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Sørensen KV, Justesen JM, Ängquist L, Bork-Jensen J, Hartmann B, Jørgensen NR, Rungby J, Sørensen HT, Vaag A, Nielsen JS, Holst JJ, Pedersen O, Linneberg A, Hansen T, Grarup N. Rare MTNR1B variants causing diminished MT2 signalling associate with elevated HbA 1c levels but not with type 2 diabetes. Diabetologia 2025; 68:1016-1030. [PMID: 40064676 PMCID: PMC12021717 DOI: 10.1007/s00125-025-06381-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 12/10/2024] [Indexed: 04/25/2025]
Abstract
AIMS/HYPOTHESIS An intronic variant (rs10830963) in MTNR1B (encoding the melatonin receptor type 2 [MT2]) has been shown to strongly associate with impaired glucose regulation and elevated type 2 diabetes prevalence. However, MTNR1B missense variants have shown conflicting results on type 2 diabetes. Thus, we aimed to gain further insights into the impact of MTNR1B coding variants on type 2 diabetes prevalence and related phenotypes. METHODS We conducted a cross-sectional study, performing MTNR1B variant burden testing of glycaemic phenotypes (N=248,454, without diabetes), other cardiometabolic phenotypes (N=330,453) and type 2 diabetes prevalence (case-control study; N=263,739) in the UK Biobank. Similar burden testing with glycaemic phenotypes was performed in Danish Inter99 participants without diabetes (N=5711), and type 2 diabetes prevalence (DD2 cohort serving as cases [N=2930] and Inter99 serving as controls [N=4243]). Finally, we evaluated the effects of MTNR1B variants on the melatonin-induced glucose regulation response in a recall-by-genotype study of individuals without diabetes. RESULTS In the UK Biobank, MTNR1B variants were not associated with cardiometabolic phenotypes, including type 2 diabetes prevalence, except that carriers of missense MTNR1B variants causing impaired MT2 signalling exhibited higher HbA1c levels compared with non-carriers (effect size, β, 0.087 SD [95% CI 0.039, 0.135]). Similarly, no significant associations were observed with phenotypes associated with glycaemic phenotypes in the Inter99 population. However, carriers of variants impairing MT2 signalling demonstrated a nominally significant lower glucose-stimulated insulin response (β -0.47 SD [95% CI -0.82, -0.11]). A reduced insulin response was also observed in carriers of variants impairing MT2 signalling (β -476.0 [95% CI -928.6, -24.4]) or the rs10830963 variant (β -390.8 [95% CI -740.1, -41.6]) compared with non-carriers after melatonin treatment. CONCLUSIONS/INTERPRETATION The higher type 2 diabetes prevalence previously observed in carriers of missense MTNR1B variants causing impairment in MT2 signalling was not replicated in the UK Biobank, yet carriers had elevated HbA1c levels. DATA AVAILABILITY Data (Inter99 cohort and recall-by-genotype study) are available on reasonable request from the corresponding author. Requests for DD2 data are through the application form at https://dd2.dk/forskning/ansoeg-om-data . Access to UK Biobank data can be requested through the UK Biobank website ( https://www.ukbiobank.ac.uk/enable-your-research ).
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Affiliation(s)
- Kimmie V Sørensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Johanne M Justesen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lars Ängquist
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jette Bork-Jensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Niklas R Jørgensen
- Department of Clinical Biochemistry, Rigshospitalet, Glostrup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Translational Research Centre, Rigshospitalet, Copenhagen, Denmark
| | - Jørgen Rungby
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Herlev Hospital, Herlev, Denmark
| | - Henrik T Sørensen
- Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
- Department of Epidemiology, Boston University, Boston, MA, USA
| | - Allan Vaag
- Steno Diabetes Center Copenhagen, Herlev Hospital, Herlev, Denmark
- Lund University Diabetes Care, Lund University, Malmö, Sweden
- Department of Endocrinology, Skåne University Hospital, Malmö, Sweden
| | - Jens S Nielsen
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Oluf Pedersen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Clinical Metabolic Research, Herlev-Gentofte Hospital, Copenhagen, Denmark
| | - Allan Linneberg
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Clinical Research and Prevention, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Wang S, Chen Z, Liang Z, Xu Q, Zhang J. Bright night sleeping environment induces diabetes and impaired glucose tolerance in non-human primates. Front Endocrinol (Lausanne) 2025; 16:1454592. [PMID: 40013312 PMCID: PMC11860132 DOI: 10.3389/fendo.2025.1454592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 01/24/2025] [Indexed: 02/28/2025] Open
Abstract
Background According to the IDF Diabetes Atlas regularly published by International Diabetes Federation, the prevalence of diabetes and impaired glucose tolerance (IGT), diabetes-related mortality and health expenditure are becoming serious eventually at the global, regional and national level. While the data alarm people, the exact cause remains unknown. It is widely accepted that glucose metabolism can be impaired by circadian rhythms disruption and sleep disturbances, both closely linked to exposure to light at night. However, there is little direct experiment on primates to study the precise extent of how serious bright sleeping environment at night impairs glucose metabolism, what the relationship is between nocturnal brightness and the development of diabetes and IGT, any difference between male and female, and whether aging and weight are involved. This study aims to address these questions in monkeys. Methods In a reduced daytime bright condition resembling human living rooms, 197 Cynomolgus (130 male, 67 female) were exposed to three distinct light intensities (13, 35, 75Lux) at night for consecutive ten months. Animals were retrospectively divided into four groups according to glucose metabolic status by the end of the experimental session, spontaneous diabetes mellitus (SDM, N=11), light-induced diabetes (LID, N=83), impaired fasting glucose tolerance (IFG, N=36), and normal glucose tolerance (NGT, N=67). Data pertaining to the glucose metabolism such as concentrations of fasting glucose, glycosylated hemoglobin, plasma insulin and C-peptide were collected monthly and analyzed. Results 1) Bright night exasperated glucose metabolism in individuals with pre-existing diabetes, led to premature death; 2) Stronger white light intensity-dependently induced diabetes and IFG in previous healthy monkeys: the brighter the light, the quicker the metabolism disturbance and IFG developed, and also the higher morbidity of LID and IFG; 3) Exposure to nocturnal light had a synergistic impairing effect on glucose metabolism with aging and weight. 4) Female were more susceptible to night brightness. Conclusions Light in sleeping environment exacerbates glucose metabolism in individuals with pre-existing diabetes, leads to IFG and diabetes in healthy primates. Moreover, the harmful effects of bright night on glucose metabolism are synergistic with aging and weight.
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Affiliation(s)
- Shuxing Wang
- Department of Anatomy, Medical School, Foshan University, Foshan, Guangdong, China
| | | | - Zihao Liang
- Department of Pharmacy, Qingyuan Hospital of Traditional Chinese Medicine, Qingyuan, Guangdong, China
| | - Qiang Xu
- Primate Research Center, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Jiankai Zhang
- Department of Anatomy, Guangdong Medical University, Dongguan, Guangdong, China
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Wang S, Cheng X, Liang Z, Chen Z, Zhang J, Xu Q. Nocturnal Light Pollution Synergistically Impairs Glucose Metabolism With Age and Weight in Monkeys. J Diabetes Res 2024; 2024:5112055. [PMID: 39950097 PMCID: PMC11824604 DOI: 10.1155/2024/5112055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 10/14/2024] [Indexed: 02/16/2025] Open
Abstract
Over the past decades, the global prevalence of Type 2 diabetes mellitus (T2D) and impaired glucose tolerance (IGT) has been increasing at an epidemic rate, yet the exact cause remains unknown. It is widely accepted that glucose metabolism can be impaired by circadian rhythms and sleep disturbances. Concurrently, exposures to light at night have been closely linked to circadian and sleep disturbances. However, there is no direct experiment on primates to demonstrate the precise extent of how serious light pollution impairs glucose metabolism, whether people will eventually become accustomed to this environment, and whether the pollution has synergistic impairing effects with aging and weight on glucose metabolism. To quantitatively address these questions, 137 cynomolgus were exposed to three distinct nocturnal light intensities for consecutive 10 months. Monthly glucose metabolism assessments were conducted. Data pertaining to the mortality rate of preexisting diabetes, incidence of light-induced diabetes and IGT, and alterations in insulin secretion were collected and analyzed. The results show that nocturnal light (1) caused premature deaths in individuals with preexisting diabetes; (2) intensity-dependently induced diabetes and IGT in previous healthy monkeys; (3) intensity-dependently reduced melatonin secretion; (4) had a synergistic impairing effect on glucose metabolism with aging and weight; and (5) although monkeys would eventually adapt to the environment, the disrupted glucose metabolism would not fully recover in most individuals. In conclusion, nocturnal light is associated with the global high prevalence of T2D and IGT. The harmful effects of light pollution on glucose metabolism are synergistic with age and weight.
