Inhibition of glucagon release by serotonin in mouse pancreatic islets

Abstract

Summary. In this work we have investigated the effect of serotonin on glucagon release in mouse pancreatic islets isolated by the collagenase technique.Incubation of the islets with serotonin (4 • 10-3mol/1) was associated with an inhibition of glucagon output both in the basal medium (3.3 mmol/l glucose) and in the presence of arginine (10 mmol/1). The inhibitory effect of serotonin on basal glucagon release was also apparent at concentrations of 2 • 10 -3 mol/l, 10 -3 tool/1 and 5 • 10 -4 mol/1. Addition of 5-hydroxytryptophan (4 • 10 -3 tool/l) to the incubation medium was without effect on basal glucagon output while it significantly reduced arginine-induced glucagon release. In contrast, tryptophan (4 X 10 -3 mol/l) provoked glucagon secretion. As inferred from our previous human studies, the present data indicate that serotonin is able to inhibit glucagon secretion. These findings provide further support for the participation of a serotoninergic mechanism in the control of A-cell function.Key words: Mouse pancreatic islets, glucagon, insulin, serotonin, 5-hydroxytryptophan, tryptophan, creatinine sulphate.In man, treatment with serotonin antagonists (cyproheptadine and methysergide) as well as with an inhibitor of serotonin synthesis (para-chlorophenylalanine) induces a potentiation of glucagon secretion. Because of these findings, we have suggested that serotonin modulates A-cell function by acting as an inhibitor [1]. To investigate this hypothesis further, in this work we have examined the effects of serotonin and its immediate precursor (5-hydroxytryptophan) on glucagon release in a preparation of isolated mouse pancreatic islets. In addition, insulin output was measured. Materials and MethodsThe preparation of pancreatic islets employed has been described in detail elsewhere [2]. Briefly, fourweek old male mice, fasted for 14 h, were used as pancreas donors. The islets were isolated by the collagenase technique [3], as modified by . Batches of 10 islets were incubated for 60 to 120 minutes in 2 ml of Krebs-Henseleit solution [5] (gas phase 95:5, CO2:O2), containing 0.2 g/100 ml bovine albumin (Cohn fraction V), 2000U of kallikrein-trypsin inhibitor (Trasylol), and 3.3 mmol/1 glucose. Conventionally, this solution will be referred to as "basal medium" throughout the text. In some experiments, arginine hydrochloride (10 mmol/1) was used as the glucagon secretagogue. Serotonin creatinine sulphate, 5-hydroxy-L-tryptophan, L-tryptophan and creatinine sulphate were added as described in the figures and text. All incubations were performed in a water bath at 37 ~ set at 60 strokes per minute.Glucagon and insulin were measured by radioimmunoassay [6,7]. Results are expressed as means + SEM. N indicates the number of independent experiments. The term experiment refers to a set of incubations performed at the same time with islets prepared from a pool of eight pancreases. Within each experiment, all factors were tested simultaneously employing from 6 to 10 incubation vials. Differences betwen values were tested...

Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells

“…Serotonin was proposed as a paracrine signal in the pancreatic islet over 40 years ago (Lundquist et al, 1971; Marco et al, 1977; Pontiroli et al, 1978). Serotonin is co-released with insulin (Ekholm et al, 1971; Jaim-Etcheverry and Zieher, 1968; Richmond et al, 1996).…”

“…Serotonin also promotes insulin granule exocytosis in a receptor-independent manner through serotonylation of small GTPases of Rab family (Paulmann et al, 2009). Numerous studies have thus established serotonin as an autocrine signal increasing beta cell function and mass during insulin resistant states, but only few have examined the impact of serotonin on other islet endocrine cells such as the glucagon secreting alpha cell (Bennet et al, 2015; Marco et al, 1977; Pontiroli et al, 1978). …”

Gastric Inhibitory Polypeptide and Insulin Secretion after Infusion of Acetylcholine, Catecholamines, and Gut Hormones

“…Except for PP, each hormone that we studied has been reported to modify the secretion of insulin in intact subjects (3, 4, 15-19, 30); most of these hormones also affect insulin secretion in vitro (3, 4, 16, [31][32][33]. Part of their in vivo action conceivably could result from their effect on GIP secretion, but we found that none of them, when infused alone, changed fasting levels of GIP.…”

Effect of Tianeptine on Glucose Tolerance with Insulin Secretion in Human: Potential Anti-Diabetic Effect of the Drug

“…This phenomenon should be associated with other findings showing that adrenalectomy is able to interfere with the glucagon induced plasma glucose rises provoked by intravenous administration of 5-HT [35]. Finally, the fact that methysergide, a 5-HT antagonist, can prevent the glucagon effects, affords additional support to the postulation that serotonin was the responsible factor for the above phenomenon by acting at the islet cells directly [28,36].…”

“…It is incorporated into the insulin granules of the former [22,23], at which level exerts a modulatory effect [24][25][26][27]. Conversely, 5-HT facilitates the secretion of glucagon from the alpha cells into the blood stream [21,[28][29][30]. Both serotonin and glucagon trigger the secretion of Ad from the adrenal glands and they excite hepatic glucogenolysis which counteract the hypoglycemic effect of the insulin released from beta cells.…”