Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene

Mulder, Hindrik; Nagorny, Cecilia; Lyssenko, Valeriya; Groop, Leif

doi:10.1007/s00125-009-1359-y

Cited by 139 publications

(118 citation statements)

References 68 publications

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“…tests of diurnal rhythmicity, were analysed by oneway ANOVA (a, c, e, g, i, k) and mean±SEM by Mann-Whitney U test (b, d, f, h, j, l); *p<0.05, **p<0.01, ***p<0.001 The bar below x-axes indicates light and dark phases of diurnal period. Continuous lines, control; dashed lines, diabetic; dotted lines, diabetic+insulin tance of the insulin-melatonin relationship and the effects of melatonin on the pancreatic beta cell [1,3,8], which are mediated by MT 1 [2,6] and MT 2 [9,10] receptors [8,33]. Previous studies have established that the effect of melatonin on the pancreatic beta cell is mediated by three intracellular pathways, as described in the introduction.…”

Section: Discussionmentioning

confidence: 98%

The insulin–melatonin antagonism: studies in the LEW.1AR1-iddm rat (an animal model of human type 1 diabetes mellitus)

et al. 2011

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Aims/hypothesis It is well documented that melatonin influences insulin secretion mediated by G-protein-coupled melatonin receptor isoforms MT1 and MT2, which are present in rat and human pancreatic islets, as well as in rat insulinoma cells. Recent investigations have proven that hyperinsulinaemic Goto-Kakizaki (GK) rats, which are a rat model of type 2 diabetic rats, and humans have decreased melatonin plasma levels, whereas a streptozotocin-induced rat model of diabetes developed reduced insulin levels combined with increased melatonin levels. Methods Plasma levels of glucose, insulin and melatonin as well as RNA expression of pineal Aanat, Hiomt (also known as Asmt), insulin receptor, adrenoceptor β1 and the clock genes Per1 and Bmal1 (also known as Arntl) were determined in male and female LEW.1AR1-iddm rats as well as in insulin-substituted LEW.1AR1-iddm rats.Results Severe hypoinsulinaemia in diabetic LEW.1AR1-iddm rats was associated with decreased body weight and increased melatonin plasma levels combined with mainly elevated expression of Aanat, Hiomt, pineal insulin receptor and adrenoceptor β1. The changes were normalised by insulin substitution. Diurnal profiles of plasma melatonin and of antagonistic clock genes Per1 and Bmal1 were maintained in diabetic and insulin-substituted rats. Conclusions/interpretation The assumed causal relation between elevated melatonin and reduced insulin levels in LEW.1AR1-iddm rats is supported by the observation that insulin substitution normalised these changes. Further support for this interpretation comes from the observation that in GK rats an increase of plasma insulin was combined with a decrease of plasma noradrenaline (norepinephrine), the most important activator of melatonin synthesis. These relationships between the noradrenergic and insulin pathway support the existence of melatonin-insulin antagonism.

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Section: Discussionmentioning

confidence: 98%

The insulin–melatonin antagonism: studies in the LEW.1AR1-iddm rat (an animal model of human type 1 diabetes mellitus)

et al. 2011

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“…The possibility has been raised that this association might be explained in part by genetic variation in the melatonin receptor 1B (MTNR1B) gene [2]. Such an effect seems plausible since (1) MTNR1B encodes a receptor for melatonin and melatonin participates in the regulation of the circadian rhythm and the pattern of sleep [2], and (2) recent studies demonstrate that genetic variation in the MTNR1B gene is associated with type 2 diabetes [3][4][5]. The gene variant could influence both sleeping problems and the risk of type 2 diabetes [2].…”

Section: Introductionmentioning

confidence: 99%

“…Such an effect seems plausible since (1) MTNR1B encodes a receptor for melatonin and melatonin participates in the regulation of the circadian rhythm and the pattern of sleep [2], and (2) recent studies demonstrate that genetic variation in the MTNR1B gene is associated with type 2 diabetes [3][4][5]. The gene variant could influence both sleeping problems and the risk of type 2 diabetes [2]. Alternatively, disturbed sleep could be a mediator of the causal pathway between this gene variant and type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

No effect by the common gene variant rs10830963 of the melatonin receptor 1B on the association between sleep disturbances and type 2 diabetes: results from the Nord-Trøndelag Health Study

et al. 2011

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Aims/hypothesis Genetic variation in the melatonin receptor 1B (MTNR1B) is associated with type 2 diabetes. Melatonin contributes to the regulation of sleep, and sleep problems are a documented risk factor for type 2 diabetes. The aim of this study was to investigate whether the MTNR1B gene variant rs10830963 is associated with sleep problems and whether this variant contributes to the association between sleep disturbances and type 2 diabetes. Methods This was a case-control study nested within the population-based Nord-Trøndelag Health Study, including 1,322 prevalent cases of type 2 diabetes and 1,447 controls. In addition, prospective data were available for 838 incident cases and 1,133 controls. Genotyping was done by TaqMan single-nucleotide polymorphism allelic discrimination analysis. ORs and 95% CIs were calculated using logistic regression models. Results Our findings confirm an association between sleep disturbances and type 2 diabetes (OR 1.69, 95% CI 1.22-2.33, p=0.0016) and between the risk allele of rs10830963 and type 2 diabetes (OR 1.12, 95% CI 1.00-1.27, p=0.0579). There was a tendency for an association between the risk allele and prevalence of sleep problems (specifically early awakening). However, the risk allele did not influence the association of sleep problems with diabetes, which was unaltered after adjustment for the MTNR1B risk allele (OR 1.69, 95% CI 1.23-2.34, p=0.0014). Results based on prospective data were similar, although non-significant. Conclusions/interpretation Our findings do not support participation of the MTNR1B gene variant rs10830963 in the well documented association between sleep disturbances and type 2 diabetes.

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“…Another gene that has recently been associated with T2DM is the melatonin receptor 1B (MTNR1B) gene which encodes for the receptor of the pineal hormone melatonin, MTNR1B, that is involved in the regulation and facilitation of sleep. Genetic variants of the MTNR1B gene, associated with gain-of-function of the MTNR1B receptor protein and a reduction in insulin secretion, have been reported in diabetic patients with abnormalities in melatonin secretion and circadian rhythm disorders of the sleep-wake cycle [63] . Another example of genetic abnormality associated with β-cell dysfunction and the risk of T2DM involves the ADRA2A gene that encodes for the alpha 2A-adrenergic receptor, which mediates the adrenergic suppression of insulin secretion [60] .…”

Section: Genes Involved In β-Cell Insulin Secretionmentioning

confidence: 99%

Recent advances in the molecular genetics of type 2 diabetes mellitus

Brunetti¹,

Chiefari²,

Foti³

2014

WJD

106

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Type 2 diabetes mellitus (T2DM) is a complex disease in which both genetic and environmental factors interact in determining impaired β-cell insulin secretion and peripheral insulin resistance. Insulin resistance in muscle, liver and fat is a prominent feature of most patients with T2DM and obesity, resulting in a reduced response of these tissues to insulin. Considerable evidence has been accumulated to indicate that heredity is a major determinant of insulin resistance and T2DM. It is believed that, among individuals destined to develop T2DM, hyperinsulinemia is the mechanism by which the pancreatic β-cell initially compensates for deteriorating peripheral insulin sensitivity, thus ensuring normal glucose tolerance. Most of these people will develop T2DM when β-cells fail to compensate. Despite the progress achieved in this field in recent years, the genetic causes of insulin resistance and T2DM remain elusive. Candidate gene association, linkage and genome-wide association studies have highlighted the role of genetic factors in the development of T2DM. Using these strategies, a large number of variants have been identified in many of these genes, most of which may influence both hepatic and peripheral insulin resistance, adipogenesis and β-cell mass and function. Recently, a new Key words: Genome-wide association study; Candidate gene; Genetic variants; High-mobility group A1; Insulin resistant diabetes Core tip: Despite the progress in clinical and laboratory investigations, the fundamental cause of type 2 diabetes mellitus (T2DM) remains uncertain. Candidate gene, linkage and genome-wide association studies have highlighted the role of genetics in the development of T2DM. Using these strategies, a large number of variants have been identified in many genes, most of which may influence an individual's risk of developing T2DM. In this review, we compile information on genetic factors that influence the risk of T2DM. In addition, we discuss the results from recent studies on the role of HMGA1 on the issue, which might be important for future breakthroughs in this field.Brunetti A, Chiefari E, Foti D. Recent advances in the molecular genetics of type 2 diabetes mellitus. World J Diabetes 2014; 5(2

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Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene

Cited by 139 publications

References 68 publications

The insulin–melatonin antagonism: studies in the LEW.1AR1-iddm rat (an animal model of human type 1 diabetes mellitus)

The insulin–melatonin antagonism: studies in the LEW.1AR1-iddm rat (an animal model of human type 1 diabetes mellitus)

No effect by the common gene variant rs10830963 of the melatonin receptor 1B on the association between sleep disturbances and type 2 diabetes: results from the Nord-Trøndelag Health Study

Recent advances in the molecular genetics of type 2 diabetes mellitus

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