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Affiliation(s)
- Shuxing Wang
- Department of Anatomy, Medical School, Foshan University, Foshan, Guangdong Province, China
| | - Xuange Cheng
- Department of Food and Pharmaceutical Sciences, Qingyuan Polytechnic, Panlong Park, Qingcheng District, Qingyuan City 511510, Guangdong Province, China
| | - Zihao Liang
- Qingyuan Hospital of Traditional Chinese Medicine, Qingyuan City, China
| | - Zhenyi Chen
- Primate Research Center, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Jiankai Zhang
- Department of Anatomy, Guangdong University, Dongguan, China
| | - Qiang Xu
- Primate Research Center, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
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Moghadam Fard A, Goodarzi P, Mottahedi M, Garousi S, Zadabhari H, Kalantari Shahijan M, Esmaeili S, Nabi-Afjadi M, Yousefi B. Therapeutic applications of melatonin in disorders related to the gastrointestinal tract and control of appetite. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:5335-5362. [PMID: 38358468 DOI: 10.1007/s00210-024-02972-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 01/19/2024] [Indexed: 02/16/2024]
Abstract
Most animals have large amounts of the special substance melatonin, which is controlled by the light/dark cycle in the suprachiasmatic nucleus. According to what is now understood, the gastrointestinal tract (GIT) and other areas of the body are sites of melatonin production. According to recent studies, the GIT and adjacent organs depend critically on a massive amount of melatonin. Not unexpectedly, melatonin's many biological properties, such as its antioxidant, anti-inflammatory, pro-apoptotic, anti-proliferative, anti-metastasis, and antiangiogenic properties, have drawn the attention of researchers more and more. Because melatonin is an antioxidant, it produces a lot of secretions in the GIT's mucus and saliva, which shields cells from damage and promotes the development of certain GIT-related disorders. Melatonin's ability to alter cellular behavior in the GIT and other associated organs, such as the liver and pancreas, is another way that it functions. This behavior alters the secretory and metabolic activities of these cells. In this review, we attempted to shed fresh light on the many roles that melatonin plays in the various regions of the gastrointestinal tract by focusing on its activities for the first time.
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Affiliation(s)
| | - Pardis Goodarzi
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehran Mottahedi
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Setareh Garousi
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Zadabhari
- Physiotherapy and Rehabilitation Faculty, Medipol University Health of Science, Istanbul, Turkey
| | | | - Saeedeh Esmaeili
- Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Bahman Yousefi
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Roberts FL, Cataldo LR, Fex M. Monoamines' role in islet cell function and type 2 diabetes risk. Trends Mol Med 2023; 29:1045-1058. [PMID: 37722934 DOI: 10.1016/j.molmed.2023.08.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/22/2023] [Accepted: 08/25/2023] [Indexed: 09/20/2023]
Abstract
The two monoamines serotonin and melatonin have recently been highlighted as potent regulators of islet hormone secretion and overall glucose homeostasis in the body. In fact, dysregulated signaling of both amines are implicated in β-cell dysfunction and development of type 2 diabetes mellitus (T2DM). Serotonin is a key player in β-cell physiology and plays a role in expansion of β-cell mass. Melatonin regulates circadian rhythm and nutrient metabolism and reduces insulin release in human and rodent islets in vitro. Herein, we focus on the role of serotonin and melatonin in islet physiology and the pathophysiology of T2DM. This includes effects on hormone secretion, receptor expression, genetic variants influencing β-cell function, melatonin treatment, and compounds that alter serotonin availability and signaling.
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Affiliation(s)
- Fiona Louise Roberts
- Lund University Diabetes Centre, Department of Clinical Sciences, Unit for Molecular Metabolism, SE-21428 Malmö, Sweden
| | - Luis Rodrigo Cataldo
- Lund University Diabetes Centre, Department of Clinical Sciences, Unit for Molecular Metabolism, SE-21428 Malmö, Sweden; The Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark
| | - Malin Fex
- Lund University Diabetes Centre, Department of Clinical Sciences, Unit for Molecular Metabolism, SE-21428 Malmö, Sweden.
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Role of Melatonin in Daily Variations of Plasma Insulin Level and Pancreatic Clock Gene Expression in Chick Exposed to Monochromatic Light. Int J Mol Sci 2023; 24:ijms24032368. [PMID: 36768693 PMCID: PMC9916459 DOI: 10.3390/ijms24032368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/14/2023] [Accepted: 01/16/2023] [Indexed: 01/27/2023] Open
Abstract
To clarify the effect of monochromatic light on circadian rhythms of plasma insulin level and pancreatic clock gene expression and its mechanism, 216 newly hatched chicks were divided into three groups (intact, sham operation and pinealectomy) and were raised under white (WL), red (RL), green (GL) or blue (BL) light for 21 days. Their plasma and pancreas were sampled at six four-hour intervals. For circadian rhythm analysis, measurements of plasma melatonin, insulin, and clock gene expression (cClock, cBmal1, cBmal2, cCry1, cCry2, cPer2, and cPer3) were made. Plasma melatonin, insulin, and the pancreatic clock gene all expressed rhythmically in the presence of monochromatic light. Red light reduced the mesor and amplitude of plasma melatonin in comparison to green light. The mesor and amplitude of the pancreatic clock gene in chickens exposed to red light were dramatically reduced, which is consistent with the drop in plasma melatonin levels. Red light, on the other hand, clearly raised the level of plasma insulin via raising the expression of cVamp2, but not cInsulin. After the pineal gland was removed, the circadian expressions of plasma melatonin and pancreatic clock gene were significantly reduced, but the plasma insulin level and the pancreatic cVamp2 expression were obviously increased, resulting in the disappearance of differences in insulin level and cVamp2 expression in the monochromatic light groups. Therefore, we hypothesize that melatonin may be crucial in the effect of monochromatic light on the circadian rhythm of plasma insulin level by influencing the expression of clock gene in chicken pancreas.
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Cyrino JC, de Figueiredo AC, Córdoba-Moreno MO, Gomes FR, Titon SCM. Day Versus Night Melatonin and Corticosterone Modulation by LPS in Distinct Tissues of Toads (Rhinella Icterica). Integr Comp Biol 2022; 62:1606-1617. [PMID: 35568500 DOI: 10.1093/icb/icac028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 04/30/2022] [Indexed: 01/05/2023] Open
Abstract
Pathogen-associated molecular patterns modulate melatonin (MEL) production in the pineal and extra-pineal sites and corticosterone (CORT) synthesis in the adrenal/interrenal and other tissues. Both MEL and CORT play essential and complex immunomodulatory roles, controlling the inflammatory response. Given that most of what we know about these interactions is derived from mammalian studies, discovering how MEL and CORT are modulated following an immune challenge in anurans would increase understanding of how conserved these immune-endocrine interactions are in vertebrates. Herein, we investigated the modulation of MEL and CORT in plasma vs. local tissues of toads (Rhinella icterica) in response to an immune challenge with lipopolysaccharide (LPS; 2 mg/kg) at day and night. Blood samples were taken 2 hours after injection (noon and midnight), and individuals were killed for tissue collection (bone marrow, lungs, liver, and intestine). MEL and CORT were determined in plasma and tissue homogenates. LPS treatment increased MEL concentration in bone marrow during the day. Intestine MEL levels were higher at night than during the day, particularly in LPS-injected toads. Bone marrow and lungs showed the highest MEL levels among tissues. Plasma MEL levels were not affected by either the treatment or the phase. Plasma CORT levels increased in LPS-treated individuals, with an accentuated increase at night. Otherwise, CORT concentration in the tissues was not affected by LPS exposure. Modulation of MEL levels in bone marrow suggests this tissue may participate in the toad's inflammatory response assembly. Moreover, MEL and CORT levels were different in tissues, pointing to an independent modulation of hormonal concentration. Our results suggest an important role of immune challenge in modulating MEL and CORT, bringing essential insights into the hormone-immune interactions during anuran's inflammatory response.
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Affiliation(s)
- João Cunha Cyrino
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo CEP 05508-090, São Paulo, Brasil
| | - Aymam Cobo de Figueiredo
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo CEP 05508-090, São Paulo, Brasil
| | - Marlina Olyissa Córdoba-Moreno
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo CEP 05508-090, São Paulo, Brasil
| | - Fernando Ribeiro Gomes
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo CEP 05508-090, São Paulo, Brasil
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Hosseini A, Samadi M, Baeeri M, Rahimifard M, Haghi-Aminjan H. The neuroprotective effects of melatonin against diabetic neuropathy: A systematic review of non-clinical studies. Front Pharmacol 2022; 13:984499. [PMID: 36120309 PMCID: PMC9470957 DOI: 10.3389/fphar.2022.984499] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/05/2022] [Indexed: 11/30/2022] Open
Abstract
Backgrounds: Diabetes can cause diabetic neuropathy (DN), a nerve injury. High blood sugar (glucose) levels can harm nerves all over your body. The nerves in your legs and feet are the most commonly affected by DN. The purpose of this study was to conduct a review of melatonin’s potential neuroprotective properties against DN. Method: A full systematic search was conducted in several electronic databases (Scopus, PubMed, and Web of Science) up to March 2022 under the PRISMA guidelines. Forty-seven studies were screened using predefined inclusion and exclusion criteria. Finally, the current systematic review included nine publications that met the inclusion criteria. Result: According to in vivo findings, melatonin treatment reduces DN via inhibition of oxidative stress and inflammatory pathways. However, compared to the diabetes groups alone, melatonin treatment exhibited an anti-oxidant trend. According to other research, DN also significantly produces biochemical alterations in neuron cells/tissues. Additionally, histological alterations in neuron tissue following DN were detected. Conclusion: Nonetheless, in the majority of cases, these diabetes-induced biochemical and histological alterations were reversed when melatonin was administered. It is worth noting that the administration of melatonin ameliorates the neuropathy caused by diabetes. Melatonin exerts these neuroprotective effects via various anti-oxidant, anti-inflammatory, and other mechanisms.
