Dietary cysteine alleviates sucrose-induced oxidative stress and insulin resistance

doi:10.1016/j.freeradbiomed.2007.01.006

Free Radical Biology and Medicine

Volume 42, Issue 7, 1 April 2007, Pages 1089-1097

https://doi.org/10.1016/j.freeradbiomed.2007.01.006 Get rights and content

Abstract

Diets that promote oxidative stress favor impairment in glucose homeostasis. In this context, increasing the cysteine intake may be beneficial by maintaining glutathione status. We have investigated the effects of dietary cysteine on oxidative stress and glucose homeostasis in rats fed a high-sucrose (HS) diet. Rats were assigned for 6 weeks to a standard diet or to HS diets in which the protein source was either an α-lactalbumin-rich whey concentrate (a cysteine-rich protein) or the total milk proteins alone or supplemented with 5.8 or 20 g N-acetylcysteine per kilogram of food. Increasing the cysteine intake prevented HS-induced oxidative stress, as assessed by blood and tissue glutathione and carbonyl levels. At the same time, the HS-induced glucose intolerance, impaired postprandial glycemic control, and decrease in muscle and liver insulin-induced activation of insulin receptor substrate 1 and Akt were prevented by increasing the level of dietary cysteine, a major original finding. Of great interest was the observation that all beneficial effects of cysteine supplementation were duplicated by the consumption of a cysteine-rich protein. These data show that increasing the cysteine intake limits HS-induced impairment of glucose homeostasis and suggest that these effects are mediated by a reduction in oxidative stress.

Introduction

Considerable attention has recently been paid to oxidative stress being a probable initiating event in the pathogenesis of insulin resistance (IR) [1], [2]. Several epidemiological surveys have reported a correlation between oxidative stress and IR [3], [4], [5]. A causative link is further suggested by experimental studies, which showed that antioxidant supplementation, with either vitamin E or α-lipoic acid, could prevent or reduce IR [6], [7], [8]. In addition, various experimental models of IR induction indicate that oxidative stress plays a critical role in the onset of this condition [9], particularly high-sucrose (HS) or high-fructose diets [10]. In these latter models, hyperglycemia, especially during the postprandial period, is acknowledged as a direct source of oxidative stress through various mechanisms that could be related to the overproduction of superoxide by the mitochondrial electron-transport chain [11]. The resulting impairment in the cellular redox state was reported to both decrease the tyrosine phosphorylation and increase the serine phosphorylation of IRS1, two events which lead to inactivation of the insulin signaling pathway [2], [12].

Glutathione (GSH; γ-glutamyl-cysteinyl-glycine) is a tripeptide involved in a variety of physiological functions. GSH is a major determinant of the intracellular redox balance and is involved in protection against free-radical-induced oxidative injuries [13]. GSH synthesis and turnover are modulated by dietary protein [14], [15] and particularly by dietary sulfur amino acids (SAA) [16], [17], [18] because they provide cysteine, the limiting amino acid for GSH synthesis. Although several experimental and clinical studies have reported an improvement in GSH status (i.e., total GSH and its redox state) in response to an increase in the dietary SAA content [19], [20], the potential benefits with regard to glycemic control are unknown.

The purpose of the current work was to investigate whether an increase in dietary cysteine intake could prevent the impairment of glucose homeostasis induced by a 6-week consumption of an HS diet. We modulated dietary cysteine intake using either a cysteine-rich protein (an α-lactalbumin-rich whey concentrate, αLAC) or cysteine per se, given as N-acetylcysteine (NAC), which is an effective cysteine donor [19].

