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-Lipoic Acid Inhibits Glycogen Synthesis in Rat Soleus Muscle via Its Oxidative Activity and the Uncoupling of Mitochondria1
Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel
2To whom correspondence should be addressed. E-mail: otirosh{at}agri.huji.ac.il.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-Lipoic acid (LA) is currently being investigated as a glucose-lowering agent for diabetes control; it is also considered a powerful dietary antioxidant. The objective of this study was to investigate the fate of glucose in isolated rat muscles incubated with LA and determine its effects on intramuscular redox status. Rat soleus muscles were incubated for up to 60 min with 2.4 mmol/L LA in the presence or absence of insulin. Intramuscular concentrations of LA were evaluated (uptake and reduction), and glycogen synthesis, glucose oxidation, intramuscular reactive oxygen species (ROS) production and mitochondrial membrane potential investigated. Insulin enhanced glycogen synthesis, whereas LA decreased rates by >50%. LA elevated ROS production and in combination with t-butylhydroperoxide, an oxidant, additively inhibited glycogen synthesis rates by 80%. Insulin acted as an antioxidant and attenuated ROS production by 30%. LA uncoupled the mitochondria and accelerated glucose oxidation 1.5-fold relative to the control. The glycogen synthesis pathway was found to be dependent on mitochondrial function because treatment with mitochondrial inhibitors eliminated the majority of glycogen synthesis. These data show that in this model, LA acts as a mild prooxidant, causing mitochondrial uncoupling and inhibition of glycogen synthesis. It appears that LA regulates glucose metabolism in the muscle differently than insulin.
KEY WORDS: • lipoic acid • insulin • oxidative stress • glycogen synthesis • redox
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,2
). The derangement created by chronic hyperglycemia leads to many long-term complications, including a high rate of cardiovascular disease, amputation due to accelerated atherosclerosis, as well as the typical complications of diabetes such as retinopathy, nephropathy and neuropathy (3
–6
).
The mitochondrial cofactor, -lipoic acid (LA), in its free form has been the focus of intensive research in nutrition and diabetes in the last few years. LA has been suggested to function as powerful antioxidant (7
) with insulin-mimetic effects, e.g., potentiating glucose uptake in vitro (8
–10
). LA has been shown to improve glucose metabolism in diabetic subjects (11
–13
) and has long been used in Germany for the relief of symptoms of diabetic neuropathy (12
,14
,15
).
LA may act as a hypoglycemic agent through stimulation of basal and insulin-activated glucose uptake; this has been documented in L6 myotubes (9
,16
), 3T3-L1 adipocytes (8
,9
,17
), cardiac myocytes (11
) and in isolated rat muscles (10
,18
,19
). In addition, LA has been shown to enhance insulin-stimulated glucose metabolism in insulin-resistant skeletal muscle of obese Zucker rats, and to stimulate glucose transport activity in skeletal muscle isolated from both lean and obese Zucker rats. (18
,20
). Although LA has been considered for use in treating diabetics, an unequivocal understanding of its mechanism of action has yet to be established, and the fate of glucose after transport in the presence of LA is poorly understood.
In the insulin-signaling pathway, LA has been shown to activate, via phosphorylation, the insulin receptor and several others components of the cascade. Therefore, it has been proposed to act as a unique insulin-mimicking compound. However, in contrast to insulin, LA can penetrate into the cell by crossing biological membranes (21
). Therefore, accumulation of LA, a disulfide-containing compound, in cells may alter the redox status and dissociate the effect of LA from the insulin-signaling pathway, leading to a different effect on glucose utilization. Another question that arises is whether the antidiabetic effect of LA is because of its antioxidant activity. The fact that LA is the only antioxidant that has been shown to perform such an activity does not support this claim. It has been demonstrated that short-term incubation of (R)-LA, (S)-LA and racemic LA (low µmol/L) in 3T3 L1 adipocytes cells induced glucose uptake by facilitating oxidative stress, whereas long-term incubation elevated cellular glutathione levels (antioxidant effect) and suppressed glucose uptake (22
). In addition, Mason and collaborators (22
) recently reported prooxidant properties of LA in chemical systems.
On the basis of its chemical structure, LA, an eight-carbon compound that contains a disulfide bond, can act as a mild oxidant inside cells. In this study, we evaluated the capacity of LA to modulate glycogen synthesis in comparison to insulin. In addition, we sought to evaluate its effect on glucose oxidation.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Bovine serum albumin (BSA), HEPES, pyruvic acid, insulin, glutathione ester (GSHe), rotenone, carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP), cytochalasin B, dithiothreitol (DTT), LA and other chemicals were purchased from Sigma Chemical (Rehovot, Israel). Dichlorodihydrofluorescein diacetate (H2DCF-DA) was from Molecular Probes (Eugene, OR). t-Butylhydroperoxide (TBH) was from Aldrich (Rehovot, Israel). [14C-U]D-glucose, [14C-U] 2-deoxyglucose and 3H-tetraphenylphosphoniume bromide (TPP) were from Amersham Pharmacia Biotech (Buckinghamshire, UK).