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Affiliation(s)
- Asieh Hosseini
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahedeh Samadi
- Neuroscience Research Center, Iran University of Medical Science, Tehran, Iran
| | - Maryam Baeeri
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mahban Rahimifard
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran
- *Correspondence: Mahban Rahimifard, ; Hamed Haghi-Aminjan,
| | - Hamed Haghi-Aminjan
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
- *Correspondence: Mahban Rahimifard, ; Hamed Haghi-Aminjan,
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Wang S, Li S, Zhai X, Rong P, He J, Liu L, He X, Liu W. Transcutaneous auricular vagal nerve stimulation releases extrapineal melatonin and reduces thermal hypersensitivity in Zucker diabetic fatty rats. Front Neurosci 2022; 16:916822. [PMID: 36033612 PMCID: PMC9403073 DOI: 10.3389/fnins.2022.916822] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 07/12/2022] [Indexed: 11/13/2022] Open
Abstract
Type 2 diabetes (T2D) is the most common comorbidity of COVID-19, and both are related to the lack of circulating melatonin. In addition, chronic pain is a common sequela of both COVID-19 and T2D. Using a neuropathic pain model produced by sciatic nerve chronic constriction injury in Zucker diabetic fatty rats, a verified preclinical genetic T2D neuropathy animal model, this study aimed to show that transcutaneous auricular vagal nerve stimulation (taVNS) could elevate plasma melatonin concentration, upregulate the expression of melatonin receptors (MTRs) in the amygdala, and relieve peripheral neuropathic pain. Furthermore, taVNS would restore melatonin levels and relieve pain even in pinealectomized rats. On the contrary, intraperitoneally injected luzindole, a melatonin receptor antagonist, would attenuate the antinociceptive effects of taVNS. In conclusion, the mechanism of the therapeutic effect of taVNS on chronic pain involves the release of extrapineal melatonin and the positive regulation of the expression of central MTRs. This beneficial efficacy should be considered during COVID-19 rehabilitation in individuals with diabetes.
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Affiliation(s)
- Shuxing Wang
- School of Medicine, Foshan University, Foshan, China
- *Correspondence: Shuxing Wang,
| | - Shaoyuan Li
- Department of Physiology, Institute of Acupuncture and Moxibustion, Academy of Chinese Medical Sciences, Beijing, China
| | - Xu Zhai
- Department of Physiology, Institute of Acupuncture and Moxibustion, Academy of Chinese Medical Sciences, Beijing, China
| | - Peijing Rong
- Department of Physiology, Institute of Acupuncture and Moxibustion, Academy of Chinese Medical Sciences, Beijing, China
| | - Jietao He
- School of Medicine, Foshan University, Foshan, China
| | - Lina Liu
- School of Medicine, Foshan University, Foshan, China
| | - Xinxin He
- School of Medicine, Foshan University, Foshan, China
| | - Wenguo Liu
- School of Medicine, Foshan University, Foshan, China
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Patel R, Parmar N, Rathwa N, Palit SP, Li Y, Garcia-Ocaña A, Begum R. A novel therapeutic combination of sitagliptin and melatonin regenerates pancreatic β-cells in mouse and human islets. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119263. [PMID: 35364117 DOI: 10.1016/j.bbamcr.2022.119263] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 02/06/2023]
Abstract
Autoimmune-led challenge resulting in β-cell loss is responsible for the development of type 1 diabetes (T1D). Melatonin, a pineal hormone or sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, has increased β-cell mass in various diabetic models and has immunoregulatory property. Both β-cell regenerative capacity and melatonin secretion decrease with ageing. Thus, we aimed to investigate the therapeutic potential of melatonin combined with sitagliptin on β-cell regeneration under glucotoxic stress, in the streptozotocin-induced young and old diabetic mouse models, and euglycemic humanized islet transplant mouse model. Our results suggest that combination therapy of sitagliptin and melatonin show an additive effect in inducing mouse β-cell regeneration under glucotoxic stress, and in the human islet transplant mouse model. Further, in the young diabetic mouse model, the monotherapies induce β-cell transdifferentiation and reduce β-cell apoptosis whereas, in the old diabetic mouse model, melatonin and sitagliptin induce β-cell proliferation and β-cell transdifferentiation, and it also reduces β-cell apoptosis. Further, in both the models, combination therapy reduces fasting blood glucose levels, increases plasma insulin levels and glucose tolerance and promotes β-cell proliferation, β-cell transdifferentiation, and reduces β-cell apoptosis. It can be concluded that combination therapy is superior to monotherapies in ameliorating diabetic manifestations, and it can be used as a future therapy for β-cell regeneration in diabetes patients.
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Affiliation(s)
- Roma Patel
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara- 390002, Gujarat, India
| | - Nishant Parmar
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara- 390002, Gujarat, India
| | - Nirali Rathwa
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara- 390002, Gujarat, India
| | - Sayantani Pramanik Palit
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara- 390002, Gujarat, India
| | - Yansui Li
- Diabetes, Obesity and Metabolism Institute and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Adolfo Garcia-Ocaña
- Diabetes, Obesity and Metabolism Institute and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Rasheedunnisa Begum
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara- 390002, Gujarat, India.
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Pfeffer M, von Gall C, Wicht H, Korf HW. The Role of the Melatoninergic System in Circadian and Seasonal Rhythms—Insights From Different Mouse Strains. Front Physiol 2022; 13:883637. [PMID: 35492605 PMCID: PMC9039042 DOI: 10.3389/fphys.2022.883637] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 03/22/2022] [Indexed: 01/01/2023] Open
Abstract
The melatoninergic system comprises the neurohormone melatonin and its molecular targets. The major source of melatonin is the pineal organ where melatonin is rhythmically produced during darkness. In mammals, melatonin biosynthesis is controlled by the central circadian rhythm generator in the suprachiasmatic nucleus (SCN) and photoreceptors in the retina. Melatonin elicits its function principally through two specific receptors called MT1 and MT2. MT1 is highly expressed in the SCN and the hypophysial pars tuberalis (PT), an important interface for control of seasonal functions. The expression of the MT2 is more widespread. The role of the melatoninergic system in the control of seasonal functions, such as reproduction, has been known for more than 4 decades, but investigations on its impact on the circadian system under normal (entrained) conditions started 2 decades later by comparing mouse strains with a fully functional melatoninergic system with mouse strains which either produce insufficient amounts of melatonin or lack the melatonin receptors MT1 and MT2. These studies revealed that an intact melatoninergic system is not required for the generation or maintenance of rhythmic behavior under physiological entrained conditions. As shown by jet lag experiments, the melatoninergic system facilitated faster re-entrainment of locomotor activity accompanied by a more rapid adaptation of the molecular clock work in the SCN. This action depended on MT2. Further studies indicated that the endogenous melatoninergic system stabilizes the locomotor activity under entrained conditions. Notably, these effects of the endogenous melatoninergic system are subtle, suggesting that other signals such as corticosterone or temperature contribute to the synchronization of locomotor activity. Outdoor experiments lasting for a whole year indicate a seasonal plasticity of the chronotype which depends on the melatoninergic system. The comparison between mice with an intact or a compromised melatoninergic system also points toward an impact of this system on sleep, memory and metabolism.
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Affiliation(s)
- Martina Pfeffer
- Institute of Anatomy II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
- *Correspondence: Martina Pfeffer,
| | - Charlotte von Gall
- Institute of Anatomy II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Helmut Wicht
- Dr. Senckenbergische Anatomie II, Fachbereich Medizin der Goethe-Universität, Frankfurt am Main, Germany
| | - Horst-Werner Korf
- Institute of Anatomy I, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
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12
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Zibolka J, Bähr I, Peschke E, Mühlbauer E, Bazwinsky-Wutschke I. Human and Rodent Cell Lines as Models of Functional Melatonin-Responsive Pancreatic Islet Cells. Methods Mol Biol 2022; 2550:329-352. [PMID: 36180704 DOI: 10.1007/978-1-0716-2593-4_35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Cell culture of different pancreatic islet cell lines, like the murine α-cell line αTC1.9, the rat β-cell lines INS-1 and INS-1 832/13, and the human δ-cell line QGP-1, can serve as valuable cell models for the analysis of melatonin-dependent modulation of hormone secretion. The paper summarizes in detail the requirements of culture for each cell line and includes batch protocols to stimulate hormone secretion and to treat cells with several melatonin concentrations as previously published. We here describe the processing of collected cell pellets or cell culture supernatants as well as different methods to analyze cell experiments after melatonin treatment on the basis of our own experience. Finally, we outlined for each cell line under which conditions the melatonin treatment should be performed to gain reproducible results.
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Affiliation(s)
- Juliane Zibolka
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Ina Bähr
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Elmar Peschke
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Eckhard Mühlbauer
- Saxon Academy of Sciences and Humanities in Leipzig, Leipzig, Germany
| | - Ivonne Bazwinsky-Wutschke
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
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13
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Tavares BS, Tsosura TVS, Mattera MSLC, Santelli JO, Belardi BE, Chiba FY, Cintra LTA, Silva CC, Matsushita DH. Effects of melatonin on insulin signaling and inflammatory pathways of rats with apical periodontitis. Int Endod J 2021; 54:926-940. [PMID: 33411973 DOI: 10.1111/iej.13474] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 12/15/2022]
Abstract
AIM To verify the effects of melatonin supplementation on insulin sensitivity, plasma concentrations of inflammatory cytokines, insulin signalling and inflammatory pathways in the soleus (SM) and extensor digitorum longus (EDL) muscles of rats with apical periodontitis (AP). METHODOLOGY Seventy-two Wistar rats were distributed into 4 groups: (a) control (C), (b) control supplemented with melatonin (M), (c) AP (AP), and (d) AP supplemented with melatonin (AP + M). AP was induced by pulp exposure of the maxillary and mandibular right first and second molars to the oral environment. After AP induction, oral supplementation with 5 mg kg-1 melatonin (diluted in drinking water) for 60 days was initiated. At the end of the treatment, the following were analysed: (1) plasma concentrations of insulin and inflammatory cytokines (TNF-α, IL-6, IL-1β and IL-10) using ELISA kits; (2) glycaemia using enzymatic assay; (3) insulin resistance using homoeostasis model assessment of insulin resistance (HOMA-IR) index; and (4) phosphorylation status of pp185 tyrosine, Akt serine, IKKα/β, and JNK in SM and EDL using Western blot. Analysis of variance of two or three factors was performed, followed by the Bonferroni test. P values < 0.05 were considered statistically significant. RESULTS AP promoted insulin resistance, significantly increased (P < 0.05) plasma concentrations of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), significantly decreased (P < 0.05) the concentration of anti-inflammatory cytokine IL-10, impaired insulin signalling in SM, and increased IKKα/β phosphorylation status in SM and EDL. Melatonin supplementation in rats with AP improved insulin sensitivity, significantly decreased (P < 0.05) TNF-α and IL-1β, significantly increased (P < 0.05) IL-10 plasma concentrations, and changed the insulin signalling in soleus muscle and IKKα/β phosphorylation status in SM and EDL muscles. CONCLUSIONS Melatonin is a potent adjuvant treatment for improving apical periodontitis-associated changes in insulin sensitivity, insulin signalling and inflammatory pathways. In addition, the negative impact of AP on general health was also demonstrated.
