Abstract
Adiponectin is an anti-diabetic and anti-atherogenic adipokine; its plasma levels are decreased in obesity, insulin resistance, and type 2 diabetes. An adiponectin-interacting protein named disulfide bond A-like protein (DsbA-L) plays an important role in the assembly of adiponectin. This study examined the hypothesis that l-cysteine (LC) regulates glucose homeostasis through the DsbA-L upregulation and synthesis and secretion of adiponectin in diabetes. 3T3L1 adipocytes were treated with LC (250 and 500 µM, 2 h) and high glucose (HG, 25 mM, 20 h). Results showed that LC supplementation significantly (p < 0.05) upregulated the DsbA-L, adiponectin, and GLUT-4 protein expression and glucose utilization in HG-treated adipocytes. LC supplementation significantly (p < 0.05) promoted the secretion of total and HMW adiponectin secretion in HG-treated adipocytes. In addition, LC significantly (p < 0.05) decreased ROS production and MCP-1 secretion in HG-treated cells. We further investigated whether MCP-1 has any role of LC on DsbA-L expression and adiponectin levels in 3T3-L1 cells. Treatment with LC prevented the decrease in DsbA-L, adiponectin, and GLUT-4 expression in 3T3L1 adipocyte cells exposed to MCP-1. Thus, this study demonstrates that DsbA-L and adiponectin upregulation mediates the beneficial effects of LC on glucose utilization by inhibiting MCP-1 secretion in adipocytes and provides a novel mechanism by which LC supplementation can improve insulin sensitivity in diabetes.
Similar content being viewed by others
References
Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y (2000) Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20:1595–1599
Lindsay RS, Walker JD, Havel PJ, Hamilton BA, Calder AA, Johnstone FD (2003) Adiponectin is present in cord blood but is unrelated to birth weight. Diabetes Care 26:2244–2249
Sun H, Zhang Y, Gao P, Li Q, Sun Y, Zhang J, Xu C (2011) Adiponectin reduces C-reactive protein expression and downregulates STAT3 phosphorylation induced by IL-6 in HepG2 cells. Mol Cell Biochem 347:183–189
Dadson K, Liu Y, Sweeney G (2011) Adiponectin action: a combination of endocrine and autocrine/paracrine effects. Front Endocrinol (Lausanne) 2:62
Liu M, Zhou L, Xu A, Lam KS, Wetzel MD, Xiang R, Zhang J, Xin X, Dong LQ, Liu F (2008) A disulfide-bond A oxidoreductase-like protein (DsbA-L) regulates adiponectin multimerization. Proc Natl Acad Sci USA 105:18302–18307
Liu M, Xiang R, Wilk SA, Zhang N, Sloane LB, Azarnoush K, Zhou L, Chen H, Xiang G, Walter CA, Austad SN, Musi N, DeFronzo RA, Asmis R, Scherer PE, Dong LQ, Liu F (2012) Fat-specific DsbA-L overexpression promotes adiponectin multimerization and protects mice from diet-induced obesity and insulin resistance. Diabetes 61:2776–2786
Sekhar RV, McKay SV, Patel SG, Guthikonda AP, Reddy VT, Balasubramanyam A, Jahoor F (2011) Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine. Diabetes Care 34:162–167
Darmaun D, Smith SD, Sweeten S, Hartman BK, Welch S, Mauras N (2008) Poorly controlled type 1 diabetes is associated with altered glutathione homeostasis in adolescents: apparent resistance to N-acetylcysteine supplementation. Pediatr Diabetes 9:577–582
Jain SK, Bull R, Rains JL, Bass PF, Levine SN, Reddy S, McVie R, Bocchini JA (2010) Low levels of hydrogen sulfide in the blood of diabetes patients and streptozotocin-treated rats causes vascular inflammation? Antioxid Redox Signal 12:1333–1337
Whiteman M, Gooding KM, Whatmore JL, Ball CI, Mawson D, Skinner K, Tooke JE, Shore AC (2010) Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide. Diabetologia 53:1722–1726
Blouet C, Mariotti F, Mikogami T, Tome D, Huneau JF (2007) Meal cysteine improves postprandial glucose control in rats fed a high-sucrose meal. J Nutr Biochem 18:519–524
Blouet C, Mariotti F, Azzout-Marniche D, Mathe V, Mikogami T, Tome D, Huneau JF (2007) Dietary cysteine alleviates sucrose-induced oxidative stress and insulin resistance. Free Radic Biol Med 42:1089–1097
Nilsson M, Stenberg M, Frid AH, Holst JJ, Bjorck IM (2004) Glycemia and insulinemia in healthy subjects after lactose-equivalent meals of milk and other food proteins: the role of plasma amino acids and incretins. Am J Clin Nutr 80:1246–1253
Akhavan T, Luhovyy BL, Brown PH, Cho CE, Anderson GH (2010) Effect of premeal consumption of whey protein and its hydrolysate on food intake and postmeal glycemia and insulin responses in young adults. Am J Clin Nutr 91:966–975