Section snippets

Materials and methods

All experiments were carried out in accordance with the guidelines of the French Committee for Animal Care, using male Wistar rats (Harlan, France) which were 6 weeks old at the beginning of the study. The rats were adapted to laboratory conditions under a reverse light–dark cycle, as previously described [21]. Five AIN-93M-modified isocaloric diets were used (Table 1): a standard starch diet (ST) and HS diets in which the protein source was either α-lactalbumin-rich whey concentrate (HS_a) or

Food intake, growth, and metabolic characterization of rats

Average food intake was not modified by the type of diet (319.3 ± 5.5 kJ/day) and neither were growth, final body weight, and retroperitoneal fat pad weight (data not shown). Fasting blood glucose levels did not differ between groups after 5 weeks (Table 2). Fasting plasma insulin levels increased over time and were higher in HS₀ and HS₁ rats than in ST rats at week 5, whereas they did not differ between ST, HS_a, and HS₂ rats (Table 2). Fasting insulin values at week 5 differed significantly as a

Discussion

Dietary SAA modulate GSH synthesis, turnover, and the body's antioxidant capacity [16], [19], [31], but the potential benefits of glucose homeostasis are unknown, in particular in the context of an HS prooxidant diet. In this study, we showed that increasing the level of dietary cysteine in HS-fed rats clearly improved body GSH status, decreased oxidative stress, and improved glucose homeostasis.

Consumption of the HS diet for 6 weeks impaired body GSH status and induced oxidative stress, as

Acknowledgments

We thank Maggy Bardoux, Florine Moraes, and Sophie Daré for biochemical assays.

References (45)

A.E. Midaoui et al.
Lipoic acid prevents hypertension, hyperglycemia, and the increase in heart mitochondrial superoxide production
Am. J. Hypertens.
(2003)
S. Jacob et al.
Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial
Free Radic. Biol. Med.
(1999)
A. Tirosh et al.
Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. A putative cellular mechanism for impaired protein kinase B activation and GLUT4 translocation
J. Biol. Chem.
(1999)
F.Q. Schafer et al.
Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple
Free Radic. Biol. Med.
(2001)
S. Hum et al.
Varied protein intake alters glutathione metabolism in rats
J. Nutr.
(1992)
C. Morand et al.
Influence of methionine availability on glutathione synthesis and delivery by the liver
J. Nutr. Biochem.
(1997)
J.P. Richie et al.
Tissue glutathione and cysteine levels in methionine-restricted rats
Nutrition
(2004)
F. Mariotti et al.
Acute ingestion of dietary proteins improves post-exercise liver glutathione in rats in a dose-dependent relationship with their cysteine content
J. Nutr.
(2004)
F. Belfiore et al.
Insulin sensitivity indices calculated from basal and OGTT-induced insulin, glucose, and FFA levels
Mol. Genet. Metab.
(1998)
S.G. West et al.
Oral L-arginine improves hemodynamic responses to stress and reduces plasma homocysteine in hypercholesterolemic men
J. Nutr.
(2005)

R.L. Levine et al.

Carbonyl assays for determination of oxidatively modified proteins

Methods Enzymol.

(1994)

M.E. Anderson

Determination of glutathione and glutathione disulfide in biological samples

Methods Enzymol.

(1985)

C.C. White et al.

Fluorescence-based microtiter plate assay for glutamate-cysteine ligase activity

Anal. Biochem.

(2003)

M. Di Buono et al.

Regulation of sulfur amino acid metabolism in men in response to changes in sulfur amino acid intakes

J. Nutr.

(2003)

D. Song et al.

Chronic N-acetylcysteine prevents fructose-induced insulin resistance and hypertension in rats

Eur. J. Pharmacol.

(2005)

A.M. Fulghesu et al.

N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome

Fertil. Steril.

(2002)

G. De Mattia et al.

Influence of reduced glutathione infusion on glucose metabolism in patients with non-insulin-dependent diabetes mellitus

Metabolism

(1998)

M. Doi et al.

Isoleucine, a potent plasma glucose-lowering amino acid, stimulates glucose uptake in C2C12 myotubes

Biochem. Biophys. Res. Commun.

(2003)

S. Nishitani et al.

Leucine promotes glucose uptake in skeletal muscles of rats

Biochem. Biophys. Res. Commun.

