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Cozma D, Siatra P, Bornstein SR, Steenblock C. Sensitivity of the Neuroendocrine Stress Axis in Metabolic Diseases. Horm Metab Res 2024; 56:65-77. [PMID: 38171373 DOI: 10.1055/a-2201-6641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Metabolic diseases are prevalent in modern society and have reached pandemic proportions. Metabolic diseases have systemic effects on the body and can lead to changes in the neuroendocrine stress axis, the critical regulator of the body's stress response. These changes may be attributed to rising insulin levels and the release of adipokines and inflammatory cytokines by adipose tissue, which affect hormone production by the neuroendocrine stress axis. Chronic stress due to inflammation may exacerbate these effects. The increased sensitivity of the neuroendocrine stress axis may be responsible for the development of metabolic syndrome, providing a possible explanation for the high prevalence of severe comorbidities such as heart disease and stroke associated with metabolic disease. In this review, we address current knowledge of the neuroendocrine stress axis in response to metabolic disease and discuss its role in developing metabolic syndrome.
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Affiliation(s)
- Diana Cozma
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Panagiota Siatra
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Stefan R Bornstein
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- School of Cardiovascular and Metabolic Medicine and Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
| | - Charlotte Steenblock
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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Cincotta AH. Brain Dopamine-Clock Interactions Regulate Cardiometabolic Physiology: Mechanisms of the Observed Cardioprotective Effects of Circadian-Timed Bromocriptine-QR Therapy in Type 2 Diabetes Subjects. Int J Mol Sci 2023; 24:13255. [PMID: 37686060 PMCID: PMC10487918 DOI: 10.3390/ijms241713255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/19/2023] [Accepted: 07/27/2023] [Indexed: 09/10/2023] Open
Abstract
Despite enormous global efforts within clinical research and medical practice to reduce cardiovascular disease(s) (CVD), it still remains the leading cause of death worldwide. While genetic factors clearly contribute to CVD etiology, the preponderance of epidemiological data indicate that a major common denominator among diverse ethnic populations from around the world contributing to CVD is the composite of Western lifestyle cofactors, particularly Western diets (high saturated fat/simple sugar [particularly high fructose and sucrose and to a lesser extent glucose] diets), psychosocial stress, depression, and altered sleep/wake architecture. Such Western lifestyle cofactors are potent drivers for the increased risk of metabolic syndrome and its attendant downstream CVD. The central nervous system (CNS) evolved to respond to and anticipate changes in the external (and internal) environment to adapt survival mechanisms to perceived stresses (challenges to normal biological function), including the aforementioned Western lifestyle cofactors. Within the CNS of vertebrates in the wild, the biological clock circuitry surveils the environment and has evolved mechanisms for the induction of the obese, insulin-resistant state as a survival mechanism against an anticipated ensuing season of low/no food availability. The peripheral tissues utilize fat as an energy source under muscle insulin resistance, while increased hepatic insulin resistance more readily supplies glucose to the brain. This neural clock function also orchestrates the reversal of the obese, insulin-resistant condition when the low food availability season ends. The circadian neural network that produces these seasonal shifts in metabolism is also responsive to Western lifestyle stressors that drive the CNS clock into survival mode. A major component of this natural or Western lifestyle stressor-induced CNS clock neurophysiological shift potentiating the obese, insulin-resistant state is a diminution of the circadian peak of dopaminergic input activity to the pacemaker clock center, suprachiasmatic nucleus. Pharmacologically preventing this loss of circadian peak dopaminergic activity both prevents and reverses existing metabolic syndrome in a wide variety of animal models of the disorder, including high fat-fed animals. Clinically, across a variety of different study designs, circadian-timed bromocriptine-QR (quick release) (a unique formulation of micronized bromocriptine-a dopamine D2 receptor agonist) therapy of type 2 diabetes subjects improved hyperglycemia, hyperlipidemia, hypertension, immune sterile inflammation, and/or adverse cardiovascular event rate. The present review details the seminal circadian science investigations delineating important roles for CNS circadian peak dopaminergic activity in the regulation of peripheral fuel metabolism and cardiovascular biology and also summarizes the clinical study findings of bromocriptine-QR therapy on cardiometabolic outcomes in type 2 diabetes subjects.
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Lee HK, Lee I, Yun J, Lee YJ, Jang EC, Min YS, Kwon SC. Relationship between job stress and impaired fasting glucose in male steel industry workers: a cross-sectional study. Ann Occup Environ Med 2023; 35:e12. [PMID: 37455849 PMCID: PMC10339050 DOI: 10.35371/aoem.2023.35.e12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 04/10/2023] [Accepted: 05/08/2023] [Indexed: 07/18/2023] Open
Abstract
Background The purpose of this study is to investigate the relationship between job stress and impaired fasting glycemia (IFG) of male workers in a manufacturing industry. Methods Data were collected from 5,886 male workers in a manufacturing industry who participated in the medical examination from June 19 to August 14, 2020 through self-reported questionnaires. The general characteristics of the subjects, shift work, high blood pressure, dyslipidemia, and job stress were included. Job stress was measured using the Korean Occupational Stress Scale (KOSS) consisting of 8 items and 43 questions. Multivariable logistic regression analysis was used to investigate the IFG association with job stress. Results Among the various factors that can cause job stress, only high job demand was associated with a risk of IFG (odds ratio, 1.43; 95% confidence interval, 1.13-1.82) especially in non-shift worker. For all other factors, no statistically significant results were obtained. Conclusions In this study of male workers engaged in the Korean steel manufacturing industry, the 'job demand' item among job stress of non-shift worker was related to IFG.
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Affiliation(s)
- Hyun-Kyo Lee
- Department of Occupational and Environmental Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Inho Lee
- Department of Occupational and Environmental Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Jisuk Yun
- Department of Occupational and Environmental Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Yong-Jin Lee
- Department of Occupational and Environmental Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Eun-Chul Jang
- Department of Occupational and Environmental Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Young-Sun Min
- Department of Occupational and Environmental Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Soon-Chan Kwon
- Department of Occupational and Environmental Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
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Borovcanin MM, Vesic K, Petrovic I, Jovanovic IP, Mijailović NR. Diabetes mellitus type 2 as an underlying, comorbid or consequent state of mental disorders. World J Diabetes 2023; 14:481-493. [PMID: 37273248 PMCID: PMC10236997 DOI: 10.4239/wjd.v14.i5.481] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 03/21/2023] [Accepted: 04/12/2023] [Indexed: 05/15/2023] Open
Abstract
Somatic disturbances that occur in parallel with psychiatric diseases are a major challenge in clinical practice. Various factors contribute to the development of mental and somatic disorders. Type 2 diabetes mellitus (T2DM) is a significant health burden worldwide, and the prevalence of diabetes in adults is increasing. The comorbidity of diabetes and mental disorders is very common. By sharing a bidirectional link, both T2DM and mental disorders influence each other in various manners, but the exact mechanisms underlying this link are not yet elucidated. The potential mechanisms of both mental disorders and T2DM are related to immune and inflammatory system dysfunction, oxidative stress, endothelial dysfunction, and metabolic disturbances. Moreover, diabetes is also a risk factor for cognitive dysfunction that can range from subtle diabetes-associated cognitive decline to pre-dementia and dementia. A complex re-lationship between the gut and the brain also represents a new therapeutic approach since gut-brain signalling pathways regulate food intake and hepatic glucose production. The aim of this minireview is to summarize and present the latest data on mutual pathogenic pathways in these disorders, emphasizing their complexity and interweaving. We also focused on the cognitive performances and changes in neurodegenerative disorders. The importance of implementing integrated approaches in treating both of these states is highlighted, along with the need for individual therapeutic strategies.
