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Espino J, Rodríguez AB, Pariente JA. Melatonin and Oxidative Stress in the Diabetic State: Clinical Implications and Potential Therapeutic Applications. Curr Med Chem 2019; 26:4178-4190. [PMID: 29637854 DOI: 10.2174/0929867325666180410094149] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 12/07/2017] [Accepted: 12/07/2017] [Indexed: 02/07/2023]
Abstract
All living organisms exhibit circadian rhythms, which govern the majority of biological functions, including metabolic processes. Misalignment of these circadian rhythms increases the risk of developing metabolic diseases. Thus, disruption of the circadian system has been proven to affect the onset of type 2 diabetes mellitus (T2DM). In this context, the pineal indoleamine melatonin is a signaling molecule able to entrain circadian rhythms. There is mounting evidence that suggests a link between disturbances in melatonin production and impaired insulin, glucose, lipid metabolism, and antioxidant capacity. Besides, several genetic association studies have causally associated various single nucleotide polymorphysms (SNPs) of the human MT2 receptor with increased risk of developing T2DM. Taken together, these data suggest that endogenous as well as exogenous melatonin may influence diabetes and associated metabolic disturbances not only by regulating insulin secretion but also by providing protection against reactive oxygen species (ROS) since pancreatic β-cells are very susceptible to oxidative stress due to their low antioxidant capacity.
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Affiliation(s)
- Javier Espino
- Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, Badajoz, Spain
| | - Ana B Rodríguez
- Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, Badajoz, Spain
| | - José A Pariente
- Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, Badajoz, Spain
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Onaolapo AY, Onaolapo OJ. Circadian dysrhythmia-linked diabetes mellitus: Examining melatonin’s roles in prophylaxis and management. World J Diabetes 2018; 9:99-114. [PMID: 30079146 PMCID: PMC6068738 DOI: 10.4239/wjd.v9.i7.99] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 06/01/2018] [Accepted: 06/08/2018] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus is a chronic, life-threatening metabolic disorder that occurs worldwide. Despite an increase in the knowledge of the risk factors that are associated with diabetes mellitus, its worldwide prevalence has continued to rise; thus, necessitating more research into its aetiology. Recent researches are beginning to link a dysregulation of the circadian rhythm to impairment of intermediary metabolism; with evidences that circadian rhythm dysfunction might play an important role in the aetiology, course or prognosis of some cases of diabetes mellitus. These evidences thereby suggest possible relationships between the circadian rhythm regulator melatonin, and diabetes mellitus. In this review, we discuss the roles of the circadian rhythm in the regulation of the metabolism of carbohydrates and other macronutrients; with emphasis on the importance of melatonin and the impacts of its deficiency on carbohydrate homeostasis. Also, the possibility of using melatonin and its analogs for the “prophylaxis” or management of diabetes mellitus is also considered.
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Affiliation(s)
- Adejoke Y Onaolapo
- Behavioural Neuroscience/Neurobiology Unit, Department of Anatomy, Ladoke Akintola University of Technology, Ogbomosho 210211, Oyo State, Nigeria
| | - Olakunle J Onaolapo
- Behavioural Neuroscience/Neuropharmacology Unit, Department of Pharmacology, Ladoke Akintola University of Technology, Osogbo 230263, Osun State, Nigeria
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Angelousi A, Kassi E, Nasiri-Ansari N, Weickert MO, Randeva H, Kaltsas G. Clock genes alterations and endocrine disorders. Eur J Clin Invest 2018; 48:e12927. [PMID: 29577261 DOI: 10.1111/eci.12927] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 03/19/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Various endocrine signals oscillate over the 24-hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock. DESIGN We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases. RESULTS Various human single nucleotide polymorphisms of brain and muscle ARNT-like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue-specific way, whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscillations. A significant correlation between the expression of propio-melanocorticotrophin and PER 2, as well as between prolactin and CLOCK, was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility, whereas oestradiol and androgens exhibited tissue-specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers. CONCLUSIONS Clock genes are associated with various endocrine disorders through complex mechanisms. However, data on humans are scarce. Moreover, clock genes exhibit a tissue-specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified.
