Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
European Journal of Nutrition
Published in: European Journal of Nutrition 8/2012

01-12-2012 | Original Contribution

Alpha-lipoic acid preserves the structural and functional integrity of red blood cells by adjusting the redox disturbance and decreasing O-GlcNAc modifications of antioxidant enzymes and heat shock proteins in diabetic rats

Authors: Mihailović Mirjana, Arambašić Jelena, Uskoković Aleksandra, Dinić Svetlana, Grdović Nevena, Marković Jelena, Poznanović Goran, Vidaković Melita

Published in: European Journal of Nutrition | Issue 8/2012

Login to get access

Abstract

Purpose

The aim of this study was to investigate whether the daily administration of α-lipoic acid (LA) during 4 weeks prevents the redox disturbance in red blood cells (RBC) described in diabetes

Methods

Multiple low-dose streptozotocin (STZ) diabetes was induced in rats by the administration of 40 mg/kg STZ intraperitoneally (i.p.) for 5 consecutive days. LA was applied at a dose of 10 mg/kg i.p. for 4 weeks, starting from the last day of STZ administration.

Results

The LA-treated diabetic rats exhibited a general systemic improvement, revealed as the near restoration of body weight and of essential biochemical parameters. The latter was displayed as decreased hyperglycemia, lower triglyceride levels and lower serum activities of alanine aminotransferases and aspartate aminotransferases that point to a general improvement of diabetes-linked organ “lesions”. The LA-treated diabetic rats also exhibited significant alleviation of oxidative stress, manifested as decreased lipid peroxidation and lower glycation levels of serum proteins and hemoglobin, while the RBC exhibited increased activities of antioxidant enzymes and elevated levels of reduced glutathione. In RBC, this was accompanied by decreased post-translational glycosylation by O-bound β-N-acetylglucosamine (O-GlcNAc) of the antioxidant enzymes superoxide dismutase and catalase and of heat shock proteins HSP70 and HSP90.