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Affiliation(s)
- B S Tavares
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, Department of Basic Sciences, School of Dentistry, São Paulo State University (UNESP), Araçatuba, Brazil
| | - T V S Tsosura
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, Department of Basic Sciences, School of Dentistry, São Paulo State University (UNESP), Araçatuba, Brazil
| | - M S L C Mattera
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, Department of Basic Sciences, School of Dentistry, São Paulo State University (UNESP), Araçatuba, Brazil
| | - J O Santelli
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, Department of Basic Sciences, School of Dentistry, São Paulo State University (UNESP), Araçatuba, Brazil
| | - B E Belardi
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, Department of Basic Sciences, School of Dentistry, São Paulo State University (UNESP), Araçatuba, Brazil
| | - F Y Chiba
- Department of Preventive and Restorative Dentistry, School of Dentistry, São Paulo State University (UNESP), Araçatuba, Brazil
| | - L T A Cintra
- Department of Preventive and Restorative Dentistry, School of Dentistry, São Paulo State University (UNESP), Araçatuba, Brazil
| | - C C Silva
- Department of Preventive and Restorative Dentistry, School of Dentistry, São Paulo State University (UNESP), Araçatuba, Brazil
| | - D H Matsushita
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, PPGMCF, SBFis, Department of Basic Sciences, School of Dentistry, São Paulo State University (UNESP), Araçatuba, Brazil
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14
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Differential Effects of Constant Light and Dim Light at Night on the Circadian Control of Metabolism and Behavior. Int J Mol Sci 2020; 21:ijms21155478. [PMID: 32751870 PMCID: PMC7432546 DOI: 10.3390/ijms21155478] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 07/28/2020] [Accepted: 07/30/2020] [Indexed: 02/07/2023] Open
Abstract
The disruption of circadian rhythms by environmental conditions can induce alterations in body homeostasis, from behavior to metabolism. The light:dark cycle is the most reliable environmental agent, which entrains circadian rhythms, although its credibility has decreased because of the extensive use of artificial light at night. Light pollution can compromise performance and health, but underlying mechanisms are not fully understood. The present review assesses the consequences induced by constant light (LL) in comparison with dim light at night (dLAN) on the circadian control of metabolism and behavior in rodents, since such an approach can identify the key mechanisms of chronodisruption. Data suggest that the effects of LL are more pronounced compared to dLAN and are directly related to the light level and duration of exposure. Dim LAN reduces nocturnal melatonin levels, similarly to LL, but the consequences on the rhythms of corticosterone and behavioral traits are not uniform and an improved quantification of the disrupted rhythms is needed. Metabolism is under strong circadian control and its disruption can lead to various pathologies. Moreover, metabolism is not only an output, but some metabolites and peripheral signal molecules can feedback on the circadian clockwork and either stabilize or amplify its desynchronization.
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15
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Krentz NAJ, Gloyn AL. Insights into pancreatic islet cell dysfunction from type 2 diabetes mellitus genetics. Nat Rev Endocrinol 2020; 16:202-212. [PMID: 32099086 DOI: 10.1038/s41574-020-0325-0] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/17/2020] [Indexed: 12/30/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is an increasingly prevalent multifactorial disease that has both genetic and environmental risk factors, resulting in impaired glucose homeostasis. Genome-wide association studies (GWAS) have identified over 400 genetic signals that are associated with altered risk of T2DM. Human physiology and epigenomic data support a central role for the pancreatic islet in the pathogenesis of T2DM. This Review focuses on the promises and challenges of moving from genetic associations to molecular mechanisms and highlights efforts to identify the causal variant and effector transcripts at T2DM GWAS susceptibility loci. In addition, we examine current human models that are used to study both β-cell development and function, including EndoC-β cell lines and human induced pluripotent stem cell-derived β-like cells. We use examples of four T2DM susceptibility loci (CDKAL1, MTNR1B, SLC30A8 and PAM) to emphasize how a holistic approach involving genetics, physiology, and cellular and developmental biology can disentangle disease mechanisms at T2DM GWAS signals.
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Affiliation(s)
- Nicole A J Krentz
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
| | - Anna L Gloyn
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
- NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK.
- Stanford Diabetes Research Centre, Stanford University, Stanford, CA, USA.
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16
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Xie S, Fan W, He H, Huang F. Role of Melatonin in the Regulation of Pain. J Pain Res 2020; 13:331-343. [PMID: 32104055 PMCID: PMC7012243 DOI: 10.2147/jpr.s228577] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 01/20/2020] [Indexed: 12/15/2022] Open
Abstract
Melatonin is a pleiotropic hormone synthesized and secreted mainly by the pineal gland in vertebrates. Melatonin is an endogenous regulator of circadian and seasonal rhythms. Melatonin is involved in many physiological and pathophysiological processes demonstrating antioxidant, antineoplastic, anti-inflammatory, and immunomodulatory properties. Accumulating evidence has revealed that melatonin plays an important role in pain modulation through multiple mechanisms. In this review, we examine recent evidence for melatonin on pain regulation in various animal models and patients with pain syndromes, and the potential cellular mechanisms.
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Affiliation(s)
- Shanshan Xie
- Department of Pediatric Dentistry, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People's Republic of China
| | - Wenguo Fan
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People's Republic of China.,Department of Anesthesiology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Hongwen He
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People's Republic of China.,Department of Oral Anatomy and Physiology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Fang Huang
- Department of Pediatric Dentistry, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People's Republic of China
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17
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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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18
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Mok JX, Ooi JH, Ng KY, Koh RY, Chye SM. A new prospective on the role of melatonin in diabetes and its complications. Horm Mol Biol Clin Investig 2019; 40:/j/hmbci.ahead-of-print/hmbci-2019-0036/hmbci-2019-0036.xml. [PMID: 31693492 DOI: 10.1515/hmbci-2019-0036] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 10/01/2019] [Indexed: 01/01/2023]
Abstract
Melatonin is a hormone secreted by the pineal gland under the control of the circadian rhythm, and is released in the dark and suppressed during the day. In the past decades, melatonin has been considered to be used in the treatment for diabetes mellitus (DM). This is due to a functional inter-relationship between melatonin and insulin. Elevated oxidative stress is a feature found in DM associated with diabetic neuropathy (DN), retinopathy (DR), nephropathy and cardiovascular disease. Reactive oxygen species (ROS) and nitrogen oxidative species (NOS) are usually produced in massive amounts via glucose and lipid peroxidation, and this leads to diabetic complications. At the molecular level, ROS causes damage to the biomolecules and triggers apoptosis. Melatonin, as an antioxidant and a free radical scavenger, ameliorates oxidative stress caused by ROS and NOS. Besides that, melatonin administration is proven to bring other anti-DM effects such as reducing cellular apoptosis and promoting the production of antioxidants.
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Affiliation(s)
- Jia Xin Mok
- School of Medical Laboratory Science, University of Otago, Dunedin 9054, New Zealand.,University of Otago, Dunedin School of Medicine, Department of Pathology, Medical Laboratory Science, Dunedin 9016, New Zealand
| | - Jack Hau Ooi
- International Medical University, School of Health Science, Kuala Lumpur 57000, Malaysia
| | - Khuen Yen Ng
- Monash University Malaysia, School of Pharmacy, Selangor 47500, Malaysia
| | - Rhun Yian Koh
- International Medical University, School of Health Science, Kuala Lumpur 57000, Malaysia
| | - Soi Moi Chye
- International Medical University, School of Health Science, Kuala Lumpur 57000, Malaysia.,School of Health Science, Division of Biomedical Science and Biotechnology, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000 Kuala Lumpur, Malaysia, Phone: +60-3-27317220, Fax: +06-3-86567229
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19
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Thompson PJ, Shah A, Ntranos V, Van Gool F, Atkinson M, Bhushan A. Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes. Cell Metab 2019; 29:1045-1060.e10. [PMID: 30799288 DOI: 10.1016/j.cmet.2019.01.021] [Citation(s) in RCA: 230] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Revised: 07/08/2018] [Accepted: 01/23/2019] [Indexed: 12/25/2022]
Abstract
Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by hyperglycemia due to progressive loss of pancreatic beta cells. Immune-mediated beta cell destruction drives the disease, but whether beta cells actively participate in the pathogenesis remains unclear. Here, we show that during the natural history of T1D in humans and the non-obese diabetic (NOD) mouse model, a subset of beta cells acquires a senescence-associated secretory phenotype (SASP). Senescent beta cells upregulated pro-survival mediator Bcl-2, and treatment of NOD mice with Bcl-2 inhibitors selectively eliminated these cells without altering the abundance of the immune cell types involved in the disease. Significantly, elimination of senescent beta cells halted immune-mediated beta cell destruction and was sufficient to prevent diabetes. Our findings demonstrate that beta cell senescence is a significant component of the pathogenesis of T1D and indicate that clearance of senescent beta cells could be a new therapeutic approach for T1D.
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Affiliation(s)
- Peter J Thompson
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Ajit Shah
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Vasilis Ntranos
- Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA
| | - Frederic Van Gool
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Mark Atkinson
- Diabetes Institute, University of Florida, Gainesville, FL 32610-0296, USA
| | - Anil Bhushan
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
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20
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Metwally MMM, Ebraheim LLM, Galal AAA. Potential therapeutic role of melatonin on STZ-induced diabetic central neuropathy: A biochemical, histopathological, immunohistochemical and ultrastructural study. Acta Histochem 2018; 120:828-836. [PMID: 30268437 DOI: 10.1016/j.acthis.2018.09.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 09/19/2018] [Accepted: 09/20/2018] [Indexed: 12/12/2022]
Abstract
The aim of the present study was to assess the therapeutic potential of melatonin (Mel) in diabetic central neuropathy in a rat model of streptozotocin (STZ)-induced diabetes. The rats were injected with 60 mg/kg STZ and diabetes was confirmed by blood glucose levels (BGL) ≥ 250 mg/dL. Mel treatment (50 mg/kg) was started 72 h before the STZ injection and continued for 45 days. In addition, normal control, vehicle (5% ethanol) control, and Mel-treated non-diabetic control were also included. STZ induced a diabetic phenotype with persistent hyperglycemia and elevated oxidative stress in the brain, liver, and kidneys compared to the control groups. In addition, the diabetic rats showed severe β-cell necrosis with reduced insulin levels, cerebral neuronopathy, myelinopathy, axonopathy, microglial and astroglial activation, and vascular damage. While Mel treatment did not prevent the development of STZ-induced diabetes mellitus and had no significant effect on the BGLs of the diabetic rats, it significantly ameliorated the diabetes-induced oxidative stress and neurodegeneration. Taken together, Mel showed potent therapeutic effects against the neurological complications of hyperglycemia and therefore can be used to treat diabetic neuropathy.
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Affiliation(s)
- Mohamed M M Metwally
- Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt
| | - Lamiaa L M Ebraheim
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt
| | - Azza A A Galal
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt.
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21
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Melatonin Uptake by Cells: An Answer to Its Relationship with Glucose? Molecules 2018; 23:molecules23081999. [PMID: 30103453 PMCID: PMC6222335 DOI: 10.3390/molecules23081999] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 08/02/2018] [Accepted: 08/06/2018] [Indexed: 02/06/2023] Open
Abstract
Melatonin, N-acetyl-5-methoxytryptamine, is an indole mainly synthesized from tryptophan in the pineal gland and secreted exclusively during the night in all the animals reported to date. While the pineal gland is the major source responsible for this night rise, it is not at all the exclusive production site and many other tissues and organs produce melatonin as well. Likewise, melatonin is not restricted to vertebrates, as its presence has been reported in almost all the phyla from protozoa to mammals. Melatonin displays a large set of functions including adaptation to light: dark cycles, free radical scavenging ability, antioxidant enzyme modulation, immunomodulatory actions or differentiation–proliferation regulatory effects, among others. However, in addition to those important functions, this evolutionary ‘ancient’ molecule still hides further tools with important cellular implications. The major goal of the present review is to discuss the data and experiments that have addressed the relationship between the indole and glucose. Classically, the pineal gland and a pinealectomy were associated with glucose homeostasis even before melatonin was chemically isolated. Numerous reports have provided the molecular components underlying the regulatory actions of melatonin on insulin secretion in pancreatic beta-cells, mainly involving membrane receptors MTNR1A/B, which would be partially responsible for the circadian rhythmicity of insulin in the organism. More recently, a new line of evidence has shown that glucose transporters GLUT/SLC2A are linked to melatonin uptake and its cellular internalization. Beside its binding to membrane receptors, melatonin transportation into the cytoplasm, required for its free radical scavenging abilities, still generates a great deal of debate. Thus, GLUT transporters might constitute at least one of the keys to explain the relationship between glucose and melatonin. These and other potential mechanisms responsible for such interaction are also discussed here.
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22
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Zibolka J, Bazwinsky-Wutschke I, Mühlbauer E, Peschke E. Distribution and density of melatonin receptors in human main pancreatic islet cell types. J Pineal Res 2018; 65:e12480. [PMID: 29464840 DOI: 10.1111/jpi.12480] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 02/12/2018] [Indexed: 12/15/2022]
Abstract
Recent investigations of our group established that melatonin modulates hormone secretion of pancreatic islets via melatonin receptor types MT1 and MT2. Expression of MT1 and MT2 has been shown in mouse, rat, and human pancreatic islets as well as in the β-, α-, and δ-cell lines INS-1, αTC1.9, and QGP-1. In view of these earlier investigations, this study was performed to analyze in detail the distribution and density of melatonin receptors on the main islet cell types in human pancreatic tissue obtained from nondiabetic and type 2 diabetic patients. Immunohistochemical analysis established the presence of MT1 and MT2 in β-, α-, and δ-cells, but notably, with differences in receptor density. In general, the lowest MT1 and MT2 receptor density was measured in α-cells compared to the 2 other cell types. In type 2 diabetic islets, MT1 and MT2 receptor density was increased in δ-cells compared to normoglycemic controls. In human islets in batch culture of a nondiabetic donor, an increase of somatostatin secretion was observed under melatonin treatment while in islets of a type 2 diabetic donor, an inhibitory influence could be observed, especially in the presence of 5.5 mmol/L glucose. These data suggest the following: i) cell-type-specific density of MT1 and MT2 receptors in human pancreatic islets, which should be considered in context of the hormone secretion of islets, ii) the influence of diabetes on density of MT1 and MT2 as well as iii) the differential impact of melatonin on somatostatin secretion of nondiabetic and type 2 diabetic islets.
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Affiliation(s)
- Juliane Zibolka
- Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Ivonne Bazwinsky-Wutschke
- Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
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23
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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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Li T, Ni L, Zhao Z, Liu X, Lai Z, Di X, Xie Z, Song X, Wang X, Zhang R, Liu C. Melatonin attenuates smoking-induced hyperglycemia via preserving insulin secretion and hepatic glycogen synthesis in rats. J Pineal Res 2018; 64:e12475. [PMID: 29437243 PMCID: PMC5947659 DOI: 10.1111/jpi.12475] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 02/02/2018] [Indexed: 12/11/2022]
Abstract
Epidemiology survey indicated that cigarette smoking is a risk factor of diabetes. However, the precise mechanisms remain to be clarified. In this study, we found that smoking caused metabolic malfunctions on pancreas and liver in experimental animal model. These were indicated by hyperglycemia, increased serum hemoglobin A1c level and decreased insulin secretion, inhibition of liver glycogen synthase (LGS), and hepatic glycogen synthesis. Mechanistic studies revealed that all these alterations were caused by the inflammatory reaction and reactive oxygen species (ROS) induced by the smoking. Melatonin treatment significantly preserved the functions of both pancreas and liver by reducing β cell apoptosis, CD68-cell infiltration, ROS production, and caspase-3 expression. The siRNA-knockdown model identified that the protective effects of melatonin were mediated by melatonin receptor-2 (MT2). This study uncovered potentially underlying mechanisms related to the association between smoking and diabetes. In addition, it is, for first time, to report that melatonin effectively protects against smoking-induced glucose metabolic alterations and the signal transduction pathway of melatonin is mainly mediated by its MT2 receptor. These observations provide solid evidence for the clinically use of melatonin to reduce smoking-related diabetes, and the therapeutic regimens are absent currently.
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Affiliation(s)
- Tianjia Li
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Leng Ni
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zhewei Zhao
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xinnong Liu
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zhichao Lai
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xiao Di
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zhibo Xie
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xitao Song
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xuebin Wang
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Rui Zhang
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Changwei Liu
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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Abstract
This chapter reviews both statistical and physiologic issues related to the pathophysiologic effects of genetic variation in the context of type 2 diabetes. The goal is to review current methodologies used to analyze disease-related quantitative traits for those who do not have extensive quantitative and physiologic background, as an attempt to bridge that gap. We leverage mathematical modeling to illustrate the strengths and weaknesses of different approaches and attempt to reinforce with real data analysis. Topics reviewed include phenotype selection, phenotype specificity, multiple variant analysis via the genetic risk score, and consideration of multiple disease-related phenotypes. Type 2 diabetes is used as the example, not only because of the extensive existing knowledge at the genetic, physiologic, clinical, and epidemiologic levels, but also because type 2 diabetes has been at the forefront of complex disease genetics, with many examples to draw from.
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Affiliation(s)
- Richard M Watanabe
- Departments of Preventive Medicine and Physiology & Biophysics, Keck School of Medicine of USC, 2250 Alcazar Street, CSC-204, Los Angeles, CA, 90089-9073, USA.
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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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Mazzoccoli G, Dagostino MP, Paroni G, Seripa D, Ciccone F, Addante F, Favuzzi G, Grandone E, Avola R, Mazza T, Fusilli C, Greco A, De Cosmo S. Analysis of MTNR1B gene polymorphisms in relationship with IRS2 gene variants, epicardial fat thickness, glucose homeostasis and cognitive performance in the elderly. Chronobiol Int 2017; 34:1083-1093. [PMID: 28708046 DOI: 10.1080/07420528.2017.1340894] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
ABSTARCT Genome-wide association studies pinpointed common variants in or near the MTNR1B gene encoding MT2 melatonin receptor to be strongly associated with fasting glucose levels. IRS2 gene polymorphisms impact insulin resistance and epicardial fat (EF) thickness, which in turn is correlated with visceral adiposity, cognitive ability and risk for metabolic plus cardiovascular disease. We aimed to discover the interactions between MTNR1B and IRS2 gene polymorphisms, insulin sensitivity, EF thickness and cognitive performance in the elderly. In 60 subjects aged 60 years and older, we evaluated five single nucleotide polymorphisms (SNPs) within the MTNR1B locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638), the Gly1057Asp variant of IRS2 gene (rs1805097), biochemical parameters, cognitive performance by the Mini Mental State Examination (MMSE) and EF thickness by transthoracic echocardiography. We found that MTNR1B and IRS2 gene variants impacted EF thickness, lipid profile and glucose homeostasis. IRS2 but not MTNR1B variants impacted MMSE scores. In conclusion, MTNR1B SNPs interact with IRS2 gene variant, correlate with the amount of epicardial adipose tissue and impact glucose homeostasis and lipid profile influencing cardiometabolic risk.