(2002)

A. Ceriello

The possible role of postprandial hyperglycaemia in the pathogenesis of diabetic complications

Diabetologia

(2003)

T. Ogihara et al.

Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase

Diabetologia

(2004)

N.K. Gopaul et al.

Oxidative stress could precede endothelial dysfunction and insulin resistance in Indian Mauritians with impaired glucose metabolism

Diabetologia

(2001)

Cited by (94)

Compared with Milk Protein, a Wheat and Pea Protein Blend Reduces High-Fat, High-Sucrose Induced Metabolic Dysregulations while Similarly Supporting Tissue Protein Anabolism in Rats
2023, Journal of Nutrition
Plant proteins (PPs) have been associated with better cardiovascular health than animal proteins (APs) in epidemiological studies. However, the underlying metabolic mechanisms remain mostly unknown.
Using a combination of cutting-edge isotopic methods, we aimed to better characterize the differences in protein and energy metabolisms induced by dietary protein sources (PP compared with AP) in a prudent or western dietary context.
Male Wistar rats (n = 44, 8 wk old) were fed for 4.5 mo with isoproteic diets differing in their protein isolate sources, either AP (100% milk) or PP (50%:50% pea: wheat) and being normal (NFS) or high (HFS) in sucrose (6% or 15% kcal) and saturated fat (7% or 20% kcal), respectively. We measured body weight and composition, hepatic enzyme activities and lipid content, and plasma metabolites. In the intestine, liver, adipose tissues, and skeletal muscles, we concomitantly assessed the extent of amino acid (AA) trafficking using a ¹⁵N natural abundance method, the rates of macronutrient routing to dispensable AA using a ¹³C natural abundance method, and the metabolic fluxes of protein synthesis (PS) and de novo lipogenesis using a ²H labeling method. Data were analyzed using ANOVA and Mixed models.
At the whole-body level, PP limited HFS-induced insulin resistance (–27% in HOMA-IR between HFS groups, P < 0.05). In the liver, PP induced lower lipid content (–17%, P < 0.01) and de novo lipogenesis (–24%, P < 0.05). In the different tissues studied, PP induced higher AA transamination accompanied by higher routings of dietary carbohydrates and lipids toward dispensable AA synthesis by glycolysis and β-oxidation, resulting in similar tissue PS and protein mass.
In growing rats, compared with AP, a balanced blend of PP similarly supports protein anabolism while better limiting whole-body and tissue metabolic dysregulations through mechanisms related to their less optimal AA profile for direct channeling to PS.
Animal and Plant Protein Sources and Cardiometabolic Health
2019, Advances in Nutrition
The sources or types of protein in the diet have long been overlooked regarding their link to cardiometabolic health. The picture is complicated by the fact that animal and plant proteins are consumed along with other nutrients and substances which make up the “protein package” so plant and animal protein come with clear nutrient clusters. This review aimed at deciphering the relation between plant and animal protein and cardiometabolic health by examining different nutritional levels (such as amino acids, protein type, protein foods, protein patterns, and associated overall dietary and nutrient patterns) and varying levels of scientific evidence [basic science, randomized controlled trials (RCTs), observational data]. Plant protein in Western countries is a robust marker of nutrient adequacy of the diet, whereas the contribution of animal protein is highly heterogeneous. Yet recent data from large cohorts have confirmed that total and animal proteins are associated with the risk of cardiovascular disease and diabetes, even when fully adjusting for lifestyle and dietary or nutritional factors. Here again, there is marked variability depending on the type of animal protein. Protein from processed red meat and total red meat on the one hand, and from legumes, nuts, and seeds on the other, are often reported at the extremes of the risk range. RCTs using purified proteins have contributed little to the topic to date, inasmuch as the findings cannot readily be extrapolated to current or near-future diets, but RCTs studying whole protein foods have shown a beneficial effect of pulses. Despite the fact that many of the benefits of plant protein reported in observational or interventional studies may stem from the protein package that they convey and the nutrients that they displace, there are also important indications that protein per se may affect cardiometabolic health via the many amino acids that are present in typically contrasting levels in plant compared with animal proteins.
