Modulating insulin secretion and inflammation against sodium arsenite toxicity by levosimendan as a novel pancreatic islets’ protector

Abstract

Levosimendan (LEVO) is a calcium sensitizer with established inotropic and vasodilator impacts associated with ATP-sensitive potassium channels (K_ATP). Although LEVO’s role in modulating oxidative stress of cardiac cells has been studied, in the current study, LEVO was used, for the first time, to investigate its preventive and therapeutic roles in pancreatic islets through viability, functionality, and inflammation pathways as well as oxidative stress against the toxicity induced by sodium arsenite (NaAsO₂). Following the optimization studies to select the proper concentrations of LEVO and NaAsO₂, isolated pancreatic islets were exposed to different combinations of NaAsO₂ and LEVO. MTT assay, glucose-dependent insulin secretion test, investigation of oxidative stress and inflammation biomarkers in addition to qualification of the expressions of P16, P38, and NF-κB genes were performed to assess different underlying mechanisms to investigate the protective role of LEVO against NaAsO₂-induced toxicity. This study demonstrated that NaAsO₂-treated pancreatic islets’ exposure to LEVO improved their viability and functionality while modulating the generation of oxidative stress and inflammatory biomarkers. Therefore LEVO caused significant recoveries in the characteristics of the islets. The main conclusion is that LEVO showed protective impacts in pancreatic islets against exposure to NaAsO₂. However, therapeutic uses of LEVO in the field of diabetes need further investigations.

HIGHLIGHTS

• Sodium arsenite is responsible for activating the oxidative stress and inflammation pathways in pancreatic islet cells and consequently decreasing their viability and function.

• Treatment of pancreatic islets with sodium arsenite results in the loss of glucose-dependent insulin secretion (GDIS) which can be alleviated by levosimendan.

• Levosimendan modulates the decreased level of secreted insulin by preventing formation of reactive oxygen species (ROS) and inactivating the inflammatory biomarkers.

• Levosimendan improves the viability and function of sodium arsenite-treated pancreatic islets by modulating insulin secretion and glucose control.

• Levosimendan acts as a protective agent against the toxicity induced by sodium arsenite in pancreatic islets through modulating the viability, oxidative stress, inflammation, and function pathways.

Graphical Abstract

Keywords:

• Diabetes
• levosimendan
• pancreatic islets
• sodium arsenite
• toxicity

Acknowledgements

We would like to thank The Institute of Pharmaceutical Sciences (TIPS) at Tehran University of Medical Sciences (TUMS) for the technical support. Authors are thankful of the INSF for Seat General Award to the MA for conducting modern researches in the field of Toxicology and Oxidative Stress.

Disclosure statement

No potential conflict of interest was reported by the author(s).

CRediT author statement

Marzieh Daniali: Conceptualization, Methodology, Formal analysis, Investigation, Resources, Writing-Original Draft Mona Navaei-Nigjeh: Conceptualization, Formal analysis, Writing-Review & Editing, Supervision Soheyl Mirzababaei: Writing-Review & Editing Maryam Baeeri: Methodology, Formal analysis Mahdi Gholami: Investigation Mahban Rahimifard: Methodology Mohammad Abdollahi: Conceptualization, Writing-Review & Editing, Supervision.

Additional information

Funding

This work was supported by the Tehran University of Medical Sciences under grant number 9411266022.