Lorcaserin Inhibit Glucose-Stimulated Insulin Secretion and Calcium Influx in Murine Pancreatic Islets
Lorcaserin is a serotonergic agonist specific to the 5-hydroxytryptamine 2c receptor (5-HT2CR) that is FDA approved for the long-term management of obesity with or without at least one weight-related comorbidity. Lorcaserin can restrain patients’ appetite and improve insulin sensitivity and hyperins...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:adfc739abd40432680c62a204c56bcf92021-11-05T07:57:56ZLorcaserin Inhibit Glucose-Stimulated Insulin Secretion and Calcium Influx in Murine Pancreatic Islets1663-981210.3389/fphar.2021.761966https://doaj.org/article/adfc739abd40432680c62a204c56bcf92021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.761966/fullhttps://doaj.org/toc/1663-9812Lorcaserin is a serotonergic agonist specific to the 5-hydroxytryptamine 2c receptor (5-HT2CR) that is FDA approved for the long-term management of obesity with or without at least one weight-related comorbidity. Lorcaserin can restrain patients’ appetite and improve insulin sensitivity and hyperinsulinemia mainly through activating 5-HT2CR in the hypothalamus. It is known that the mCPP, a kind of 5-HT2CR agonist, decreases plasma insulin concentration in mice and previous research in our laboratory found that mCPP inhibited glucose-stimulated insulin secretion (GSIS) by activating 5-HT2CR on the β cells. However, the effect of lorcaserin on GSIS of pancreatic β cell has not been studied so far. The present study found that 5-HT2CR was expressed in both mouse pancreatic β cells and β-cell–derived MIN6 cells. Dose-dependent activation of 5-HT2CR by lorcaserin suppressed GSIS and SB242084 or knockdown of 5-HT2CR abolished lorcaserin’s effect in vitro. Additionally, lorcaserin also suppressed GSIS in high-fat diet (HFD)-fed mice in dose-dependent manner. Lorcaserin did not change insulin synthesis ATP content, but lorcaserin decrease cytosolic free calcium level [(Ca2+)i] in MIN6 cells stimulated with glucose and also inhibit insulin secretion and (Ca2+)i in MIN6 treated with potassium chloride. Furthermore, stimulation with the L-type channel agonist, Bay K8644 did not restore GSIS in MIN6 exposed to lorcaserin. Lorcaserin inhibits the cAMP generation of MIN6 cells and pretreatment with the Gα i/o inhibitor pertussis toxin (PTX), abolished lorcaserin-induced suppression of GSIS in β cells, while membrane-permeable cAMP analogue db-cAMP had same effect as PTX. These date indicated lorcaserin coupled to PTX-sensitive Gα i/o proteins in β cells reduced intracellular cAMP level and Ca2+ influx, thereby causing GSIS dysfunction of β cell. These results highlight a novel signaling mechanism of lorcaserin and provide valuable insights into the further investigation of 5-HT2CR functions in β-cell biology and it also provides guidance for the clinical application of lorcaserin.Muhan JingShanshan WangDing LiZeyu WangZiwen LiYichen LuTong SunTong SunChen QiuFang ChenFang ChenHaijuan YuWei ZhangWei ZhangFrontiers Media S.A.articlelorcaseringlucose-stimulated insulin secretionbeta cell5-HT 2C Robesitytype 2 diabetes mellitusTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021) |
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| collection |
DOAJ |
| language |
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| topic |
lorcaserin glucose-stimulated insulin secretion beta cell 5-HT 2C R obesity type 2 diabetes mellitus Therapeutics. Pharmacology RM1-950 |
| spellingShingle |
