Melatonin Effects on Glucose Metabolism: Time To Unlock the Controversy

Melatonin has been investigated mostly for its role in sleep and circadian regulation. The recent discovery of MTNR1B as a novel T2D risk gene has sparked great interest in the role of melatonin in glucose control among diabetologists and basic researchers alike. Despite intensive research, there are seemingly conflicting data regarding the effects of melatonin and MTNR1B genotype on glucose control, and disagreement on whether melatonin may increase or decrease fasting glucose, glucose tolerance, and T2D risk. The concurrence of elevated melatonin concentrations with food intake in human decreases glucose tolerance, whereas high melatonin during fasting may facilitate β cell recovery. Shift workers, night eaters, and melatonin users are susceptible to the adverse effects brought about by the concurrence of food intake and high melatonin levels. The past decade has witnessed a revival of interest in the hormone melatonin, partly attributable to the discovery that genetic variation in MTNR1B – the melatonin receptor gene – is a risk factor for impaired fasting glucose and type 2 diabetes (T2D). Despite intensive investigation, there is considerable confusion and seemingly conflicting data on the metabolic effects of melatonin and MTNR1B variation, and disagreement on whether melatonin is metabolically beneficial or deleterious, a crucial issue for melatonin agonist/antagonist drug development and dosing time. We provide a conceptual framework – anchored in the dimension of 'time' – to reconcile paradoxical findings in the literature. We propose that the relative timing between elevated melatonin concentrations and glycemic challenge should be considered to better understand the mechanisms and therapeutic opportunities of melatonin signaling in glycemic health and disease. The past decade has witnessed a revival of interest in the hormone melatonin, partly attributable to the discovery that genetic variation in MTNR1B – the melatonin receptor gene – is a risk factor for impaired fasting glucose and type 2 diabetes (T2D). Despite intensive investigation, there is considerable confusion and seemingly conflicting data on the metabolic effects of melatonin and MTNR1B variation, and disagreement on whether melatonin is metabolically beneficial or deleterious, a crucial issue for melatonin agonist/antagonist drug development and dosing time. We provide a conceptual framework – anchored in the dimension of 'time' – to reconcile paradoxical findings in the literature. We propose that the relative timing between elevated melatonin concentrations and glycemic challenge should be considered to better understand the mechanisms and therapeutic opportunities of melatonin signaling in glycemic health and disease. the term originates from the Latin words circa, 'around', and dies, 'day': an endogenous biological rhythm with a period of ∼24 h that is self-sustaining and can persist independently of external environmental and behavioral influences. the ability of the body to take up glucose (sugar) from the circulation system into organs and tissues such as muscle and adipose tissue. high blood sugar. This is a major medical concern that affects people with both T1D and T2D. There are two main types: (i) fasting hyperglycemia (blood sugar >130 mg/dl after 8 h of no eating or drinking), and (ii) post-prandial hyperglycemia (blood sugar >180 mg/dl 2 h after eating). Chronic hyperglycemia can cause damage to nerves, blood vessels, and organs, which are common complications of diabetes. resistance to the effects of insulin on glucose uptake, metabolism, or storage; resistance is manifested by decreased insulin-stimulated glucose transport and metabolism in adipocytes and skeletal muscle, as well as by impaired suppression of hepatic glucose production. a natural hormone that is mainly synthesized and released into bloodstream by the pineal gland in a circadian manner: circulating concentrations are high at night but are nearly undetectable during the day in both diurnal and nocturnal mammals. It is well known as a phase marker of the timing of the central clock, for its central role in the entrainment of the circadian system, as a marker of the length of the night (for seasonal biology), and for its soporific properties. the gene encoding the high-affinity melatonin receptor 1B (also known as MT2), a member of the melatonin receptor family that is expressed in many tissues. SNPs in MTNR1B are associated with increased fasting blood glucose levels and T2D incidence according to several genome-wide association studies. a cell type in pancreatic islets that synthesizes insulin and thereby plays a dominant role in the regulation of glucose metabolism. When the blood glucose concentration increases, for example, after a meal, the β cells secrete the hormone insulin to reduce blood glucose. recovery of β cell function (i.e., insulin secretion) can be achieved by temporary suppression of insulin secretion, for example, by reducing peripheral insulin demand. This appears to confer a degree of β cell protection by replenishing insulin secretory capacity and reducing oxidative/endoplasmic reticulum (ER) stress. a work schedule that differs from the traditional 9:00 am–5:00 pm day. It can involve evening or night shifts, early morning shifts, or rotating shifts. a metabolic disorder resulting from the interaction between a genetic predisposition and behavioral and environmental risk factors. T2D is characterized by insulin resistance and subsequent progressive loss or dysfunction of pancreatic insulin-producing β cells, resulting in multiple long-term complications and organ damage.