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Affiliation(s)
- Gianluigi Mazzoccoli
- a Department of Medical Sciences , Division of Internal Medicine and Chronobiology Unit
| | - Mariangela Pia Dagostino
- b Department of Medical Sciences , Geriatrics Unit and Gerontology-Geriatrics Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza" , San Giovanni Rotondo , Italy
| | - Giulia Paroni
- b Department of Medical Sciences , Geriatrics Unit and Gerontology-Geriatrics Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza" , San Giovanni Rotondo , Italy
| | - Davide Seripa
- b Department of Medical Sciences , Geriatrics Unit and Gerontology-Geriatrics Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza" , San Giovanni Rotondo , Italy
| | - Filomena Ciccone
- b Department of Medical Sciences , Geriatrics Unit and Gerontology-Geriatrics Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza" , San Giovanni Rotondo , Italy
| | - Filomena Addante
- b Department of Medical Sciences , Geriatrics Unit and Gerontology-Geriatrics Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza" , San Giovanni Rotondo , Italy
| | - Giovanni Favuzzi
- c Research Laboratory of Thrombosis and Hemostasis, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", Opera di Padre Pio da Pietrelcina , San Giovanni Rotondo , Italy
| | - Elvira Grandone
- c Research Laboratory of Thrombosis and Hemostasis, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", Opera di Padre Pio da Pietrelcina , San Giovanni Rotondo , Italy
| | - Roberto Avola
- d Department of Biomedical and Biotechnological Sciences , University of Catania , Catania , Italy
| | - Tommaso Mazza
- e Bioinformatics Unit, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", Opera di Padre Pio da Pietrelcina , San Giovanni Rotondo , Italy
| | - Caterina Fusilli
- e Bioinformatics Unit, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", Opera di Padre Pio da Pietrelcina , San Giovanni Rotondo , Italy
| | - Antonio Greco
- b Department of Medical Sciences , Geriatrics Unit and Gerontology-Geriatrics Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza" , San Giovanni Rotondo , Italy
| | - Salvatore De Cosmo
- a Department of Medical Sciences , Division of Internal Medicine and Chronobiology Unit
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Forrestel AC, Miedlich SU, Yurcheshen M, Wittlin SD, Sellix MT. Chronomedicine and type 2 diabetes: shining some light on melatonin. Diabetologia 2017; 60:808-822. [PMID: 27981356 DOI: 10.1007/s00125-016-4175-1] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 11/18/2016] [Indexed: 12/19/2022]
Abstract
In mammals, the circadian timing system drives rhythms of physiology and behaviour, including the daily rhythms of feeding and activity. The timing system coordinates temporal variation in the biochemical landscape with changes in nutrient intake in order to optimise energy balance and maintain metabolic homeostasis. Circadian disruption (e.g. as a result of shift work or jet lag) can disturb this continuity and increase the risk of cardiometabolic disease. Obesity and metabolic disease can also disturb the timing and amplitude of the clock in multiple organ systems, further exacerbating disease progression. As our understanding of the synergy between the timing system and metabolism has grown, an interest has emerged in the development of novel clock-targeting pharmaceuticals or nutraceuticals for the treatment of metabolic dysfunction. Recently, the pineal hormone melatonin has received some attention as a potential chronotherapeutic drug for metabolic disease. Melatonin is well known for its sleep-promoting effects and putative activity as a chronobiotic drug, stimulating coordination of biochemical oscillations through targeting the internal timing system. Melatonin affects the insulin secretory activity of the pancreatic beta cell, hepatic glucose metabolism and insulin sensitivity. Individuals with type 2 diabetes mellitus have lower night-time serum melatonin levels and increased risk of comorbid sleep disturbances compared with healthy individuals. Further, reduced melatonin levels, and mutations and/or genetic polymorphisms of the melatonin receptors are associated with an increased risk of developing type 2 diabetes. Herein we review our understanding of molecular clock control of glucose homeostasis, detail the influence of circadian disruption on glucose metabolism in critical peripheral tissues, explore the contribution of melatonin signalling to the aetiology of type 2 diabetes, and discuss the pros and cons of melatonin chronopharmacotherapy in disease management.
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Affiliation(s)
- Andrew C Forrestel
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 693, Rochester, NY, 14642, USA
| | - Susanne U Miedlich
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 693, Rochester, NY, 14642, USA
| | - Michael Yurcheshen
- UR Medicine Sleep Center, Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Steven D Wittlin
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 693, Rochester, NY, 14642, USA
| | - Michael T Sellix
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 693, Rochester, NY, 14642, USA.
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Mulder H. Melatonin signalling and type 2 diabetes risk: too little, too much or just right? Diabetologia 2017; 60:826-829. [PMID: 28303303 DOI: 10.1007/s00125-017-4249-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 02/06/2017] [Indexed: 01/29/2023]
Abstract
Of the associations of genetic variants with type 2 diabetes, the one of an SNP in an intron of the gene encoding the melatonin receptor 1B (MTNR1B) has been remarkably robust. Work from our group and others has provided support for a model where carriers of this risk G allele exhibit increased MTNR1B expression in islets of Langerhans. Most published studies to date favour that melatonin's action on the beta cell is inhibition of insulin secretion. Hence, our model proposes that this inhibitory effect of melatonin is exaggerated in carriers of the MTNR1B risk G allele. This would explain why this genetic association causes reduced insulin secretion and greater risk of future type 2 diabetes, as has been observed in numerous studies. Concurrently, another body of work has shown that rare MTNR1B alleles, which could perturb receptor function, also associate with type 2 diabetes. In this commentary, it is suggested that such apparently conflicting observations can be reconciled by the fact that non-coding (intronic; frequent) and coding (exonic; rare) alleles of MTNR1B give rise to different phenotypes. Thus, altered gene transcription may explain why SNPs, which do not alter coding sequences, exhibit cell-specific effects. In contrast, SNPs that change protein sequences are more likely to exert generalised effects since an altered protein will appear in all cells expressing the gene.
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Affiliation(s)
- Hindrik Mulder
- Unit of Molecular Metabolism, Lund University Diabetes Centre, Jan Waldenströms gata 35, SE-205 02, Malmö, Sweden.
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30
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Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes. Cell Metab 2016; 23:1067-1077. [PMID: 27185156 DOI: 10.1016/j.cmet.2016.04.009] [Citation(s) in RCA: 180] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Revised: 02/18/2016] [Accepted: 04/13/2016] [Indexed: 12/16/2022]
Abstract
Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increased MTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.
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Rong PJ, Zhao JJ, Li YQ, Litscher D, Li SY, Gaischek I, Zhai X, Wang L, Luo M, Litscher G. Auricular acupuncture and biomedical research—A promising Sino-Austrian research cooperation. Chin J Integr Med 2015; 21:887-894. [DOI: 10.1007/s11655-015-2090-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Indexed: 11/28/2022]
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Sharma S, Singh H, Ahmad N, Mishra P, Tiwari A. The role of melatonin in diabetes: therapeutic implications. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2015; 59:391-9. [PMID: 26331226 DOI: 10.1590/2359-3997000000098] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 07/06/2015] [Indexed: 01/27/2023]
Abstract
Melatonin referred as the hormone of darkness is mainly secreted by pineal gland, its levels being elevated during night and low during the day. The effects of melatonin on insulin secretion are mediated through the melatonin receptors (MT1 and MT2). It decreases insulin secretion by inhibiting cAMP and cGMP pathways but activates the phospholipaseC/IP3 pathway, which mobilizes Ca2+from organelles and, consequently increases insulin secretion. Both in vivo and in vitro, insulin secretion by the pancreatic islets in a circadian manner, is due to the melatonin action on the melatonin receptors inducing a phase shift in the cells. Melatonin may be involved in the genesis of diabetes as a reduction in melatonin levels and a functional interrelationship between melatonin and insulin was observed in diabetic patients. Evidences from experimental studies proved that melatonin induces production of insulin growth factor and promotes insulin receptor tyrosine phosphorylation. The disturbance of internal circadian system induces glucose intolerance and insulin resistance, which could be restored by melatonin supplementation. Therefore, the presence of melatonin receptors on human pancreatic islets may have an impact on pharmacotherapy of type 2 diabetes.
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Affiliation(s)
- Shweta Sharma
- School of Biotechnology, Rajiv Gandhi Technical University, Bhopal, Madhya Pradesh, India
| | - Hemant Singh
- School of Biotechnology, Rajiv Gandhi Technical University, Bhopal, Madhya Pradesh, India
| | - Nabeel Ahmad
- School of Biotechnology, IFTM University, Uttar Pradesh, India
| | - Priyanka Mishra
- School of Biotechnology, Rajiv Gandhi Technical University, Bhopal, Madhya Pradesh, India
| | - Archana Tiwari
- School of Biotechnology, Rajiv Gandhi Technical University, Bhopal, Madhya Pradesh, India
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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: 81] [Impact Index Per Article: 8.1] [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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Renström F, Koivula RW, Varga TV, Hallmans G, Mulder H, Florez JC, Hu FB, Franks PW. Season-dependent associations of circadian rhythm-regulating loci (CRY1, CRY2 and MTNR1B) and glucose homeostasis: the GLACIER Study. Diabetologia 2015; 58:997-1005. [PMID: 25707907 DOI: 10.1007/s00125-015-3533-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 02/02/2015] [Indexed: 12/21/2022]
Abstract
AIMS/HYPOTHESIS The association of single nucleotide polymorphisms (SNPs) proximal to CRY2 and MTNR1B with fasting glucose is well established. CRY1/2 and MTNR1B encode proteins that regulate circadian rhythmicity and influence energy metabolism. Here we tested whether season modified the relationship of these loci with blood glucose concentration. METHODS SNPs rs8192440 (CRY1), rs11605924 (CRY2) and rs10830963 (MTNR1B) were genotyped in a prospective cohort study from northern Sweden (n = 16,499). The number of hours of daylight exposure during the year ranged from 4.5 to 22 h daily. Owing to the non-linear distribution of daylight throughout the year, season was dichotomised based on the vernal and autumnal equinoxes. Effect modification was assessed using linear regression models fitted with a SNP × season interaction term, marginal effect terms and putative confounding variables, with fasting or 2 h glucose concentrations as outcomes. RESULTS The rs8192440 (CRY1) variant was only associated with fasting glucose among participants (n = 2,318) examined during the light season (β = -0.04 mmol/l per A allele, 95% CI -0.08, -0.01, p = 0.02, p interaction = 0.01). In addition to the established association with fasting glucose, the rs11605924 (CRY2) and rs10830963 (MTNR1B) loci were associated with 2 h glucose concentrations (β = 0.07 mmol/l per A allele, 95% CI 0.03, 0.12, p = 0.0008, n = 9,605, and β = -0.11 mmol/l per G allele, 95% CI -0.15, -0.06, p < 0.0001, n = 9,517, respectively), but only in participants examined during the dark season (p interaction = 0.006 and 0.04, respectively). Repeated measures analyses including data collected 10 years after baseline (n = 3,500) confirmed the results for the CRY1 locus (p interaction = 0.01). CONCLUSIONS/INTERPRETATION In summary, these observations suggest a biologically plausible season-dependent association between SNPs at CRY1, CRY2 and MTNR1B and glucose homeostasis.
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Affiliation(s)
- Frida Renström
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Clinical Research Center Building 91, Level 10, Jan Waldenströms gata 35, SE-205 02, Malmö, Sweden,
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Wang S, Zhai X, Li S, McCabe MF, Wang X, Rong P. Transcutaneous vagus nerve stimulation induces tidal melatonin secretion and has an antidiabetic effect in Zucker fatty rats. PLoS One 2015; 10:e0124195. [PMID: 25880500 PMCID: PMC4400163 DOI: 10.1371/journal.pone.0124195] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Accepted: 02/26/2015] [Indexed: 01/29/2023] Open
Abstract
Melatonin plays a protective role in type 2 diabetes (T2D) through regulation of glucose metabolism. Whether transcutaneous vagus nerve stimulation (taVNS) is antidiabetic and whether a modulated melatonin production is involved in the antidiabetic mechanism of taVNS is unknown. In this study, once daily 30min noninvasive taVNS was administered in Zucker diabetic fatty (ZDF, fa/fa) and Zucker lean (ZL, +/fa) littermates under anesthesia for 5 consecutive weeks. The acute and chronic influences of taVNS on the secretion of melatonin were studied as well as the effects of taVNS on blood glucose metabolism. We found that naïve ZDF rats develop hyperglycemia naturally with age. Each taVNS session would trigger a tidal secretion of melatonin both during and after the taVNS procedure and induce an acute two-phase glycemic change, a steep increase followed by a gradual decrease. Once daily taVNS sessions eventually reduced the glucose concentration to a normal level in seven days and effectively maintained the normal glycemic and plasma glycosylated hemoglobin (HbAlc) levels when applied for five consecutive weeks. These beneficial effects of taVNS also exist in pinealectomized rats, which otherwise would show overt and continuous hyperglycemia, hyperinsulinemia, and high HbAlc levels. We concluded that multiple taVNS sessions are antidiabetic in T2D through triggering of tidal secretion of melatonin. This finding may have potential importance in developing new approaches to the treatment of T2D, which is highly prevalent, incurable with any current approaches, and very costly to the world.
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Affiliation(s)
- Shuxing Wang
- Department of Anatomy, Xinxiang Medical University, Xinxiang, Henan Province, China
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
- MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Guangdong Landau Biotechnology Inc. Ltd., Guangzhou, Guangdong, China
- * E-mail: (SW); (PR)
| | - Xu Zhai
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - Shaoyuan Li
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - Michael F. McCabe
- MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Xing Wang
- Department of Anatomy, Xinxiang Medical University, Xinxiang, Henan Province, China
| | - Peijing Rong
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
- * E-mail: (SW); (PR)
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36
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Farhadi N, Doosti A, Mohammadi J, Mohammadi R. Effects of orally-administered melatonin and long-term exposure to light and dark on serum indices and gene expression of insulin and glucagon in male Wistar rats. BIOL RHYTHM RES 2015. [DOI: 10.1080/09291016.2015.1020201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Tosini G, Owino S, Guillaume JL, Jockers R. Understanding melatonin receptor pharmacology: latest insights from mouse models, and their relevance to human disease. Bioessays 2014; 36:778-87. [PMID: 24903552 PMCID: PMC4151498 DOI: 10.1002/bies.201400017] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Melatonin, the neuro-hormone synthesized during the night, has recently seen an unexpected extension of its functional implications toward type 2 diabetes development, visual functions, sleep disturbances, and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein-coupled receptors, named MT1 and MT2 , which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse MT1 and MT2 receptors, including MT1 /MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models.
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Affiliation(s)
- Gianluca Tosini
- Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, GA, USA
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38
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Karamitri A, Vincens M, Chen M, Jockers R. [Involvement of melatonin MT2 receptor mutants in type 2 diabetes development]. Med Sci (Paris) 2013; 29:778-84. [PMID: 24005634 DOI: 10.1051/medsci/2013298018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Genetic and environmental factors participate in the development of type 2 diabetes (T2D). Genome-wide association studies have revealed new genetic variants associated with T2D, including the rs10830963 variant located in the intron of the MTNR1B gene. This gene encodes the melatonin MT2 receptor, a member of the family of G protein-coupled receptors involved in the regulation of circadian and seasonal rhythms. This surprising result stimulated new investigations in the field of T2D to better understand the role of MT2 receptors and circadian rhythms in this emerging disease. The current article intends to cover this issue starting from the discovery of the first MTNR1B gene variants until the establishment of a functional link between MTNR1B variants and the risk of developing T2D and finishes by proposing some hypotheses that might potentially explain the importance of impaired MT2 function in T2D development.
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Karamitri A, Renault N, Clement N, Guillaume JL, Jockers R. Minireview: Toward the establishment of a link between melatonin and glucose homeostasis: association of melatonin MT2 receptor variants with type 2 diabetes. Mol Endocrinol 2013; 27:1217-33. [PMID: 23798576 DOI: 10.1210/me.2013-1101] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The existence of interindividual variations in G protein-coupled receptor sequences has been recognized early on. Recent advances in large-scale exon sequencing techniques are expected to dramatically increase the number of variants identified in G protein-coupled receptors, giving rise to new challenges regarding their functional characterization. The current minireview will illustrate these challenges based on the MTNR1B gene, which encodes the melatonin MT2 receptor, for which exon sequencing revealed 40 rare nonsynonymous variants in the general population and in type 2 diabetes (T2D) cohorts. Functional characterization of these MT2 mutants revealed 14 mutants with loss of Gi protein activation that associate with increased risk of T2D development. This repertoire of disease-associated mutants is a rich source for structure-activity studies and will help to define the still poorly understood role of melatonin in glucose homeostasis and T2D development in humans. Defining the functional defects in carriers of rare MT2 mutations will help to provide personalized therapies to these patients in the future.
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Affiliation(s)
- Angeliki Karamitri
- Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, Paris, France
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40
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Konenkov VI, Klimontov VV, Michurina SV, Prudnikova MA, Ishenko IJ. Melatonin and diabetes: from pathophysiology to the treatment perspectives. DIABETES MELLITUS 2013. [DOI: 10.14341/2072-0351-3751] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Pineal hormone melatonin synchronizes insulin secretion and glucose homeostasis with solar periods. Misalliance between melatonin-mediated circadian rhythms and insulin secretion characterizes diabetes mellitus type 1 (T1DM) and type 2 (T2DM). Insulin deficiency in T1DM is accompanied by increased melatonin production. Conversely, T2DM is characterized by diminished melatonin secretion. In genome-wide association studies the variants of melatonin receptor MT2 gene (rs1387153 and rs10830963) were associated with fasting glucose, beta-cell function and T2DM. In experimental models of diabetes melatonin enhanced beta-cell proliferation and neogenesis, improved insulin resistance and alleviated oxidative stress in retina and kidneys. However, further investigation is required to assess the therapeutic value of melatonin in diabetic patients.
