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Hypoglycemic and Hypolipidemic Effects of Leucine, Zinc, and Chromium, Alone and in Combination, in Rats with Type 2 Diabetes

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Abstract

For the increasing development of diabetes, dietary habits and using appropriate supplements can play important roles in the treatment or reduction of risk for this disease. The objective of this study was to investigate the effects of leucine (Leu), zinc (Zn), and chromium (Cr) supplementation, alone or in combination, in rats with type 2 diabetes (T2D). Seventy-seven adult male Wistar rats were randomly assigned in 11 groups, using nutritional supplements and insulin (INS) or glibenclamide (GLC). Supplementing Leu significantly reduced blood glucose, triglycerides (TG), nonesterified fatty acids (NEFA), low-density lipoprotein (LDL), and increased high-density lipoprotein (HDL) concentrations compared to vehicle-treated T2D animals, and those improvements were associated with reduced area under the 2-h blood glucose response curve (AUC). Supplementation of T2D animals with Zn improved serum lipid profile as well as blood glucose concentrations but was not comparable with the INS, GLC, and Leu groups. Supplementary Cr did not improve blood glucose and AUC in T2D rats, whereas it reduced serum TG and LDL and increased HDL concentrations. In conclusion, supplementation of diabetic rats with Leu was more effective in improving blood glucose and consequently decreasing glucose AUC than other nutritional supplements. Supplementary Zn and Cr only improved serum lipid profile. The combination of the nutritional supplements did not improve blood glucose level. Nevertheless, supplementation with Leu-Zn, Leu-Cr, Zn-Cr, and Leu-Zn-Cr led to an improved response in serum lipid profile over each supplement given alone.

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References

  1. International Diabetes Federation. IDF Diabetes, 7 ed. Brussels, Belgium: International Diabetes Federation, 2015

  2. Kahn SE, Porte DJ (1990) The pathophysiology of type II (noninsulindependent) diabetes mellitus: implications for treatment. In: Rifkin H, Porte DJ (eds) Ellenberg and Rijkin’s diabetes mellitus: theory and practice. Elsevier Science, New York, pp 436–456

    Google Scholar 

  3. Ball AJ, Flatt PR, McClenaghan NH (2000) Desensitization of sulphonylurea- and nutrient-induced insulin secretion following prolonged treatment with glibenclamide. Eur J Pharmacol 408:327–333

    Article  CAS  PubMed  Google Scholar 

  4. Inzucchi SE, Bergenstal RM, BuseJB DM, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR (2015) Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 38:140–149

    Article  PubMed  Google Scholar 

  5. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, Düring M, Matthews DR (2009) Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)- 2 study. Diabetes Care 32:84–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Van Raalte DH, Diamant M (2011) Glucolipotoxicity and beta cells in type 2 diabetes mellitus: target for durable therapy? Diabetes Res Clin Pract 93:S37–S46

    Article  CAS  PubMed  Google Scholar 

  7. Ley SH, Hamdy O, Mohan V, Hu FB (1999) Prevention and management of type 2 diabetes: dietary components and nutritional strategies. Lancet 383:1999–2007

    Article  Google Scholar 

  8. Macotela Y, Emanuelli B, Bang AM, Espinoza DO, Boucher J, Beebe K, Gall W, Kahn CR (2011) Dietary leucine—an environmental modifier of insulin resistance acting on multiple levels of metabolism. PLoS One 6(6):e21187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wu G, Bazer FW, Zhaolai D, Li D, Wang J, Wu Z (2014) Amino acid nutrition in animals: protein synthesis and beyond. Annu Rev Anim Biosci 2:387–417

    Article  CAS  PubMed  Google Scholar 

  10. Kelleher SL, McCormick NH, Velasquez V, Lopez V (2011) Zinc in specialized secretory tissues: roles in the pancreas, prostate, and mammary gland. Adv Nutr 2:101–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rutter GA, Chabosseau P, Bellomo EA, Maret W, Mitchell RK, Hodson DJ, Solomou A, Hu M (2016) Intracellular zinc in insulin secretion and action: a determinant of diabetes risk? Proc Nutr Soc 75:61–72

    Article  CAS  PubMed  Google Scholar 

  12. Tamaki M, Fujitani Y, Hara A, Uchida T, Tamura Y, Takeno K, Kawaguchi M, Watanabe T, Ogihara T, Fukunaka A, Shimizu T, Mita T, Kanazawa A, Imaizumi MO, Abe T, Kiyonari H, Hojyo S, Fukada T, Kawauchi T, Nagamatsu S, Hirano T, Kawamori R, Watada H (2013) The diabetessusceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J Clin Invest 123:4513–4524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Miranda ER, Dey CS (2004) Effect of chromium and zinc on insulin signaling in skeletal muscle cells. Biol Trace Elem Res 101:19–36

    Article  CAS  PubMed  Google Scholar 

  14. Tang X, Shay NF (2001) Zinc has an insulin-like effect on glucose transport mediated by phosphoinositol-3-kinase and Akt in 3T3-L1 fibroblasts and adipocytes. J Nutr 131:1414–1420

    CAS  PubMed  Google Scholar 

  15. Davis CM, Vincent JB (1997) Chromium oligopeptide activates insulin receptor tyrosine kinase activity. Biochemistry 36:4382–4385

