1 Department of Physiology, Faculty of Medical Sciences, New University of Lisbon, Campo Mártires da Pátria 130, 1169-056 Lisbon; 2 Department of Chemistry and Biochemistry, Center for Studies in Biochemistry and Physiology, Faculty of Sciences, University of Lisbon, Campo Grande, 1749-016 Lisbon; 3 Superior School of Health Egas Moniz, Quinta da Granja, Monte da Caparica, 2829-511 Caparica; 4 Institute of Scientific Research Bento da Rocha Cabral, Calçada Bento da Rocha Cabral No. 14, 1250-047 Lisbon; and 5 Portuguese Diabetes Association, 1250-203 Lisbon, Portugal
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We tested the hypothesis that
hepatic nitric oxide (NO) and glutathione (GSH) are involved in the
synthesis of a putative hormone referred to as hepatic
insulin-sensitizing substance HISS. Insulin action was assessed in
Wistar rats using the rapid insulin sensitivity test (RIST). Blockade
of hepatic NO synthesis with NG-nitro-L-arginine methyl ester
(L-NAME, 1.0 mg/kg intraportal) decreased insulin
sensitivity by 45.1 ± 2.1% compared with control (from
287.3 ± 18.1 to 155.3 ± 10.1 mg glucose/kg,
P < 0.05). Insulin sensitivity was restored to
321.7 ± 44.7 mg glucose/kg after administration of an NO donor,
intraportal SIN-1 (5 mg/kg), which promotes GSH nitrosation, but not
after intraportal sodium nitroprusside (20 nmol · kg1 · min
1), which
does not nitrosate GSH. We depleted hepatic GSH using the GSH
synthesis inhibitor l-buthionine-[S,R]-sulfoximine (BSO, 2 mmol/kg body wt ip for 20 days), which reduced insulin sensitivity by
39.1%. Insulin sensitivity after L-NAME was not
significantly different between BSO- and sham-treated animals. SIN-1
did not reverse the insulin resistance induced by L-NAME in
the BSO-treated group. These results support our hypothesis that NO and
GSH are essential for insulin action.
hepatic nitric oxide synthase; hepatic parasympathetic nerves; type 2 diabetes
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
INSULIN SENSITIVITY IS MEDIATED by a neurohumoral mechanism through which the liver releases a putative hormone referred to as hepatic insulin-sensitizing substance (HISS) (35, 36). HISS enters the blood and sensitizes skeletal muscle to insulin action, accounting for ~55% of total insulin action (13, 14). Therefore, insulin action consists of two components: an HISS-dependent and an HISS-independent component. HISS release is dependent on the activation of hepatic muscarinic receptors and is mediated by nitric oxide (NO) produced in the liver (7, 27, 37). HISS synthesis is also controlled by the prandial status: it is maximal in the postprandial state and minimal in the fasted state (10). Because hepatic glutathione (GSH) levels are also dependent on prandial status (31), we tested the hypothesis that GSH and NO control HISS release.
Decreased levels of the thiol GSH in several tissues are a common finding in experimental and human diabetes, in which increased oxidative stress appears to occur (29, 38). Various studies suggest that increased oxidative stress is the major cause for insulin resistance observed in diabetes, by either impairing insulin secretion or insulin hemodynamic effects at the skeletal muscle (6, 20, 22, 23). Recent publications contradict this hypothesis by stating that GSH depletion in rats results in impaired glucose tolerance but preserved adipocyte and skeletal muscle insulin responsiveness, as well as insulin secretion, without an increase in oxidative stress markers (10). Khamaisi et al. (10) suggest that the impaired glucose tolerance observed after GSH depletion is a direct effect of the lack of GSH in the liver, and not an indirect consequence of increased oxidative stress.
