Melatonin and plasma glucose level: the hypothesis of a direct action of melatonin on hepatocyte glucose metabolism

Abstract

Hyper- and hypoglycaemic effects of melatonin have been described in a variety of animals with pineal removed or given exogeneous melatonin. The mechanism by which melatonin modulates the plasma glucose level remains uncertain. Indirect action through hormones like insulin, glucagon, growth hormones or catecholamines has been suggested. Melatonin has been shown to influence plasma insulin level, pancreatic islet cell insulin secretion; modulate the liver receptor concentration of insulin and glucagon. A central site of action in the brain has also been suggested. Alternatively, melatonin may also act directly on the liver to affect glucose metabolism. We have demonstrated in isolated mouse hepatocytes a single class of high affinity 2-[125I]iodomelatonin binding sites with the pharmacological properties of ML1 receptor subclass. The binding was also inhibited by guanosine nucleotides like GTPÁS and Gpp(NH)p but not adenosine nucleotides suggesting that the action of melatonin on hepatocytes is coupled to a G-protein. Similarly, 2-[125I]iodomelatonin binding sites have also been demonstrated in the whole quail liver homogenates and purified cell nuclei of rat liver. Melatonin injection and high plasma glucose level changed 2-[125I]iodomelatonin binding in the whole mouse liver homogenates. Plasma glucose was elevated by mid-light intraperitoneal injection of melatonin (4 mg/kg and 40 mg/kg body weight) in a dose-dependent manner with maximum elevation achieved 1 h post-injection. 2-[125I]Iodomelatonin binding at this time showed increased Kd with no changes in Bmax. When the plasma glucose returned to normal in 2 h, the binding remained lowered with increased Kd but no changes in Bmax. Elevation of plasma glucose by 2-deoxyglucose injection (500 mg/kg), on the other hand, decreased the binding by decreasing the Bmax without affecting the Kd. Suppression of plasma glucose by insulin injection (3 IU/kg) did not change the binding. Thus, melatonin may act directly on the liver to elevate the plasma glucose level and changes in plasma glucose level itself may in turn affect hepatic melatonin binding.