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Affiliation(s)
- Milica M Borovcanin
- Department of Psychiatry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34 000, Serbia
| | - Katarina Vesic
- Department of Neurology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34 000, Serbia
| | - Ivica Petrovic
- Department of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34 000, Serbia
| | - Ivan P Jovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34 000, Serbia
| | - Nataša R Mijailović
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34 000, Serbia
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Zhao Y, Tan DC, Peng B, Yang L, Zhang SY, Shi RP, Chong CM, Zhong ZF, Wang SP, Liang QL, Wang YT. Neuroendocrine-Immune Regulatory Network of Eucommia ulmoides Oliver. Molecules 2022; 27:molecules27123697. [PMID: 35744822 PMCID: PMC9229650 DOI: 10.3390/molecules27123697] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/23/2022] [Accepted: 05/31/2022] [Indexed: 02/04/2023] Open
Abstract
Eucommia ulmoides Oliver (E. ulmoides) is a popular medicinal herb and health supplement in China, Japan, and Korea, and has a variety of pharmaceutical properties. The neuroendocrine-immune (NEI) network is crucial in maintaining homeostasis and physical or psychological functions at a holistic level, consistent with the regulatory theory of natural medicine. This review aims to systematically summarize the chemical compositions, biological roles, and pharmacological properties of E. ulmoides to build a bridge between it and NEI-associated diseases and to provide a perspective for the development of its new clinical applications. After a review of the literature, we found that E. ulmoides has effects on NEI-related diseases including cancer, neurodegenerative disease, hyperlipidemia, osteoporosis, insomnia, hypertension, diabetes mellitus, and obesity. However, clinical studies on E. ulmoides were scarce. In addition, E. ulmoides derivatives are diverse in China, and they are mainly used to enhance immunity, improve hepatic damage, strengthen bones, and lower blood pressure. Through network pharmacological analysis, we uncovered the possibility that E. ulmoides is involved in functional interactions with cancer development, insulin resistance, NAFLD, and various inflammatory pathways associated with NEI diseases. Overall, this review suggests that E. ulmoides has a wide range of applications for NEI-related diseases and provides a direction for its future research and development.
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Affiliation(s)
- Yi Zhao
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; (Y.Z.); (D.-C.T.); (B.P.); (L.Y.); (S.-Y.Z.); (R.-P.S.); (C.-M.C.); (Z.-F.Z.); (S.-P.W.)
| | - De-Chao Tan
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; (Y.Z.); (D.-C.T.); (B.P.); (L.Y.); (S.-Y.Z.); (R.-P.S.); (C.-M.C.); (Z.-F.Z.); (S.-P.W.)
| | - Bo Peng
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; (Y.Z.); (D.-C.T.); (B.P.); (L.Y.); (S.-Y.Z.); (R.-P.S.); (C.-M.C.); (Z.-F.Z.); (S.-P.W.)
| | - Lin Yang
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; (Y.Z.); (D.-C.T.); (B.P.); (L.Y.); (S.-Y.Z.); (R.-P.S.); (C.-M.C.); (Z.-F.Z.); (S.-P.W.)
| | - Si-Yuan Zhang
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; (Y.Z.); (D.-C.T.); (B.P.); (L.Y.); (S.-Y.Z.); (R.-P.S.); (C.-M.C.); (Z.-F.Z.); (S.-P.W.)
| | - Rui-Peng Shi
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; (Y.Z.); (D.-C.T.); (B.P.); (L.Y.); (S.-Y.Z.); (R.-P.S.); (C.-M.C.); (Z.-F.Z.); (S.-P.W.)
| | - Cheong-Meng Chong
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; (Y.Z.); (D.-C.T.); (B.P.); (L.Y.); (S.-Y.Z.); (R.-P.S.); (C.-M.C.); (Z.-F.Z.); (S.-P.W.)
| | - Zhang-Feng Zhong
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; (Y.Z.); (D.-C.T.); (B.P.); (L.Y.); (S.-Y.Z.); (R.-P.S.); (C.-M.C.); (Z.-F.Z.); (S.-P.W.)
| | - Sheng-Peng Wang
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; (Y.Z.); (D.-C.T.); (B.P.); (L.Y.); (S.-Y.Z.); (R.-P.S.); (C.-M.C.); (Z.-F.Z.); (S.-P.W.)
| | - Qiong-Lin Liang
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Lab of Microanalytical Methods & Instrumentation, Department of Chemistry, Center for Synthetic and Systems Biology, Tsinghua University, Beijing 100084, China
- Correspondence: (Q.-L.L.); (Y.-T.W.); Tel.: +86-010-6277-2263 (Q.-L.L.); +853-8822-4691 (Y.-T.W.); Fax: +86-010-6277-2263 (Q.-L.L.); +853-2884-1358 (Y.-T.W.)
| | - Yi-Tao Wang
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; (Y.Z.); (D.-C.T.); (B.P.); (L.Y.); (S.-Y.Z.); (R.-P.S.); (C.-M.C.); (Z.-F.Z.); (S.-P.W.)
- Correspondence: (Q.-L.L.); (Y.-T.W.); Tel.: +86-010-6277-2263 (Q.-L.L.); +853-8822-4691 (Y.-T.W.); Fax: +86-010-6277-2263 (Q.-L.L.); +853-2884-1358 (Y.-T.W.)
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Ehtewish H, Arredouani A, El-Agnaf O. Diagnostic, Prognostic, and Mechanistic Biomarkers of Diabetes Mellitus-Associated Cognitive Decline. Int J Mol Sci 2022; 23:6144. [PMID: 35682821 PMCID: PMC9181591 DOI: 10.3390/ijms23116144] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/29/2022] [Accepted: 03/29/2022] [Indexed: 01/27/2023] Open
Abstract
Cognitive dysfunctions such as mild cognitive impairment (MCI), Alzheimer's disease (AD), and other forms of dementia are recognized as common comorbidities of type 2 diabetes mellitus (T2DM). Currently, there are no disease-modifying therapies or definitive clinical diagnostic and prognostic tools for dementia, and the mechanisms underpinning the link between T2DM and cognitive dysfunction remain equivocal. Some of the suggested pathophysiological mechanisms underlying cognitive decline in diabetes patients include hyperglycemia, insulin resistance and altered insulin signaling, neuroinflammation, cerebral microvascular injury, and buildup of cerebral amyloid and tau proteins. Given the skyrocketing global rates of diabetes and neurodegenerative disorders, there is an urgent need to discover novel biomarkers relevant to the co-morbidity of both conditions to guide future diagnostic approaches. This review aims to provide a comprehensive background of the potential risk factors, the identified biomarkers of diabetes-related cognitive decrements, and the underlying processes of diabetes-associated cognitive dysfunction. Aging, poor glycemic control, hypoglycemia and hyperglycemic episodes, depression, and vascular complications are associated with increased risk of dementia. Conclusive research studies that have attempted to find specific biomarkers are limited. However, the most frequent considerations in such investigations are related to C reactive protein, tau protein, brain-derived neurotrophic factor, advanced glycation end products, glycosylated hemoglobin, and adipokines.