In the present study, we investigate a possible interaction between
hepatic NO and GSH levels in the liver on HISS-dependent insulin
action. Insulin sensitivity was assessed using the rapid insulin
sensitivity test (RIST), which is a modified euglycemic clamp. We
compared the capacity of the two NO donors 3-morpholinosidnonimine (SIN-1) and sodium nitroprusside (SNP) to restore insulin response after hepatic NO synthase (NOS) blockade with
NG-nitro-L-arginine methyl ester
hydrochloride (L-NAME). We also determined the effect of
the -glutamylcysteine synthase inhibitor L-buthionine-[S,R]-sulfoximine (BSO), which
depletes hepatic GSH levels, on insulin sensitivity. The capacity of
the NO donor SIN-1 to reverse insulin resistance induced by
L-NAME in hepatic GSH-depleted rats was assessed. Our
results were consistent with the hypothesis that HISS synthesis in the
liver requires NO as well as GSH.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Presurgical Protocols
Animals were treated according to the Laboratory Animal Care Guidelines of the European Union (86/609/CEE) and the National Institutes of Health. Male Wistar rats (8-9 wk old) were housed one per cage, with a 12:12-h light-dark cycle under controlled temperature. Rats were fed standard rat chow (Panlab A04, Charles River) ad libitum, except for the day before surgery, when the rats were fasted overnight and then allowed access to food for 1 h. Experiments began between 9 and 10 AM. Rats were anesthetized with pentobarbital sodium (65 mg/kg ip), and anesthesia was maintained throughout the experiment by continuous infusion of pentobarbital sodium (1.0 mg/ml, 1.0 ml · 100 g body wtGSH Depletion
Five-week-old male Wistar rats received BSO (BSO group, n = 5) or saline (sham group, n = 6). BSO was dissolved in saline and administered at 2 mmol · kgSurgical Preparation
The trachea was cannulated (polyethylene fusing PE-240; Becton Dickinson) to allow spontaneous respiration. The arteriovenous (a-v) loop previously described (15) was primed with a saline-heparin solution (200 IU/ml). The a-v loop forms a vascular shunt connected by cannulation (PE-50; Becton Dickinson) of the carotid artery with the arterial side of the loop and cannulation of the left jugular vein with the venous side of the loop. Arterial blood samples (25 µl) were obtained by puncture of the loop sleeve. Arterial blood pressure was monitored by briefly clamping the venous outlet of the loop. The patency of flow in the shunt was also monitored by recording pressure from the nonoccluded loop. Insulin, glucose, and anesthetic were administered intravenously by puncturing (infusion line PE50 with a cut 23 gauge needle at the end) the loop on the venous side. The portal vein was cannulated with a 24-gauge iv intravenous catheter (Jelco, Johnson & Johnson Medical) after laparotomy.Rats were allowed to stabilize from the surgical intervention for 50 min before any procedures were carried out. Arterial blood samples were collected every 5 min after stabilization, and glucose concentrations were immediately analyzed by the oxidase method with a glucose analyzer (1500 YSI SPORT, Yellow Springs Instruments) until three successive stable glucose concentrations were obtained. The mean of these three values is referred to as the basal glucose level.
RIST
The RIST, which is a modified euglycemic clamp reproducible for four consecutive tests in the same animal, has previously been described (15).Insulin infusion was started using an infusion pump (Perfusor, Braun)
to administer the dose of insulin (50 mU/kg iv) over 5 min. After 1 min
of insulin infusion, arterial blood glucose was measured, and glucose
infusion (D-glucose-saline, 100 mg/ml iv) was started at a
rate of 5 mg · kg1 · min
1.
According to arterial glucose concentrations measured at 2-min intervals, the infusion rate of the glucose pump was readjusted to
maintain euglycemia. When no further glucose infusion was required, usually within 35 min, the test period was concluded. The amount of
glucose infused after insulin administration quantifies insulin sensitivity and is referred to as the RIST index (mg glucose/kg) (15).
HISS Quantification
The RIST index is composed of two components: the HISS-dependent component and the HISS-independent component. In this study, the HISS-independent component, or insulin action per se, is obtained by inhibition of hepatic NO release through direct administration of L-NAME into the portal vein. The HISS-dependent component of insulin action is calculated by subtracting the RIST index obtained after NOS blockade from the control RIST index, as previously reported (27, 35).Experimental Protocols
Effect of intraportal administration of the NOS antagonist L-NAME on insulin sensitivity. After the control RIST was performed, L-NAME (1 mg/kg) was infused intraportally over 5 min. A stable basal arterial glucose concentration was determined, and a new RIST was performed, 30 min after L-NAME infusion. After restabilization, consecutive RISTs were performed at 90, 140, and 190 min after L-NAME infusion to evaluate the duration of action of the L-NAME dose (n = 5).
