Propofol inhibits stromatoxin-1-sensitive voltage-dependent K+ channels in pancreatic β-cells and enhances insulin secretion

Munenori Kusunoki; Mikio Hayashi; Tomohiro Shoji; Takeo Uba; Hiromasa Tanaka; Chisato Sumi; Yoshiyuki Matsuo; Kiichi Hirota

doi:10.7717/peerj.8157

Propofol inhibits stromatoxin-1-sensitive voltage-dependent K⁺ channels in pancreatic β-cells and enhances insulin secretion

PeerJ. 2019 Dec 2:7:e8157. doi: 10.7717/peerj.8157. eCollection 2019.

Authors

Munenori Kusunoki^{1

2}, Mikio Hayashi³, Tomohiro Shoji^{1

2}, Takeo Uba^{1

2}, Hiromasa Tanaka², Chisato Sumi^{1

2}, Yoshiyuki Matsuo², Kiichi Hirota²

Affiliations

¹ Department of Anesthesiology, Kansai Medical University, Hirakata, Japan.
² Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University, Hirakata, Japan.
³ Department of Cell Physiology, Institute of Biomedical Science, Kansai Medical University, Hirakata, Japan.

Abstract

Background: Proper glycemic control is an important goal of critical care medicine, including perioperative patient care that can influence patients' prognosis. Insulin secretion from pancreatic β-cells is generally assumed to play a critical role in glycemic control in response to an elevated blood glucose concentration. Many animal and human studies have demonstrated that perioperative drugs, including volatile anesthetics, have an impact on glucose-stimulated insulin secretion (GSIS). However, the effects of the intravenous anesthetic propofol on glucose metabolism and insulin sensitivity are largely unknown at present.

Methods: The effect of propofol on insulin secretion under low glucose or high glucose was examined in mouse MIN6 cells, rat INS-1 cells, and mouse pancreatic β-cells/islets. Cellular oxygen or energy metabolism was measured by Extracellular Flux Analyzer. Expression of glucose transporter 2 (GLUT2), potassium channels, and insulin mRNA was assessed by qRT-PCR. Protein expression of voltage-dependent potassium channels (Kv2) was also assessed by immunoblot. Propofol's effects on potassium channels including stromatoxin-1-sensitive Kv channels and cellular oxygen and energy metabolisms were also examined.

Results: We showed that propofol, at clinically relevant doses, facilitates insulin secretion under low glucose conditions and GSIS in MIN6, INS-1 cells, and pancreatic β-cells/islets. Propofol did not affect intracellular ATP or ADP concentrations and cellular oxygen or energy metabolism. The mRNA expression of GLUT2 and channels including the voltage-dependent calcium channels Cav1.2, Kir6.2, and SUR1 subunit of K_ATP, and Kv2 were not affected by glucose or propofol. Finally, we demonstrated that propofol specifically blocks Kv currents in β-cells, resulting in insulin secretion in the presence of glucose.

Conclusions: Our data support the hypothesis that glucose induces membrane depolarization at the distal site, leading to K_ATP channel closure, and that the closure of Kv channels by propofol depolarization in β-cells enhances Ca²⁺ entry, leading to insulin secretion. Because its activity is dependent on GSIS, propofol and its derivatives are potential compounds that enhance and initiate β-cell electrical activity.

Keywords: Anesthetic; Glucose; Insulin; Kv channel; Pancreatic β-cells; Propofol; Stromatoxin-1.

Grants and funding

This work was supported by JSPS KAKENHI Grant Numbers JP26670693 and JP18K08877 to Kiichi Hirota and Grant Number JP16K10975 to Yoshiyuki Matsuo. It was also supported by a research grant B from Kansai Medical University to Chisato Sumi, a research grant from Kansai Medical University (KMU) research consortium to Kiichi Hirota, and a research grant from Katano Kai to Kiichi Hirota. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.