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Affiliation(s)
- Hanan Ehtewish
- Division of Biological and Biomedical Sciences (BBS), College of Health & Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Doha 34110, Qatar;
| | - Abdelilah Arredouani
- Division of Biological and Biomedical Sciences (BBS), College of Health & Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Doha 34110, Qatar;
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Doha 34110, Qatar
| | - Omar El-Agnaf
- Division of Biological and Biomedical Sciences (BBS), College of Health & Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Doha 34110, Qatar;
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Doha 34110, Qatar
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Buckert M, Hartmann M, Monzer N, Wolff K, Nawroth P, Fleming T, Streibel C, Henningsen N, Wild B. Pronounced cortisol response to acute psychosocial stress in type 2 diabetes patients with and without complications. Horm Behav 2022; 141:105120. [PMID: 35220091 DOI: 10.1016/j.yhbeh.2022.105120] [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: 02/18/2021] [Revised: 12/23/2021] [Accepted: 01/13/2022] [Indexed: 11/04/2022]
Abstract
It is increasingly recognized that psychological stress is linked with type 2 diabetes mellitus and its late complications. Thus, the aim of the current study was to investigate the psychophysiological response to acute psychosocial stress in patients with type 2 diabetes. In total, 53 type 2 diabetes patients with complications, 16 type 2 diabetes patients without complications, and 47 age and gender matched non-diabetic participants underwent the Trier Social Stress Test. Subjective as well as biological parameters (i.e., blood levels of cortisol, adrenocorticotropic hormone (ACTH), norepinephrine, methylglyoxal) were assessed repeatedly before and after stress induction. Data were analyzed by means of multilevel regression. Patients with type 2 diabetes showed an exaggerated cortisol response to acute stress as compared to age matched control participants (diabetes*T2 est. = 1.23, p < .001), while stress-induced alterations of ACTH and subjective parameters did not differ. Norepinephrine levels were lower among patients (diabetes est. = -4.36, p = .044) and tended to decrease earlier than in controls. The subjective reaction of type 2 diabetes patients with complications was stronger than that of patients without complications (complication*T2 est. = -1.83, p = .032), while their endocrine response to stress was similar. Stress had no effect on methylglyoxal level, and there were no group differences regarding methylglyoxal response. These results show that the cortisol reactivity of patients with type 2 diabetes to acute psychosocial stress is increased compared to a control group. Thus, alterations of the hypothalamus-pituitary-adrenal axis - especially regarding its dynamic regulation - are a plausible link between psychological stress and type 2 diabetes and its complications.
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Affiliation(s)
- M Buckert
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany.
| | - M Hartmann
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany
| | - N Monzer
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany
| | - K Wolff
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany
| | - P Nawroth
- Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), Heidelberg, Germany
| | - T Fleming
- Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
| | - C Streibel
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany
| | - N Henningsen
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany
| | - B Wild
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany.
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Gu X, Ge L, Ren B, Fang Y, Li Y, Wang Y, Xu H. Glucocorticoids Promote Extracellular Matrix Component Remodeling by Activating YAP in Human Retinal Capillary Endothelial Cells. Front Cell Dev Biol 2022; 9:738341. [PMID: 34970541 PMCID: PMC8712730 DOI: 10.3389/fcell.2021.738341] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/14/2021] [Indexed: 11/13/2022] Open
Abstract
Remodeling of extracellular matrix (ECM) components of endothelial cells is the main cause of retinal vascular basement membrane (BM) thickening, which leads to the initiation and perpetuation of microvasculopathy of diabetic retinopathy (DR). Excessive amounts of glucocorticoids (GCs) are related to the presence and severity of DR, however transcriptional effects of GCs on the biology of human retinal capillary endothelial cells (HRCECs) and its impacts on DR are still unclear. Here, we showed that GC (hydrocortisone) treatment induced ECM component [fibronectin (FN) and type IV collagen (Col IV)] expression and morphological changes in HRCECs via the glucocorticoid receptor (GR), which depended on the nuclear translocation of YAP coactivator. Mechanistically, GCs induced stress fiber formation in HRCECs, while blocking stress fiber formation inhibited GC-induced YAP nuclear translocation. Overexpression of FN, but not Col IV, activated YAP through the promotion of stress fiber formation via ECM-integrin signaling. Thus, a feedforward loop is established to sustain YAP activity. Using mRNA sequencing of HRCECs with overexpressed YAP or GC treatment, we found a similarity in Gene Ontology (GO) terms, differentially expressed genes (DEGs) and transcription factors (TFs) between the two RNA-seq datasets. In vivo, YAP was activated in retina vascular ECs of STZ-induced diabetic mice, and TF prediction analysis of published RNA-seq data of dermal vascular ECs from T2DM patients showed that GR and TEAD (the main transcription factor for YAP) were enriched. Together, GCs activate YAP and promote ECM component (FN and Col IV) remodeling in retinal capillary endothelial cells, and the underlying regulatory mechanism may provide new insights into the vascular BM thickening of the retina in the early pathogenesis of DR.
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Affiliation(s)
- Xianliang Gu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Key Lab of Visual Damage & Regeneration and Restoration of Chongqing, Chongqing, China
| | - Lingling Ge
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Key Lab of Visual Damage & Regeneration and Restoration of Chongqing, Chongqing, China
| | - Bangqi Ren
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Key Lab of Visual Damage & Regeneration and Restoration of Chongqing, Chongqing, China
| | - Yajie Fang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Key Lab of Visual Damage & Regeneration and Restoration of Chongqing, Chongqing, China
| | - Yijian Li
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Key Lab of Visual Damage & Regeneration and Restoration of Chongqing, Chongqing, China
| | - Yi Wang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Key Lab of Visual Damage & Regeneration and Restoration of Chongqing, Chongqing, China
| | - Haiwei Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Key Lab of Visual Damage & Regeneration and Restoration of Chongqing, Chongqing, China
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Zhang M, Cui C, Lin Y, Cai J. Ameliorating effect on glycolipid metabolism and chemical profile of Millettia speciosa champ. extract. JOURNAL OF ETHNOPHARMACOLOGY 2021; 279:114360. [PMID: 34166739 DOI: 10.1016/j.jep.2021.114360] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/25/2021] [Accepted: 06/19/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Millettia speciosa Champ., also called Niu dali, is a fabaceous medicinal plant mainly distributed in southeast China, where it is a functional food for developing physical strength, and often used traditionally in medicinal treatment of numbness of the wrists, diabetes, hepatitis, and so on. AIM OF THE STUDY To investigate the chemical profile, ameliorating effects of MSC on glycolipid metabolism in diabetic mice and to identify the possible mechanism of action. MATERIALS AND METHODS High-performance liquid chromatography coupled with electrospray ionization quadrupole time of flight mass spectrometry (HPLC-ESI-QTOF-MS) was applied to analyze the chemical compositions from M. speciosa extract (MSC). MSC was orally administered to high-fat diet and STZ-induced diabetic mice at doses of 4.55, 9.10 and 13.65 mg/(kg·d) respectively for 10 weeks. Indices of glycolipid metabolism, including fasting blood glucose (FBG), fasting insulin, insulin resistance index (IRI), blood lipids, HPA-axis hormones, and related gene expressions were evaluated. RESULTS 86 compounds were tentatively identified from MSC, counting for 91.97% of the total extract, mainly including 23 alkaloids (including 2 cyanogenetic glycosides firstly identified in this species, total content accounted to 39.71%), 23 flavonoids (11.91%), 17 acids (including 3 amino acids, 9 phenolic acids and 5 organic acids; 9.2%), 9 terpenoids and steroids (20.13%), 7 esters (3.33%), 3 lignans (3.73%), 3 saccharides (4.0%) and 1 anthraquinone (0.18%). MSC could ameliorate the glycolipid disorder in diabetic mice markedly, and significant regulations on CRH and ACTH hormones were observed. Moreover, the cellular morphology of liver and pancreas were significantly improved and the expressions of IRS2, PI3K, Akt and GLUT4 were significantly up-regulated by MSC treatment. CONCLUSION This was the first time to study the chemical profile and ameliorating effect on glycolipid metabolism of M. speciosa. It was found to be rich in flavonoids and alkaloids, which might support the potential relation of material foundation and the activity in regulating glycolipid metabolism. The ameliorating effect on glycolipid disorder in diabetic mice might be associated to the regulation of related hormones of the HPA axis and the IRS2/PI3K/Akt/GLUT4 signalling pathway. It was of great significance for advanced directed separation and pharmacological activity research of MSC.
