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Anesthetic Pharmacology: Research Report

Glucose Use in Fasted Rats Under Sevoflurane Anesthesia and Propofol Anesthesia

Sato, Kanako MD; Kitamura, Takayuki MD; Kawamura, Gaku MD; Mori, Yoshiteru MD; Sato, Rui MD; Araki, Yuko MD; Yamada, Yoshitsugu MD, PhD

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doi: 10.1213/ANE.0b013e31829e4028
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Several clinical studies1–3 suggested that hyperglycemia during surgery increases the incidence of complications during the postoperative period. Both decreased glucose use and increased glucose production, which are associated with endocrine–metabolic responses to surgical stress, contribute to stress-induced hyperglycemia.4,5 We previously reported that sevoflurane anesthesia significantly decreases glucose use in fed rats, whereas propofol anesthesia produces no significant effects on glucose use6; however, we cannot simply extrapolate these findings to clinical practices, because most patients are required to fast before surgery and energy demand/supply imbalance related to fasting alters glucose metabolism. Both attenuation in insulin secretion and impairment of insulin sensitivity can be causative of the decreased glucose use related to surgical stress. Volatile anesthetics attenuate insulin secretion7–10; however, the effects of propofol on insulin secretion have not been elucidated. It was reported that tumor necrosis factor-α (TNF-α) and high molecular weight adiponectin (HMW adiponectin) modulate insulin sensitivity11–15; however, the effects of general anesthesia on secretion of TNF-α and HMW adiponectin have not been elucidated. Here, we examined glucose metabolism during the IV glucose tolerance test (IVGTT) under sevoflurane anesthesia and propofol anesthesia in fasted rats, focusing on insulin secretion and insulin sensitivity. Adenosine triphosphate-sensitive potassium channels (KATP channels) in β-islet cells play an important role in insulin secretion16; thus, parts of rats were pretreated with either glibenclamide (a KATP-channel inhibitor) or diazoxide (a KATP-channel opener) to elucidate the mechanisms underlying insulin secretion under sevoflurane or propofol anesthesia in this study. Furthermore, we measured TNF-α and HMW adiponectin levels in plasma to elucidate the involvement of these adipocytokines in insulin sensitivity under sevoflurane or propofol anesthesia.

METHODS

Experimental Protocols

The animal care committee of our institute approved the experimental protocols in this study. We purchased 8-week-old male Wistar rats (Nippon Bio-Supply Center, Tokyo, Japan). Rats were housed in a regulated environment for 2 weeks; room temperature was maintained at 25°C, a 12-hour light–dark cycle (7:00 AM and 7:00 PM) was used, and rats were allowed free access to a standard diet containing 24% protein, 5% fat, 6% ash, 3% fiber, 8% water, and 54% nitrogen-free extract (Oriental Yeast Co., Ltd., Tokyo, Japan) and water. On the day of the experiments, all rats were aged 10 weeks. Each rat was made to fast for 15 hours before the experiment; however, each rat was allowed free access to water until the experiment began. We performed the experiments between 9:00 AM and 3:00 PM. For the prevention of hypothermia during the experiments, we used a heat lamp and a heating pad for the rats.