Effect of dietary glutathione supplementation on the immune responses and the fatty acid and amino acid composition in Chinese mitten crab, Eriocheir sinensis
2019, Aquaculture Reports
Citation Excerpt :
Moreover, supplementation with dietary sulphur-containing amino acids in weaning piglets has been shown to reduce inflammation (Liu et al., 2019). Additionally, increased cysteine (Cys) in rats served to enhance antioxidant defences in the plasma (Clemence et al., 2007). Glycine (Gly) has also been shown to prevent oxidative stress-induced damage by reducing the concentration of key enzymes responsible for free radical production (Alvarado et al., 2006).
Chinese mitten crab (Eriocheir sinensis) is an important aquatic commercial species in China. Due to the deterioration of the local aquaculture environment, the output and quality of Chinese mitten crab have been heavily influenced. Glutathione (GSH) is a tripeptide, that, when administered via diet, has been shown to improve the growth and enhance immune function in livestock and poultry. However, whether GSH could be developed as a special feed supplement for Chinese mitten crab remains unclear. Therefore, in the present study, a total of 200 crabs were divided into five groups fed with experimental diets supplemented with 0, 300, 600, 900, and 1200 mg/kg of GSH for 65 days. Results showed that supplementation with 600 mg/kg GSH significantly improved growth performance with the percentage of polyunsaturated fatty acids (PUFAs) increasing and the percentage of saturated fatty acids significantly decreasing in the hepatopancreas. Further, crabs fed diets supplemented with 900 mg/kg of GSH enhanced the levels of glutamic acid, glycine, cysteine, serine and alanine compared to the control group. Diets supplemented with 600 or 900 mg/kg of GSH significantly improved the total protein, albumin (Alb), and globulin (Glb) contents in haemolymph. Moreover, crabs fed diets supplemented with 900 mg/kg GSH exhibited the highest myeloperoxidase activity and complement component 3 and 4 levels in the haemolymph, with the highest mRNA expression of immune related genes (alf1, alf2, alf3, crus1 and crus2) observed in the 600 and 900 mg/kg GSH groups. The present study has effectively shown that supplementation of E. sinensis diets with GSH served to enhance physiological and immunological functioning, which would subsequently enhance the overall health of the animal while also improving the economic yield from Chinese aquaculture.
Animal and plant proteins: Which effects on cardiometabolic health?
2019, Medecine des Maladies Metaboliques
Les sources ou les types de protéines dans l’alimentation ont longtemps été négligés en ce qui concerne leur lien avec la santé cardio-métabolique. Les « protéines animales » ou « végétales », sont consommées avec d’autres nutriments et substances si bien que la consommation de protéines provenant de différentes sources est associée, dans les aliments et dans les régimes, à des profils d’apport en nutriments. En raison des choix du consommateur, elle est aussi associée à des profils de consommation diététiques. Nous commencerons dans cet article par comprendre ces dernières relations, qui sont assez complexes, avant de résumer les données récentes qui ont associé la consommation de protéines animales et végétales au risque cardiovasculaire et diabétique. Nous verrons à ce titre les différences entre « protéines » animales et végétales, et les différences au sein des protéines animales (avec le cas assez particulier de la viande rouge transformée et de la viande rouge totale), et nous observerons qu’elles persistent même lorsqu’on tient compte des différences de mode de vie et des facteurs alimentaires/nutritionnels des consommateurs. Nous nous pencherons ensuite sur les essais cliniques randomisés, conduits avec des ingrédients protéiques purifiés ou avec des aliments riches en protéines, qui tendent à soutenir un bénéfice de certaines sources protéiques végétales, comme les légumineuses, vis-à-vis de facteurs de risque cardio-métabolique. Nous finirons par évoquer la possibilité que les effets des protéines végétales/animales puissent être aussi dues à leur profil différent en acides aminés. Nous conclurons qu’au total la littérature reste insuffisante, mais qu’elle indique les effets différentiels des « protéines » animales et végétales sur le risque cardio-métabolique pourraient provenir à la fois – et selon un niveau de preuve croissant :