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Affiliation(s)
- Min Zhang
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Caihong Cui
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Yanduan Lin
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Jinyan Cai
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
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Kokkinopoulou I, Diakoumi A, Moutsatsou P. Glucocorticoid Receptor Signaling in Diabetes. Int J Mol Sci 2021; 22:ijms222011173. [PMID: 34681832 PMCID: PMC8537243 DOI: 10.3390/ijms222011173] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 10/04/2021] [Accepted: 10/12/2021] [Indexed: 12/20/2022] Open
Abstract
Stress and depression increase the risk of Type 2 Diabetes (T2D) development. Evidence demonstrates that the Glucocorticoid (GC) negative feedback is impaired (GC resistance) in T2D patients resulting in Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivity and hypercortisolism. High GCs, in turn, activate multiple aspects of glucose homeostasis in peripheral tissues leading to hyperglycemia. Elucidation of the underlying molecular mechanisms revealed that Glucocorticoid Receptor (GR) mediates the GC-induced dysregulation of glucose production, uptake and insulin signaling in GC-sensitive peripheral tissues, such as liver, skeletal muscle, adipose tissue, and pancreas. In contrast to increased GR peripheral sensitivity, an impaired GR signaling in Peripheral Blood Mononuclear Cells (PBMCs) of T2D patients, associated with hyperglycemia, hyperlipidemia, and increased inflammation, has been shown. Given that GR changes in immune cells parallel those in brain, the above data implicate that a reduced brain GR function may be the biological link among stress, HPA hyperactivity, hypercortisolism and hyperglycemia. GR polymorphisms have also been associated with metabolic disturbances in T2D while dysregulation of micro-RNAs—known to target GR mRNA—has been described. Collectively, GR has a crucial role in T2D, acting in a cell-type and context-specific manner, leading to either GC sensitivity or GC resistance. Selective modulation of GR signaling in T2D therapy warrants further investigation.
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Ortega VA, Mercer EM, Giesbrecht GF, Arrieta MC. Evolutionary Significance of the Neuroendocrine Stress Axis on Vertebrate Immunity and the Influence of the Microbiome on Early-Life Stress Regulation and Health Outcomes. Front Microbiol 2021; 12:634539. [PMID: 33897639 PMCID: PMC8058197 DOI: 10.3389/fmicb.2021.634539] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
Stress is broadly defined as the non-specific biological response to changes in homeostatic demands and is mediated by the evolutionarily conserved neuroendocrine networks of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Activation of these networks results in transient release of glucocorticoids (cortisol) and catecholamines (epinephrine) into circulation, as well as activation of sympathetic fibers innervating end organs. These interventions thus regulate numerous physiological processes, including energy metabolism, cardiovascular physiology, and immunity, thereby adapting to cope with the perceived stressors. The developmental trajectory of the stress-axis is influenced by a number of factors, including the gut microbiome, which is the community of microbes that colonizes the gastrointestinal tract immediately following birth. The gut microbiome communicates with the brain through the production of metabolites and microbially derived signals, which are essential to human stress response network development. Ecological perturbations to the gut microbiome during early life may result in the alteration of signals implicated in developmental programming during this critical window, predisposing individuals to numerous diseases later in life. The vulnerability of stress response networks to maladaptive development has been exemplified through animal models determining a causal role for gut microbial ecosystems in HPA axis activity, stress reactivity, and brain development. In this review, we explore the evolutionary significance of the stress-axis system for health maintenance and review recent findings that connect early-life microbiome disturbances to alterations in the development of stress response networks.
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Affiliation(s)
- Van A Ortega
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,International Microbiome Centre, Cumming School of Medicine, Health Sciences Centre, University of Calgary, Calgary, AB, Canada
| | - Emily M Mercer
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,International Microbiome Centre, Cumming School of Medicine, Health Sciences Centre, University of Calgary, Calgary, AB, Canada.,Department of Pediatrics, University of Calgary, Calgary, AB, Canada
| | - Gerald F Giesbrecht
- Department of Pediatrics, University of Calgary, Calgary, AB, Canada.,Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada.,Owerko Centre, The Alberta Children's Hospital Research Institute, Calgary, AB, Canada
| | - Marie-Claire Arrieta
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,International Microbiome Centre, Cumming School of Medicine, Health Sciences Centre, University of Calgary, Calgary, AB, Canada.,Department of Pediatrics, University of Calgary, Calgary, AB, Canada
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12
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Panagiotou C, Lambadiari V, Maratou E, Geromeriati C, Artemiadis A, Dimitriadis G, Moutsatsou P. Insufficient glucocorticoid receptor signaling and flattened salivary cortisol profile are associated with metabolic and inflammatory indices in type 2 diabetes. J Endocrinol Invest 2021; 44:37-48. [PMID: 32394161 DOI: 10.1007/s40618-020-01260-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 04/15/2020] [Indexed: 12/22/2022]
Abstract
PURPOSE Impaired negative feedback and hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis characterizes type 2 diabetes mellitus (T2DM). The glucocorticoid receptor (GR) is a key mediator of HPA axis negative feedback; however, its role in linking hypercortisolemia and T2DM-associated hyperglycemia, hyperlipidemia and inflammation is not yet known. METHODS In peripheral mononuclear cells (PBMC) from 31 T2DM patients and 24 healthy controls, we measured various GR-signaling parameters such as phosphorylated GR (pGR-S211), GRα/GRβ gene expression and GC-sensitivity [using the basal and dexamethasone (DEX)-induced leucine zipper (GILZ) and FK506 binding-protein (FKBP5) mRNA levels as well as the basal interleukin (IL)-1β protein levels]. Diurnal salivary cortisol curve parameters such as the cortisol awaking response (CAR) and area under the curve (AUCtotal and AUCi) as well as inflammatory and metabolic indices were also determined. RESULTS T2DM patients exhibited diminished pGR-S211 protein content, increased GRβ, decreased basal GILZ and FKBP5 mRNA levels and increased IL-1β levels. Flattened DEX-induced GILZ and FKBP5 response curves and a flattened salivary cortisol profile characterized T2DM patients. Significant associations of GR measures and saliva cortisol curve parameters with biochemical and clinical characteristics were found. CONCLUSION Our novel data implicate an insufficient GR signaling in PBMCs in T2DM patients and HPA axis dysfunction. The significant associations of GR-signaling parameters with inflammatory and metabolic indices implicate that GR may be the critical link between HPA axis dysfunction, hypercortisolemia and diabetes-associated metabolic disturbances. Our findings provide significant insights into the contribution of GR-mediated mechanisms in T2DM aetiopathology and therapy.
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Affiliation(s)
- C Panagiotou
- Department of Clinical Biochemistry, National and Kapodistrian University of Athens, School of Medicine, University General Hospital Attikon, Rimini 1, Haidari, 12462, Athens, Greece
| | - V Lambadiari
- Second Department of Internal Medicine and Research Institute, University General Hospital Attikon, Haidari, Greece
| | - E Maratou
- Department of Clinical Biochemistry, National and Kapodistrian University of Athens, School of Medicine, University General Hospital Attikon, Rimini 1, Haidari, 12462, Athens, Greece
| | - C Geromeriati
- Department of Clinical Biochemistry, National and Kapodistrian University of Athens, School of Medicine, University General Hospital Attikon, Rimini 1, Haidari, 12462, Athens, Greece
| | - A Artemiadis
- Medical School, University of Cyprus, Nicosia, Cyprus
| | - G Dimitriadis
- Second Department of Internal Medicine and Research Institute, University General Hospital Attikon, Haidari, Greece
| | - P Moutsatsou
- Department of Clinical Biochemistry, National and Kapodistrian University of Athens, School of Medicine, University General Hospital Attikon, Rimini 1, Haidari, 12462, Athens, Greece.