Rats were assigned to 3 groups: awake rats subjected to IVGTT (group A, n = 8), rats subjected to IVGTT under sevoflurane anesthesia (group S, n = 23), and rats subjected to IVGTT under propofol anesthesia (group P, n = 23). Anesthesia for surgical preparation was induced with sevoflurane (Maruishi Pharmaceutical Co., Ltd., Osaka, Japan) in all rats. Rats in group A underwent surgical preparation under spontaneous breathing; anesthesia was maintained with sevoflurane (2.5% in 1 L/min oxygen via a face mask). Rats in groups S and P underwent tracheotomy. After tracheal intubation, sevoflurane (2.5% in 1 L/min oxygen) was administered via a tracheal tube, and the lungs were mechanically ventilated. A 19-gauge catheter was inserted into the right jugular vein, and another 19-gauge catheter was inserted into the right carotid artery. In group A, the catheters were tunneled subcutaneously and externalized at the back of the neck. After surgical preparation, we administered IV 100 IU heparin to each rat for maintenance of the patency of the catheters. Rats in group A were allowed to recover from anesthesia by discontinuing sevoflurane administration, and physiological saline was administered IV with a bolus dose of 4 mL/kg followed by continuous infusion at a rate of 10 mL·kg−1·h−1. In group S, sevoflurane administration (2.5% in 1 L/min oxygen) was continued, and physiological saline was administered IV with a bolus dose of 4 mL/kg followed by continuous infusion at a rate of 10 mL·kg−1·h−1. In group P, sevoflurane administration was discontinued, but a lipid-based formulation of propofol with a concentration of 10 mg/mL (AstraZeneca K. K., Osaka, Japan) was administered IV with a bolus dose of 4 mL/kg followed by continuous infusion at a rate of 4 mL·kg−1·h−1, and physiological saline was administered IV at a rate of 6 mL·kg−1·h−1. The doses of sevoflurane and propofol were selected according to the protocol of our previous study.6

Thirty minutes after surgical preparation (T-0), we sampled 1 mL arterial blood. Then, 0.5 g/kg glucose was administered IV, and we sampled 1 mL arterial blood at 5 and 15 minutes after glucose administration (T-5 and T-15, respectively).6 We used a sterile glucose solution with a concentration of 0.5 g/mL (Otsuka Pharmaceutical Factory, Inc., Tokushima, Japan). Rats in groups S and P were divided into 3 subgroups. Just before glucose administration, rats in groups S[-] (n = 8) and P[-] (n = 8) received no pretreatment, rats in groups S[g] (n = 8) and P[g] (n = 7) were pretreated with 1 mg/kg glibenclamide17 (Sigma-Aldrich Japan, Tokyo, Japan), and rats in groups S[d] (n = 7) and P[d] (n = 8) were pretreated with 5 mg/kg diazoxide (Sigma-Aldrich Japan). Initially, we administered 10 mg/kg diazoxide17 to a few rats under general anesthesia. Immediately after the administration, most rats died. We, thus, pretreated rats with 5 mg/kg diazoxide. Glibenclamide and diazoxide were dissolved in dimethyl sulfoxide (Sigma-Aldrich Japan) to a concentration of 3 and 15 mg/mL, respectively.

Glucose, Insulin, TNF-α, and HMW Adiponectin Levels

Immediately after blood sampling, blood glucose levels were measured using Medisafe (Terumo, Tokyo, Japan). Each blood sample was spun in a prerefrigerated centrifuge (4°C) at 1000g for 15 minutes. We divided plasma into 3 equal aliquots and stored them at −60°C until analyses. Plasma insulin, TNF-α, and HMW adiponectin levels were measured by the enzyme-linked immunosorbent assay using AKRIN-010T, AKRTN-010, and AKMAN-011 (Shibayagi Co., Ltd., Gunma, Japan), respectively. Initially, we examined the influence of propofol, lipid emulsion containing 10% w/v of soybean oil, 1.2% w/v of lecithin, and 2.25% w/v of glycerin (Intralipid fluid solution 10%; Fresenius Kabi Japan, Tokyo, Japan), and dimethyl sulfoxide on the assay; propofol at a concentration of 100 μg/mL or less, lipid emulsion at a concentration of 1% v/v or less, and dimethyl sulfoxide at a concentration of 1% v/v or less did not influence the assay.

Insulin Sensitivity

We calculated the quantitative insulin sensitivity check index18 (QUICKI) in each rat: QUICKI = 1/(log [blood glucose level at T-0 {µIU/mL}] + log [plasma insulin level at T-0 {mg/dL}]).

Statistical Analysis

Parametric data are shown as means ± SD. For overall comparisons of serial data within each group, we used 1-way repeated-measures analysis of variance (ANOVA). For overall comparisons of serial data among the 3 groups, we used 2-way repeated-measures ANOVA: a between-subject factor was group and a within-subject factor was time. We used Mauchly test to check the sphericity condition; statistical significance was set at P < 0.01. When the sphericity condition was met, statistical significance was set at P < 0.01 for repeated-measures ANOVA. When the sphericity condition was not met, we applied Greenhouse-Geisser correction to account for the within-subject correlation; statistical significance was set at adjusted P < 0.01 for repeated-measures ANOVA. We used 1-way ANOVA for comparisons of parametric data at each time point among the 3 groups; statistical significance was set at P < 0.01. When a significant difference was noted, Scheffé F test was applied for multiple comparisons; statistical significance was set at adjusted P < 0.01.