(i) des apports différents en acides aminés;
(ii) des nutriments et autres substances intimement associés à la fraction protéique dans les aliments qui les contiennent;
(iii) à une modification des profils de consommation diététiques due aux arbitrages du consommateur entre les différents aliments vecteurs de ces protéines, eux même associés à d’autres aliments.
Sources or types of protein in the diet have long been neglected with regard to their link to cardiometabolic health. “Animal” or “plant” proteins are consumed with other nutrients and substances, so that the consumption of proteins, strictly speaking, from different sources is associated via foods and diets with patterns of nutrient intake. As a result of consumers’ choices, it is also associated with dietary patterns. In this article, we will begin by understanding these last complex relationships in western countries, before summarizing recent data that have associated animal and plant protein intakes with cardiovascular and diabetic risk. We will examine the differences between animal and vegetable “proteins” and those within animal proteins (with the rather particular case of processed red meat and total red meat), and how they persist even when differences in lifestyle and food/nutritional factors of consumers are taken into account. We will then consider the randomized clinical trials, conducted with purified protein ingredients or protein-rich foods, that tend to support a benefit of certain plant protein sources, such as legumes, with respect to cardiometabolic risk factors. Finally, we will discuss the possibility that the effects of vegetable/animal proteins may be mediated by their different amino acid profiles. We will conclude that, overall, the literature remains insufficient but indicates the differential effects of animal and plant “proteins” on cardiometabolic risk could come from both – and according to an increasing level of evidence – (i) different intakes of amino acids, (ii) nutrients and other substances intimately associated with the protein fraction in foods containing them, and (iii) a change in dietary consumption patterns due to the consumers’ trade-offs among the foods which convey these proteins and the foods to which they are associated.
Bovine α-lactalbumin hydrolysates (α-LAH) attenuate high-fat diet induced nonalcoholic fatty liver disease by modulating hepatic lipid metabolism in C57BL/6J mice
2019, Journal of Functional Foods
The effect of bovine α-lactalbumin hydrolysates (α-LAH) on attenuating high-fat diet (HFD) induced nonalcoholic fatty liver disease (NAFLD) was investigated. C57BL/6J mice were fed with HFD for 8 weeks to mimic the clinical features of NAFLD, and then were fed with HFD and bovine α-LAH at different doses (100, 200 and 400 mg/kg b.w.) for another 12 weeks to investigate the beneficial effects of bovine α-LAH on NAFLD. Our data showed that bovine α-LAH markedly reversed the increase of body weight gain, tissue weight, serum lipids, liver injury markers, and serum pro-inflammatory cytokines induced by HFD in C57BL/6J mice. Bovine α-LAH supplementation also ameliorated fat accumulation and oxidative stress, down-regulated PPARγ associated gene expression, and up-regulated PPARα associated gene expression in the liver of mice fed HFD. These findings suggested that bovine α-LAH is effective in attenuating HFD induced NAFLD in C57BL/6J mice.
Importance of protein and amino acid metabolism in the prevention and management of the metabolic syndrome. Modulation by n-3 fatty acids
2018, Cahiers de Nutrition et de Dietetique
