Elsevier

Life Sciences

Volume 88, Issues 1–2, 3 January 2011, Pages 96-103
Life Sciences

Differential effects of propofol and isoflurane on glucose utilization and insulin secretion

https://doi.org/10.1016/j.lfs.2010.10.032Get rights and content

Abstract

Aims

Volatile anesthetics, such as isoflurane, reverse glucose-induced inhibition of pancreatic adenosine triphosphate-sensitive potassium (KATP) channel activity, resulting in reduced insulin secretion and impaired glucose tolerance. No previous studies have investigated the effects of intravenous anesthetics, such as propofol, on pancreatic KATP channels. We investigated the cellular mechanisms underlying the effects of isoflurane and propofol on pancreatic KATP channels and insulin secretion.

Main methods

Intravenous glucose tolerance tests (IVGTT) were performed on male rabbits. Pancreatic islets were isolated from male rats and used for a perifusion study, measurement of intracellular ATP concentration ([ATP]i), and patch clamp experiments.

Key findings

Glucose stimulus significantly increased insulin secretion during propofol anesthesia, but not isoflurane anesthesia, in IVGTT study. In perifusion experiments, both islets exposed to propofol and control islets not exposed to anesthetic had a biphasic insulin secretory response to a high dose of glucose. However, isoflurane markedly inhibited glucose-induced insulin secretion. In a patch clamp study, the relationship between ATP concentration and channel activity could be fitted by the Hill equation with a half-maximal inhibition of 22.4, 15.8, and 218.8 μM in the absence of anesthetic, and with propofol, and isoflurane, respectively. [ATP]i and single KATP channel conductance did not differ in islets exposed to isoflurane or propofol.

Significance

Our results indicate that isoflurane, but not propofol, decreases the ATP sensitivity of KATP channels and impairs glucose-stimulated insulin release. These differential actions of isoflurane and propofol on ATP sensitivity may explain the differential effects of isoflurane and propofol on insulin release.

Introduction

It has been known since the 1970s that volatile anesthetics can impair insulin secretion and glucose utilization (Camu, 1976, Diltoer and Camu, 1988, Iwasaka et al., 1996, Kitamura et al., 2009, Saho et al., 1997, Tanaka et al., 2005, Vore et al., 2001). Pancreatic adenosine triphosphate-sensitive potassium (KATP) channels are known to play an important role in insulin secretion (Henquin, 2000). A recent in vivo rat study showed that the nonspecific KATP channel inhibitor glibenclamide was able to prevent isoflurane-induced hyperglycemia and restore insulin secretion, suggesting a role for pancreatic β-cell KATP channels in this phenomenon, while intravenous sufentanil–propofol–morphine anesthesia was not associated with hyperglycemia (Zuurbier et al., 2008).

A previous study by our group using intravenous glucose tolerance tests (IVGTT) in rabbits and patch clamp experiments showed that isoflurane-induced inhibition of insulin secretion is mediated by the isoflurane-induced opening of KATP channels in β-cells (Tanaka et al., 2009). However, the cellular mechanisms of these effects were unclear. We speculated that one of three mechanisms governs this process. First, isoflurane by itself might decrease the intracellular ATP-to-ADP ratio in pancreatic β-cells. Second, isoflurane could directly affect single KATP channel conductance. Third, isoflurane could reduce the ATP sensitivity of pancreatic KATP channels. All three could result in isoflurane-induced opening of KATP channels in β-cells. In contrast with isoflurane, the effects of propofol on KATP channels in pancreatic β-cells have not been studied.

Thus, we hypothesized that propofol, but not isoflurane, preserves the inhibition of pancreatic KATP channel activity induced by glucose. We also hypothesized that isoflurane reduces the sensitivity of glucose-induced inhibition of pancreatic KATP channel activity. To test this hypothesis, we first performed IVGTTs and a perifusion study to confirm the differential effects of isoflurane and propofol on glucose-induced insulin secretion in whole animals and in isolated islets, respectively. We next investigated whether anesthetics could influence the electrical activity of β-cells isolated from rat pancreatic islets using perforated whole-cell current-clamp recordings. The effects of anesthetics on intracellular ATP concentrations ([ATP]i), single KATP channel conductance, and ATP sensitivity in pancreatic β-cells were studied by measurement of [ATP]i and inside-out patch clamping to clarify the cellular mechanisms of glucose-induced insulin secretion in the presence of anesthetics.

Section snippets

Materials and methods

This study was approved by the Animal Investigation Committee of Tokushima University (Tokushima, Japan) and was conducted according to the animal use guidelines of the American Physiological Society (Bethesda, MD).

Hemodynamics during the IVGTT

There were no statistically significant differences in hemodynamics between groups under baseline conditions (Table 1). Administration of isoflurane significantly decreased mean arterial pressure. There was no significant change in heart rate in either group.

Glucose and insulin levels during the IVGTT

Mean plasma glucose and IRI concentrations are shown in Fig. 2, Fig. 3, respectively. Concentrations of glucose and IRI at baseline and before glucose administration were comparable across groups. After iv administration of 0.6 g/kg glucose,

Discussion

In this study, we have demonstrated that isoflurane inhibits glucose-induced enhanced insulin release in both an in vivo IVGTT study and in a pancreatic islet perifusion study, whereas propofol did not affect glucose-induced insulin secretion. These results are in agreement with previous evidence indicating that volatile anesthetics impair insulin secretion and glucose utilization (Camu, 1976, Diltoer and Camu, 1988, Iwasaka et al., 1996, Kitamura et al., 2009, Saho et al., 1997, Tanaka et al.,

Conclusions

Isoflurane, but not propofol, impaired glucose-stimulated insulin release from isolated rat pancreatic islets and in an in vivo IVGTT study. These differential effects of isoflurane and propofol on insulin release may be caused by the differential sensitivity of KATP channels in pancreatic β-cells; isoflurane decreases the ATP sensitivity of KATP channels, resulting in inhibition of glucose-stimulated KATP channel closure. In contrast, propofol has no effect on single KATP channel activity.

Conflict of interest statement

The authors have nothing to declare in any of a conflict of interest.

Acknowledgements

This work was supported in part by a Grant-in Aid for Scientific Research (C, 19591800) and (C, 22591710) from the Japan Society for the Promotion of Science, Tokyo, Japan. This study was presented at the Annual Meeting of the American Society of Anesthesiologists, San Francisco, CA, on October 17th, 2007.

References (31)

  • W.D. Gu et al.

    Modifying cardiovascular risk in diabetes mellitus

    Anesthesiology

    (2003)
  • J.C. Henquin

    Triggering and amplifying pathways of regulation of insulin secretion by glucose

    Diabetes

    (2000)
  • H. Iwasaka et al.

    Glucose intolerance during prolonged sevoflurane anaesthesia

    Canadian Journal of Anaesthesia

    (1996)
  • S. Kashyap et al.

    A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes

    Diabetes

    (2003)
  • T. Kawano et al.

    Clinically relevant concentrations of propofol have no effect on adenosine triphosphate-sensitive potassium channels in rat ventricular myocytes

    Anesthesiology

    (2002)
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