Activation of Melatonin Signaling Promotes β-Cell Survival and Function

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by pancreatic islet failure due to loss of β-cell secretory function and mass. Studies have identified a link between a variance in the gene encoding melatonin (MT) receptor 2, T2DM, and impaired insulin secretion. This genetic linkage raises the question whether MT signaling plays a role in regulation of β-cell function and survival in T2DM. To address this postulate, we used INS 832/13 cells to test whether activation of MT signaling attenuates proteotoxicity-induced β-cell apoptosis and through which molecular mechanism. We also used nondiabetic and T2DM human islets to test the potential of MT signaling to attenuate deleterious effects of glucotoxicity and T2DM on β-cell function. MT signaling in β-cells (with duration designed to mimic typical nightly exposure) significantly enhanced activation of the cAMP-dependent signal transduction pathway and attenuated proteotoxicity-induced β-cell apoptosis evidenced by reduced caspase-3 cleavage (∼40%), decreased activation of stress-activated protein kinase/Jun-amino-terminal kinase (∼50%) and diminished oxidative stress response. Activation of MT signaling in human islets was shown to restore glucose-stimulated insulin secretion in islets exposed to chronic hyperglycemia as well as in T2DM islets. Our data suggest that β-cell MT signaling is important for the regulation of β-cell survival and function and implies a preventative and therapeutic potential for preservation of β-cell mass and function in T2DM.

The case for too little melatonin signalling in increased diabetes risk

“…Our data suggested that decreased melatonin signalling through deleterious MT2 receptor activity increases type 2 diabetes risk. These conclusions were in line with various studies done in rodents, beta cells and human cohorts, which showed that high melatonin levels, or the administration of melatonin or of melatonergic agonists, lead to decreased (and not augmented) risk of diabetes [9,13,14]. Indeed, for instance, a 12 year prospective study including 370 women who developed type 2 diabetes and 370 matched control participants showed that decreased levels of melatonin secretion during the night is independently associated with a higher risk of developing type 2 diabetes [13].…”

“…Therefore, in studies that aim to analyse the effect of melatonin physiologically, it is crucial to be aware that results found in nocturnal rodents can be opposite to those in diurnal humans. For instance, there are conflicting in vitro studies on the impact of melatonin on insulin secretion from rodent and human islets; in rodent beta cells melatonin was shown to decrease insulin secretion [1,8], whilst in one study of human islets, melatonin was observed to potentiate insulin secretion [9].…”

Short-term sleep deprivation with nocturnal light exposure alters time-dependent glucagon-like peptide-1 and insulin secretion in male volunteers

“…In this context, a role for melatonin in the insulin secretory response of ␤-cells to GLP-1 stimulation has been suggested. Thus, it has been shown that short-term exposure to melatonin attenuates the stimulatory effects elicited by GLP-1 in vitro, whereas more prolonged exposure times (12 h), resembling the natural overnight exposure to high melatonin levels, have been associated with enhanced sensitivity to GLP-1 stimulation (11,22). These findings support the hypothesis that ␤-cells may be more sensitive to GLP-1 effects in the morning than at the beginning of the dark period.…”

Chronomedicine and type 2 diabetes: shining some light on melatonin

“…Together, these data suggest that melatonin can have both stimulatory and inhibitory influences on insulin secretion. Notably, in vitro melatonin administration protects beta cells from the deleterious effects of glucose toxicity, improving beta cell survival, and reducing oxidative stress responses in both INS-1 832/13 rodent beta cells and isolated human islets from individuals with type 2 diabetes [115,116]. In vivo, chronic treatment with melatonin (10 mg kg −1 day −1 ) was also able to partially restore beta cell mass in a rat model of streptozotocin (STZ)-induced diabetes [117].…”

“…Evidence from animal and human studies indicates that melatonin or synthetic melatonin receptor agonists can alter glucose homeostasis [5,145,153]. The study of isolated human islets from both healthy and type 2 diabetic donors has revealed that melatonin can normalise glucose-stimulated insulin secretion following exposure to hyperglycaemia [115]. Moreover, recent randomised controlled trials suggest that chronic treatment with melatonin in combination with oral blood glucose lowering agents improves fasting and postprandial glycaemic control and reduces HbA 1c levels [152,154].…”