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Affiliation(s)
- Anna Angelousi
- Department of Pathophysiology, Endocrine Unit, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Eva Kassi
- Department of Biochemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Narjes Nasiri-Ansari
- Department of Biochemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Martin O Weickert
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
- Division of Translational and Experimental Medicine, Warwick Medical School, University of Warwick, Coventry, UK
- Centre for Applied Biological & Exercise Sciences, Coventry University, Coventry, UK
| | - Harpal Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
- Division of Translational and Experimental Medicine, Warwick Medical School, University of Warwick, Coventry, UK
- Centre for Applied Biological & Exercise Sciences, Coventry University, Coventry, UK
| | - Gregory Kaltsas
- 1st Department of Propaedeutic Internal Medicine, Medical School, Laikon Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Li Y, Wu H, Liu N, Cao X, Yang Z, Lu B, Hu R, Wang X, Wen J. Melatonin exerts an inhibitory effect on insulin gene transcription via MTNR1B and the downstream Raf‑1/ERK signaling pathway. Int J Mol Med 2017; 41:955-961. [PMID: 29207116 DOI: 10.3892/ijmm.2017.3305] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 11/03/2017] [Indexed: 11/06/2022] Open
Abstract
The pineal hormone melatonin influences the secretion of insulin by pancreatic islets via the G‑protein‑coupled melatonin receptors 1 and 2 that are expressed in pancreatic β‑cells. Genome‑wide association studies indicate that melatonin receptor 1B (MTNR1B) single nucleotide polymorphisms are tightly associated with type 2 diabetes mellitus (T2DM). However, the underlying mechanism is unclear. Raf‑1 serves a critical role in the mitogen‑activated protein kinase (MAPK) pathways in β‑cell survival and proliferation and, therefore, may be involved in the mechanism by which melatonin impacts on T2DM through MTNR1B. In the present study, the mRNA expression of the two mouse insulin genes Ins1 and Ins2 was investigated in MIN6 cells treated with different concentrations of melatonin, and insulin secretion was detected under the same conditions. Following the overexpression or silencing of MTNR1B, the activities of components of the MAPK signaling pathway, including Raf‑1 and ERK, were evaluated. The impact of MTNR1B knockdown on the melatonin‑regulated insulin gene expression and insulin secretion were also investigated. The results demonstrated that exogenous melatonin inhibited the expression of insulin mRNA in the MIN6 cells. Insulin secretion by the MIN6 cells, however, was not affected by melatonin. The MAPK signaling pathway was inhibited in MIN6 cells by treatment with melatonin or the overexpression of MTNR1B. The knockdown of MTNR1B totally attenuated the regulating effect of melatonin on insulin gene expression. Additionally, the inductive effect of melatonin on the expression of insulin mRNA was attenuated when the activities of Raf‑1 or ERK were blocked using the chemical inhibitors GW5074 and U0126, respectively. It may be concluded that melatonin exerts an inhibitory effect on insulin transcription via MTNR1B and the downstream MAPK signaling pathway.
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Affiliation(s)
- Yanliang Li
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Huihui Wu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Naijia Liu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Xinyi Cao
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Zhen Yang
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Bin Lu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Renming Hu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Xuanchun Wang
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jie Wen
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
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Komai AM, Musovic S, Peris E, Alrifaiy A, El Hachmane MF, Johansson M, Wernstedt Asterholm I, Olofsson CS. White Adipocyte Adiponectin Exocytosis Is Stimulated via β3-Adrenergic Signaling and Activation of Epac1: Catecholamine Resistance in Obesity and Type 2 Diabetes. Diabetes 2016; 65:3301-3313. [PMID: 27554468 DOI: 10.2337/db15-1597] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 08/09/2016] [Indexed: 11/13/2022]
Abstract
We investigated the physiological regulation of adiponectin exocytosis in health and metabolic disease by a combination of membrane capacitance patch-clamp recordings and biochemical measurements of short-term (30-min incubations) adiponectin secretion. Epinephrine or the β3-adrenergic receptor (AR) agonist CL 316,243 (CL) stimulated adiponectin exocytosis/secretion in cultured 3T3-L1 and in primary subcutaneous mouse adipocytes, and the stimulation was inhibited by the Epac (Exchange Protein directly Activated by cAMP) antagonist ESI-09. The β3AR was highly expressed in cultured and primary adipocytes, whereas other ARs were detected at lower levels. 3T3-L1 and primary adipocytes expressed Epac1, whereas Epac2 was undetectable. Adiponectin secretion could not be stimulated by epinephrine or CL in adipocytes isolated from obese/type 2 diabetic mice, whereas the basal (unstimulated) adiponectin release level was elevated twofold. Gene expression of β3AR and Epac1 was reduced in adipocytes from obese animals, and corresponded to a respective ∼35% and ∼30% reduction at the protein level. Small interfering RNA-mediated knockdown of β3AR (∼60%) and Epac1 (∼50%) was associated with abrogated catecholamine-stimulated adiponectin secretion. We propose that adiponectin exocytosis is stimulated via adrenergic signaling pathways mainly involving β3ARs. We further suggest that adrenergically stimulated adiponectin secretion is disturbed in obesity/type 2 diabetes as a result of the reduced expression of β3ARs and Epac1 in a state we define as "catecholamine resistance."