Effect of intravenous vs. intraportal administration of the NO
donor SNP on L-NAME-induced insulin resistance.
The RIST index was determined before and 60 min after intraportal
infusion of L-NAME (1 mg/kg, 5-min bolus). SNP (20 nmol · kg1 · min
1) was
administered intraportally (n = 6) or intravenously
(n = 5) 90 min after L-NAME. After a basal
glucose level was established, a new RIST was performed.
Effect of intraportal administration of the NO donor SIN-1 on L-NAME-induced insulin resistance. The RIST index was determined before and 60 min after intraportal infusion of L-NAME (1 mg/kg, 5-min bolus). SIN-1 (5 mg/kg, 5-min bolus) was infused intraportally (n = 6) 90 min after L-NAME infusion, and the RIST was repeated.
Effect of GSH depletion on insulin sensitivity and determination of the HISS-dependent component of insulin action. A control RIST was performed as described in the BSO (2 mmol/kg body wt ip, 20 days, n = 5) and sham (intraperitoneal saline, n = 6) groups to evaluate insulin sensitivity. Thereafter, the RIST index was determined 60 min after intraportal infusion of L-NAME (1 mg/kg, 5-min bolus) in the BSO or sham group to evaluate HISS action.
Effect of the NO donor SIN-1 on L-NAME-induced insulin resistance in GSH-depleted rats. SIN-1 (5 mg/kg, 5-min bolus) was infused intraportally 90 min after L-NAME, and the RIST was repeated in the BSO (n = 5) and sham (n = 6) groups. Rats were allowed to stabilize between each RIST.
Hepatic GSH determination.
After the RISTs were performed in the BSO and sham groups, the liver
was rapidly dissected out, immediately frozen on liquid nitrogen, and
stored at 70°C until further analysis. Liver GSH was determined by
the peroxidase-reductase assay following a method described by Marinho
et al. (16).
Drugs
BSO, L-NAME, SNP, SIN-1, and D-glucose were purchased from Sigma-Aldrich; human insulin (Humulin, regular) from Lilly, pentobarbital (Eutasil) from Sanofi, and heparin from Braun. All chemicals were dissolved in saline.Data Analysis
Data were analyzed by repeated-measures ANOVA followed by the Tukey-Kramer multiple comparison test in each group. GSH quantification data were compared using the Student's t-test. Values are means ± SE. Differences were accepted as statistically significant at P < 0.05. Whenever a P value is not indicated, differences are not statistically significant. ![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Effect of Intraportal Administration of the NOS Antagonist L-NAME on Insulin Sensitivity
The control RIST was 202.4 ± 11.1 mg glucose/kg (n = 5). At 30 min after intraportal L-NAME (1 mg/kg) administration, the RIST index was reduced to 139.8 ± 26.7 mg glucose/kg, which corresponds to a statistically nonsignificant decrease of 28.9 ± 14.9% in insulin sensitivity. At 90 min after L-NAME administration, the RIST index was 80.2 ± 6.1 mg glucose/kg, which corresponds to a 59.5 ± 4.3% decrease in insulin sensitivity (P < 0.001). At 140 min after L-NAME administration, the RIST index was 97.3 ± 24.0 mg glucose/kg, and insulin sensitivity was decreased by 50.7 ± 12.9% (P < 0.01). Finally, at 190 min after the L-NAME bolus, the RIST index was 112.8 ± 17.7 mg glucose/kg, with a 43.4 ± 9.8% decrease compared with control values (P < 0.01). According to these results, the maximal L-NAME effect on insulin sensitivity was achieved 90-190 min after the drug infusion. The mean arterial blood pressure increased after L-NAME infusion from 119.3 ± 4.0 to 141.4 ± 3.2 mmHg at 20 min (P < 0.01) and 131.7 ± 6.7 mmHg after 190 min.Effect of Intravenous vs. Intraportal Administration of the NO Donor SNP on L-NAME-Induced Insulin Resistance