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41
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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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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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Bähr I, Mühlbauer E, Albrecht E, Peschke E. Evidence of the receptor-mediated influence of melatonin on pancreatic glucagon secretion via the Gαq protein-coupled and PI3K signaling pathways. J Pineal Res 2012; 53:390-8. [PMID: 22672634 DOI: 10.1111/j.1600-079x.2012.01009.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Melatonin has been shown to modulate glucose metabolism by influencing insulin secretion. Recent investigations have also indicated a regulatory function of melatonin on the pancreatic α-cells. The present in vitro and in vivo studies evaluated whether melatonin mediates its effects via melatonin receptors and which signaling cascade is involved. Incubation experiments using the glucagon-producing mouse pancreatic α-cell line αTC1 clone 9 (αTC1.9) as well as isolated pancreatic islets of rats and mice revealed that melatonin increases glucagon secretion. Preincubation of αTC1.9 cells with the melatonin receptor antagonists luzindole and 4P-PDOT abolished the glucagon-stimulatory effect of melatonin. In addition, glucagon secretion was lower in the pancreatic islets of melatonin receptor knockout mice than in the islets of the wild-type (WT) control animals. Investigations of melatonin receptor knockout mice revealed decreased plasma glucagon concentrations and elevated mRNA expression levels of the hepatic glucagon receptor when compared to WT mice. Furthermore, studies using pertussis toxin, as well as measurements of cAMP concentrations, ruled out the involvement of Gαi- and Gαs-coupled signaling cascades in mediating the glucagon increase induced by melatonin. In contrast, inhibition of phospholipase C in αTC1.9 cells prevented the melatonin-induced effect, indicating the physiological relevance of the Gαq-coupled pathway. Our data point to the involvement of the phosphatidylinositol 3-kinase signaling cascade in mediating melatonin effects in pancreatic α-cells. In conclusion, these findings provide evidence that the glucagon-stimulatory effect of melatonin in pancreatic α-cells is melatonin receptor mediated, thus supporting the concept of melatonin-modulated and diurnal glucagon release.
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MESH Headings
- Animals
- Cell Line
- Cyclic AMP/metabolism
- Diabetes Mellitus, Type 2/enzymology
- Disease Models, Animal
- Dose-Response Relationship, Drug
- GTP-Binding Protein alpha Subunits, Gq-G11/metabolism
- Gene Expression Regulation
- Glucagon/blood
- Glucagon/metabolism
- Glucagon-Secreting Cells/drug effects
- Glucagon-Secreting Cells/enzymology
- Glucagon-Secreting Cells/metabolism
- Liver/drug effects
- Liver/metabolism
- Male
- Melanins/pharmacology
- Mice
- Mice, Knockout
- Pertussis Toxin/pharmacology
- Phosphatidylinositol 3-Kinase/metabolism
- RNA, Messenger/metabolism
- Rats
- Rats, Wistar
- Receptor, Melatonin, MT1/deficiency
- Receptor, Melatonin, MT1/drug effects
- Receptor, Melatonin, MT1/genetics
- Receptor, Melatonin, MT2/deficiency
- Receptor, Melatonin, MT2/drug effects
- Receptor, Melatonin, MT2/genetics
- Receptors, Glucagon/drug effects
- Receptors, Glucagon/genetics
- Receptors, Glucagon/metabolism
- Signal Transduction/drug effects
- Tetrahydronaphthalenes/pharmacology
- Tissue Culture Techniques
- Tryptamines/pharmacology
- Type C Phospholipases/metabolism
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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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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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Abstract
PURPOSE OF REVIEW Recent advances in the regulation of pancreatic secretion by neural and hormonal mechanisms are discussed in this review. RECENT FINDINGS It has been shown that the multidrug-resistance protein MRP4 may play a role in the efflux of cAMP from exocrine cells and neurokinin receptors are important in substance P-mediated inhibition of ductal bicarbonate secretion. Leptin attenuates glucagon secretion by downregulating glucagon gene expression, whereas ghrelin upregulates glucagon release by elevating intracellular calcium and phosphorylation of extracellular signal-regulated kinase (ERK). Cytokine interleukin 6 is secreted from muscles during exercise and induces the release of GLP-1 that stimulates insulin secretion. Osteocalcin and 17β-estradiol mediate their effects through G protein-coupled receptors, resulting in ERK phosphorylation and activation of protein kinase-dependent signaling pathways. Melatonin and ghrelin inhibit insulin secretion through inhibitory G proteins, whereas aldosterone may attenuate insulin secretion by increasing oxidative stress in islets cells. Finally, the pattern of innervation of human pancreatic islets has been examined and demonstrated to be very different from that in the mouse. SUMMARY Many different receptors and signaling pathways govern the complex biology of pancreatic secretion. Elucidation of these cellular mechanisms will aid in drug discovery and treatment as well as prevention of pancreatic diseases.
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Mühlbauer E, Albrecht E, Bazwinsky-Wutschke I, Peschke E. Melatonin influences insulin secretion primarily via MT(1) receptors in rat insulinoma cells (INS-1) and mouse pancreatic islets. J Pineal Res 2012; 52:446-59. [PMID: 22288848 DOI: 10.1111/j.1600-079x.2012.00959.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Several studies have revealed that melatonin affects the insulin secretion via MT(1) and MT(2) receptor isoforms. Owing to the lack of selective MT(1) receptor antagonists, we used RNA interference technology to generate an MT(1) knockdown in a clonal β-cell line to evaluate whether melatonin modulates insulin secretion specifically via the MT(1) receptor. Incubation experiments were carried out, and the insulin concentration in supernatants was measured using a radioimmunoassay. Furthermore, the intracellular cAMP was determined using an enzyme-linked immunosorbent assay. Real-time RT-PCR indicated that MT(1) knockdown resulted in a significant increase in the rIns1 mRNA and a significantly elevated basal insulin secretion of INS-1 cells. Incubation with melatonin decreased the amount of glucagon-like peptide 1 or inhibited the glucagon-stimulated insulin release of INS-1 cells, while, in MT(1) -knockdown cells, no melatonin-induced reduction in insulin secretion could be found. No decrease in 3-isobutyl-1-methylxanthine-stimulated intracellular cAMP in rMT(1) -knockdown cells was detectable after treatment with melatonin either, and immunocytochemistry proved that MT(1) knockdown abolished phosphorylation of cAMP-response-element-binding protein. In contrast to the INS-1 cells, preincubation with melatonin did not sensitize the insulin secretion of rMT(1) -knockdown cells. We also monitored insulin secretion from isolated islets of wild-type and melatonin-receptor knockout mice ex vivo. In islets of wild-type mice, melatonin treatment resulted in a decrease in insulin release, whereas melatonin treatment of islets from MT(1) knockout and MT(1/2) double-knockout mice did not show a significant effect. The data indicate that melatonin inhibits insulin secretion, primarily via the MT(1) receptor in rat INS-1 cells and isolated mouse islets.
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Peschke E, Hofmann K, Pönicke K, Wedekind D, Mühlbauer E. Catecholamines are the key for explaining the biological relevance of insulin-melatonin antagonisms in type 1 and type 2 diabetes. J Pineal Res 2012; 52:389-96. [PMID: 21929683 DOI: 10.1111/j.1600-079x.2011.00951.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
In this paper, we analyze the biological relevance of melatonin in diabetogenesis. As has recently been demonstrated, melatonin decreases insulin secretion via specific melatonin receptor isoforms (MT1 and MT2) in the pancreatic β-cells. In addition, type 2 diabetic rats, as well as patients, exhibit decreased melatonin levels, whereas the levels in type 1 diabetic rats are increased. The latter effects were normalized by insulin substitution, which signifies that a specific receptor-mediated insulin-melatonin antagonism exists. These results are in agreement with several recent genome-wide association studies, which have identified a number of single nucleotide polymorphisms in the MTNR1B gene, encoding the MT2 receptor, that were closely associated with a higher prognostic risk of developing type 2 diabetes. We hypothesize that catecholamines, which decrease insulin levels and stimulate melatonin synthesis, control insulin-melatonin interactions. The present results support this assertion as we show that catecholamines are increased in type 1 but are diminished in type 2 diabetes. Another important line of inquiry involves the fact that melatonin protects the β-cells against functional overcharge and, consequently, hinders the development of type 2 diabetes. In this context, it is striking that at advanced ages, melatonin levels are reduced and the incidence of type 2 diabetes is increased. Thus, melatonin appears to have a protective biological role. Here, we strongly repudiate misconceptions, resulting from observations that melatonin reduces the plasma insulin level, that the blockage of melatonin receptors would be of benefit in the treatment of type 2 diabetes.
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Affiliation(s)
- E Peschke
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
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48
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Mühlbauer E, Albrecht E, Hofmann K, Bazwinsky-Wutschke I, Peschke E. Melatonin inhibits insulin secretion in rat insulinoma β-cells (INS-1) heterologously expressing the human melatonin receptor isoform MT2. J Pineal Res 2011; 51:361-72. [PMID: 21585522 DOI: 10.1111/j.1600-079x.2011.00898.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Melatonin exerts some of its effects via G-protein-coupled membrane receptors. Two membrane receptor isoforms, MT1 and MT2, have been described. The MT1 receptor is known to inhibit second messenger cyclic adenosine monophosphate (cAMP) signaling through receptor-coupling to inhibitory G-proteins (G(i) ). Much less is known about the MT2 receptor, but it has also been implicated in signaling via G(i) -proteins. In rat pancreatic β-cells, it has recently been reported that the MT2 receptor plays an inhibitory role in the cyclic guanosine monophosphate (cGMP) pathway. This study addresses the signaling features of the constitutively expressed human recombinant MT2 receptor (hMT2) and its impact on insulin secretion, using a rat insulinoma β-cell line (INS-1). On the basis of a specific radioimmunoassay, insulin secretion was found to be more strongly reduced in the clones expressing hMT2 than in INS-1 controls, when incubated with 1 or 100 nm melatonin. Similarly, cAMP and cGMP levels, measured by specific enzyme-linked immunosorbent assays (ELISAs), were reduced to a greater extent in hMT2 clones after melatonin treatment. In hMT2-expressing cells, the inhibitory effect of melatonin on insulin secretion was blocked by pretreatment with pertussis toxin, demonstrating the coupling of the hMT2 to G(i) -proteins. These results indicate that functional hMT2 expression leads to the inhibition of cyclic nucleotide signaling and a reduction in insulin release. Because genetic variants of the hMT2 receptor are considered to be risk factors in the development of type 2 diabetes, our results are potentially significant in explaining and preventing the pathogenesis of this disease.
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