chain reaction analysis indicated that the chronic administration of GCs at ZT0 upregulated genes related to glycolysis and lipid synthesis and downregulated genes related to fatty acid β-oxidation in the liver more remarkably than administration at ZT12. Both DEX-treated groups displayed severely altered expression patterns of the core clock genes Bmal1 and Per2 in the liver and in fat. In addition, the expression of glutamate aspartate transporter, glial fibrillary acidic protein and glutamate transporter-1, astrocyte-related genes important for maintaining nervous system functions, was drastically decreased in the hippocampus of DEX-treated rats, especially when DEX was given at ZT0. In conclusion, our findings confirm that the severity of side effects, indicated by altered lipid metabolism and behavioral activity, depends on the timing of GC administration and is associated with the degree of glucocorticoid receptor dysfunction after dosing at disparate time points.
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Affiliation(s)
- Tao Wu
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Jianguo Jiang
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Luna Yang
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Haifeng Li
- b Children's Hospital , Zhejiang University School of Medicine , Zhejiang , China
| | - Wanjing Zhang
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Yangyang Chen
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Binggong Zhao
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Boda Kong
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Ping Lu
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Zhenzhen Zhao
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Jiawei Zhu
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Zhengwei Fu
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
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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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Tovchiga OV. The influence of goutweed (Aegopodium podagraria L.) tincture and metformin on the carbohydrate and lipid metabolism in dexamethasone-treated rats. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 16:235. [PMID: 27450405 PMCID: PMC4957838 DOI: 10.1186/s12906-016-1221-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 07/14/2016] [Indexed: 01/26/2023]
Abstract
Background Diabetes mellitus and metabolic syndrome are the common problems of the modern society. The interest in herbal medicines increases, and often they are used in combination with conventional drugs. Aegopodium podagraria L. (goutweed) is a plant widely used in traditional medicine. Hypoglycemic effect of goutweed aerial part tincture has been previously shown in alloxan-induced diabetic mice and in rats receiving excess of fructose and hydrochlorothiazide. The effects of co-administration of the tincture with widely used antihyperglycemic drugs have not been verified. The objective of this study is to determine the efficacy of goutweed tincture and its combination with metformin using the model reproducing the pathogenetic mechanisms of the metabolic syndrome and type 2 diabetes. Methods The animals were divided into 5 groups, as follows: intact control, dexamethasone (untreated), dexamethasone + metformin, 50 mg/kg; dexamethasone + A. podagraria tincture, 1 ml/kg intragastrically; dexamethasone + metformin, 50 mg/kg intragastrically + A. podagraria tincture, 1 ml/kg intragastrically. Dexamethasone was used at a dose of 5 mg/kg subcutaneously for 5 days. Insulin tolerance test and oral glucose tolerance test were performed, triglycerides, total lipids, total and HDL cholesterol content in plasma were determined, LDL cholesterol content was calculated, glycogen content in the liver was measured. Results Goutweed tincture combined with metformin increased its effect on the basal glycemia and on the results of the short insulin test. In the oral glucose tolerance test the lowest area under glucose curve and average glycemia value were seen in animals receiving this combination. Only metformin tended toward the reduction of liver glycogen. The decrease in triglycerides and increment of HDL cholesterol content (caused by the tincture), as well as tendency towards the decrease in total lipids level (caused by metformin) were observed against a background of the investigated combination, though the ability of GW tincture to reduce LDL cholesterol content and the same tendency seen against a background of metformin were eliminated when these preparations were administered together. Conclusion It has been shown that goutweed tincture combined with the respectively low dose of metformin partially increases the efficacy of the latter in dexamethasone-treated rats. Graphical abstract Goutweed tincture combined with the respectively low dose of metformin partially increases the efficacy of the latter in dexamethasone-treated rats![]()
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