Neither intraportal (142.5 ± 15.8 mg glucose/kg, n = 6) nor intravenous (110.5 ± 34.1 mg glucose/kg, n = 5) infusion of SNP (20 nmol · kg
|
|
Effect of Intraportal Administration of the NO Donor SIN-1 on L-NAME-Induced Insulin Resistance
The control RIST index of 271.3 ± 37.6 mg glucose/kg was significantly reduced to 152.2 ± 21.3 mg glucose/kg (P < 0.01) after intraportal infusion of L-NAME (1 mg/kg, n = 5). Intraportal administration of SIN-1 (5 mg/kg) completely reversed the inhibition caused by L-NAME (321.7 ± 44.7 mg glucose/kg; Fig. 3). After L-NAME infusion, the mean arterial blood pressure increased from 115.8 ± 8.5 to 127.5 ± 5.3 mmHg and remained at this level during the RIST. The mean arterial blood pressure decreased (from 123.3 ± 5.4 to 80.8 ± 6.5 mmHg, P < 0.001) after SIN-1 administration but remained constant during the RIST.
|
Effect of GSH Depletion on Insulin Sensitivity and Determination of the HISS-Dependent Component of Insulin Action
The RIST index was significantly lower in the BSO group (158.4 ± 12.2 mg glucose/kg, n = 5; Fig. 4) than in the sham group (260.2 ± 15.6 mg glucose/kg, n = 6, P < 0.001; Fig. 5). Therefore, GSH depletion with BSO reduced insulin sensitivity by 39.1%. Intraportal infusion of L-NAME (1 mg/kg) decreased the RIST index in the BSO and sham groups. In the BSO group, the RIST index after L-NAME was 109.0 ± 9.1 mg glucose/kg, corresponding to a change from control of 30.6 ± 4.4% (Fig. 4); in the sham group, the RIST index was 121.2 ± 12.8 mg glucose/kg, corresponding to a change from control of 52.3 ± 5.8% (P < 0.05; Fig. 5). HISS action, quantified by subtracting the post-L-NAME RIST from the control RIST, was 138.9 ± 22.8 mg glucose/kg for the sham group and only 49.3 ± 8.6 mg glucose/kg for the BSO group (P < 0.01), which corresponds to a 64.4% reduction of HISS action after BSO treatment.
|
|
Effect of the NO Donor SIN-1 on L-NAME-Induced Insulin Resistance in BSO-Treated Rats
In the BSO group, intraportal SIN-1 (5 mg/kg) did not reverse the decrease in insulin sensitivity caused by L-NAME (77.8 ± 12.4 mg glucose/kg; Fig. 4). However, in the sham group, SIN-1 completely restored insulin sensitivity (258.1 ± 18.5 mg glucose/kg, P < 0.001; Fig. 5).Hepatic GSH Determination
GSH concentration was decreased in the BSO group, as expected. The GSH levels were 5.9 ± 0.4 µmol/g fresh liver in the sham group and 3.0 ± 0.4 µmol/g fresh liver in the BSO group, which corresponds to a decrease of 49.2% (P < 0.001; Fig. 6).
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A novel neurohumoral regulatory mechanism for insulin action was recently reported (13). According to this mechanism, insulin action at the skeletal muscle consists of two components: one is mediated through hepatic NO, and the other is independent of NO production in the liver (28). The hepatic NO-dependent component is responsible for the release of a putative hormone referred to as HISS, which accounts for ~55% of the whole body insulin action (14). Recent studies (14) have demonstrated that HISS release is impaired in the fasted state and maximal in the immediate postprandial state. It has also been suggested that lack of HISS release after feeding leads to insulin resistance typical of type 2 diabetes (13). Hepatic GSH levels are depleted during fasting (31), and serum GSH levels are decreased in type 2 diabetes (17, 33, 34), suggesting the involvement of GSH in HISS release, as well as in insulin action. Our findings confirm the hypothesis that hepatic GSH, together with NO, is required for full HISS-dependent insulin action.
In the fed state, insulin resistance induced by NOS antagonism can be restored by providing NO to the liver (7, 27). According to Sadri and Lautt (27), intraportal administration of L-NAME at 1 mg/kg significantly reduced the response to insulin, whereas administration of the same dose intravenously did not cause a significant decrease in the insulin response. Insulin sensitivity was restored after administration of intraportal, but not intravenous, SIN-1. These experiments support the hypothesis that hepatic NO mediates the HISS-dependent component of insulin action (13, 27).
In the present work, we studied the ability of different NO donors to
reverse HISS-dependent insulin resistance. Two NO donors with distinct
chemistries were used. SIN-1 decomposes nonenzymatically to yield NO
and superoxide (O): the reaction of GSH with
NO/O
20-fold more efficient than the
reaction of GSH with ONOO
(19). In addition,
ONOO
formation is partially outcompeted by the rapid
reaction of NO/O
The other NO donor used in the present study, SNP, releases NO promptly
and spontaneously, without O
In the light of the facts presented, we suggest that intraportal SIN-1
was able to reverse L-NAME-induced insulin resistance because it mimics hepatic NOS activity by releasing
NO/O
Several lines of evidence suggest that increased oxidative stress may
play a role in peripheral insulin resistance (4, 20, 22).
Subjecting muscle and fat cells to oxidative stress has been shown to
result in a dramatic decrease of insulin-stimulated glucose transport
(12, 25, 32) and glycogen synthesis (3). In
adipocytes, H2O2 impairs various metabolic
effects of insulin, including the stimulation of glucose uptake
activity, through alterations in the expression and translocation
capacity of the glucose transporter GLUT-4 (10, 25). It
was also reported that oxidative stress has an inhibitory effect on
tyrosine phosphorylation of the insulin receptor -subunit
(8).
Decreased GSH levels were found in adipocytes exposed to an H2O2-generating system (26) and also in blood and tissues of diabetic rats (17, 33, 34), which raises the possibility that decreased GSH impairs insulin action through enhancement of oxidative stress. Nevertheless, diminished glucose tolerance was observed in GSH-depleted rats, although in vitro insulin responsiveness in skeletal muscle and adipocytes was preserved (10). Khamaisi et al. (10) describe the intriguing observation that GSH depletion by BSO was progressively associated with abnormal glucose tolerance tests, which could not be attributed to impaired insulin secretion or insulin action in skeletal muscle or adipose tissue. According to these authors, GSH levels in the muscle were reduced by 14 ± 1% in skeletal muscle; nevertheless, the muscle responsiveness to insulin, assessed ex vivo by measuring 2-deoxyglucose uptake in the absence and presence of insulin, was not significantly different in BSO-treated and control animals, although in vivo impaired glucose tolerance was observed (10).
Other studies (21, 24) report beneficial metabolic effects of antioxidants when administered to diabetic subjects. De Mattia et al. (4) state that GSH infusion increases total glucose uptake in type 2 diabetes patients.
The exposure to oxidative stress conditions is characterized by
decreased GSH-to-GSSG ratio, decreased GLUT-4 protein and mRNA
expression, and generation of lipid peroxidation products (3, 10,
25, 32). However, these oxidative stress markers were not
altered in BSO-treated compared with control rats by administration of
BSO at 2 mmol · kg1 · day
1
(10). With regard to the possible effects of oxidative
stress induced by GSH depletion on insulin action, administration of BSO at 2 mmol · kg
1 · day
1
allowed us to assess the isolated effect of GSH depletion without mimicking the complex reactions associated with oxidative stress (10, 12). GSH depletion by BSO did not significantly
affect basal or insulin-stimulated glucose uptake in adipocyte and
skeletal muscle cell lines, in contrast with
H2O2 exposure, which significantly impaired
glucose uptake activity in the same conditions (10). This
supports the hypothesis that the effects of GSH depletion by BSO on
insulin sensitivity are not secondary to oxidative stress.
Our hypothesis is that decreased hepatic GSH levels promote an HISS-dependent impairment of insulin responsiveness in skeletal muscle. In BSO-treated rats, GSH levels decreased by 49.8% and insulin sensitivity decreased by 39.1%. After L-NAME infusion, the RIST index was similar in the BSO and sham groups, indicating that HISS-independent insulin action was normal and that GSH depletion affected HISS action only. Moreover, SIN-1 administration completely restored insulin sensitivity in the sham but not in the BSO group. We, therefore, suggest that insulin resistance observed in BSO-treated rats is due to hepatic GSH depletion and subsequent decreased ability to synthesize GSNO, which we hypothesize is involved in HISS release.
We have shown that in the fasted state, when HISS release is suppressed, intraportal SIN-1 administration is not able to restore HISS-dependent insulin action (unpublished observations), probably because hepatic GSH levels are reduced in the fasted state (31).
Our findings support the hypothesis that NO and GSH are essential in HISS synthesis/release. Additional studies are required to evaluate the role of GSH/NO in animal models of insulin resistance having in mind further pharmacological manipulations to increase HISS-dependent insulin sensitivity.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Prof. M. C. Santos for help with the glutathione quantification technique and Profs. P. F. Costa and A. I. Santos for helpful discussions.
![]() |
FOOTNOTES |
---|
This study was supported by Fundação da Ciência e Tecnologia (FCT) Grants POCTI/SAU/14009/1998 and POCTI/NSE42397/2001 and by Associação Protectora dos Diabéticos de Portugal. M. P. Guarino was supported by FCT Fellowship BD/4916/2001.
Address for reprint requests and other correspondence: M. P. Macedo, Dept. of Physiology, Faculty of Medical Sciences, New University of Lisbon, Campo Mártires da Pátria 130, 1169-056 Lisbon, Portugal (E-mail: mpmacedo.biot{at}fcm.unl.pt).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published December 4, 2002;10.1152/ajpgi.00423.2002
Received 26 September 2002; accepted in final form 2 December 2002.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Baron, A,
Zhu JS,
Marshall S,
Irsula O,
Brechtel G,
and
Keech C.
Insulin resistance after hypertension induced by the nitric oxide synthesis inhibitor L-NMMA in rats.
Am J Physiol Endocrinol Metab
269:
E709-E715,
1995
2.
Bates, JN,
Baker MT,
Guerra R,
and
Harrison DG.
Nitric oxide generation from nitroprusside by vascular tissue.
Biochem Pharmacol
42:
S157-S165,
1991[ISI][Medline].
3.
Blair, A,
Hajduch E,
Litherland G,
and
Hundal S.
Regulation of glucose transport and glycogen synthesis in L6 muscle cells during oxidative stress.
J Biol Chem
274:
36293-36299,
1999
4.
De Mattia, G,
Bravi MC,
Laurenti O,
Cassone-Faldetta M,
Armiento A,
Ferri C,
and
Balsano F.
Influence of reduced glutathione infusion on glucose metabolism in patients with non-insulin-dependent diabetes mellitus.
Metabolism
47:
993-997,
1998[ISI][Medline].
5.
Feelish, M,
and
Noak E.
Nitric oxide (NO) formation from nitrovasodilators occurs independently of hemoglobin or non-heme iron.
Eur J Pharmacol
142:
465-469,
1987[ISI][Medline].
6.
Giugliano, D,
Ceriello A,
and
Paolisso G.
Oxidative stress and diabetic vascular complications.
Diabetes Care
19:
257-267,
1996[Abstract].
7.
Guarino, MP,
Correia NC,
Raposo J,
and
Macedo MP.
Nitric oxide synthase inhibition decreases output of hepatic insulin sensitizing substance (HISS), which is reversed by SIN-1 but not by nitroprusside.
Proc West Pharmacol Soc
44:
25-26,
2001[Medline].
8.
Hansen, L,
Ikeda Y,
Olsen G,
Busch A,
and
Mosthaf L.
Insulin signalling is inhibited by micromolar concentrations of H2O2.
J Biol Chem
274:
25078-25084,
1999
9.
Hogg, N,
Singh RJ,
and
Kalyanaraman B.
Production of hydroxyl radicals from the simultaneous generation of superoxide and nitric oxide.
FEBS Lett
382:
223-228,
1996[ISI][Medline].
10.
Khamaisi, M,
Kavel O,
Rosenstock M,
Porat M,
Yuli M,
Kaiser N,
and
Rudich A.
Effect of inhibition of glutathione synthesis on insulin action: in vivo and in vitro studies using buthionine sulfoximine.
Biochem J
349:
579-586,
2000[ISI][Medline].
11.
Kharitonov, V,
Sundquist A,
and
Sharma V.
Kinetics of nitrosation of thiols by nitric oxide in the presence of oxygen.
J Biol Chem
270:
28158-28164,
1995
12.
Kozlovsky, N,
Rudich A,
Potashnik R,
Ebina Y,
Murakami T,
and
Bashan N.
Transcriptional activation of the glut1 gene in response to oxidative stress in l6 myotubes.
J Biol Chem
272:
33367-33372,
1997
13.
Lautt, WW.
The HISS story overview: a novel hepatic neurohumoral regulation of peripheral insulin sensitivity in health and diabetes.
Can J Physiol Pharmacol
77:
553-562,
1999[ISI][Medline].
14.
Lautt, WW,
Macedo MP,
Sadri P,
Takayama S,
Duarte-Ramos F,
and
Legare DJ.
Hepatic parasympathetic (HISS) control of insulin determined by feeding and fasting.
Am J Physiol Gastrointest Liver Physiol
281:
G29-G36,
2001
15.
Lautt, WW,
Wang X,
Sadri P,
Legare DL,
and
Macedo MP.
Rapid insulin sensitivity test (RIST).
Can J Physiol Pharmacol
76:
1080-1086,
1998[ISI][Medline].
16.
Marinho, HS,
Baptista M,
and
Pinto RE.
Glutathione metabolism in hepatomous liver of rats treated with diethylnitrosamine.
Biochim Biophys Acta
1360:
157-168,
1997[ISI][Medline].
17.
Martina, V,
Bruno GA,
Zumpano E,
Origlia C,
Quaranta L,
and
Pescarm GP.
Administration of glutathione in patients with type 2 diabetes mellitus increases the platelet constitutive nitric oxide synthase activity and reduces PAI-1.
J Endocrinol Invest
24:
37-41,
2001[ISI][Medline].
18.
Mayer, B,
Pfeiffer S,
Schrammel A,
Koesling D,
Schmidt K,
and
Brunner F.
A new pathway of nitric oxide/cyclic GMP signalling involving S-nitrosoglutathione.
J Biol Chem
273:
3264-3270,
1998
19.
Mayer, B,
Schrammel A,
Klatt P,
Koesling D,
and
Schmidt K.
Peroxynitrite-induced accumulation of cyclic GMP in endothelial cells and stimulation of purified soluble guanylyl cyclase.
J Biol Chem
270:
17355-17360,
1995
20.
Nourooz Zadeh, J,
Rahimi A,
Tajaddini Sarmadi J,
Tritschler H,
Rosen P,
Halliwell B,
and
Betteridge D.
Relationships between plasma measures of oxidative stress and metabolic control in NIDDM.
Diabetologia
40:
647-653,
1997[Medline].
21.
Paolisso, G,
D'Amore A,
Balbi V,
Volpe C,
Galzerano D,
Giugliano D,
Sgambato S,
Varricchio M,
and
Dónofrio F.
Plasma vitamin C affects glucose homeostasis in healthy subjects and in non-insulin-dependent diabetics.
Am J Physiol Endocrinol Metab
266:
E261-E268,
1994
22.
Paolisso, G,
D'Amore A,
Di Maro G,
Galzerano D,
Tesauro P,
Varrichio M,
and
D'Onofrio F.
Evidence for a relationship between free radicals and insulin action in the elderly.
Metabolism
42:
659-663,
1993[ISI][Medline].
23.
Paolisso, G,
D'Amore A,
Volpe C,
Balbi V,
Saccomanno F,
Galzerano D,
Giugliano D,
Varrichio M,
and
D'Onofrio F.
