Melatonin inhibits insulin secretion and decreases PKA levels without interfering with glucose metabolism in rat pancreatic islets

Abstract

The effect of melatonin (0.1 microM) on freshly isolated islets from adult rats was investigated. Melatonin caused a marked decrease of insulin secretion by islets in response to glucose. The mechanism involved was then examined. Melatonin did not interfere with glucose metabolism as indicated by the measurement of glucose oxidation. However, the content of the protein kinase A (PKA) catalytic alpha-subunit was significantly decreased in islets exposed to melatonin for 1 hr in the presence of 8.3 mM glucose, whereas that of the protein kinase C (PKC) alpha-subunit remained unchanged. Melatonin also inhibited forskolin-induced insulin secretion, a well known activator of adenylate cyclase (AC) activity. This may explain the low content of insulin found in islets incubated in the presence of melatonin for 3 hr. In fact, 3',5' -cyclic adenosine monophosphate (cAMP), a product of AC activity, stimulates insulin synthesis. These findings led us to postulate that a down-regulation of the PKA signaling pathway may be the mechanism involved in the melatonin inhibition of the process of glucose-induced insulin secretion.

The insulin–melatonin antagonism: studies in the LEW.1AR1-iddm rat (an animal model of human type 1 diabetes mellitus)

“…It was confirmed that melatonin inhibits the cAMP and cGMP pathways and consequently decreases insulin release [2,8,14,15]. In addition, the effects of melatonin are mediated by G q -proteins, phospholipase C and the second messenger IP 3 , which mobilises Ca 2+ from intracellular stores, resulting in increase of insulin [12,13]. In this context, recent investigations have analysed the plasma levels of melatonin in slightly hyperinsulinaemic GotoKakizaki (GK) rats, a rat model of type 2 diabetes [16], as well as in a hypoinsulinaemic streptozotocin-induced rat model of type 1 diabetes.…”

“…tests of diurnal rhythmicity, were analysed by oneway ANOVA (a, c, e, g, i, k) and mean±SEM by Mann-Whitney U test (b, d, f, h, j, l); *p<0.05, **p<0.01, ***p<0.001 The bar below x-axes indicates light and dark phases of diurnal period. Continuous lines, control; dashed lines, diabetic; dotted lines, diabetic+insulin tance of the insulin-melatonin relationship and the effects of melatonin on the pancreatic beta cell [1,3,8], which are mediated by MT 1 [2,6] and MT 2 [9,10] receptors [8,33]. Previous studies have established that the effect of melatonin on the pancreatic beta cell is mediated by three intracellular pathways, as described in the introduction.…”

“…tion from pancreatic islets as well as from rat insulinoma beta cell line (INS1) cells via a direct effect on the beta cell, which occurs in a concentration-dependent manner [1][2][3]. It is generally accepted that, in addition to nuclear and cytosolic binding sites, melatonin exerts its biological effects through specific, high-affinity, pertussis toxinsensitive, G i protein-coupled, seven-transmembrane melatonin receptor isoforms MT 1 and MT 2 [4,5].…”

Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene

“…The inhibitory effect of melatonin on insulin release from rat islets was later confirmed [60]. Melatonin stimulates the release of glucagon from perifused human islets [55]; insulin release was also stimulated, presumably indirectly through glucagon.…”

Regulation of core clock genes in human islets

“…We could demonstrate that mRNA expression of MTNR1B in pancreatic islets was increased in carriers of the risk variant [4]. Because melatonin exerts an inhibitory effect on glucose-stimulated insulin secretion (GSIS) [4,8,9], we hypothesized that the observed impairment of insulin secretion in the examined patient cohorts was due to a gain of function of the risk allele [10].…”