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Affiliation(s)
- Ali M Komai
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden
| | - Saliha Musovic
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden
| | - Eduard Peris
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden
| | - Ahmed Alrifaiy
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden
| | - Mickaël F El Hachmane
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden
| | - Marcus Johansson
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden
| | - Ingrid Wernstedt Asterholm
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden
| | - Charlotta S Olofsson
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden
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Calvo J, Maldonado M. The role of melatonin in autoimmune and atopic diseases. AIMS MOLECULAR SCIENCE 2016. [DOI: 10.3934/molsci.2016.2.158] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
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Kahya MC, Naziroğlu M, Çiğ B. Melatonin and selenium reduce plasma cytokine and brain oxidative stress levels in diabetic rats. Brain Inj 2015; 29:1490-6. [DOI: 10.3109/02699052.2015.1053526] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Peschke E, Bähr I, Mühlbauer E. Experimental and clinical aspects of melatonin and clock genes in diabetes. J Pineal Res 2015; 59:1-23. [PMID: 25904189 DOI: 10.1111/jpi.12240] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 04/20/2015] [Indexed: 12/15/2022]
Abstract
The pineal hormone melatonin influences insulin secretion, as well as glucagon and somatostatin secretion, both in vivo and in vitro. These effects are mediated by two specific, high-affinity, seven transmembrane, pertussis toxin-sensitive, Gi-protein-coupled melatonin receptors, MT1 and MT2. Both isoforms are expressed in the β-cells, α-cells as well as δ-cells of the pancreatic islets of Langerhans and are involved in the modulation of insulin secretion, leading to inhibition of the adenylate cyclase-dependent cyclic adenosine monophosphate as well as cyclic guanosine monophosphate formation in pancreatic β-cells by inhibiting the soluble guanylate cyclase, probably via MT2 receptors. In this way, melatonin also likely inhibits insulin secretion, whereas using the inositol triphosphate pathway after previous blocking of Gi-proteins by pertussis toxin, melatonin increases insulin secretion. Desynchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genomewide association studies pinpointing variances of the MT2 receptor as a risk factor for this rapidly spreading metabolic disturbance. As melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. Observations of the circadian expression of clock genes (Clock, Bmal1, Per1,2,3, and Cry1,2) in pancreatic islets, as well as in INS1 rat insulinoma cells, may indicate that circadian rhythms are generated in the β-cells themselves. The circadian secretion of insulin from pancreatic islets is clock-driven. Disruption of circadian rhythms and clock function leads to metabolic disturbances, for example, type 2 diabetes. The study of melatonin-insulin interactions in diabetic rat models has revealed an inverse relationship between these two hormones. Both type 2 diabetic rats and patients exhibit decreased melatonin levels and slightly increased insulin levels, whereas type 1 diabetic rats show extremely reduced levels or the absence of insulin, but statistically significant increases in melatonin levels. Briefly, an increase in melatonin levels leads to a decrease in stimulated insulin secretion and vice versa. Melatonin levels in blood plasma, as well as the activity of the key enzyme of melatonin synthesis, AA-NAT (arylalkylamine-N-acetyltransferase) in pineal, are lower in type 2 diabetic rats compared to controls. In contrast, melatonin and pineal AA-NAT mRNA are increased and insulin receptor mRNA is decreased in type 1 diabetic rats, which also indicates a close relationship between insulin and melatonin. As an explanation, it was hypothesized that catecholamines, which reduce insulin levels and stimulate melatonin synthesis, control insulin-melatonin interactions. This conviction stems from the observation that catecholamines are increased in type 1 but are diminished in type 2 diabetes. In this context, another important line of inquiry involves the fact that melatonin protects β-cells against functional overcharge and, consequently, hinders the development of type 2 diabetes.
