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Kisspeptin-Activated Autophagy Independently Suppresses Non-Glucose-Stimulated Insulin Secretion from Pancreatic ?-Cells.

ABSTRACT: Previous studies have demonstrated the important role of kisspeptin in impaired glucose-stimulated insulin secretion (GSIS). In addition, it was reported that the activation of autophagy in pancreatic ?-cells decreases insulin secretion by selectively degrading insulin granules. However, it is currently unknown whether kisspeptin suppresses GSIS in ?-cells by activating autophagy. To investigate the involvement of autophagy in kisspeptin-regulated insulin secretion, we overexpressed Kiss1 in NIT-1 cells to mimic the long-term exposure of pancreatic ?-cells to kisspeptin during type 2 diabetes (T2D). Interestingly, our data showed that although kisspeptin potently decreases the intracellular proinsulin and insulin ((pro)insulin) content and insulin secretion of NIT-1 cells, autophagy inhibition using bafilomycin A1 and Atg5 siRNAs only rescues basal insulin secretion, not kisspeptin-impaired GSIS. We also generated a novel in vivo model to investigate the long-term exposure of kisspeptin by osmotic pump. The in vivo data demonstrated that kisspeptin lowers GSIS and (pro)insulin levels and also activated pancreatic autophagy in mice. Collectively, our data demonstrated that kisspeptin suppresses both GSIS and non-glucose-stimulated insulin secretion of pancreatic ?-cells, but only non-glucose-stimulated insulin secretion depends on activated autophagic degradation of (pro)insulin. Our study provides novel insights for the development of impaired insulin secretion during T2D progression.

SUBMITTER: Huang C

PROVIDER: S-EPMC6877614 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Kisspeptin-Activated Autophagy Independently Suppresses Non-Glucose-Stimulated Insulin Secretion from Pancreatic β-Cells.

Huang Chien C Wang Hao-Yi HY Wang Mu-En ME Hsu Meng-Chieh MC Wu Yi-Hsieng Samuel YS Jiang Yi-Fan YF Wu Leang-Shin LS Jong De-Shien DS Chiu Chih-Hsien CH

Scientific reports 20191125 1

Previous studies have demonstrated the important role of kisspeptin in impaired glucose-stimulated insulin secretion (GSIS). In addition, it was reported that the activation of autophagy in pancreatic β-cells decreases insulin secretion by selectively degrading insulin granules. However, it is currently unknown whether kisspeptin suppresses GSIS in β-cells by activating autophagy. To investigate the involvement of autophagy in kisspeptin-regulated insulin secretion, we overexpressed Kiss1 in NIT ...[more]

PMID: 31767891

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Project 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.

Dataset Information

Kisspeptin-Activated Autophagy Independently Suppresses Non-Glucose-Stimulated Insulin Secretion from Pancreatic ?-Cells.

Publications

Kisspeptin-Activated Autophagy Independently Suppresses Non-Glucose-Stimulated Insulin Secretion from Pancreatic β-Cells.

Similar Datasets

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