Conclusion

LA through its powerful antioxidant activity preserves the structural and functional integrity of RBC in diabetes. The RBC can then assume a more efficient role as the first line of systemic defense against diabetic complications arising from oxidative stress–induced damage of other tissues and organs.
Literature
1.
Maritim AC, Sanders RA, Watkins JB (2003) Diabetes mellitus is a metabolic disorder characterized by hyperglycemia and insufficiency of secretion or action of endogenous insulin. J Biochem Mol Toxicol 17:24–38CrossRef
2.
Lapolla A, Traldi P, Fedele D (2005) Importance of measuring products of non-enzymatic glycation of proteins. Clinical Biochem 38:103–115CrossRef
3.
Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820CrossRef
4.
Chung SS, Ho EC, Lam KS, Chung SK (2003) Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol 14:233–236CrossRef
5.
Atalay M, Oksala NK, Laaksonen DE, Khanna S, Nakao C, Lappalainen J, Roy S, Hänninen O, Sen CK (2004) Exercise training modulates heat shock protein response in diabetic rats. J Appl Physiol 97:605–611CrossRef
6.
Najemnikova E, Rodgers CR, Locke M (2007) Altered heat stress response following streptozotocin-induced diabetes. Cell Stress Chaperones 4:342–352CrossRef
7.
Singh M, Shin S (2009) Changes in erythrocyte aggregation and deformability in diabetes mellitus: a brief review. Indian J Exp Biol 47:7–15
8.
Tsantes AE, Bonovas S, Travlou A, Sitaras NM (2006) Redox imbalance, macrocytosis, and RBC homeostasis. Antioxid Redox Signal 8:1205–1216CrossRef
9.
Crawford JH, Isbell TS, Huang Z, Shiva S, Chacko BK, Schechter AN, Darley-Usmar VM, Kerby JD, Lang JD, Kraus D Jr, Ho C, Gladwin MT, Patel RP (2006) Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation. Blood 107:566–574CrossRef
10.
Selvin E, Steffes MW, Zhu H, Matsushita K, Wagenknecht L, Pankow J, Coresh J, Brancati FL (2010) Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 362:800–811CrossRef
11.
Sailaja YR, Baskar R, Saralakumari D (2003) The antioxidant status during maturation of reticulocytes to erythrocytes in type 2 diabetics. Free Radic Biol Med 35:133–139CrossRef
12.
Marinkovic D, Zhang XX, Yalcin S, Luciano PJ, Brugnara C, Huber T, Ghaffari S (2007) Foxo3 is required for the regulation of oxidative stress in erythropoiesis. J Clin Invest 117:2133–2144CrossRef
13.
Mates JM, Perez-Gomez C, Olalla L, Segura JM, Blanca M (2000) Allergy to drugs: antioxidant enzymic activities, lipid peroxidation and protein oxidative damage in human blood. Cell Biochem Funct 18:77–84CrossRef
14.
Atalay M, Oksala N, Lappalainen J, Laaksonen D, Sen CK, Roy S (2009) Heat shock proteins in diabetes and wound healing. Curr Protein Pept Sci 10:85–95CrossRef
15.
Benjamin IJ, McMillan DR (1998) Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease. Circ Res 83:117–132CrossRef
16.
Maritim AC, Sanders RA, Watkins JB (2003) Effects of alpha-lipoic acid on biomarkers of oxidative stress in streptozotocin-induced diabetic rats. J Nutr Biochem 14:288–294CrossRef
17.
Sen CK, Packer L (2000) Thiol homeostasis and supplements in physical exercise. Am J Clin Nutr 72:653–669
18.
Packer L, Kraemer K, Rimbach G (2001) Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 17:888–895CrossRef
19.
Shotton HR, Broadbent S, Lincoln J (2004) Prevention and partial reversal of diabetes-induced changes in enteric nerves of the rat ileum by combined treatment with alpha-lipoid acid and evening primrose oil. Auton Neurosci 111:57–65CrossRef
20.
Bhatti F, Mankhey RW, Asico L, Quinn MT, Welch WJ, Maric C (2005) Mechanisms of antioxidant and pro-oxidant effects of alphalipoic acid in the diabetic and non-diabetic kidney. Kideny Int 67:1371–1380CrossRef
21.
Jiang YJ, Gong DX, Liu HB, Yang CM, Sun ZX, Kong CZ (2008) Ability of alpha-lipoic acid to reverse the diabetic cystopathy in a rat model. Acta Pharmacol Sin 29:713–719CrossRef
22.
Ungvari Z, Pacher P, Kecskemeti V, Papp G, Szollár L, Koller A (1999) Increased myogenic tone in skeletal muscle arterioles of diabetic rats. Possible role of increased activity of smooth muscle Ca channels and protein kinase C. Cardiovasc Res 43:1018–1028CrossRef
23.
Drabkin D, Austin H (1935) Spectrophotometric studies preparations from washed blood cells. J Biol Chem 112:51–55
24.
Parker KM, England JD, DaCosta J, Hess EL, Goldstein DE (1981) Improved colorimetric assay for glycosylated hemoglobin. Clin Chem 27:669–672
25.
Dubowski KM (1960) Measurements of hemoglobin derivatives. In: Sunderman FW, Sunderman FW Jr (eds) Hemoglobin: its metabolites and precursors. Lippincott Co, Philadelphia, pp 49–60
26.
Kawatsu H, Nakanishi Y, Takeda H (1987) Methemoglobin determination in Eel blood. Nippon Suisan Gakkaishi 53:9–14CrossRef
27.
Oyaizu M (1986) Studies on product of browning reaction prepared from glucose amine. Jpn J Nutr 44:307–315CrossRef