Les protéines sont composées d’acides aminés qui ont deux fonctions essentielles : permettre l’accrétion et le renouvellement des protéines corporelles, et fournir des métabolites qui jouent des rôles physiologiques importants pour le maintien du bon fonctionnement de l’organisme, tels que le glutathion (dérivé de la cystéine) et le monoxyde d’azote ou NO (dérivé de l’arginine). De ce fait, ces acides aminés et leurs métabolites sont impliqués dans l’initiation et la progression du syndrome métabolique (SynMét). Un nombre croissant d’études montre que les acides gras polyinsaturés (AGPI) n-3 peuvent contrôler le métabolisme protéique ou celui de certains acides aminés, ce qui fait d’eux des candidats prometteurs à de nouvelles approches nutritionnelles. Dans cette revue, nous décrivons les effets favorables d’un apport d’AGPI n-3 dans un contexte de SynMét : 1) dans un objectif de prévention du SynMét, pour ralentir la mise en place de l’insulino-résistance, de la dysfonction endothéliale (avec un rôle du NO) et du stress oxydant (avec un rôle du glutathion). Les données suggèrent que l’apport d’huile végétale riche en 18 :3 n-3 (ALA) favorise la synthèse de glutathion à partir de cystéine et celle du NO à partir de l’arginine, comme le font des protéines végétales riches en cystéine et en arginine; 2) lors de la prise en charge du SynMét, et plus spécifiquement de l’obésité, pour limiter le catabolisme protéique et donc, la perte de masse musculaire qui peut accompagner la perte de poids imposée au patient. Les mécanismes régulés par les AGPI n-3 sont semblables à ceux observés lors d’autres situations de catabolisme protéique.
Proteins are made of amino acids that have two essential functions : to enable the accretion and renewal of body proteins, and to provide metabolites that play important physiological roles in maintaining the proper functioning of the body, such as glutathione (metabolite of cysteine) and nitric oxide or NO (metabolite of arginine. In consequence, amino acids and their metabolites are involved in the initiation and development of the metabolic syndrome (MetSynd). There is growing evidence that n-3 polyunsaturated fatty acids (PUFA) can regulate protein or amino acid metabolism, which makes them promising candidates for innovating nutritional strategies. In this review, we describe the favourable effects of an intake of n-3 (PUFA) in the context of metabolic syndrome : 1) for the prevention of the MetSynd, to slow down the development of insulin resistance, endothelial dysfunction (with a role of NO) and oxidative stress (with a role of glutathione). The addition of vegetable oil rich in 18 :3 n-3 (ALA) may promote the synthesis of glutathione from cysteine and NO from arginine, as do vegetable proteins rich in cysteine and arginine; 2) during the management of MetSynd, and in particular of obesity, to limit protein catabolism and thus the loss of muscle mass that may result from the weight loss imposed to the patient. The mechanisms regulated by n-3 PUFAs are similar to those observed in other situations of protein catabolism.

View all citing articles on Scopus

¹: Supported by an MRT grant from the French Ministry for Research, Present address: College of Medicine of Yeshiva University, Diabetes Research and Training Center, Department of Medicine, Bronx, NY 10463, USA.

View full text

Original ContributionDietary cysteine alleviates sucrose-induced oxidative stress and insulin resistance

Abstract

Introduction

Section snippets

Materials and methods

Food intake, growth, and metabolic characterization of rats

Discussion

Acknowledgments

Am. J. Hypertens.

Free Radic. Biol. Med.

J. Biol. Chem.

Free Radic. Biol. Med.

J. Nutr.

J. Nutr. Biochem.

Nutrition

J. Nutr.

Mol. Genet. Metab.

J. Nutr.

Methods Enzymol.

Methods Enzymol.

Anal. Biochem.

J. Nutr.

Eur. J. Pharmacol.

Fertil. Steril.

Metabolism

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

The possible role of postprandial hyperglycaemia in the pathogenesis of diabetic complications

Diabetologia

Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase

Diabetologia

Oxidative stress could precede endothelial dysfunction and insulin resistance in Indian Mauritians with impaired glucose metabolism

Diabetologia

Original Contribution
Dietary cysteine alleviates sucrose-induced oxidative stress and insulin resistance