TNF-α levels are shown as median [25th, 75th percentiles]. We used Kruskal-Wallis test for comparisons of nonparametric data at each time point among the 3 groups; statistical significance was set at P < 0.01. When a significant difference was noted, Steel-Dwass test was applied for multiple comparisons; statistical significance was set at adjusted P < 0.01. Statistical analyses were performed using StatView 5.0 (SAS Institute, Cary, NC) and JMP Pro 9.0.2. (SAS Institute).

RESULTS

Glucose and Insulin Levels in Groups A, S[-], and P[-]

Table 1 shows the time course of glucose and insulin levels during IVGTT in groups A, S[-], and P[-]. Glucose levels significantly changed during IVGTT in groups A, S[-], and P[-] (P < 0.0001, P < 0.0001, and P < 0.0001, respectively, 1-way repeated-measures ANOVA). Two-way repeated-measures ANOVA with group as a between-subject factor and time as a within-subject factor for comparisons of time course of glucose levels during IVGTT among groups A, S[-], and P[-] detected a significant effect of group (P < 0.0001), a significant effect of time (P < 0.0001), and a significant interaction effect of group and time (P < 0.0001). There were significant differences in glucose levels at T-0 among groups A, S[-], and P[-] (P = 0.0009, 1-way ANOVA); however, glucose levels in groups S[-] and P[-] were not significantly different from those in group A (adjusted P = 0.5474 and P = 0.0154, respectively, Scheffé F test). There were also significant differences in glucose levels at T-5 and T-15 among groups A, S[-], and P[-] (P = 0.0004 and P < 0.0001, respectively, 1-way ANOVA); group S[-] showed significantly higher glucose levels than group A at T-5 and T-15 (adjusted P = 0.0011 and P < 0.0001, respectively, Scheffé F test), while glucose levels at T-5 and T-15 in group P[-] were not significantly different from those in group A (adjusted P = 0.8529 and P = 0.8202, respectively, Scheffé F test).

Table 1
Table 1:
Glucose and Insulin Levels During the IV Glucose Tolerance Test in Groups A, S[-], and P[-]

Insulin levels significantly changed during IVGTT in groups A and S[-] (P = 0.0013 and P = 0.0006, respectively, 1-way repeated-measures ANOVA) but not in group P[-] (adjusted P = 0.0107, 1-way repeated-measures ANOVA). Two-way repeated-measures ANOVA with group as a between-subject factor and time as a within-subject factor for comparisons of time course of insulin levels during IVGTT among groups A, S[-], and P[-] detected a significant effect of group (P < 0.0001), a significant effect of time (adjusted P < 0.0001), and a significant interaction effect of group and time (adjusted P < 0.0001). There were significant differences in insulin levels at T-0, T-5, and T-15 among groups A, S[-], and P[-] (P < 0.0001, P < 0.0001, and P < 0.0001, respectively, 1-way ANOVA); insulin levels at T-0, T-5, and T-15 in group S[-] were not significantly different from those in group A (adjusted P = 0.7590, P = 0.9803, and = 0.9993, respectively, Scheffé F test), while group P[-] showed significantly higher insulin levels than group A at T-0, T-5, and T-15 (adjusted P < 0.0001, P < 0.0001, and P < 0.0001, respectively, Scheffé F test).

QUICKI in Groups A, S[-], and P[-]

QUICKI was 0.284 ± 0.020, 0.322 ± 0.030, and 0.220 ± 0.008 in groups A, S[-], and P[-], respectively. There were significant differences in QUICKI among groups A, S[-], and P[-] (P < 0.0001, 1-way ANOVA); group S[-] showed significantly higher QUICKI than group A (adjusted P = 0.0084, Scheffé F test), while group P[-] showed significantly lower QUICKI than group A (adjusted P < 0.0001, Scheffé F test).

TNF-α and HMW Adiponectin Levels in Groups A, S[-], and P[-]

Table 2 shows the time course of TNF-α and HMW adiponectin levels during IVGTT in groups A, S[-], and P[-]. TNF-α levels <20 pg/mL were not detectable in our assay. In group A, TNF-α was detected in 5 rats at T-0 but not detected in all rats at T-5 and T-15. In group S[-], TNF-α was detected in 6 rats at T-0 but not detected in all rats at T-5 and T-15. In group P[-], TNF-α was detected in all rats at T-0, T-5, and T-15. Significant differences in TNF-α levels were detected at T-0, T-5, and T-15 among groups A, S[-], and P[-] (P = 0.0039, P < 0.0001, and P < 0.0001, respectively, Kruskal-Wallis test). There were no significant differences in TNF-α levels between groups A and S[-] at T-0, T-5, and T-15 (adjusted P = 0.5021, P = 1.0000, and P = 1.0000, respectively, Steel-Dwass test). There were no significant differences in TNF-α levels between groups A and P[-] at T-0 (adjusted P = 0.1556, Steel-Dwass test); however, group P[-] showed significantly higher TNF-α levels at T-5 and T-15 than group A (adjusted P = 0.0012 and P = 0.0012, respectively, Steel-Dwass test).

Table 2
Table 2:
Tumor Necrosis Factor-α and High Molecular Weight Adiponectin Levels During the IV Glucose Tolerance Test in Groups A, S[-], and P[-]

No significant changes in HMW adiponectin levels were observed during IVGTT in groups A and P[-] (P = 0.0380 and P = 0.9819, respectively, 1-way repeated-measures ANOVA), while significant changes in HMW adiponectin levels were observed during IVGTT in group S[-] (P = 0.0061, 1-way repeated-measures ANOVA). Two-way repeated-measures ANOVA with group as a between-subject factor and time as a within-subject factor for comparisons of time course of HMW adiponectin levels during IVGTT among groups A, S[-], and P[-] detected a significant effect of time (adjusted P = 0.0077), but the effect of group and the interaction effect of group and time were not significant (P = 0.1622 and adjusted P = 0.1499, respectively). There were significant differences in HMW adiponectin levels at T-0 among groups A, S[-], and P[-] (P = 0.0083, 1-way ANOVA); however, HMW adiponectin levels in groups S[-] and P[-] were not significantly different from those in group A (adjusted P = 0.7710 and P = 0.0121, respectively, Scheffé F test). There were no significant differences in HMW adiponectin levels at T-5 and T-15 among groups A, S[-], and P[-] (P = 0.0470 and P = 0.7631, respectively, 1-way ANOVA).

Effects of Glibenclamide and Diazoxide on Glucose and Insulin Levels Under Sevoflurane Anesthesia

Table 3 shows the time course of glucose and insulin levels during IVGTT in groups S[-], S[g], and S[d]. Glucose levels significantly changed during IVGTT in groups S[g] and S[d] (P < 0.0001 and P < 0.0001, respectively, 1-way repeated-measures ANOVA). Two-way repeated-measures ANOVA with group as a between-subject factor and time as a within-subject factor for comparisons of time course of glucose levels during IVGTT among groups S, S[g], and S[d] detected a significant effect of group (P = 0.0081) and a significant effect of time (P < 0.0001), but the interaction effect of group and time was not significant (P = 0.0359). There were no significant differences in glucose levels at T-0 and T-5 among groups S, S[g], and S[d] (P = 0.2084 and P = 0.0684, respectively, 1-way ANOVA). There were significant differences in glucose levels at T-15 among groups S, S[g], and S[d] (P = 0.0008, 1-way ANOVA); group S[g] showed significantly lower glucose levels than group S[-] (adjusted P = 0.0031, Scheffé F test), while glucose levels in group S[d] were not significantly different from those in group S[-] (adjusted P = 0.9946, Scheffé F test).

Table 3
Table 3:
Effects of Glibenclamide and Diazoxide on Glucose and Insulin Levels During the IV Glucose Tolerance Test Under Sevoflurane Anesthesia

Insulin levels significantly changed during IVGTT in groups S[g] and S[d] (P = 0.0033 and P < 0.0001, respectively, 1-way repeated-measures ANOVA). Two-way repeated-measures ANOVA with group as a between-subject factor and time as a within-subject factor for comparisons of time course of insulin levels during IVGTT among groups S, S[g], and S[d] detected a significant effect of group (P = 0.0049), a significant effect of time (P < 0.0001), and a significant interaction effect of group and time (P = 0.0003). There were no significant differences in insulin levels at T-0 and T-5 among groups S, S[g], and S[d] (P = 0.1532 and P = 0.0302, respectively, 1-way ANOVA). There were significant differences in insulin levels at T-15 among groups S, S[g], and S[d] (P = 0.0029, 1-way ANOVA); group S[g] showed significantly higher insulin levels than group S[-] (adjusted P = 0.0063, Scheffé F test), while insulin levels in group S[d] were not significantly different from those in group S[-] (adjusted P = 0.9557, Scheffé F test).

Mean arterial blood pressure at T-15 in groups S[-], S[g], and S[d] was 67 ± 17, 77 ± 20, and 66 ± 15 mm Hg, respectively; there were no significant differences (P = 0.4336, 1-way ANOVA). Heart rate at T-15 in groups S[-], S[g], and S[d] was 354 ± 38, 371 ± 33, and 367 ± 37 beats/min, respectively; there were no significant differences (P = 0.6178, 1-way ANOVA).

Effects of Glibenclamide and Diazoxide on Glucose and Insulin Levels Under Propofol Anesthesia

Table 4 shows the time course of glucose and insulin levels during IVGTT in groups P[-], P[g], and P[d]. Glucose levels significantly changed during IVGTT in groups P[g] and P[d] (P < 0.0001 and P < 0.0001, respectively, 1-way repeated-measures ANOVA). Two-way repeated-measures ANOVA with group as a between-subject factor and time as a within-subject factor for comparisons of time course of glucose levels during IVGTT among groups P, P[g], and P[d] detected a significant effect of group (P < 0.0001), a significant effect of time (P < 0.0001), and a significant interaction effect of group and time (P = 0.0003). There were no significant differences in glucose levels at T-0 among groups P, P[g], and P[d] (P = 0.1503, 1-way ANOVA). There were significant differences in glucose levels at T-5 and T-15 among groups P, P[g], and P[d] (P < 0.0001 and P < 0.0001, 1-way ANOVA); group P[g] showed significantly lower glucose levels at T-5 and T-15 than group P[-] (adjusted P = 0.0001 and P < 0.0001, respectively, Scheffé F test), and group P[d] showed significantly lower glucose levels at T-5 and T-15 than group P[-] (adjusted P = 0.0058 and P = 0.0014, respectively, Scheffé F test).

Table 4
Table 4:
Effects of Glibenclamide and Diazoxide on Glucose and Plasma Insulin Levels During the IV Glucose Tolerance Test Under Propofol Anesthesia

Insulin levels significantly changed during IVGTT in groups P[g] and P[d] (P < 0.0001 and adjusted P = 0.0015, respectively, 1-way repeated-measures ANOVA). Two-way repeated-measures ANOVA with group as a between-subject factor and time as a within-subject factor for comparisons of time course of insulin levels during IVGTT among groups P, P[g], and P[d] detected a significant effect of group (P = 0.0016), a significant effect of time (P < 0.0001), and a significant interaction effect of group and time (P < 0.0001). There were no significant differences in insulin levels at T-0 among groups P, P[g], and P[d] (P = 0.0191, 1-way ANOVA). There were significant differences in insulin levels at T-5 among groups P, P[g], and P[d] (P = 0.0054, 1-way ANOVA); however, insulin levels in groups P[g] and P[d] were not significantly different from those in group P[-] (adjusted P = 0.0139 and P = 0.9991, respectively, Scheffé F test). There were also significant differences in insulin levels at T-15 among groups P, P[g], and P[d] (P < 0.0001, respectively, 1-way ANOVA); group P[g] showed significantly higher insulin levels than group P[-] (adjusted P = 0.0018, respectively, Scheffé F test), while insulin levels in group P[d] were not significantly different from those in group P[-] (adjusted P = 0.4162, respectively, Scheffé F test).

Mean arterial blood pressure at T-15 in groups P[-], P[g], and P[d] was 88 ± 28, 96 ± 12, and 91 ± 29 mm Hg, respectively; there were no significant differences (P = 0.8119, 1-way ANOVA). Heart rate at T-15 in groups P[-], P[g], and P[d] was 375 ± 45, 415 ± 49, and 392 ± 42 beats/min, respectively; there were no significant differences (P = 0.2590, 1-way ANOVA).

DISCUSSION

Changes in glucose levels during IVGTT reflect glucose use. Glucose use is regulated by both insulin secretion and insulin sensitivity. The hyperinsulinemic normoglycemic clamp is considered the “gold standard” to examine insulin sensitivity.19 Because we performed IVGTT to examine the effects of sevoflurane or propofol anesthesia on glucose use, it was impossible to apply the hyperinsulinemic normoglycemic clamp to test insulin sensitivity in this study. Thus, we calculated QUICKI using glucose levels and insulin levels just before glucose administration to assess insulin sensitivity.

Before glucose administration, group S[-] showed similar glucose and insulin levels to group A and significantly higher QUICKI than group A. After glucose administration, group S[-] showed significantly higher glucose levels than group A and similar insulin levels to group A. These results suggest 2 aspects of glucose use under sevoflurane anesthesia. First, sevoflurane anesthesia attenuates glucose-induced insulin secretion without significant modification to basic insulin secretion. Second, sevoflurane anesthesia does not impair insulin sensitivity.

Before glucose administration, group P[-] showed similar glucose levels and significantly higher insulin levels with significantly lower QUICKI compared with group A. After glucose administration, group P[-] showed similar glucose levels to group A and significantly higher insulin levels than group A. These results suggest 2 aspects of glucose use under propofol anesthesia. First, propofol anesthesia enhances insulin secretion. Second, propofol anesthesia impairs insulin sensitivity.

Insulin secretion is a predominant factor affecting glucose use. Insulin secretion is regulated by KATP channels in β-islet cells; inhibition of KATP channels in β-islet cells stimulates insulin secretion, whereas opening of KATP channels in β-islet cells attenuates insulin secretion.16 KATP channels are expressed not only in β-islet cells but also in other cells, such as cardiac myocytes, nonvascular smooth muscle cells, and vascular smooth muscle cells. The structure of KATP channels can be divided into 2 subunits (i.e., a pore-forming subunit and a regulatory subunit), and each KATP channel has cell-specific structure; the pore-forming subunit and the regulatory subunit of KATP channels in β-islet cells is Kir6.2 and SUR1, respectively.20–22 Both glibenclamide (a KATP-channel inhibitor) and diazoxide (a KATP-channel opener) have high affinity for SUR1.23,24 Under sevoflurane anesthesia, glibenclamide significantly increased insulin levels after glucose administration, while diazoxide produced no significant effects on insulin levels after glucose administration. We, thus, consider that sevoflurane attenuates glucose-induced insulin secretion by opening KATP channels in β-islet cells via SUR1.

Regardless of glucose administration, hyperinsulinemia was observed in rats under propofol anesthesia. Under propofol anesthesia, glibenclamide significantly increased insulin levels after glucose administration, while diazoxide produced no significant effects on insulin levels after glucose administration. Although the effects of propofol on insulin secretion have not been elucidated, an in vitro study25 demonstrated the inhibitory effects of propofol on KATP channels consisting of Kir6.2 and SUR1; the inhibitory effects were mediated by Kir6.2 but not by SUR1. Taken together, we suppose that propofol enhances insulin secretion by inhibiting KATP channels in β-islet cells via Kir6.2. Propofol could not completely inhibit KATP channels in β-islet cells at the dose tested in this study; therefore, additional inhibitory effects of glibenclamide on the channels via SUR1 resulted in the significant increases in insulin levels. The opening effects of diazoxide on KATP channels in β-islet cells via SUR1 could not antagonize the inhibitory effects of propofol on the channels via Kir6.2. It is interesting to note that diazoxide significantly decreased glucose levels after glucose administration under propofol anesthesia without affecting insulin levels, suggesting the possible modifying effects of diazoxide on insulin sensitivity under propofol anesthesia.

Insulin sensitivity is another factor affecting glucose use. Because a lipid-based formulation of propofol is used, propofol anesthesia is always accompanied with acute lipid load. Acute lipid load impairs insulin sensitivity.26–29 Several studies reported the involvement of TNF-α and HMW adiponectin in insulin sensitivity.11–15

Before glucose administration, TNF-α was undetectable in a few rats in groups A and S[-], while TNF-α was detected in all rats in group P[-]. After glucose administration, TNF-α was undetectable in all rats in groups A and S[-], while TNF-α was detected in all rats in group P[-]; TNF-α levels at T-5 and T-15 in group P[-] were significantly higher than those in group A. The increased TNF-α levels attenuate insulin sensitivity11,14; therefore, we suppose that the higher TNF-α levels may reflect insulin-resistive conditions under propofol anesthesia. After glucose administration, HMW adiponectin levels significantly increased in group S[-]; however, no significant changes were observed in groups A and P[-]. In addition, HMW adiponectin levels in groups S[-] and P[-] were not significantly different from those in group A throughout the experimental period. It was reported that the decreased HMW adiponectin levels are associated with insulin resistance.12–15 We, therefore, suggest that HMW adiponectin may not be causative of insulin-resistive conditions under propofol anesthesia.

There were 3 major limitations in this study. First, all rats underwent surgical preparation under sevoflurane anesthesia; therefore, we cannot discount the residual effects of sevoflurane anesthesia on glucose metabolism in awake rats and rats under propofol anesthesia. Second, all rats were made to fast for 15 hours before the experiment. Because fasting significantly modifies metabolism with complicated mechanisms, it is, therefore, possible that the different lengths of fasting periods before the experiment resulted in different glucose metabolism under general anesthesia. Third, TNF-α was detectable in most rats in groups A and S[-] before glucose administration, whereas TNF-α was undetectable in all rats in groups A and S[-] after glucose administration. Unfortunately, considering the half-life of TNF-α, we cannot elucidate the mechanisms underlying the rapid decreases in TNF-α levels in this study.

In conclusion, both insulin secretion and insulin sensitivity are involved in the different effects of sevoflurane anesthesia and propofol anesthesia on glucose use in fasted rats.

DISCLOSURES

Name: Kanako Sato, MD.

Contribution: This author helped design and conduct the study, analyze the data, and prepare the manuscript.

Attestation: Kanako Sato approved the final manuscript. Kanako Sato attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Takayuki Kitamura, MD.

Contribution: This author helped design and conduct the study, analyze the data, and prepare the manuscript.

Attestation: Takayuki Kitamura approved the final manuscript. Takayuki Kitamura attests to the integrity of the original data and the analysis reported in this manuscript. Takayuki Kitamura is the archival author.

Name: Gaku Kawamura, MD.

Contribution: This author helped design and conduct the study, analyze the data, and prepare the manuscript.

Attestation: Gaku Kawamura approved the final manuscript. Gaku Kawamura attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Yoshiteru Mori, MD.

Contribution: This author helped analyze the data and prepare the manuscript.

Attestation: Yoshiteru Mori approved the final manuscript.

Name: Rui Sato, MD.

Contribution: This author helped analyze the data and prepare the manuscript.

Attestation: Rui Sato approved the final manuscript.

Name: Yuko Araki, MD.

Contribution: This author helped analyze the data and prepare the manuscript.

Attestation: Yuko Araki approved the final manuscript.

Name: Yoshitsugu Yamada, MD, PhD.

Contribution: This author helped analyze the data and prepare the manuscript.

Attestation: Yoshitsugu Yamada approved the final manuscript.

This manuscript was handled by: Marcel E. Durieux, MD, PhD.

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