Experimental and clinical aspects of melatonin and clock genes in diabetes

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 b-cells, a-cells as well as d-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 b-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 b-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 insulinmelatonin 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 b-cells ag...

Chronomedicine and type 2 diabetes: shining some light on melatonin

“…We face a paradox here since melatonin can acutely decrease insulin secretion and enhance glucagon release [48,49,151] but preliminary clinical data suggest that chronic melatonin treatment improves glycaemic control and reduces HbA 1c in diabetic patients [152,154], the implication being that normalisation of circadian glucose homeostasis by chronically administered melatonin could outweigh the acute effects of melatonin. Because much of the data showing a positive effect of melatonin is pre-clinical and generated using nocturnal rodents that were administered exceedingly high concentrations of melatonin at a time of heightened food intake, it is difficult to draw solid conclusions regarding its potential efficacy in a clinical setting.…”

“…The pros and cons of melatonin therapy for glycaemic control in humans With regard to treatment of type 2 diabetes with melatonin, the number of controlled clinical trials is somewhat limited, and the results are often mixed, with both positive and negative effects on glycaemic control being reported [27,145,151,152]. Evidence from animal and human studies indicates that melatonin or synthetic melatonin receptor agonists can alter glucose homeostasis [5,145,153].…”

Salivary melatonin levels and sleep-wake rhythms in pregnant women with hypertensive and glucose metabolic disorders: A prospective analysis

“…There are also melatonin receptors present in the beta cells of the pancreas. MT2 receptors in beta cells of the pancreas are involved in insulin secretion adjustment as they block cyclic adenosine monophosphate (cAMP), an important metabolism signal that controls insulin secretion, and induce the formation of cyclic guanosine monophosphate (cGMP) (28).…”

The role of melatonin in development of gestational diabetes mellitus

“…В ткани поджелудоч-ной железы выявлены мембранные МТ1, МТ2 и G-протеинсвязанные (GPR50) рецепторы, а также мРНк ядерных рецепторов, через ко-торые мелатонин осуществляет модулирующее влияние на секрецию инсулина и глюкагона [46][47][48]. кроме того, в поджелудочной железе, так же как и в других тканях, имеются автоном-ные циркадные гены (Bmal, Clock, Per1, Cry1), через которые реализуется синхронизирующее влияние циркадного ритма эпифизарного мела-тонина на β-и α-клетки [49]. В ночное время су-ток наблюдается высокая продукция мелатони-на, но низкая секреция инсулина, а днем наобо-рот [31,50].…”

“…В ночное время су-ток наблюдается высокая продукция мелатони-на, но низкая секреция инсулина, а днем наобо-рот [31,50]. Мелатонин стимулирует секрецию глюкагона α-клетками поджелудочной железы, что определяет циркадный ритм продукции и метаболизма глюкозы [49,51]. Влияние мела-тонина на панкреатические α-и β-клетки и на секрецию инсулина обеспечивается комплек-сом различных типов межклеточных и внутри-клеточных сигнальных путей [52].…”