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13
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Cai J, Zhang J, Li S, Lin Y, Xiao X, Guo J. Comprehensive chemical analysis of Zhenshu Tiaozhi formula and its effect on ameliorating glucolipid metabolic disorders in diabetic rats. Biomed Pharmacother 2021; 133:111060. [PMID: 33378969 DOI: 10.1016/j.biopha.2020.111060] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 11/16/2020] [Accepted: 11/20/2020] [Indexed: 10/22/2022] Open
Abstract
The present study aims to reveal the compositions of Zhenshu TiaoZhi formula (FTZ) comprehensively, and investigate whether FTZ ameliorate glucolipid metabolism disorders in diabetic rats with the involvement of glucocorticoids in peripheral insulin-sensitive tissues. The fingerprint was established based on 11 batches of FTZ samples and chemical compostions of FTZ were identified by ultra performance liquid chromatography-time of flight/mass spectrometry (UPLC-TOF/MS). High-fat diet (HFD) and streptozotocin (STZ) induced diabetic rats were orally administrated with 3 and 6 g/kg body weight of FTZ for 8 weeks. Indices of glucolipid metabolism, including fasting blood glucose (FBG), fasting insulin, insulin resistance index (IRI) and blood lipids were evaluated after treatment of FTZ. The levels of HPA axis hormones were examined. Reverse transcription-polymerase chain reaction (RT-PCR) was adopted to investigate the relative mRNA expressions of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and glucolipid metabolic indicators. A reference fingerprint was established and 93 compounds of FTZ were tentatively identified. In vivo, FTZ treatment exerted antidiabetic and antidyslipidemic effects while decreased the level of corticotropin releasing hormone (CRH). 11β-HSD1 mRNA showed similar trajectory in both liver, adipose and skeletal muscle tissues, which was up-regulated in diabetic group and ameliorated in FTZ groups. Furthermore, the expressions of glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK) and adipose triglyceride lipase (ATGL) were down-regulated in liver and skeletal muscle. These results elucidated the compositions of FTZ comprehensively and indicated its effect on ameliorating glucolipid metabolism of diabetic rats involved hypothalamus-pituitary-adrenal (HPA) axis homeostasis. Down-regulating 11β-HSD1 in insulin-sensitive tissues might be a potential mechanism of FTZ in treating type 2 diabetes mellitus (T2DM).
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Affiliation(s)
- Jinyan Cai
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Jingjing Zhang
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Shanshan Li
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Yanduan Lin
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Xue Xiao
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
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14
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Lin Y, Zhang Z, Wang S, Cai J, Guo J. Hypothalamus-pituitary-adrenal Axis in Glucolipid metabolic disorders. Rev Endocr Metab Disord 2020; 21:421-429. [PMID: 32889666 DOI: 10.1007/s11154-020-09586-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/26/2020] [Indexed: 02/07/2023]
Abstract
With the change of life style, glucolipid metabolic disorders (GLMD) has become one of the major chronic disorders causing public health and clinical problems worldwide. Previous studies on GLMD pay more attention to peripheral tissues. In fact, the central nervous system (CNS) plays an important role in controlling the overall metabolic balance. With the development of technology and the in-depth understanding of the CNS, the relationship between neuro-endocrine-immunoregulatory (NEI) network and metabolism had been gradually illustrated. As the hub of NEI network, hypothalamus-pituitary-adrenal (HPA) axis is important for maintaining the balance of internal environment in the body. The relationship between HPA axis and GLMD needs to be further studied. This review focuses on the role of HPA axis in GLMD and reviews the research progress on drugs for GLMD, with the hope to provide the direction for exploring new drugs to treat GLMD by taking the HPA axis as the target and improve the level of prevention and control of GLMD.
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Affiliation(s)
- Yanduan Lin
- Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China
| | - Ziwei Zhang
- Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China
| | - Siyu Wang
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China
| | - Jinyan Cai
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China.
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China.
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15
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Kumar M, Chail M. Sucrose and saccharin differentially modulate depression and anxiety-like behavior in diabetic mice: exposures and withdrawal effects. Psychopharmacology (Berl) 2019; 236:3095-3110. [PMID: 31073738 DOI: 10.1007/s00213-019-05259-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 04/26/2019] [Indexed: 01/08/2023]
Abstract
RATIONALE Sugar has addictive potential owing to increase in monoaminergic-transmission at pleasure and reward centers of brain. Insulin dysfunction triggered synaptic monoamine deficit is associated with sugar overeating and craving-related psychological changes in diabetic patients. Sugar-substitute (saccharin) is non-caloric artificial sweetener that may alleviate brain disorders in diabetes. OBJECTIVES In present study, effects of sucrose and sugar-substitute (saccharin) exposures and withdrawal on depression and anxiety-like behavior in type 2 diabetic mice were assessed. METHODS Swiss albino mice were injected with streptozotocin (135 mg/kg). After induction of diabetes, mice were exposed to a two-bottle water-water, 10% sucrose-water, or 10% saccharin-water choice paradigm for 28 days. Separate groups were employed to assess withdrawal effect of sucrose or saccharin in diabetic mice. Monoamine oxidase (MAO), corticosterone, thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH) were quantified after behavioral tests. RESULTS Diabetic mice manifested preference towards 10% sucrose or saccharin over water. Sucrose-overeating by diabetic mice amplified symptoms of depression and anxiety; however, withdrawal further exaggerated these behavioral abnormalities. Substitution of sucrose by 10% saccharin attenuated the depressive and anxiety-like behavior in comparison to diabetic mice that were exposed separately to water-water or sucrose-water alone, and with respect to normal mice. Although withdrawal from saccharin resurfaced behavioral anomalies in diabetic mice, however, these were significantly low in comparison with withdrawal from sucrose or normal group. Reinstatement of exposure to saccharin mitigated symptoms of depression and anxiety in diabetic mice. CONCLUSION Preference of sucrose overeating augments while saccharin mitigates depressive and anxiety behavior during diabetes.
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Affiliation(s)
- Manish Kumar
- Department of Pharmacology, Swift School of Pharmacy, Ghaggar Sarai, Rajpura, Punjab, 140401, India.
| | - Monica Chail
- Department of Pharmacology, Swift School of Pharmacy, Ghaggar Sarai, Rajpura, Punjab, 140401, India
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16
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Liu X, Jiang J, Liu X, Luo Z, Wang Y, Dong X, Wei D, Huo W, Yu S, Li L, Jin S, Wang C, Mao Z. Gender-Specific Independent and Combined Effects of the Cortisol-to-Cortisone Ratio and 11-Deoxycortisol on Prediabetes and Type 2 Diabetes Mellitus: From the Henan Rural Cohort Study. J Diabetes Res 2019; 2019:4693817. [PMID: 31281850 PMCID: PMC6589245 DOI: 10.1155/2019/4693817] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 02/25/2019] [Accepted: 05/12/2019] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE The aim of the study was to investigate the independent and combined effects of the cortisol-to-cortisone ratio (F/E) and 11-deoxycortisol on prediabetes and type 2 diabetes mellitus (T2DM) among different genders. METHODS A case-control study was performed including 2676 participants from the Henan Rural Cohort Study. Liquid chromatography-tandem mass spectrometry was used to assess serum cortisol, cortisone, and 11-deoxycortisol. Conditional logistic regression was performed to estimate the associations between hormones and outcomes. RESULTS After adjusting for multiple variables, the negative associations of F/E and 11-dexyocortisol with T2DM were observed in females (T3 vs. T1: OR = 0.56, 95% CI: 0.39-0.80 for F/E; T3 vs. T1: OR = 0.44, 95% CI: 0.27-0.73 for 11-dexyocortisol). However, only 11-dexyocortisol showed a negative association with prediabetes both in males and females. Compared with the combination of low F/E and 11-dexyocortisol, the combination of middle F/E and high 11-dexyocortisol was significantly associated with prediabetes (OR = 0.29, 95% CI: 0.12-0.71) in males. Furthermore, the combination of high F/E and 11-dexyocortisol was associated with the lowest odds of prediabetes (OR = 0.39, 95% CI: 0.21-0.73) and T2DM (OR = 0.25, 95% CI: 0.12-0.52) in females. CONCLUSIONS Serum F/E level was negatively associated with T2DM only in females whereas serum 11-deoxycortisol level was negatively associated with prediabetes in males and with prediabetes and T2DM in females. Additionally, their combination has a synergistic effect on T2DM.
