Chronomedicine and type 2 diabetes: shining some light on melatonin

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.

Central Circadian Clock Regulates Energy Metabolism

“…Suppression of melatonin secretion by pinealectomy abolished the blood glucose circadian rhythm in rats under a non-circadian scheduled feeding regimen without altering blood insulin levels (la Fleur et al, 2001b). Pinealectomy impaired glucose tolerance, which could be corrected by exogenous melatonin administration (Forrestel et al, 2017). The chronic melatonin administration was shown to improve insulin sensitivity and ameliorate obesity in some animal models (Agil et al, 2013; Nduhirabandi et al, 2011), but was also shown to cause glucose intolerance in other studies (Cagnacci et al, 2001; Rubio-Sastre et al, 2014).…”

Developmental Programming of Adult Disease: Reprogramming by Melatonin?

“…It is noteworthy that circadian disruption can increase the risk of CVD, diabetes, cancer, and metabolic syndrome [28,29]. In contrast, melatonin, a chronobiotic hormone, has been considered as a chronotherapeutic drug for these NCDs [28]. Additionally, several lines of evidence indicate that melatonin interacts with these proposed mechanisms contributing to programmed process.…”

Role of Melatonin, Galanin, and RFamide Neuropeptides QRFP26 and QRFP43 in the Neuroendocrine Control of Pancreatic β-Cell Function

“…In fact, because of its widespread production, melatonin acts in both endocrine and paracrine/autocrine manner. Furthermore, its effects have been shown in the cardiovascular and immune system, and on the regulation of metabolic functions (6–8). …”

“…Furthermore, melatonin was found to inhibit cAMP levels and insulin secretion in INS-1 832/13 β-cells, and these effects were further enhanced in β-cells overexpressing MTNR1B (22). Of note, melatonin is a prescription drug for improving sleep and for jet lag (8); therefore, it should be carefully administered in individuals with sleep disturbances, particularly in obese patients and carriers of the MNTR1B risk allele. However, administration of melatonin has been shown to improve sleep quality independently of rs10830963 genotype, despite the negative effect on insulin secretion (22).…”