lorcaserin glucose-stimulated insulin secretion beta cell 5-HT 2C R obesity type 2 diabetes mellitus Therapeutics. Pharmacology RM1-950 Muhan Jing Shanshan Wang Ding Li Zeyu Wang Ziwen Li Yichen Lu Tong Sun Tong Sun Chen Qiu Fang Chen Fang Chen Haijuan Yu Wei Zhang Wei Zhang Lorcaserin Inhibit Glucose-Stimulated Insulin Secretion and Calcium Influx in Murine Pancreatic Islets |
| description |
Lorcaserin is a serotonergic agonist specific to the 5-hydroxytryptamine 2c receptor (5-HT2CR) that is FDA approved for the long-term management of obesity with or without at least one weight-related comorbidity. Lorcaserin can restrain patients’ appetite and improve insulin sensitivity and hyperinsulinemia mainly through activating 5-HT2CR in the hypothalamus. It is known that the mCPP, a kind of 5-HT2CR agonist, decreases plasma insulin concentration in mice and previous research in our laboratory found that mCPP inhibited glucose-stimulated insulin secretion (GSIS) by activating 5-HT2CR on the β cells. However, the effect of lorcaserin on GSIS of pancreatic β cell has not been studied so far. The present study found that 5-HT2CR was expressed in both mouse pancreatic β cells and β-cell–derived MIN6 cells. Dose-dependent activation of 5-HT2CR by lorcaserin suppressed GSIS and SB242084 or knockdown of 5-HT2CR abolished lorcaserin’s effect in vitro. Additionally, lorcaserin also suppressed GSIS in high-fat diet (HFD)-fed mice in dose-dependent manner. Lorcaserin did not change insulin synthesis ATP content, but lorcaserin decrease cytosolic free calcium level [(Ca2+)i] in MIN6 cells stimulated with glucose and also inhibit insulin secretion and (Ca2+)i in MIN6 treated with potassium chloride. Furthermore, stimulation with the L-type channel agonist, Bay K8644 did not restore GSIS in MIN6 exposed to lorcaserin. Lorcaserin inhibits the cAMP generation of MIN6 cells and pretreatment with the Gα i/o inhibitor pertussis toxin (PTX), abolished lorcaserin-induced suppression of GSIS in β cells, while membrane-permeable cAMP analogue db-cAMP had same effect as PTX. These date indicated lorcaserin coupled to PTX-sensitive Gα i/o proteins in β cells reduced intracellular cAMP level and Ca2+ influx, thereby causing GSIS dysfunction of β cell. These results highlight a novel signaling mechanism of lorcaserin and provide valuable insights into the further investigation of 5-HT2CR functions in β-cell biology and it also provides guidance for the clinical application of lorcaserin. |
| format |
article |
| author |
Muhan Jing Shanshan Wang Ding Li Zeyu Wang Ziwen Li Yichen Lu Tong Sun Tong Sun Chen Qiu Fang Chen Fang Chen Haijuan Yu Wei Zhang Wei Zhang |
| author_facet |
Muhan Jing Shanshan Wang Ding Li Zeyu Wang Ziwen Li Yichen Lu Tong Sun Tong Sun Chen Qiu Fang Chen Fang Chen Haijuan Yu Wei Zhang Wei Zhang |
| author_sort |
Muhan Jing |
| title |
Lorcaserin Inhibit Glucose-Stimulated Insulin Secretion and Calcium Influx in Murine Pancreatic Islets |
| title_short |
Lorcaserin Inhibit Glucose-Stimulated Insulin Secretion and Calcium Influx in Murine Pancreatic Islets |
| title_full |
Lorcaserin Inhibit Glucose-Stimulated Insulin Secretion and Calcium Influx in Murine Pancreatic Islets |
| title_fullStr |
Lorcaserin Inhibit Glucose-Stimulated Insulin Secretion and Calcium Influx in Murine Pancreatic Islets |
| title_full_unstemmed |
Lorcaserin Inhibit Glucose-Stimulated Insulin Secretion and Calcium Influx in Murine Pancreatic Islets |
| title_sort |
lorcaserin inhibit glucose-stimulated insulin secretion and calcium influx in murine pancreatic islets |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/adfc739abd40432680c62a204c56bcf9 |
| work_keys_str_mv |
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| _version_ |
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