28.
Dinis TCP, Madeira VMC, Almeida LM (1994) Action of phenolic derivates (acetoaminophen, salicylate and 5 aminosalicylate) as inhibitors of membrane lipid peroxidation and as peroxyl radical scavengers. Arch Biochem Biophys 315:161–169CrossRef
29.
Yokozawa T, Chen CP, Dong E, Tanaka T, Nonaka GI, Nishioka I (1998) Study on the inhibitory effect of tannins and flavonoids against the 1, 1-diphenyl-2 picrylhydrazyl radical. Biochem Pharmacol 56:213–222CrossRef
30.
Johnson RN, Metcalf PA, Baker JR (1983) Fructosamine: a new approach to the estimation of serum glycosylprotein. An index of diabetic control. Clin Chim Acta 127:87–95CrossRef
31.
Laurell CB (1972) Electrophoretic and electroimmunochemical analysis of proteins. Scand J Clin Lab Invest 29:21–37CrossRef
32.
Gambal D (1971) Simple, rapid procedure for isolating serum albumin. Biochem Biophys Acta 251:54–56CrossRef
33.
Lowry OH, Rosebrough NL, Farr AL, Randall RI (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275
34.
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358CrossRef
35.
36.
Habig WH, Pubst MJ, Jakoby WB (1974) Glutathione S-transferase. J Biol Chem 249:7130–7139
37.
Beutler E (1982) Catalase. In: Beutler E (ed) Red cell metabolism, a manual of biochemical methods. Grune and Stratton, Inc, New York, pp 105–106
38.
Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and simple assay for superoxide dismutase. J Biol Chem 247:3170–3175
39.
Jackson P, Tjian R (1988) Purification and analysis of RNA polymerase II transcription factors by using wheat germ agglutinin affinity chromatography. Proc Natl Acad Sci USA 86:1781–1785CrossRef
40.
Laemmli UK (1970) Cleavage of structural proteins during the assembly of heat of bacteriophage T4. Nature 227:680–685CrossRef
41.
Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gel to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76:4350–4354CrossRef
42.
Torregiani F, Umansky-Zeverin M, Riqueline B, Rasia R (1997) Hemorheological alterations in diabetic patients. Clin Hemorheol 15:678–690
43.
Biewenga GP, Guido RM M, Haenen GRM M, Bast A (1997) The pharmacology of the antioxidant lipoic acid. Gen Pharmac 29:315–331CrossRef
44.
Calabrese V, Renis M, Calderone A, Russso A, Barcellona ML, Rizza V (1996) Stress proteins and SH-groups in oxidant-induced cell damage after acute ethanol administration in rat. Free Radic Biol Med 20:391–397CrossRef
45.
46.
Kleinman WA, Komninou D, Leutzinger Y, Colosimo S, Cox J, Lang CA, Richie JP Jr (2003) Protein glutathiolation in human blood. Biochem Pharmacol 65:741–746CrossRef
47.
Ceriello A (2000) Oxidative stress and glycemic regulation. Metabolism 49:27–29CrossRef
48.
Hart G (1997) Dynamic O-glycosylation of nuclear and cytosolic proteins. Annu Rev Biochem 66:315–335CrossRef
49.
Yi X, Maeda N (2006) α-Lipoic acid prevents the increase in atherosclerosis induced by diabetes in apolipoprotein E–deficient mice fed high-fat/low-cholesterol diet. Diabetes 55:2238–2244CrossRef
50.
Siems WG, Sommerburg O, Grune T (2000) Erythrocyte free radical and energy metabolism. Clin Nephrol 53:9–17
51.
Lawall H, Angelkort B (1999) Correlation between rheological parameters and erythrocyte velocity in nailfold capillaries in patients with diabetes mellitus. Clin Hemorheol Microcirc 20:41–47
52.
Tureckў L, Kupcovǎ V, Szǎntovǎ M (1999) Alpha 2-macroglobulin in the blood of patients with diabetes mellitus. Bratisl Lek List 100:25–27
53.
Srour MA, Bilto YY, Juma M, Irhimen MR (2000) Exposure of human erythrocytes to oxygen radicals causes loss of deformability, increased osmotic fragility, lipid peroxidation and protein degradation. Clin Hemorheol Microcirc 23:13–21
54.
Packer L, Witt E, Tritschler H (1995) Alpha lipoic acid as a biological antioxidant. Free Rad Biol Med 19:227–250CrossRef
55.
Gupta S, Kataria M, Gupta PK, Murganandan S, Yashroy RC (2004) Protective role of extracts of neem seeds in diabetes caused by streptozotocin in rats. J Ethnopharmacol 90:185–189CrossRef
56.
Ramesh B, Pugalendi KV (2005) Impact of umbelliferone on erythrocyte redox status in STZ-diabetic rats. Yale J Biol Med 78:131–138
57.
Anwar MM, Meki ARM (2003) Oxidative stress in streptozotocin-induced diabetic rats: effects of garlic oil and melatonin. Comp Biochem Physiol A Mol Integr Physiol 135:539–547CrossRef
58.
Sadi G, Güray T (2009) Gene expressions of Mn-SOD and GPx-1 in streptozotocin induced diabetes: effect of antioxidants. Mol Cell Biochem 327:127–134CrossRef
59.
Shelton MD, Chock PB, Mieyal JJ (2005) Glutaredoxin: role in reversible protein S-glutathionylation and regulation of redox signal transduction and protein translocation. Antioxid Redox Signal 7:348–366CrossRef
60.
Wang J, Boja ES, Tan W, Tekle E, Fales HM, English S, Mieyal JJ, Chock PB (2001) Reversible glutathionylation regulates actin polymerization in A431 cells. J Biol Chem 276:47763–47766