Evidence for a relationship between oxidative stress and insulin action in non-insulin-dependent (NIDDM) diabetic patients.
Metabolism
43:
1426-1429,
1994[ISI][Medline].
24.
Paolisso, G,
Di Maro G,
Pizza G,
D'Amore A,
Sgambato S,
Tesauro P,
Varricchio M,
and
Dónofrio F.
Plasma GSH/GSSG affects glucose homeostasis in healthy subjects and in non-insulin-dependent diabetics.
Am J Physiol Endocrinol Metab
263:
E435-E440,
1992
25.
Rudich, A,
Tirosh A,
Potashnik R,
Hemi R,
Kanety H,
and
Bashan N.
Prolonged oxidative stress impairs insulin-induced GLUT-4 translocation in 3T3-L1 adipocytes.
Diabetes
47:
1562-1569,
1998[Abstract].
26.
Rudich, A,
Tirosh A,
Potashnik R,
Khamiasi M,
and
Bashan N.
Lipoic acid protects against oxidative stress induced impairment in insulin stimulation of PKB and glucose transport in 3T3-L1 adipocytes.
Diabetologia
42:
949-957,
1999[ISI][Medline].
27.
Sadri, P,
and
Lautt WW.
Blockade of hepatic nitric oxide synthase causes insulin resistance.
Am J Physiol Gastrointest Liver Physiol
277:
G101-G108,
1999
28.
Sadri, P,
and
Lautt WW.
Insulin resistance caused by nitric oxide synthase inhibition.
Proc West Pharmacol Soc
40:
19-20,
1997[Medline].
29.
Samiec, P,
Drews Botsch C,
Flagg E,
Kurtz J,
Sternberg P,
Reed R,
and
Jones D.
Glutathione in human plasma: decline in association with aging, age-related macular degeneration and diabetes.
Free Radic Biol Med
24:
699-704,
1998[ISI][Medline].
30.
Schrammel, A,
Pfeiffer S,
Schmidt K,
Koesling D,
and
Mayer B.
Activation of soluble guanylyl cyclase by the nitrovasodilator 3-morpholinosydnonimine involves formation of S-nitrosoglutathione.
Mol Pharmacol
54:
207-212,
1998
31.
Tateishi, N,
Higashi T,
Naruse A,
Nakashima K,
and
Shiozaki H.
Rat liver glutathione: possible role as a reservoir of cysteine.
J Nutr
107:
51-60,
1997.
32.
Tirosh, A,
Potashnik R,
Bashan N,
and
Rudich A.
Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes.
J Biol Chem
274:
10595-10602,
1999
33.
Vaziri, ND,
Wang XQ,
Oveisi F,
and
Rad B.
Induction of oxidative stress by glutathione depletion causes severe hypertension in normal rats.
Hypertension
36:
142-146,
2000
34.
Vijayalingam, S,
Parthiban A,
Shanmugasundaram KR,
and
Mohan V.
Abnormal antioxidant status in impaired glucose tolerance and non-insulin-dependent-diabetes mellitus.
Diabet Med
13:
715-719,
1996[ISI][Medline].
35.
Xie, H,
and
Lautt WW.
Insulin resistance of skeletal muscle produced by hepatic parasympathetic interruption.
Am J Physiol Endocrinol Metab
270:
E858-E863,
1996
36.
Xie, H,
and
Lautt WW.
Induction of insulin resistance by cholinergic blockade with atropine in the cat.
J Auton Pharmacol
15:
361-369,
1995[ISI][Medline].
37.
Xie, H,
Tsybenko V,
Johnson M,
and
Lautt WW.
Insulin resistance of glucose response produced by hepatic denervation.
Can J Physiol Pharmacol
71:
175-178,
1993[ISI][Medline].
38.
Yoshida, K,
Hirokawa J,
Tagami S,
Kawakami Y,
Urata Y,
and
Kondo T.
Weakened cellular scavenging activity against oxidative stress in diabetes mellitus: regulation of glutathione synthesis and efflux.
Diabetologia
38:
201-210,
1995[ISI][Medline].