Jain SK, Velusamy T, Croad JL, Rains JL, Bull R (2009) l-cysteine supplementation lowers blood glucose, glycated hemoglobin, CRP, MCP-1, and oxidative stress and inhibits NF-kappaB activation in the livers of Zucker diabetic rats. Free Radic Biol Med 46:1633–1638
Song D, Hutchings S, Pang CC (2005) Chronic N-acetylcysteine prevents fructose-induced insulin resistance and hypertension in rats. Eur J Pharmacol 508:205–210
Diniz YS, Rocha KK, Souza GA, Galhardi CM, Ebaid GM, Rodrigues HG, Novelli Filho JL, Cicogna AC, Novelli EL (2006) Effects of N-acetylcysteine on sucrose-rich diet-induced hyperglycaemia, dyslipidemia and oxidative stress in rats. Eur J Pharmacol 543:151–157
Xia Z, Guo Z, Nagareddy PR, Yuen V, Yeung E, McNeill JH (2006) Antioxidant N-acetylcysteine restores myocardial Mn-SOD activity and attenuates myocardial dysfunction in diabetic rats. Eur J Pharmacol 544:118–125
Haber CA, Lam TK, Yu Z, Gupta N, Goh T, Bogdanovic E, Giacca A, Fantus IG (2003) N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress. Am J Physiol Endocrinol Metab 285:E744–E753
Ho E, Chen G, Bray TM (1999) Supplementation of N-acetylcysteine inhibits NFkappaB activation and protects against alloxan-induced diabetes in CD-1 mice. FASEB J 13:1845–1854
Kaneto H, Kajimoto Y, Miyagawa J, Matsuoka T, Fujitani Y, Umayahara Y, Hanafusa T, Matsuzawa Y, Yamasaki Y, Hori M (1999) Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity. Diabetes 48:2398–2406
Tanaka Y, Gleason CE, Tran PO, Harmon JS, Robertson RP (1999) Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc Natl Acad Sci USA 96:10857–10862
Pieper GM, Siebeneich W (1998) Oral administration of the antioxidant, N-acetylcysteine, abrogates diabetes-induced endothelial dysfunction. J Cardiovasc Pharmacol 32:101–105
Adachi Y, Yoshikawa Y, Sakurai H (2007) Antidiabetic zinc(II)-N-acetyl-L-cysteine complex: evaluations of in vitro insulinomimetic and in vivo blood glucose-lowering activities. BioFactors 29:213–223
Hsu CC, Yen HF, Yin MC, Tsai CM, Hsieh CH (2004) Five cysteine-containing compounds delay diabetic deterioration in Balb/cA mice. J Nutr 134:3245–3249
Lin CC, Yin MC, Hsu CC, Lin MP (2004) Effect of five cysteine-containing compounds on three lipogenic enzymes in Balb/cA mice consuming a high saturated fat diet. Lipids 39:843–848
Liu Z, Li J, Zeng Z, Liu M, Wang M (2008) The antidiabetic effects of cysteinyl metformin, a newly synthesized agent, in alloxan- and streptozocin-induced diabetic rats. Chem Biol Interact 173:68–75
Iyer SS, Accardi CJ, Ziegler TR, Blanco RA, Ritzenthaler JD, Rojas M, Roman J, Jones DP (2009) Cysteine redox potential determines pro-inflammatory IL-1beta levels. PLoS ONE 4:e5017
An Z, Wang H, Song P, Zhang M, Geng X, Zou MH (2007) Nicotine-induced activation of AMP-activated protein kinase inhibits fatty acid synthase in 3T3L1 adipocytes: a role for oxidant stress. J Biol Chem 282:26793–26801
Candiloros H, Muller S, Zeghari N, Donner M, Drouin P, Ziegler O (1995) Decreased erythrocyte membrane fluidity in poorly controlled IDDM Influence of ketone bodies. Diabetes Care 18:549–551
Manna P, Gungor N, McVie R, Jain SK (2014) Decreased cystathionine-gamma-lyase (CSE) activity in livers of type 1 diabetic rats and peripheral blood mononuclear cells (PBMC) of type 1 diabetic patients. J Biol Chem 289:11767–11778
Manna P, Jain SK (2015) Obesity, oxidative stress, adipose tissue dysfunction and the associated health risks: causes and therapeutic strategies. Metab Syndr Relat Disord 13:423–444
Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946
Combs TP, Wagner JA, Berger J, Doebber T, Wang WJ, Zhang BB, Tanen M, Berg AH, O’Rahilly S, Savage DB, Chatterjee K, Weiss S, Larson PJ, Gottesdiener KM, Gertz BJ, Charron MJ, Scherer PE, Moller DE (2002) Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. Endocrinology 143:998–1007
Berg AH, Combs TP, Du X, Brownlee M, Scherer PE (2001) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:947–953
Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L (2001) Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest 108:1875–1881
Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC, Matsuzawa Y (2001) Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50:1126–1133
Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R (2001) Adiponectin gene expression is inhibited by beta-adrenergic stimulation via protein kinase A in 3T3-L1 adipocytes. FEBS Lett 507:142–146
Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, Kamon J, Satoh H, Yano W, Froguel P, Nagai R, Kimura S, Kadowaki T, Noda T (2002) Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 277:25863–25866
Tajiri Y, Hiramatsu S, Karashima T, Mimura K, Umeda F (2002) Adiponectin as a reliable marker for insulin resistance in type 2 diabetic patients (Abstract). Diabetes 51(Suppl. 2):A305
Matsubara M, Maruoka S, Katayose S (2002) Inverse relationship between plasma adiponectin and leptin concentrations in normal-weight and obese women. Eur J Endocrinol 147:173–180
Haque WA, Shimomura I, Matsuzawa Y, Garg A (2002) Serum adiponectin and leptin levels in patients with lipodystrophies. J Clin Endocrinol Metab 87:2395
Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y (2001) PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50:2094–2099
Hirose H, Kawai T, Yamamoto Y, Taniyama M, Tomita M, Matsubara K, Okazaki Y, Ishii T, Oguma Y, Takei I, Saruta T (2002) Effects of pioglitazone on metabolic parameters, body fat distribution, and serum adiponectin levels in Japanese male patients with type 2 diabetes. Metabolism 51:314–317
Yang WS, Jeng CY, Wu TJ, Tanaka S, Funahashi T, Matsuzawa Y, Wang JP, Chen CL, Tai TY, Chuang LM (2002) Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 25:376–380
Tao C, Sifuentes A, Holland WL (2014) Regulation of glucose and lipid homeostasis by adiponectin: effects on hepatocytes, pancreatic beta cells and adipocytes. Best Pract Res Clin Endocrinol Metab 28:43–58
Unger RH, Scherer PE (2010) Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity. Trends Endocrinol Metab 21:345–352
Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, Imai Y, Nagai R, Kadowaki T (2006) Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care 29:1357–1362
Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, Wagner JA, Wu M, Knopps A, Xiang AH, Utzschneider KM, Kahn SE, Olefsky JM, Buchanan TA, Scherer PE (2004) Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem 279:12152–12162
Kim CS, Park HS, Kawada T, Kim JH, Lim D, Hubbard NE, Kwon BS, Erickson KL, Yu R (2006) Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J Obes (Lond) 30:1347–1355
Longo PL, Artese HP, Rabelo MS, Kawamoto D, Foz AM, Romito GA, Dib SA, Mayer MP (2014) Serum levels of inflammatory markers in type 2 diabetes patients with chronic periodontitis. J Appl Oral Sci 22:103–108
de Lemos JA, Morrow DA, Sabatine MS, Murphy SA, Gibson CM, Antman EM, McCabe CH, Cannon CP, Braunwald E (2003) Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes. Circulation 107:690–695
Kahn SE, Hull RL, Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840–846
Fu Z, Gilbert ER, Liu D (2013) Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev 9:25–53
Fernandez-Sanchez A, Madrigal-Santillan E, Bautista M, Esquivel-Soto J, Morales-Gonzalez A, Esquivel-Chirino C, Durante-Montiel I, Sanchez-Rivera G, Valadez-Vega C, Morales-Gonzalez JA (2011) Inflammation, oxidative stress, and obesity. Int J Mol Sci 12:3117–3132
Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114:1752–1761
Jain SK (1989) Hyperglycemia can cause membrane lipid peroxidation and osmotic fragility in human red blood cells. J Biol Chem 264:21340–21345
Rains JL, Jain SK (2011) Oxidative stress, insulin signaling, and diabetes. Free Radic Biol Med 50:567–575
Quan Y, Jiang CT, Xue B, Zhu SG, Wang X (2011) High glucose stimulates TNFalpha and MCP-1 expression in rat microglia via ROS and NF-kappaB pathways. Acta Pharmacol Sin 32:188–193
Younce CW, Kolattukudy PE (2010) MCP-1 causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing a novel zinc-finger protein, MCPIP. Biochem J 426:43–53
Huang S, Czech MP (2007) The GLUT4 glucose transporter. Cell Metab 5:237–252
Acknowledgments
The authors are supported by grants from NCCAM of the National Institutes of Health (RO1 AT007442), the Malcolm Feist Endowed Chair in Diabetes from LSUHSC, Shreveport. The authors thank Georgia Morgan for excellent editing of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors have declared that no conflict of interest exists.
Rights and permissions
About this article
Cite this article
Achari, A.E., Jain, S.K. l-Cysteine supplementation increases adiponectin synthesis and secretion, and GLUT4 and glucose utilization by upregulating disulfide bond A-like protein expression mediated by MCP-1 inhibition in 3T3-L1 adipocytes exposed to high glucose. Mol Cell Biochem 414, 105–113 (2016). https://doi.org/10.1007/s11010-016-2664-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-016-2664-7