Blockade of multiple monoamines receptors reduce insulin secretion from pancreatic β-cells

Abstract

Clinical use of olanzapine frequently causes severe hyperglycemia as an adverse effect. In this study, we elucidated mechanisms by which olanzapine reduced insulin secretion using the hamster pancreatic β-cell line HIT-T15. Reverse transcriptional-PCR analysis revealed expression of dopamine (D2, D3 and D4), serotonin (5-HT2A, 5-HT2B, 5-HT2C, and 5-HT6), and histamine (H1 and H2) receptors in HIT-T15 cells. Olanzapine decreased insulin secretion from HIT-T15 cells at clinically relevant concentrations (64–160 nM). A dopamine D2 agonist, D3 antagonist, and D4 antagonist suppressed insulin secretion, whereas a D2 antagonist and D3 agonist increased it. A serotonin 5-HT2B agonist slightly increased insulin secretion, while a 5-HT2C antagonist slightly decreased it. Other agonists and antagonists for serotonin receptors did not affect insulin secretion. A histamine H1 agonist increased insulin secretion, whereas an H1 antagonist and H2 agonist suppressed it. Our results suggest that dopamine (D2, D3 and D4), serotonin (5-HT2B and 5-HT2C), and histamine (H1 and H2) receptors, which are expressed on pancreatic β-cells, directly modulate insulin secretion from pancreatic β-cells. Thus, olanzapine may induce hyperglycemia in clinical settings by suppressing insulin secretion from pancreatic β-cells through inhibition of dopamine D3, serotonin 5-HT2B and 5-HT2C, and histamine H1 receptors.

Lorcaserin Inhibit Glucose-Stimulated Insulin Secretion and Calcium Influx in Murine Pancreatic Islets

“…Some research found 5-HT 2C R is expressed in pancreas and islet of mouse and human (Bonhaus et al, 1995;Zhang et al, 2013;Nagata et al, 2019), although the precise expression is still controversial (Bennet et al, 2015;Bennet et al, 2016). Since previous results in our laboratory showed that 5-HT 2C R was expressed in mouse islets and MIN6 by Western blot and qPCR (Zhang et al, 2013).…”

“…5-HT receptors include seven distinct families (at least 14 different receptors) and virtually all 5-HT receptors are G protein-coupled with the exception of 5-HT3 receptors (Wyler et al, 2017). Almost all 5-HT receptors in human islets (Amisten et al, 2013;Bennet et al, 2015) and in rodent islets (Ohara-Imaizumi et al, 2013;Bennet et al, 2016;Nagata et al, 2019) were found and activating of different 5-HT receptors also has contradictory effect on GSIS of pancreatic β cells (Zhang et al, 2013;Bennet et al, 2015;Kim et al, 2015;Bennet et al, 2016). Previous research in our laboratory found that activating of 5-HT 2C R on β cells by mCPP inhibited GSIS of mouse islets and MIN6 cells, which indicated that activation of 5-HT 2C R leaded to dysfunction of insulin secretion (Zhang et al, 2013).…”

“…5-HT 2C R knockout mice in hypothalamus produces insulin resistance and type 2 diabetes, with hyperphagia, obesity, hyperinsulinemia, and impaired glucose tolerance (Zhou et al, 2007;Xu et al, 2008;Xu et al, 2010), where 5-HT 2C R agonists are effective in improving glucose tolerance and hyperinsulinemia in murine models of obesity and insulin resistance (Zhou et al, 2007;Higgins et al, 2015;Burke et al, 2017), suggesting that 5-HT 2C R is involved in improving insulin sensitivity and hyperinsulinemia. The expression of 5-HT 2C R was also detected in the pancreas, isolated islets and pancreatic β-cell line (Bonhaus et al, 1995;Zhang et al, 2013;Nagata et al, 2019) and was increased in the islets of db/db mouse, an animal model for type 2 diabetes (Zhang et al, 2013). 5-HT is synthesized and co-secreted along with insulin in pancreatic β cells, potentially acting as a local autocrine/paracrine signal on insulin secretion (Ohta et al, 2011) and Interferes with the synthesis of 5-HT synthesis in beta cells impairs insulin secretion (Kim et al, 2015).…”

P2Y1 purinergic receptor identified as a diabetes target in a small-molecule screen to reverse circadian β-cell failure

“…Of these, four target ion channels (tacrine hydrochloride, suloctidil, dyclonine hydrochloride, and IVM) ( Figure 2B and C ; Karlsson and Ahrén, 1992 ; Chatelain et al, 1984 ; Khanna et al, 2011 ; Chen and Kubo, 2018 ; Freeman et al, 1988 ; de Gaetano et al, 1976 ; Kornhuber et al, 2008 ; Sahdeo et al, 2014 ; Roghani et al, 1999 ; Ikeda, 2003 ). Five target seven-transmembrane G-protein coupled receptors (GPCRs) that signal through phospholipase C (PLC) and diacylglycerol (DAG) to activate insulin secretion and β-cell gene transcription (benzalkonium chloride, carbachol, isoetharine mesylate, pipamperone, and IVM) ( Figure 2B and C ; Chen and Kubo, 2018 ; Higashijima et al, 1990 ; Rinne et al, 2015 ; Bierman, 1983 ; Van Craenenbroeck et al, 2006 ; Nagata et al, 2019 ; Ratajewski et al, 2015 ; Ohtani et al, 2011 ). Similar to the hit compounds of our screen, our previous results showed that carbachol, a muscarinic G q -coupled receptor agonist, and the DAG mimetic PMA rescue insulin secretion in Bmal1 -/- islets ( Perelis et al, 2015 ).…”

Pharmacologic rescue of circadian β-cell failure through P2Y1 purinergic receptor identified by small-molecule screen

“…Five target seven-transmembrane G-protein coupled receptors (GPCRs) that signal through phospholipase C (PLC) and diacylglycerol (DAG) to activate insulin secretion and β-cell gene transcription (benzalkonium chloride, carbachol, isoetharine mesylate, pipamperone, and ivermectin) ( Figs 2B-C) (17,(24)(25)(26)(27)(28)(29)(30). Similar to the hit compounds of our screen, our previous results showed that carbachol, a muscarinic Gq-coupled receptor agonist, and the DAG mimetic PMA rescue insulin secretion in Bmal1 -/islets (10).…”