Animals and muscle preparation.
Male Sprague-Dawley rats (Harlan Laboratories, Jerusalem, Israel), weighing 100–120 g were housed in a controlled environment (22–24°C and 12 h light:12 h dark) for up to a week before the experiments. They consumed food (Teklad Global 18% Protein Rodent sterilized diet; Harlan Laboratories) and water ad libitum. All animals were cared for under the guidelines set forth by the Animal Care Committee of the Hebrew University, Jerusalem, Israel. Food was restricted for 10–12 h before the experiments. Rats were anesthetized with 5 mg/100 g body pentobarbital sodium administered intraperitoneally and then soleus muscles were gently removed. All muscles were of approximately the same weight (30–40 mg).
Experimental design.
At 2.4 mmol/L, LA caused 50% inhibition of glycogen synthesis (see results below) and this concentration was used in the study. Concentrations of up to 5 mmol/L have been used previously in in vitro studies of LA in diabetes research. The short exposure time of the muscles to LA is consistent with the pharmacokinetics of LA (short 30-min biological half-life) (23
).
Evaluation of intramuscular lipoic acid uptake: HPLC-electrochemical detection.
Soleus muscles treated with LA were washed with ice-cold Krebs-Henseleit bicarbonate buffer, treated with 70:30, 40 g/L m-phosphoric acid/methanol, respectively. All samples were immediately frozen in liquid nitrogen and stored at -80°C, until HPLC analysis. Immediately before the assay, samples were thawed, vortexed and then centrifuged at 15,000 x g for 2 min. The clear supernatant was removed and injected into the HPLC system.
A C-18 RP (15 cm x 4.6 mm) column (GL Science, Tokyo, Japan) and a coulometric detector (ESA, Coularray, Chelmsford, MA) were used. The mobile phase, consisting of 50% (v/v) of solution A [50 mmol/L NaH2PO4, (pH 2.7)], and 50% (v/v) of solution B [70% (v/v) acetonitrile and 30% (v/v) methanol] was delivered using an isocratic solvent delivery module (ESA) set at a flow rate of 1.2 mL/min. The retention time for LA is 5.3 min (24
–26
).
Effect of LA on glucose incorporation into glycogen.
Glucose incorporation into glycogen was determined in soleus muscles surgically excised and incubated in a shaking water bath. Tissues were placed in sealed vials containing oxygenated Krebs-Henseleit bicarbonate buffer supplemented with 1 g/L BSA, 5 mmol/L HEPES and 2 mmol/L pyruvate (27
). After preincubation for 30 min, muscles were transferred to a second set of vials. Muscle from each rat was placed in medium containing 5 mmol/L glucose and 7.46 Bq/L [14C-D]glucose. Contralateral muscles served as the control for the various treatments as indicated in the figure legends. After 60 min of incubation under 95% O2/5% CO2, muscles were boiled for 30 min in 7.7 mmol/L KOH and precipitated at 4°C in three volumes of ethanol and Na2SO4. After centrifugation for 20 min at 4000 x g, radioactivity was determined in the precipitates.
Effect of LA or other treatments on muscle glucose uptake rate (transport).
Glucose uptake was evaluated by the method of Klip and collaborators (9
) used for L6 muscle cells. Soleus muscles were preincubated for 20 min as already described. After preincubation, muscles were transferred to a second set of vials. Muscles were placed in medium containing 10 µmol/L [14C-U] 2-deoxyglucose (60 mCi/mmol), and treated as indicated in the figure legend. After 10 min of incubation under 95% O2/5% CO2, muscle was washed three times with ice-cold Krebs-Henseleit bicarbonate buffer dissolved in NaOH (1 mol/L) and radioactivity was measured. Cytochalasin B reduced glucose uptake rate in soleus muscle by 60–70%. Results were calculated by subtracting uptake rates in muscles that were not treated with cytochalasin B to correct for transporter-independent glucose uptake and nonspecific radioactivity readings.
Measurement of the effect of LA treatment on glucose oxidation in muscles.
Soleus muscles were preincubated for 30 min as already described. After preincubation, muscles were transferred to a second set of vials. One muscle from each rat was placed in medium containing glucose (5 mmol/L) and [14C-U]D-glucose (0.5 mCi/L), and the contralateral muscle was incubated with glucose. After 120 min of incubation under 95% O2/5% CO2, 14CO2 production from [14C-U] glucose was measured to determine glucose oxidation.
Measurement of intramuscular reactive oxygen species (ROS).
Intramuscular peroxides were detected using H2DCF-DA. Tissues were placed in sealed vials containing oxygenated Krebs-Henseleit bicarbonate buffer supplemented with 1 g/L BSA, 5 mmol/L HEPES and 2 mmol/L pyruvate. After preincubation for 30 min, muscles were transferred to a second set of vials containing glucose (5 mmol/L) and 2',7'-dichlorodihydrofluorescin (DCFH; 10 µmol/L) for 60 min incubation and then muscles were pulverized. After centrifugation for 10 min at 3500 x g, dichlorofluorescein (DCF) emission was recorded. Fluorescence settings were Ex = 485 and Em = 530.
Measurement of the effect of LA on intramuscular mitochondrial membrane potential.
Intramuscular mitochondrial membrane potential was detected using radioactively labeled TPP. Tissues were placed in sealed vials containing oxygenated Krebs-Henseleit bicarbonate buffer supplemented with 1 g/L BSA, 5 mmol/L HEPES and 2 mmol/L pyruvate. After preincubation for 30 min, muscles were transferred to a second set of vials containing 5 mmol/L glucose with and without LA. After 60 min of incubation under 95% O2/5% CO2, muscles were treated with 2 nmol/L TPP for 30 min and then washed with cold incubation buffer (4°C) and boiled for an additional 30 min in 7.7 mmol/L KOH. Three volumes of ethanol and Na2SO4 were added. After centrifugation, radioactivity was determined in the supernatant of before.
Statistical analysis.
Data were analyzed by t test for comparison of two groups and one-way or two-way ANOVA for factorial experiments. Where necessary, data were log transformed before analysis to stabilized variances. Differences were considered significant at P < 0.05 using Fisher’s protected least significant difference test or Dunnett’s t test. SPSS 8 (SPSS, Chicago, IL) was used for all analyses.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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).
|
LA significantly decreased glycogen synthesis relative to its basal rate. Insulin upregulated the synthesis of glycogen, as was expected. However, in the presence of LA, the effect of insulin was attenuated, indicating that LA counteracts insulin action (Table 1
). To evaluate whether the effect of LA on glycogen synthesis was related to redox control, muscles were exposed to the oxidant TBH. Indeed, TBH also decreased glycogen synthesis (Table 1)
. LA and TBH decreased glycogen production additively by 80% when both were included (Table 1)
.
|
). The prooxidant effect of LA occurred even at low extramuscular concentrations of 0.25 mmol/L. The oxidizing effect of LA was the same as was observed when TBH was used (Fig. 2
B). We hypothesized that glycogen synthesis may be regulated by an insulin-dependent redox control mechanism. To investigate this, effect of insulin on ROS was evaluated. Indeed, insulin decreased ROS production 30%. Moreover, insulin significantly decreased ROS production after LA treatment (Fig. 3
).
|
|
), but eliminated LA-induced ROS production (Fig. 4
). When DTT was included at 10 mmol/L, it prevented the inhibitory effect of LA on glycogen synthesis (Table 2)
.
|
|
). The elevated glucose oxidation by the mitochondria could be a result of mitochondrial uncoupling generated by the oxidizing effect of LA. Exposing soleus muscles to the mitochondrial uncoupler FCCP or to the mitochondrial electron-transfer chain inhibitor rotenone arrested glycogen production (Fig. 6
). We investigated whether there was a direct effect of LA on mitochondrial membrane potential. Treatment with LA dissipated the mitochondrial membrane potential by 30% (Fig. 7
), indicating a reduction in mitochondrial efficiency leading to inhibition of glycogen synthesis.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,29
). It is generally accepted that intracellular redox status plays an important role in the modulation of insulin action. LA is an effective modulator of cellular redox status (7
). Treating isolated soleus muscles with either TBH or LA elevated glucose uptake. This effect can be considered as an insulin-mimicking property of oxidants that can interact with critical thiols of the insulin receptor and activate it (17
). However, in contrast to insulin, LA can cross biological membranes (21
) and thereby alter the redox status of cells. Treating isolated muscles with elevated concentrations of LA dose dependently inhibited glycogen synthesis (data not presented). An effective intracellular concentration of 
750 µmol/L reduced the glycogen synthesis rate in the muscle by 50%. The reduced form, which is the active antioxidant form of LA, was not detected. It has repeatedly been shown that under certain conditions antioxidants may also act as prooxidants and LA is no exception.
LA acts as a powerful antioxidant only after long-term incubation in cell cultures (17
,30
). However after short-term incubation and rapid uptake by tissue or cells, it might function dose dependently as a prooxidant (17
). The long-term in vivo balance between the two opposite effects is unclear. The beneficial role of LA supplementation in patients with NIDDM could be manifested by a mild prooxidant activity of the compound, leading to cellular adaptation against oxidative stress in addition to the attenuation of reductive stress (over accumulation of reducing equivalents) in diabetes (31
).
In the isolated soleus muscle model used in this study, direct exposure of the muscle to LA increased glucose uptake. However, the term insulin mimetic compound (LA) (9
) may be misleading because insulin also stimulates glycogen synthesis.
TBH, an oxidant, had the same effect as LA on glucose uptake and the glycogen synthesis rate. Because of its chemical structure, LA can act as a mild oxidant molecule before conversion to its reduced form, dihydrolipoic acid. More specifically, LA has been shown to oxidize sulfhydryl groups of cellular components in the insulin-signaling pathway and thereby modulate their activity (17
). Indeed, in the isolated muscle model, LA appears to play the part of a mild oxidant. Glycogen synthesis was found to be sensitive to oxidant treatment. Both LA and TBH, in combination and separately, inhibited glycogen storage. Interestingly and in accordance with the observation of a redox control mechanism of glycogen synthesis, insulin decreased muscle endogenous ROS production and stimulated glycogen synthesis. Insulin also lowered the effect of LA on ROS production.
When the effect of the intracellular antioxidant, GSHe, on the oxidative effect of LA was tested, GSHe negated LA-dependent ROS production but did not prevent its inhibitory effect on glycogen synthesis. These data indicate that LA may play an oxidative role inside the muscle cell in a conserved site that can not be protected by GSHe. Indeed, by using DTT, a powerful thiol-reducing agent that can move freely in the cell, protection against the inhibitory effect of LA on glycogen synthesis was observed. Alternatively, GSH could have only recycled the DCF phenolic radical and preserved it in the DCFH nonfluorescent, reduced form with no real protection against LA. The chemical structure of the dithiolane ring in LA is active enough to function as the oxidizing compound without the need for endogenous ROS production. GSHe, therefore, was unable to detoxify it and to ameliorate the oxidizing effect.
Because LA caused a 1.5-fold increase in muscle glucose oxidation, the mitochondria, which are a sensitive target for oxidative damage (32
,33
), were suggested to be the site of LA action. It was observed previously that pharmacologic agents that uncouple the mitochondria attenuate glycogen synthesis (34
). Mitochondria are both a source of ROS and a sensitive target for oxidative damage (35
). The increase in glucose oxidation is probably due to mitochondrial uncoupling by LA and acceleration of the mitochondrial tricarboxylic acid cycle in an attempt to compensate for the loss of membrane potential due to LA.
One theory suggests that during uncoupling, the electron transport chain works more efficiently. The increase in efficiency leads to less leakage of electrons and therefore, much less ROS generation (36
–38
). Therefore, some of the LA-induced increase in ROS production is probably not due to an increase in endogenous ROS but to the oxidizing effect of LA itself. Indeed, only part of the augmented ROS generation by LA was attenuated by insulin treatment. The sensitivity of glycogen synthesis to mitochondrial damage was further established by the use of FCCP and rotenone, which completely eliminated glycogen synthesis.
As an alternative to LA induction of oxidative stress and mitochondrial damage, the mitochondrial uncoupling effect of LA could be due to its fatty acid–like structure. However, LA acted very much like TBH in all other aspects of glucose metabolism examined, suggesting a prooxidant effect.
It has been suggested that LA in its free form, as an antioxidant or as an insulin-mimicking compound, should be administered in doses up to 2 g/d or 100 mg/(kg · d) in animal models. However, if treatment is for long time periods, possible deleterious prooxidant activities of the compound should be considered. Concentrations of LA after a single intravenous injection of 200 mg or oral supplementation of 600 mg reached 50 µmol/L plasma at 30 min (23
). Increased prooxidant potency in vivo compared with in vitro might explain its direct glucose uptake–inducing effect in vivo, shown by Moini et al. (17
) to be an oxidant-dependent effect.
In conclusion, this paper has highlighted the glycogen synthesis–inhibiting and prooxidant properties of the dietary antioxidant LA in a biological system of glucose metabolism in muscles.
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FOOTNOTES |
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3 Abbreviations used: BSA, bovine serum albumin; DCF, dichlorofluorescein; DCFH, 2',7'-dichlorodihydrofluorescin; DTT, dithiothreitol; FCCP, carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone; GSHe, glutathione ester; H2DCF-DA, dichlorodihydrofluorescein diacetate; LA, -lipoic acid; NIDDM, noninsulin-dependent diabetes mellitus; ROS, reactive oxygen species; TBH, t-butylhydroperoxide; TPP, 3H-tetraphenylphosphoniume bromide.
Manuscript received 6 May 2002. Initial review completed 29 May 2002. Revision accepted 10 July 2002.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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