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Affiliation(s)
| | - Ina Bähr
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle, Germany
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Matuszek MA, Anton A, Thillainathan S, Armstrong NJ. Increased Insulin following an Oral Glucose Load, Genetic Variation near the Melatonin Receptor MTNR1B, but No Biochemical Evidence of Endothelial Dysfunction in Young Asian Men and Women. PLoS One 2015. [PMID: 26196519 PMCID: PMC4510533 DOI: 10.1371/journal.pone.0133611] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Aim To identify biochemical and genetic variation relating to increased risk of developing type 2 diabetes mellitus and cardiovascular disease in young, lean male and female adults of different ethnicities. Method Fasting blood and urine and non-fasting blood following oral glucose intake were analysed in 90 Caucasians, South Asians and South East/East Asians. Results There were no differences in age, birthweight, blood pressure, body mass index, percent body fat, total energy, percentage of macronutrient intake, microalbumin, leptin, cortisol, adrenocorticotropic hormone, nitric oxide metabolites, C-reactive protein, homocysteine, tumor necrosis factor-α, interleukin-6, von Willebrand factor, vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, and tissue plasminogen activator. Fasting total cholesterol (P = .000), triglycerides (P = .050), low density lipoprotein (P = .009) and non-fasting blood glucose (15 min) (P = .024) were elevated in South Asians compared with Caucasians, but there was no significant difference in glucose area under curve (AUC). Non-fasting insulin in South Asians (15–120 min), in South East/East Asians (60–120 min), and insulin AUC in South Asians and South East/East Asians, were elevated compared with Caucasians (P≤0.006). The molar ratio of C-peptide AUC/Insulin AUC (P = .045) and adiponectin (P = .037) were lower in South Asians compared with Caucasians. A significant difference in allele frequency distributions in Caucasians and South Asians was found for rs2166706 (P = 0.022) and rs10830963 (P = 0.009), which are both near the melatonin receptor MTNR1B. Conclusions Elevated non-fasting insulin exists in young South Asians of normal fasting glucose and insulin. Hepatic clearance of insulin may be reduced in South Asians. No current biochemical evidence exists of endothelial dysfunction at this stage of development. MTNR1B signalling may be a useful therapeutic target in Asian populations in the prevention of type 2 diabetes mellitus.
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Affiliation(s)
- Maria A. Matuszek
- School of Medical Sciences, University of New South Wales, Sydney, Australia
- * E-mail:
| | - Angelyn Anton
- School of Medical Sciences, University of New South Wales, Sydney, Australia
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Fitzgerald PJ. Noradrenaline transmission reducing drugs may protect against a broad range of diseases. ACTA ACUST UNITED AC 2014; 34:15-26. [PMID: 25271382 DOI: 10.1111/aap.12019] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
1 A growing body of evidence suggests that the signalling molecule, noradrenaline (NA), plays a pathophysiological role in a broad range of psychiatric, neurological and peripheral disorders. Both preclinical and clinical data suggest that elevated NA signalling may be involved in the aetiology of major diseases such as depression, Alzheimer's disease and diabetes mellitus. 2 The molecular pathways by which NA may cause the manifestation of disease remain poorly understood, although they may include G protein-coupled receptor modulation of the Ras/MAP kinase, Stat3 and PI3K pathways, among others. In both individual animals and humans, NA tone may be elevated largely due to genetics, but also because of the exposure to marked psychological stress or trauma, or other environmental factors. 3 As NA is involved in the 'fight or flight' response by the sympathetic nervous system, this transmitter may be elevated in a large number of organisms due to evolutionary selection of enhancing responses to immediate environmental dangers. Likewise, acetylcholine signalling by the parasympathetic ('rest and digest') nervous system may be relatively diminished. This putative autonomic imbalance may result in diminished engagement in homeostatic processes, resulting in the emergence and progression of a number of diseases throughout the body. 4 In this scenario, a large number of individuals may benefit from chronic use of pharmacological agents - such as clonidine, guanfacine, propranolol or prazosin - that diminish NA signalling throughout the body. If so, NA transmission lowering drugs may protect against a wide range of diseases.
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Affiliation(s)
- P J Fitzgerald
- Department of Psychology, Texas A&M University, College Station, Texas, 77843, USA
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She M, Laudon M, Yin W. Melatonin receptors in diabetes: a potential new therapeutical target? Eur J Pharmacol 2014; 744:220-3. [PMID: 25160745 DOI: 10.1016/j.ejphar.2014.08.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Revised: 08/08/2014] [Accepted: 08/18/2014] [Indexed: 01/13/2023]
Abstract
Melatonin is synthesized and secreted mainly by the pineal gland in a circadian fashion, and it thus mediates endogenous circadian rhythms and influences other physiological functions. Both the G-protein coupled receptors MT1 (encoded by MTNR1A) and MT2 (encoded by MTNR1B) in mammals mediate the actions of melatonin. Evidence from in vivo and in vitro studies proved a key role of melatonin in the regulation of glucose metabolism and the pathogenesis of diabetes, as further confirmed by the recent studies of human genetic variants of MTNR1B. Remarkably, it was also suggested that genetic variations within MTNR1B disordered β-cells function directly, i.e. insulin secretion. This indicated the functional link between MT2 and T2D risk at the protein level, and it may represent the prevailing pathomechanism for how impaired melatonin signaling causes metabolic disorders and increases the T2D risk. It is speculated that melatonin and its receptors may be a new therapeutic avenue in diabetes.
