Does free fatty acid infusion impair insulin action also through an increase in oxidative stress?

Paolisso, Giuseppe; Gambardella, A.; Tagliamonte, Maria; Saccomanno, F.; Salvatore, Teresa; Gualdiero, Pasquale; D’Onofrio, Manuel; Howard, Barbara V.

doi:10.1210/jcem.81.12.8954022

Cited by 82 publications

(48 citation statements)

References 15 publications

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“…Clinically, the ability of antioxidants to improve insulin sensitivity in obesity and type 2 diabetes mellitus is still somewhat controversial (Caballero 1993 in increased levels of circulating markers of oxidative stress and co-infusion of GSH partially prevents wholebody insulin resistance and thwarts the elevations in oxidative stress markers caused by 6 h of FFA elevation (Paolisso et al 1996). Our collaborative studies in humans (Xiao et al 2008) show that oral taurine prevents wholebody insulin resistance caused by prolonged (48 h) IH infusion and this is accompanied by a reduction in the plasma levels of markers of oxidative stress, namely MDA and 4-hydroxynonenal.…”

Section: Discussionmentioning

confidence: 99%

Effect of N-acetyl-l-cysteine on insulin resistance caused by prolonged free fatty acid elevation

Pereira¹,

Shah²,

Fantus³

et al. 2015

Journal of Endocrinology

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Circulating free fatty acids (FFAs) are elevated in obesity and cause insulin resistance. The objective of the current study was to determine whether the antioxidant N-acetyl-L-cysteine (NAC) prevented hepatic and peripheral insulin resistance caused by prolonged elevation of plasma FFAs. Chronically cannulated Wistar rats received saline (SAL), Intralipid plus heparin (IH), IH plus NAC, or NAC i.v. infusion for 48 h. Insulin sensitivity was determined using the hyperinsulinemic-euglycemic clamp with tritiated glucose tracer. IH induced hepatic and peripheral insulin resistance (P!0.05). NAC co-infusion did not prevent insulin resistance in the liver, although it was able to prevent peripheral insulin resistance. Prolonged IH infusion did not appear to induce oxidative stress in the liver because hepatic content of protein carbonyl, malondialdehyde, and reduced to oxidized glutathione ratio did not differ across treatment groups. In alignment with our insulin sensitivity results, IH augmented skeletal muscle protein carbonyl content and this was prevented by NAC co-infusion. Taken together, our results indicate that oxidative stress mediates peripheral, but not hepatic, insulin resistance resulting from prolonged plasma FFA elevation. Thus, in states of chronic plasma FFA elevation, such as obesity, antioxidants may protect against peripheral but not hepatic insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Effect of N-acetyl-l-cysteine on insulin resistance caused by prolonged free fatty acid elevation

Pereira¹,

Shah²,

Fantus³

et al. 2015

Journal of Endocrinology

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“…In humans, lipid-induced insulin resistance correlated with oxidative stress [32][33][34]. Co-infusion of reduced glutathione with Intralipid for 6 h improved whole-body glucose disposal as compared with lipid infusion alone [21]. Lipidinduced muscle insulin resistance in humans is associated with increased protein kinase C (PKC)-δ and -βII membrane translocation and decreased inhibitor of nuclear factor κB-α, evidence of IκB kinase β (IKKβ) activation [35].…”

Section: Discussionmentioning

confidence: 99%

“…Of note, oxidative stress can activate the JNK [19] and nuclear factor κB [17] proinflammatory pathways and endoplasmic reticulum stress [20]. Lipid-induced insulin resistance in healthy humans is associated with oxidative stress [21].…”

Section: Introductionmentioning

confidence: 99%

“…In both healthy subjects and in type 2 diabetic patients, restoration of redox balance by infusion of glutathione improved insulin sensitivity and beta cell function [26]. Infusion of reduced glutathione, an antioxidant, partially prevented lipid-induced insulin resistance in healthy humans [21]. The effects of NAC and TAU in lipid-induced insulin resistance and beta cell dysfunction have not been investigated in humans.…”

Section: Introductionmentioning

confidence: 99%

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Oral taurine but not N-acetylcysteine ameliorates NEFA-induced impairment in insulin sensitivity and beta cell function in obese and overweight, non-diabetic men

2007

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Aims/hypothesis Antioxidants have been shown to ameliorate lipid-induced impairment of insulin action and beta cell function, both in vitro and in animal studies. The aim of the present study was to examine the effects of two orally administered antioxidants, N-acetylcysteine (NAC) and taurine (TAU), on lipotoxicity in humans. Methods Nine non-diabetic men, who were either overweight or obese, underwent three studies each, 4-6 weeks apart, in random order: (1) i.v. infusion of saline for 48 h (SAL); (2) i.v. infusion of Intralipid and heparin for 48 h to mimic chronic elevation of plasma NEFA (IH); and (3) IH infusion for 48 h with concurrent oral NAC (IH+NAC). Six men underwent similar studies except for study 3, where instead of NAC they received a 2 week pretreatment with oral TAU (IH+TAU). Results For both the NAC and TAU studies, a 48 h IH infusion alone without antioxidant impaired insulin sensitivity (S I , 63% and 62% of SAL in NAC and TAU studies, respectively) and beta cell function, as evidenced by a reduction in disposition index (DI, 55% and 54% of SAL in NAC and TAU studies, respectively). NAC failed to prevent the lipid-induced increase in levels of the plasma oxidative stress marker malondialdehyde and did not prevent the lipid-induced reduction in S I or DI, whereas TAU completely prevented the rise in malondialdehyde and decreased 4-hydroxynonenal, and significantly improved S I (91% of SAL) and DI (81% of SAL). Conclusions/interpretation Oral TAU ameliorates lipidinduced functional beta cell decompensation and insulin resistance in humans, possibly by reducing oxidative stress.ClinicalTrials.gov ID no. NCT0018873

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confidence: 99%

Elevated post-prandial free fatty acids are associated with cardiac sympathetic overactivity in Type II diabetic patients

Manzella¹,

Grella²,

Marfella³

et al. 2002

Diabetologia

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Elevated post-prandial free fatty acids are associated with cardiac sympathetic overactivity in Type II diabetic patients decrome, Roche, Basel, Switzerland (CH)] and FFA (routine microfluormetric method) concentrations [5] were also assessed. Furthermore, all patients had all metabolites assessed at fasting as well as at pre-prandial and 2-h post-prandial conditions. All subjects gave their informed consent before participating in the study which was approved by the ethics committee of our institutions.All data are shown as means ± SD. Changes in plasma metabolites and LF/HF ratio were calculated as the difference between post-prandial and pre-prandial values. Analysis of variance (ANOVA) was used to calculate differences among the different experimental conditions. A p value of less than 0.05 was shown, Scheffe's test was also applied to analyse which intervention most influenced the overall difference between groups. Partial correlations were used to examine the association between the two variables independently of covariates. A p value of 0.05 was chosen as the level of significance.Despite oral hypoglycaemic agents, post-prandial glucose and FFA concentrations were more augmented than in preprandial and fasting conditions (Table 1). Similarly, analysis of HRV parameters provided evidence that LF to HF ratio was more elevated in post-prandial than in pre-prandial and fasting conditions ( Table 1). Independent of changes in plasma glucose concentrations, changes in post-prandial FFA correlated with changes in the post-prandial LF/HF ratio (r=0.57; p<0.001) and with changes in plasma TBARS (r=0.49; p<0.01) and TEAC (r=0.46; p<0.02) concentrations. After adjustment for changes in plasma glucose concentrations, changes in the LF/HF ratio were also correlated with the changes in plasma TBARS (r=0.52; p<0.003) and TEAC (r=0.50; p<0.002).Our study shows that increased post-prandial plasma FFA concentrations are associated with an enhanced degree of oxidative stress and of LF/HF ratio, an index of cardiac sympathovagal balance. Such data seems particularly relevant for explaining the relationship among plasma FFA, oxidative stress and sudden death in Type II diabetic patients. In fact, it has been shown that increased plasma FFA concentrations are a pro-oxidant factor [5] and that unbalanced sympathetic or parasympathetic tone seems linked to a degree of oxidative stress [6]. Furthermore, plasma concentrations are responsible for many cases of sudden death [7] despite the absence of documented pre-existing heart disease [7]. Chronic administration of an antioxidant agent such vitamin E has been shown to lower oxidative stress in Type II diabetic patients and to re-balance cardiac sympathetic activity [6], the latter phenomenon being associated with a decline in plasma catecholamine concentrations [6]. Notwithstanding, the concept that antioxidants are

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Does free fatty acid infusion impair insulin action also through an increase in oxidative stress?

Cited by 82 publications

References 15 publications

Effect of N-acetyl-l-cysteine on insulin resistance caused by prolonged free fatty acid elevation

Effect of N-acetyl-l-cysteine on insulin resistance caused by prolonged free fatty acid elevation

Oral taurine but not N-acetylcysteine ameliorates NEFA-induced impairment in insulin sensitivity and beta cell function in obese and overweight, non-diabetic men

Elevated post-prandial free fatty acids are associated with cardiac sympathetic overactivity in Type II diabetic patients

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