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Affiliation(s)
- Xue Liu
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Jingjing Jiang
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaotian Liu
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhicheng Luo
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Yan Wang
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaokang Dong
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Dandan Wei
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Wenqian Huo
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Songcheng Yu
- Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Linlin Li
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Shuna Jin
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chongjian Wang
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhenxing Mao
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
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17
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Paley CA, Johnson MI. Abdominal obesity and metabolic syndrome: exercise as medicine? BMC Sports Sci Med Rehabil 2018; 10:7. [PMID: 29755739 PMCID: PMC5935926 DOI: 10.1186/s13102-018-0097-1] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 04/26/2018] [Indexed: 12/18/2022]
Abstract
Background Metabolic syndrome is defined as a cluster of at least three out of five clinical risk factors: abdominal (visceral) obesity, hypertension, elevated serum triglycerides, low serum high-density lipoprotein (HDL) and insulin resistance. It is estimated to affect over 20% of the global adult population. Abdominal (visceral) obesity is thought to be the predominant risk factor for metabolic syndrome and as predictions estimate that 50% of adults will be classified as obese by 2030 it is likely that metabolic syndrome will be a significant problem for health services and a drain on health economies. Evidence shows that regular and consistent exercise reduces abdominal obesity and results in favourable changes in body composition. It has therefore been suggested that exercise is a medicine in its own right and should be prescribed as such. Purpose of this review This review provides a summary of the current evidence on the pathophysiology of dysfunctional adipose tissue (adiposopathy). It describes the relationship of adiposopathy to metabolic syndrome and how exercise may mediate these processes, and evaluates current evidence on the clinical efficacy of exercise in the management of abdominal obesity. The review also discusses the type and dose of exercise needed for optimal improvements in health status in relation to the available evidence and considers the difficulty in achieving adherence to exercise programmes. Conclusion There is moderate evidence supporting the use of programmes of exercise to reverse metabolic syndrome although at present the optimal dose and type of exercise is unknown. The main challenge for health care professionals is how to motivate individuals to participate and adherence to programmes of exercise used prophylactically and as a treatment for metabolic syndrome.
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Affiliation(s)
- Carole A Paley
- 1Research & Development (Ward 12), Airedale NHS Foundation Trust, Skipton Road, Steeton, Keighley, West Yorkshire BD20 6TD UK.,2School of Clinical and Applied Sciences, Leeds Beckett University, Portland Building, City Campus, Leeds, LS1 3HE UK
| | - Mark I Johnson
- 2School of Clinical and Applied Sciences, Leeds Beckett University, Portland Building, City Campus, Leeds, LS1 3HE UK
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Takiguchi T, Koide H, Nagano H, Nakayama A, Fujimoto M, Tamura A, Komai E, Shiga A, Kono T, Higuchi S, Sakuma I, Hashimoto N, Suzuki S, Miyabayashi Y, Ishiwatari N, Horiguchi K, Nakatani Y, Yokote K, Tanaka T. Multihormonal pituitary adenoma concomitant with Pit-1 and Tpit lineage cells causing acromegaly associated with subclinical Cushing's disease: a case report. BMC Endocr Disord 2017; 17:54. [PMID: 28865461 PMCID: PMC5581437 DOI: 10.1186/s12902-017-0203-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 08/21/2017] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND A functional pituitary adenoma can produce multiple anterior-pituitary hormones, such as growth hormone (GH) -producing adenomas (GHoma) with prolactin or thyrotropin stimulating hormone production in the same lineage. However, it is very rare that acromegaly shows subclinical Cushing's disease (SCD) beyond the lineage. Here we describe the involvement of intratumoral coexistence with 2 types of hormone-producing cells associated with different lineage in acromegaly concomitant with SCD. CASE PRESENTATION In our study, we performed clinical evaluation of the patient showing acromegaly with SCD. To elucidate the mechanisms of this pathology, we analyzed immunohistochemistry and gene expression of anterior-pituitary hormones and transcriptional factors in the resected pituitary tumor. On immunohistochemical staining, most of the tumor cells were strongly stained for GH antibody, while some cells were strongly positive for adrenocorticotropic hormone (ACTH). Gene expression analysis of a transsphenoidal surgery sample of the pituitary gland revealed that ACTH-related genes, such as POMC, Tpit, and NeuroD1 mRNA, had higher expression in the tumor tissue than the nonfunctional adenoma but lower expression compared to an adenoma of typical Cushing's disease. Further, double-labeling detection methods with a fluorescent stain for ACTH and GH demonstrated the coexistence of ACTH-positive cells (GH-negative) among the GH-positive cells in the tumor. Additionally, Pit-1 expression was reduced in the ACTH-positive cells from tumor tissue primary culture. CONCLUSION Here we described a case of a pituitary tumor diagnosed with acromegaly associated with SCD. We performed quantitative-expression analyses of transcriptional factors of the tumor tissue and immunohistochemistry analysis of tumor-derived primary culture cells, which suggested that the multihormonal pituitary adenoma concomitant with Pit-1 and Tpit lineage cells caused acromegaly associated with SCD.
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Affiliation(s)
- Tomoko Takiguchi
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Hisashi Koide
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Hidekazu Nagano
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Akitoshi Nakayama
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
| | - Masanori Fujimoto
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Ai Tamura
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Eri Komai
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Akina Shiga
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Takashi Kono
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Seiichiro Higuchi
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Ikki Sakuma
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Naoko Hashimoto
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Sawako Suzuki
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Yui Miyabayashi
- Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
| | - Norio Ishiwatari
- Department of Neurological Surgery, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Kentaro Horiguchi
- Department of Neurological Surgery, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Yukio Nakatani
- Department of Pathology, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Koutaro Yokote
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
| | - Tomoaki Tanaka
- Department of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, 260-8670 Japan
- Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Chiba, 260-8670 Japan
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Tang F, Wang G, Lian Y. Association between anxiety and metabolic syndrome: A systematic review and meta-analysis of epidemiological studies. Psychoneuroendocrinology 2017; 77:112-121. [PMID: 28027497 DOI: 10.1016/j.psyneuen.2016.11.025] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 11/11/2016] [Accepted: 11/18/2016] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Epidemiological studies have repeatedly investigated the association between anxiety and metabolic syndrome (MetS). However, the results have been inconsistent. We performed a meta-analysis of observational studies to summarize the evidence regarding the relation of anxiety and MetS risk. METHODS We performed a systematic literature search of all studies published in PubMed and EMBASE from its inception to June 2016. Cross-sectional and cohort studies that reported an association between the two conditions in adults were included. Data on prevalence, incidence, unadjusted or adjusted odds ratio (OR), and 95% CI were extracted or provided independently by the authors. Random effects model was used to report the pooled OR. The I2 statistic was used to assess heterogeneity. Egger's test and Begger's test were used to evaluate the publication bias. RESULTS The search yielded 18 cross-sectional studies and two cohort studies. The pooled finding from cross-sectional studies showed that anxiety had a significant positive association with MetS (OR 1.07, 95% CI 1.01-1.12), with moderate heterogeneity (I2=45.7%, P=0.018). Findings from two cohort studies indicated that the association between anxiety and MetS was insignificant. CONCLUSION Our results suggest that there is an association between anxiety and MetS. In individuals with MetS anxiety should be detected and managed. Further prospective studies are needed to explore the bidirectional association between anxiety and MetS.
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Affiliation(s)
- Fang Tang
- Health Management Center, Qianfoshan Hospital Affiliated to Shandong University, Jinan, China
| | - Gangpu Wang
- Department of General Surgery, The Fourth Hospital of Jinan City, Jinan, China
| | - Ying Lian
- Department of Case Administration, Qianfoshan Hospital Affiliated to Shandong University, Jinan, China.
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20
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Tenk J, Mátrai P, Hegyi P, Rostás I, Garami A, Szabó I, Solymár M, Pétervári E, Czimmer J, Márta K, Mikó A, Füredi N, Párniczky A, Zsiborás C, Balaskó M. In Obesity, HPA Axis Activity Does Not Increase with BMI, but Declines with Aging: A Meta-Analysis of Clinical Studies. PLoS One 2016; 11:e0166842. [PMID: 27870910 PMCID: PMC5117724 DOI: 10.1371/journal.pone.0166842] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 11/05/2016] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Obesity is one of the major public health challenges worldwide. It involves numerous endocrine disorders as etiological factors or as complications. Previous studies strongly suggested the involvement of the hypothalamic-pituitary-adrenal (HPA) axis activity in obesity, however, to date, no consistent trend in obesity-associated alterations of the HPA axis has been identified. Aging has been demonstrated to aggravate obesity and to induce abnormalities of the HPA axis. Thus, the question arises whether obesity is correlated with peripheral indicators of HPA function in adult populations. OBJECTIVES We aimed to meta-analyze literature data on peripheral cortisol levels as indicators of HPA activity in obesity during aging, in order to identify possible explanations for previous contradictory findings and to suggest new approaches for future clinical studies. DATA SOURCES 3,596 records were identified through searching of PubMed, Embase and Cochrane Library Database. Altogether 26 articles were suitable for analyses. STUDY ELIGIBILITY CRITERIA Empirical research papers were eligible provided that they reported data of healthy adult individuals, included body mass index (BMI) and measured at least one relevant peripheral cortisol parameter (i.e., either morning blood cortisol or 24-h urinary free cortisol). STATISTICAL METHODS We used random effect models in each of the meta-analyses calculating with the DerSimonian and Laird weighting methods. I-squared indicator and Q test were performed to assess heterogeneity. Meta-regression was applied to explore the effect of BMI and age on morning blood and urinary free cortisol levels. To assess publication bias Egger's test was used. RESULTS Obesity did not show any correlation with the studied peripheral cortisol values. On the other hand, peripheral cortisol levels declined with aging within the obese, but not in the non-obese groups. CONCLUSIONS Our analysis demonstrated that obesity or healthy aging does not lead to enhanced HPA axis activity, peripheral cortisol levels rather decline with aging.
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Affiliation(s)
- Judit Tenk
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Mátrai
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Institute of Bioanalysis, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Department of Translational Medicine, University of Pécs, Pécs, Hungary
- Hungarian Academy of Sciences - University of Szeged, Momentum Gastroenterology Multidisciplinary Research Group, Szeged, Hungary
| | - Ildikó Rostás
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - András Garami
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Imre Szabó
- Department of Gastroenterology, First Department of Internal Medicine, University of Pécs, Pécs, Hungary
| | - Margit Solymár
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Erika Pétervári
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - József Czimmer
- Department of Gastroenterology, First Department of Internal Medicine, University of Pécs, Pécs, Hungary
| | - Katalin Márta
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Department of Translational Medicine, University of Pécs, Pécs, Hungary
| | - Alexandra Mikó
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Nóra Füredi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Andrea Párniczky
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Department of Translational Medicine, University of Pécs, Pécs, Hungary
| | - Csaba Zsiborás
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Márta Balaskó
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
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21
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Diz-Chaves Y, Gil-Lozano M, Toba L, Fandiño J, Ogando H, González-Matías LC, Mallo F. Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis. J Endocrinol 2016; 230:R77-94. [PMID: 27325244 DOI: 10.1530/joe-16-0118] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 06/20/2016] [Indexed: 12/25/2022]
Abstract
Diabetes mellitus exerts metabolic stress on cells and it provokes a chronic increase in the long-term activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, perhaps thereby contributing to insulin resistance. GLP-1 receptor (GLP-1R) agonists are pleiotropic hormones that not only affect glycaemic and metabolic control, but they also produce many other effects including activation of the HPA axis. In fact, several of the most relevant effects of GLP-1 might involve, at least in part, the modulation of the HPA axis. Thus, the anorectic activity of GLP-1 could be mediated by increasing CRF at the hypothalamic level, while its lipolytic effects could imply a local increase in glucocorticoids and glucocorticoid receptor (GC-R) expression in adipose tissue. Indeed, the potent activation of the HPA axis by GLP-1R agonists occurs within the range of therapeutic doses and with a short latency. Interestingly, the interactions of GLP-1 with the HPA axis may underlie most of the effects of GLP-1 on food intake control, glycaemic metabolism, adipose tissue biology and the responses to stress. Moreover, such activity has been observed in animal models (mice and rats), as well as in normal humans and in type I or type II diabetic patients. Accordingly, better understanding of how GLP-1R agonists modulate the activity of the HPA axis in diabetic subjects, especially obese individuals, will be crucial to design new and more efficient therapies for these patients.
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Affiliation(s)
- Yolanda Diz-Chaves
- Laboratory of EndocrinologyCenter for Biomedical Research - CINBIO, University of Vigo, Vigo, Spain Instituto de Investigación Sanitaria Galicia Sur - IISGSVigo, Spain
| | - Manuel Gil-Lozano
- Laboratory of EndocrinologyCenter for Biomedical Research - CINBIO, University of Vigo, Vigo, Spain Instituto de Investigación Sanitaria Galicia Sur - IISGSVigo, Spain
| | - Laura Toba
- Laboratory of EndocrinologyCenter for Biomedical Research - CINBIO, University of Vigo, Vigo, Spain Instituto de Investigación Sanitaria Galicia Sur - IISGSVigo, Spain
| | - Juan Fandiño
- Laboratory of EndocrinologyCenter for Biomedical Research - CINBIO, University of Vigo, Vigo, Spain Instituto de Investigación Sanitaria Galicia Sur - IISGSVigo, Spain
| | - Hugo Ogando
- Laboratory of EndocrinologyCenter for Biomedical Research - CINBIO, University of Vigo, Vigo, Spain Instituto de Investigación Sanitaria Galicia Sur - IISGSVigo, Spain
| | - Lucas C González-Matías
- Laboratory of EndocrinologyCenter for Biomedical Research - CINBIO, University of Vigo, Vigo, Spain Instituto de Investigación Sanitaria Galicia Sur - IISGSVigo, Spain
| | - Federico Mallo
- Laboratory of EndocrinologyCenter for Biomedical Research - CINBIO, University of Vigo, Vigo, Spain Instituto de Investigación Sanitaria Galicia Sur - IISGSVigo, Spain
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Rahmani B, Ghasemi R, Dargahi L, Ahmadiani A, Haeri A. Neurosteroids; potential underpinning roles in maintaining homeostasis. Gen Comp Endocrinol 2016; 225:242-250. [PMID: 26432100 DOI: 10.1016/j.ygcen.2015.09.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 09/14/2015] [Accepted: 09/28/2015] [Indexed: 12/31/2022]
Abstract
The neuroactive steroids which are synthesized in the brain and nervous system are known as "Neurosteroids". These steroids have crucial functions such as contributing to the myelination and organization of the brain connectivity. Under the stressful circumstances, the concentrations of neurosteroid products such as allopregnanolone (ALLO) and allotetrahydrodeoxycorticosterone (THDOC) alter. It has been suggested that these stress-derived neurosteroids modulate the physiological response to stress. Moreover, it has been demonstrated that the hypothalamic-pituitary-adrenal (HPA) axis mediates the physiological adaptation following stress in order to maintain homeostasis. Although several regulatory pathways have been introduced, the exact role of neurosteroids in controlling HPA axis is not clear to date. In this review, we intend to discern specific pathways associated with regulation of HPA axis in which neuroactive steroids have the main role. In this respect, we propose pathways that may be initiated after neurosteroidogenesis in different brain subregions following acute stress which are potentially capable of activating or inhibiting the HPA axis.
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Affiliation(s)
- Behrouz Rahmani
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Rasoul Ghasemi
- Department of Physiology and Neurophysiology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leila Dargahi
- NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolhassan Ahmadiani
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Ali Haeri
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Berczi I. Neuroimmune Regulation in Health and Disease. INSIGHTS TO NEUROIMMUNE BIOLOGY 2016:3-26. [DOI: 10.1016/b978-0-12-801770-8.00001-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Sindelar DK, Carson MW, Morin M, Shaw J, Barr RJ, Need A, Alexander-Chacko J, Coghlan M, Gehlert DR. LLY-2707, a novel nonsteroidal glucocorticoid antagonist that reduces atypical antipsychotic-associated weight gain in rats. J Pharmacol Exp Ther 2014; 348:192-201. [PMID: 24163440 DOI: 10.1124/jpet.113.205864] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Weight gain and diabetes have been reported during treatment with atypical antipsychotic drugs (AAPDs). Patients treated with the glucocorticoid receptor antagonist (GRA) and the progesterone receptor antagonist (PRA) mifepristone [estra-4,9-dien-3-one, 11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-(11β,17β)-(9CI)] experienced significant reduction in the weight gain observed when patients were treated with olanzapine or risperidone. To understand the pharmacology responsible for this finding, we discovered LLY-2707 [N-(5-(tert-butyl)-3-(2-fluoro-5-methylpyridin-4-yl)-2-methyl-1H-indol-7-yl)methanesulfonamide], a novel and selective GRA, and evaluated its utility in preclinical models of AAPD-associated weight gain and diabetes. In vitro, LLY-2707 was a highly selective and potent GRA. GR occupancy in vivo was assessed using ex vivo binding where LLY-2707 inhibited [(3)H]dexamethasone binding to the liver. Modest but statistically significant decreases in brain ex vivo binding were observed with high doses of CORT-108297 [(R)-4α-(ethoxymethyl)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline] and LLY-2707, but mifepristone inhibited at all doses. Central activity of the GRAs was confirmed by their ability to suppress amphetamine-induced increases in locomotor activity. The increases in the body weight of female rats treated with olanzapine (2 mg/kg PO) over 14 days were reduced in a dose-dependent manner by coadministration of LLY-2707. Similar decreases, although less robust, in body weight were seen with mifepristone and CORT-108297. In addition, sGRAs prevented the glucose excursion after intragastric olanzapine infusions consistent with a direct effect on the hyperglycemia observed during treatment with AAPDs. At doses effectively preventing weight gain, LLY-2707 did not substantially interfere with the dopamine D2 receptor occupancy by olanzapine. Therefore, GRA coadministration may provide a novel treatment modality to prevent the weight gain and diabetes observed during treatment with AAPDs.
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Affiliation(s)
- Dana K Sindelar
- Neuroscience and Endocrine Divisions, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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25
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Cognitive and motor perturbations in elderly with longstanding diabetes mellitus. Nutrition 2013; 30:628-35. [PMID: 24800665 DOI: 10.1016/j.nut.2013.11.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 10/11/2013] [Accepted: 11/06/2013] [Indexed: 01/21/2023]
Abstract
Type 2 diabetes mellitus is a chronic disease characterized by insulin resistance; inflammation; oxidative stress; vascular damage; and dysfunction of glucose, protein, and lipid metabolisms. However, comparatively less attention has been paid to neurologic alterations seen in elderly individuals with type 2 diabetes. We review clinical, metabolic, and biochemical aspects of diabetic encephalopathy (DE) and propose that quality of dietary lipids is closely linked to DE. This implies that preventive nutritional interventions may be designed to improve DE.
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26
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Popovic D, Popovic B, Plecas-Solarovic B, Pešić V, Markovic V, Stojiljkovic S, Vukcevic V, Petrovic I, Banovic M, Petrovic M, Vujisic-Tesic B, Ostojic MC, Ristic A, Damjanovic SS. The interface of hypothalamic-pituitary-adrenocortical axis and circulating brain natriuretic peptide in prediction of cardiopulmonary performance during physical stress. Peptides 2013; 47:85-93. [PMID: 23876603 DOI: 10.1016/j.peptides.2013.07.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Revised: 07/08/2013] [Accepted: 07/08/2013] [Indexed: 11/16/2022]
Abstract
Brain natriuretic peptide (NT-pro-BNP) was implicated in the regulation of hypothalamic-pituitary-adrenocortical (HPA) responses to psychological stressors. However, HPA axis activation in different physical stress models and its interface with NT-pro-BNP in the prediction of cardiopulmonary performance is unclear. Cardiopulmonary test on a treadmill was used to assess cardiopulmonary parameters in 16 elite male wrestlers (W), 21 water polo player (WP) and 20 sedentary age-matched subjects (C). Plasma levels of NT-pro-BNP, cortisol and adrenocorticotropic hormone (ACTH) were measured using immunoassay sandwich technique, radioimmunoassay and radioimmunometric techniques, respectively, 10min before test (1), at beginning (2), at maximal effort (3), at 3rdmin of recovery (4). In all groups, NT-pro-BNP decreased between 1 and 2; increased from 2 to 3; and remained unchanged until 4. ACTH increased from 1 to 4, whereas cortisol increased from 1 to 3 and stayed elevated at 4. In all groups together, ΔNT-pro-BNP2/1 predicted peak oxygen consumption (B=37.40, r=0.38, p=0.007); cortisol at 3 predicted heart rate increase between 2 and 3 (r=-0.38,B=-0.06, p=0.005); cortisol at 2 predicted peak carbon-dioxide output (B=2.27, r=0.35, p<0.001); ΔACTH3/2 predicted peak ventilatory equivalent for carbon-dioxide (B=0.03, r=0.33, p=0.003). The relation of cortisol at 1 with NT-pro-BNP at 1 and 3 was demonstrated using logistic function in all the participants together (for 1/cortisol at 1 B=63.40, 58.52; r=0.41, 0.34; p=0.003, 0.013, respectively). ΔNT-pro-BNP2/1 linearly correlated with ΔACTH4/3 in WP and W (r=-0.45, -0.48; p=0.04, 0.04, respectively). These results demonstrate for the first time that HPA axis and NT-pro-BNP interface in physical stress probably contribute to integrative regulation of cardiopulmonary performance.
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Affiliation(s)
- Dejana Popovic
- Division of Cardiology, Faculty of Medicine, University of Belgrade, Visegradska 26, 11000 Belgrade, Serbia.
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