61.
Eaton P, Wright N, Hearse DJ, Shattock MJ (2002) Glyceraldehyde phosphate dehydrogenase oxidation during cardiac ischemia and reperfusion. J Mol Cell Cardiol 34:1549–1560CrossRef
62.
Adachi T, Pimentel DR, Heibeck T, Hou X, Lee YJ, Jiang B, Ido Y, Cohen RA (2004) S-Glutathiolation of Ras mediates redox-sensitive signaling by angiotensin II in vascular smooth muscle cells. J Biol Chem 279:29857–29862CrossRef
63.
Rice-Evans C, Baysal E (1987) Iron-mediated oxidative stress in erythrocytes. Biochem J 244:191–196
64.
Fernandez-Real JM, Lopez-Bermejo A, Ricart W (2005) Iron stores, blood donation, and insulin sensitivity and secretion. Clin Chem 51:1201–1205CrossRef
65.
Muller L, Menzel H (1990) Studies on the efficacy of lipoate and dihydrolipoate in the alteration of cadmium2 + toxicity in isolated hepatocytes. Biochim Biophys Acta 1052:386–391CrossRef
66.
Murray RK, Granner DK, Rodwell VW (2006) Harper′s illustrated biochemistry, 27th edn. McGraw Hill Companies, Asia
67.
Coleman MD, Tolley HL, Desai AK (2001) Monitoring antioxidant effects using methaemoglobin formation in diabetic erythrocytes. Br J Diabetes Vasc Dis 1:88–92CrossRef
68.
Adachi T, Ohta K, Hirano K, Hayashi K, Marklund SL (1991) Non-enzymatic glycation of human extracellular superoxide dismutase. Biochem J 279:263–267
69.
Blakynty R, Harding JJ (1992) Glycation (non-enzymatic glycosylation) inactivates glutathione reductase. Biochem J 288:303–307
70.
Alberti KGMM, Press CM (1982) The biochemistry of the complications of diabetes mellitus. In: Keen H, Jarrett J (eds) Complications of Diabetes, 2nd edn. Edward Arnold, London, pp 231–270
71.
Selvaraj N, Bobby Z, Sathiyapriya V (2006) Effect of lipid peroxides and antioxidants on glycation of hemoglobin: an in vitro study on human erythrocytes. Clinica Chimica Acta 366:190–195CrossRef
72.
Seghrouchni I, Drai J, Bannier EJ, Riviére J, Calmard P, Garcia I, Orgiazzi J, Revol A (2002) Oxidative stress parameters in type I, type II and insulin-treated type 2 diabetes mellitus; insulin treatment efficiency. Clinica Chimica Acta 321:89–96CrossRef
73.
Love DC, Hanover JA (2005) The hexosamine signaling pathway: deciphering the “O-GlcNAc code”. Sci STKE 312:13
74.
Ku N-O, Omary MB (1994) Expression, glycosylation, and phosphorylation of human keratins 8 18 in insect cells. Exp Cell Res 211:24–35CrossRef
75.
Wang Z, Park K, Comer F, Hsieh-Wilson LC, Saudek CD, Hart GW (2009) Site-specific GlcNAcylation of human erythrocyte proteins. Diabetes 58:309–317CrossRef
76.
Oda A, Bannai C, Yamaoka T, Katori T, Matsushima T, Yamashita K (1994) Inactivation of CuZn-superoxide dismutase by in vitro glycosylation and in erythrocytes of diabetic patients. Horm Metab Res 26:1–4CrossRef
77.
Hooper PL, Hooper JJ (2005) Loss of defense against stress: diabetes and heat shock proteins. Diabetes Technol Ther 7:204–208CrossRef
78.
McCraty MF (2001) Down-regulation of microglial activation may represent a practical strategy for combating neurodegenerative disorders. Med Hypotheses 57:313–317CrossRef
79.
Strokov IA, Manukhina EB, Bakhtina LY, Malyshev IY, Zoloev GK, Kazikhanova SI, Ametov AS (2000) The function of endogenous protective systems in patients with insulin-dependent diabetes mellitus and polyneuropathy: effect of antioxidant therapy. Bull Exp Biol Med 130:986–990
Metadata
Title
Alpha-lipoic acid preserves the structural and functional integrity of red blood cells by adjusting the redox disturbance and decreasing O-GlcNAc modifications of antioxidant enzymes and heat shock proteins in diabetic rats
Authors
Mihailović Mirjana
Arambašić Jelena
Uskoković Aleksandra
Dinić Svetlana
Grdović Nevena
Marković Jelena
Poznanović Goran
Vidaković Melita
Publication date
01-12-2012
Publisher
Springer-Verlag
Published in
European Journal of Nutrition / Issue 8/2012
Print ISSN: 1436-6207
Electronic ISSN: 1436-6215
DOI
https://doi.org/10.1007/s00394-011-0275-3

Other articles of this Issue 8/2012

European Journal of Nutrition 8/2012 Go to the issue

Review

Regulation of antimicrobial peptide gene expression by nutrients and by-products of microbial metabolism

Original Contribution

Silk and silkworm pupa peptides suppress adipogenesis in preadipocytes and fat accumulation in rats fed a high-fat diet

Original Contribution

Bias in protein and potassium intake collected with 24-h recalls (EPIC-Soft) is rather comparable across European populations

Original Contribution

Effect of docosahexaenoic acid on hypoxia/reoxygenation injury in human coronary arterial smooth muscle cells

Original Contribution

Soy intake and risk of type 2 diabetes mellitus in Chinese Singaporeans

Original Contribution

Protective effects of olive oil phenolics and gallic acid on hydrogen peroxide-induced apoptosis
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits