Abstract
Type 2 diabetes mellitus (T2DM) describes a group of metabolic disorders characterized by defects in insulin secretion and insulin sensitivity. Insulin secretion from pancreatic β-cells is an important factor in the etiology of T2DM, though the complex regulation and mechanisms of insulin secretion from β-cells remains to be fully elucidated. High plasma levels of serotonin (5-hydroxytryptamine; 5-HT) have been reported in T2DM patients, though the potential effect on insulin secretion is unclear. However, it is known that the 5-HT receptor 2C (5-HT2CR) agonist, mCPP, decreases plasma insulin concentration in mice. As such, we aimed to investigate the expression of the 5-HT2CR in pancreatic islets of diabetic mice and the role of 5-HT2CR signaling in insulin secretion from pancreatic β-cells. We found that 5-HT2CR expression was significantly increased in pancreatic islets of db/db mice. Furthermore, treatment with a 5-HT2CR antagonist (SB242084) increased insulin secretion from pancreatic islets isolated from db/db mice in a dose-dependent manner, but had no effect in islets from control mice. The effect of a 5-HT2CR agonist (mCPP) and antagonist (SB242084) were further studied in isolated pancreatic islets from mice and Min-6 cells. We found that mCPP significantly inhibited insulin secretion in Min-6 cells and isolated islets in a dose-dependent manner, which could be reversed by SB242084 or RNA interference against 5-HT2CR. We also treated Min-6 cells with palmitic acid for 24 h, and found that the expression of 5-HT2CR increased in a dose-dependent manner; furthermore, the inhibition of insulin secretion in Min-6 cells induced by palmitic acid could be reversed by SB242084 or RNA interference against 5-HT2CR. Taken together, our data suggests that increased expression of 5-HT2CR in pancreatic β-cells might inhibit insulin secretion. This unique observation increases our understanding of T2DM and suggests new avenues for potential treatment.
Highlights
Type 2 diabetes mellitus (T2DM) is a chronic metabolic syndrome caused by insulin deficiency [1]
We found that SB242084 treatment could improve insulin secretion from pancreatic islets isolated from db/db mice in a dose-dependent manner (Fig. 2A), but SB242084 had no significant effect on pancreatic islets from control mice (Fig. 2B)
The results showed that RNA interference of 5-HT2CR could reverse the inhibitory effect of mCPP on insulin secretion in Min-6 cells (Fig. 6), which was in accordance with the effect of SB242084
Summary
Type 2 diabetes mellitus (T2DM) is a chronic metabolic syndrome caused by insulin deficiency [1]. In addition to blood glucose, lipids, cytokines and hormones can all affect insulin secretion, as such the mechanisms underlying the dysfunction of pancreatic b-cells in T2DM patients is complex and is far from being fully understood [2]. Recent studies have demonstrated that the nervous system can regulate insulin secretion from pancreatic b-cells through neurotransmitters and their respective receptors expressed in b-cells [5]. The cholinergic nerves [6] and the sympathoadrenal axis [7] can modulate insulin secretion from pancreatic b-cells, demonstrating that the nervous system can regulate insulin secretion directly, and in addition to indirect effects on metabolism through the regulation of food intake, body temperature, sleep and activity [8]. It has been suggested that pancreatic b-cells can secrete 5-HT by themselves, which could represent a form of autocrine regulation [12]
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