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Affiliation(s)
- Meihua She
- Institute of Cardiovascular Research, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China; Department of Biochemistry and Molecular Biology, School of Pharmaceutical and Biological Science, University of South China, Hengyang, China
| | - Moshe Laudon
- Drug Discovery, Neurim Pharmaceuticals Ltd., Tel Aviv, Israel
| | - Weidong Yin
- Institute of Cardiovascular Research, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China; Department of Biochemistry and Molecular Biology, School of Pharmaceutical and Biological Science, University of South China, Hengyang, China.
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Abstract
: Ulcerative colitis (UC), an inflammatory bowel disease, affects many people across the globe, and its prevalence is increasing steadily. Inflammation and oxidative stress play a vital role in the perpetuation of inflammatory process and the subsequent DNA damage associated with the development of UC. UC induces not only local but also systemic damage, which involves the perturbation of multiple molecular pathways. Furthermore, UC leads to an increased risk of colorectal cancer, the third most common malignancy in humans. Most of the drugs used for the treatment of UC are unsatisfactory because they are generally mono-targeted, relatively ineffective and unaffordable for many people. Thus, agents that can target multiple molecular pathways and are less expensive have enormous potential to treat UC. Melatonin has beneficial effects against UC in experimental and clinical studies because of its ability to modulate several molecular pathways of inflammation, oxidative stress, fibrosis, and cellular injury. However, many novel targets are yet to be explored on which melatonin may act to exert its favorable effects in UC. It is time to explore improved intervention strategies with melatonin in UC on the basis of studies investigating different molecular targets using proteomic and genomic approaches. This review identifies various molecular targets for melatonin with the intent of providing novel strategies for combating UC and the associated extraintestinal manifestations of this debilitating disease.
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Affiliation(s)
- Gopabandhu Jena
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Punjab, India
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Park JH, Shim HM, Na AY, Bae KC, Bae JH, Im SS, Cho HC, Song DK. Melatonin prevents pancreatic β-cell loss due to glucotoxicity: the relationship between oxidative stress and endoplasmic reticulum stress. J Pineal Res 2014; 56:143-153. [PMID: 24168371 DOI: 10.1111/jpi.12106] [Citation(s) in RCA: 27] [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: 08/22/2013] [Accepted: 10/25/2013] [Indexed: 12/31/2022]
Abstract
Prolonged hyperglycemia results in pancreatic β-cell dysfunction and apoptosis, referred to as glucotoxicity. Although both oxidative and endoplasmic reticulum (ER) stresses have been implicated as major causative mechanisms of β-cell glucotoxicity, the reciprocal importance between the two remains to be elucidated. The aim of this study was to evaluate the differential effect of oxidative stress and ER stress on β-cell glucotoxicity, by employing melatonin which has free radical-scavenging and antioxidant properties. As expected, in β-cells exposed to prolonged high glucose levels, cell viability and glucose-stimulated insulin secretion (GSIS) were significantly impaired. Melatonin treatment markedly attenuated cellular apoptosis by scavenging reactive oxygen species via its plasmalemmal receptor-independent increase in antioxidant enzyme activity. However, treatments with antioxidants alone were insufficient to recover the impaired GSIS. Interestingly, 4-phenylbutyric acid (4-PBA), a chemical chaperone that attenuate ER stress by stabilizing protein structure, alleviated the impaired GSIS, but not apoptosis, suggesting that glucotoxicity induces oxidative and ER stress independently. We found that cotreatment of glucotoxic β-cells with melatonin and 4-PBA dramatically improved both their survival and insulin secretion. Taken together, these results suggest that ER stress may be the more critical mechanism for prolonged high-glucose-induced GSIS impairment, whereas oxidative stress appears to be more critical for the impaired β-cell viability. Therefore, combinatorial therapy of melatonin with an ER stress modifier may help recover pancreatic β-cells under glucotoxic conditions in type 2 diabetes.
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Affiliation(s)
- Jae-Hyung Park
- Department of Physiology, Keimyung University School of Medicine, Daegu, Korea
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Mao H, Wang H, Ma S, Xu Y, Zhang H, Wang Y, Niu Z, Fan G, Zhu Y, Gao XM. Bidirectional regulation of bakuchiol, an estrogenic-like compound, on catecholamine secretion. Toxicol Appl Pharmacol 2014; 274:180-9. [DOI: 10.1016/j.taap.2013.11.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 10/31/2013] [Accepted: 11/01/2013] [Indexed: 01/19/2023]
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Effects of insulin on norepinephrine- and acetylcholine-induced membrane currents of pinealocytes from healthy Wistar and type 2 diabetic GK rats. Cell Tissue Res 2013; 355:437-46. [PMID: 24292719 DOI: 10.1007/s00441-013-1748-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Accepted: 10/18/2013] [Indexed: 01/04/2023]
Abstract
The neurohormone melatonin is synthesized by the pineal gland under the stimulation of norepinephrine (NE). Its synthesis is inhibited by acetylcholine (ACh) and by insulin. Type 2 diabetic Goto Kakizaki (GK) rats have higher insulin and lower melatonin plasma levels than healthy Wistar rats. We investigate membrane potentials and currents of isolated pinealocytes in both rat strains and the influence of NE, ACh and insulin by using the perforated patch whole cell clamp technique. Pinealocyte membranes displayed a high resting Na(+) conductance. Stimulation with NE further increased this Na(+) conductance, which led to a slight depolarization in unclamped cells. The amplitude of the NE-evoked current was similar in both rat strains but the current fraction carried by Na(+) was stronger in GK rats. Stimulation with ACh induced a transient inward current and depolarization. These effects were much more pronounced in the pinealocytes of GK rats. The NE-induced current, the ACh-induced current and the membrane depolarization were reduced by pre-administration of insulin in Wistar pinealocytes. Our results provide the first electrophysiological evidence for the modulation, by insulin, of the effects of NE and ACh in pinealocytes of normal rats. The pinealocytes of type 2 diabetic rats were not responsive to insulin. This might explain the reported correlation between the decreased insulin receptor mRNA transcript levels in GK rat pinealocytes and the lack of effect of insulin on ion channels in their cell membranes.
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Melatonin and pancreatic islets: interrelationships between melatonin, insulin and glucagon. Int J Mol Sci 2013; 14:6981-7015. [PMID: 23535335 PMCID: PMC3645673 DOI: 10.3390/ijms14046981] [Citation(s) in RCA: 115] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Revised: 03/07/2013] [Accepted: 03/11/2013] [Indexed: 12/15/2022] Open
Abstract
The pineal hormone melatonin exerts its influence in the periphery through activation of two specific trans-membrane receptors: MT1 and MT2. Both isoforms are expressed in the islet of Langerhans and are involved in the modulation of insulin secretion from β-cells and in glucagon secretion from α-cells. De-synchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genome-wide association studies identifying particularly the MT2 as a risk factor for this rapidly spreading metabolic disturbance. Since melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. This factor has hitherto been underestimated; the disruption of diurnal signaling within the islet may be one of the most important mechanisms leading to metabolic disturbances. The study of melatonin–insulin interactions in diabetic rat models has revealed an inverse relationship: an increase in melatonin levels leads to a down-regulation of insulin secretion and vice versa. Elucidation of the possible inverse interrelationship in man may open new avenues in the therapy of diabetes.
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Morceli G, Honorio-França AC, Fagundes DLG, Calderon IMP, França EL. Antioxidant effect of melatonin on the functional activity of colostral phagocytes in diabetic women. PLoS One 2013; 8:e56915. [PMID: 23437270 PMCID: PMC3577679 DOI: 10.1371/journal.pone.0056915] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2012] [Accepted: 01/16/2013] [Indexed: 01/24/2023] Open
Abstract
Melatonin is involved in a number of physiological and oxidative processes, including functional regulation in human milk. The present study investigated the mechanisms of action of melatonin and its effects on the functional activity of colostral phagocytes in diabetic women. Colostrum samples were collected from normoglycemic (N = 38) and diabetic (N = 38) women. We determined melatonin concentration, superoxide release, bactericidal activity and intracellular Ca(2+) release by colostral phagocytes treated or not with 8-(Diethylamino) octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8) and incubated with melatonin and its precursor (N-acetyl-serotonin-NAS), antagonist (luzindole) and agonist (chloromelatonin-CMLT). Melatonin concentration was higher in colostrum samples from hyperglycemic than normoglycemic mothers. Melatonin stimulated superoxide release by colostral phagocytes from normoglycemic but not hyperglycemic women. NAS increased superoxide, irrespective of glycemic status, whereas CMTL increased superoxide only in cells from the normoglycemic group. Phagocytic activity in colostrum increased significantly in the presence of melatonin, NAS and CMLT, irrespective of glycemic status. The bactericidal activity of colostral phagocytes against enterophatogenic Escherichia coli (EPEC) increased in the presence of melatonin or NAS in the normoglycemic group, but not in the hyperglycemic group. Luzindole blocked melatonin action on colostrum phagocytes. Phagocytes from the normoglycemic group treated with melatonin exhibited an increase in intracellular Ca(2+) release. Phagocytes treated with TMB-8 (intracellular Ca(2+) inhibitor) decreased superoxide, bactericidal activity and intracellular Ca(2+) release in both groups. The results obtained suggest an interactive effect of glucose metabolism and melatonin on colostral phagocytes. In colostral phagocytes from normoglycemic mothers, melatonin likely increases the ability of colostrum to protect against EPEC and other infections. In diabetic mothers, because maternal hyperglycemia modifies the functional activity of colostrum phagocytes, melatonin effects are likely limited to anti-inflammatory processes, with low superoxide release and bactericidal activity.
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Affiliation(s)
- Gliciane Morceli
- Post Graduate Program in Gynecology, Obstetrics and Mastology of Botucatu Medical School, São Paulo State University/Unesp, Botucatu, São Paulo, Brazil
| | - Adenilda C. Honorio-França
- Institute of Biological and Health Science, Federal University of Mato Grosso, Barra do Garças, Mato Grosso, Brazil
| | - Danny L. G. Fagundes
- Post Graduate Program in Gynecology, Obstetrics and Mastology of Botucatu Medical School, São Paulo State University/Unesp, Botucatu, São Paulo, Brazil
| | - Iracema M. P. Calderon
- Post Graduate Program in Gynecology, Obstetrics and Mastology of Botucatu Medical School, São Paulo State University/Unesp, Botucatu, São Paulo, Brazil
| | - Eduardo L. França
- Institute of Biological and Health Science, Federal University of Mato Grosso, Barra do Garças, Mato Grosso, Brazil
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Matteucci E, Della Bartola L, Giampietro O. Differences in circadian time structure of diastolic blood pressure between diabetes mellitus and essential hypertension. Diabetol Metab Syndr 2012; 4:51. [PMID: 23245213 PMCID: PMC3538704 DOI: 10.1186/1758-5996-4-51] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Accepted: 11/23/2012] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Abnormal circadian blood pressure patterns have been associated with cardiovascular disease in diabetes mellitus. We have described that the acrophase of diastolic blood pressure (DBP) registered in type 1 diabetes (T1D) patients was significantly earlier than normal and DBP ecphasia was more pronounced in patients with lower heart rate variability during deep breathing. The aim of this study was to compare the circadian rhythm characteristics of BP among different groups: normotensive (NT) control subjects, patients affected by T1D and type 2 diabetes (T2D), and patients with essential hypertension (HT). FINDINGS We retrospectively evaluated ambulatory blood pressure monitoring records in 30 NT, 20 T1D, 20 T2D, 20 HT whose fasting plasma glucose and HbA1c were contemporaneously measured. The four groups were well-matched regarding age, gender, and BMI.Systolic blood pressure (SBP) and DBP midline-estimating statistic of rhythm were higher in T1D, T2D, and HT groups. DBP ecphasia was present only in the diabetic individuals: the acrophase of DBP occurred four hours earlier than normal in T1D group, whereas two hours earlier in T2D group. In a multiple regression analysis, only HbA1c and SBP acrophase were statistically significant correlates of DBP acrophase. CONCLUSIONS People with diabetes mellitus, both type 1 and type 2, have their circadian acrophase of DBP occurring 2-4 hours earlier than normotensive and hypertensive subjects. Altered circadian timing of DBP, potential trigger of cardiovascular events, seems to be a distinguishing feature of diabetes mellitus and correlates with the previous 2-3 months of glycaemic control.
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Affiliation(s)
- Elena Matteucci
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, Pisa, 56126, Italy
| | - Luca Della Bartola
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, Pisa, 56126, Italy
| | - Ottavio Giampietro
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, Pisa, 56126, Italy
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Abstract
Circadian rhythms are ubiquitous in biological systems and regulate metabolic processes throughout the body. Misalliance of these circadian rhythms and the systems they regulate has a profound impact on hormone levels and increases risk of developing metabolic diseases. Melatonin, a hormone secreted by the pineal gland, is one of the major signaling molecules used by the master circadian oscillator to entrain downstream circadian rhythms. Several recent genetic studies have pointed out that a common variant in the gene that encodes the melatonin receptor 2 (MTNR1B) is associated with impaired glucose homeostasis, reduced insulin secretion, and an increased risk of developing type 2 diabetes. Here, we try to review the role of this receptor and its signaling pathways in respect to glucose homeostasis and development of the disease.
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MESH Headings
- Circadian Rhythm/genetics
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/genetics
- Female
- Genetic Variation
- Humans
- Insulin/blood
- Insulin/metabolism
- Insulin Secretion
- Insulin-Secreting Cells
- Male
- Melatonin/biosynthesis
- Receptor, Melatonin, MT1/blood
- Receptor, Melatonin, MT1/genetics
- Receptor, Melatonin, MT2/blood
- Receptor, Melatonin, MT2/genetics
- Risk Factors
- Signal Transduction
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Affiliation(s)
- Cecilia Nagorny
- Unit of Molecular Metabolism, Department of Clinical Sciences in Malmoe, Lund University Diabetes Centre, 20502, Malmoe, Sweden.
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Bazwinsky-Wutschke I, Wolgast S, Mühlbauer E, Albrecht E, Peschke E. Phosphorylation of cyclic AMP-response element-binding protein (CREB) is influenced by melatonin treatment in pancreatic rat insulinoma β-cells (INS-1). J Pineal Res 2012; 53:344-57. [PMID: 22616931 DOI: 10.1111/j.1600-079x.2012.01004.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The pineal hormone melatonin exerts its influence on the insulin secretion of pancreatic islets by a variety of signalling pathways. The purpose of the present study was to analyse the impact of melatonin on the phosphorylated transcription factor cAMP-response element-binding protein (pCREB). In pancreatic rat insulinoma β-cells (INS-1), pCREB immunofluorescence intensities in cell nuclei using digitised confocal image analysis were measured to semi-quantify differences in the pCREB immunoreactivity (pCREB-ir) caused by different treatments. Increasing concentrations of forskolin or 3-isobutyl-1-methylxanthine (IBMX) resulted in a dose-dependent rise of the mean fluorescence intensity in pCREB-ir nuclear staining. Concomitant melatonin application significantly decreased pCREB-ir in INS-1 cells after 30-min, 1-hr and 3-hr treatment. The melatonin receptor antagonists luzindole and 4-phenyl-2-propionamidotetraline (4P-PDOT) completely abolished the pCREB phosphorylation-decreasing effect of melatonin, indicating that both melatonin receptor isoforms (MT(1) and MT(2)) are involved. In a transfected INS-1 cell line expressing the human MT(2) receptor, melatonin caused the greatest reduction in pCREB after IBMX treatment compared with nontransfected INS-1 cells, indicating a crucial influence of melatonin receptor density on pCREB regulation. Furthermore, the downregulation of pCREB by melatonin is concomitantly associated with a statistically significant downregulation of Camk2d transcript levels, as measured after 3 hr. In conclusion, the present study provides evidence that the phosphorylation level of CREB is modulated in pancreatic β-cells by melatonin. Mediated via CREB, melatonin regulates the expression of genes that play an important functional role in the regulation of β-cell signalling pathways.
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MESH Headings
- 1-Methyl-3-isobutylxanthine/pharmacology
- Animals
- Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics
- Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism
- Cell Line, Tumor
- Colforsin/pharmacology
- Cyclic AMP Response Element-Binding Protein/metabolism
- Dose-Response Relationship, Drug
- Fluorescent Antibody Technique
- Humans
- Insulin-Secreting Cells/drug effects
- Insulin-Secreting Cells/metabolism
- Insulinoma/genetics
- Insulinoma/metabolism
- Melatonin/pharmacology
- Microscopy, Confocal
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Phosphorylation
- Rats
- Receptor, Melatonin, MT1/drug effects
- Receptor, Melatonin, MT1/metabolism
- Receptor, Melatonin, MT2/drug effects
- Receptor, Melatonin, MT2/genetics
- Receptor, Melatonin, MT2/metabolism
- Signal Transduction/drug effects
- Tetrahydronaphthalenes/pharmacology
- Time Factors
- Transfection
- Tryptamines/pharmacology
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Burgess HJ. Melatonin: An Adjunctive Treatment for Cardiometabolic Disease? Sleep 2012; 35:1319-20. [DOI: 10.5665/sleep.2100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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