    Article  CAS  PubMed  Google Scholar 

  16. Vincent JB (2014) Is chromium pharmacologically relevant? J Trace Elem Med Biol 28:397–405

    Article  CAS  PubMed  Google Scholar 

  17. Campos-Ferraz PL, Bozza T, Nicastro H, Lancha AH Jr (2013) Distinct effects of leucine or a mixture of the branched-chain amino acids (leucine, isoleucine, and valine) supplementation on resistance to fatigue, and muscle and liver-glycogen degradation, in trained rats. Nutrition 29:1388–1394

    Article  CAS  PubMed  Google Scholar 

  18. Guo K, Yu YH, Hou J, Zhang Y (2010) Chronic leucine supplementation improves glycemic control in etiologically distinct mouse models of obesity and diabetes mellitus. Nutr Metab (Lond) 7:57

    Article  Google Scholar 

  19. Nicastro H, da Luz CR, Chaves DF, Bechara LR, Voltarelli VA, Rogero MM, Lancha AH Jr (2012) Does branched-chain amino acids supplementation modulate skeletal muscle remodeling through inflammation modulation? Possible mechanisms of action. J Nutr Metab 2012:136937

    Article  PubMed  PubMed Central  Google Scholar 

  20. Zhang Y, Guo K, LeBlanc RE, Loh D, Schwartz GJ, Yu YH (2007) Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes 56:1647–1654

    Article  CAS  PubMed  Google Scholar 

  21. Capdor J, Foster M, Petocz P, Samman S (2013) Zinc and glycemic control: a metaanalysis of randomised placebo controlled supplementation trials in humans. J Trace Elem Med Biol 27:137–142

    Article  CAS  PubMed  Google Scholar 

  22. Jayawardena R, Ranasinghe P, Galappatthy P, Malkanthi R, Constantine G, Katulanda P (2012) Effects of zinc supplementation on diabetes mellitus: a systematic review and meta-analysis. Diabetol Metab Syndr 4:13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Martin J, Wang ZQ, Zhang XH, Wachtel D, Volaufova J, Matthews DE, Cefalu WT (2001) Chromium picolinate supplementation attenuates body weight gain and increases insulin sensitivity in subjects with type 2 diabetes. Diabetes Care 29:1826–1832

    Article  Google Scholar 

  24. Rabinovitz H, Friedensohn A, Leibovitz A, Gabay G, Rocas C, Habot B (2004) Effect of chromium supplementation on blood glucose and lipid levels in type 2 diabetes mellitus elderly patients. Int J Vitam Nutr Res 74:178–182

    Article  CAS  PubMed  Google Scholar 

  25. Racek J, Trefil L, Rajdl D, Mudrova V, Hunter D, Senfrl V (2006) Influence of chromium-enriched yeast on blood glucose and insulin variables, blood lipids, and markers of oxidative stress in subjects with type 2 diabetes mellitus. Biol Trace Elem Res 109:215–230

    Article  CAS  PubMed  Google Scholar 

  26. Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Gadbois TM, Reaven GM (2000) A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism 49:1390–1394

    Article  CAS  PubMed  Google Scholar 

  27. Song MK, Rosenthal MJ, Song AM, Uyemura K, Yang H, Ament ME, Yamaguchi DT, Cornford EM (2009) Body weight reduction in rats by oral treatment with zinc plus cyclo-(his-pro). British J Pharmacol 158:442–450

    Article  CAS  Google Scholar 

  28. Sahin S, Vijaya J, Mehmet T, Sahin N, Zikim G, Komorowski JR (2011) The effects of chromium complex and level on glucose metabolism and memory acquisition in rats fed high-fat diet. Biol Trace Elem Res 143:1018–1030

    Article  CAS  PubMed  Google Scholar 

  29. Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P (2005) Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res 52:313–320

    Article  CAS  PubMed  Google Scholar 

  30. Sahin K, Onderci M, Tuzcu M, Ustundag B, Cikim G, Ozercan IH, Sriramoju V, Juturu V, Komorowski JR (2007) Effect of chromium on carbohydrate and lipid metabolism in a rat model of type 2 diabetes mellitus: the fat-fed, streptozotocin-treated rat. Metabolism 56:1233–1240

    Article  CAS  PubMed  Google Scholar 

  31. Juturu V, Kazim S, Tuzcu M, Cikim G, Komorowski JR (2008) Effects of chromium histidinate supplementation on insulin sensitivity and lipid profile in rat models of insulin resistance and of type 2 diabetes FASEB J 22:1 Supplement1104.1

  32. Albersen M, Lin G, Fandel TM, Zhang H, Qiu X, Lin CS, Lue TF (2011) Functional, metabolic and morphological characteristics of a novel rat model of type 2 diabetes-associated erectile dysfunction. Urology 78(476):e1–476.e8

    Google Scholar 

  33. Gannon MC, Nuttall FQ, Saeed A, Jordan K, Hoover H (2003) An increase indietary protein improves the blood glucose response in persons with type 2 diabetes. Am J Clin Nutr 78:734–741

    CAS  PubMed  Google Scholar 

  34. Kalogeropoulou D, LaFave L, Schweim K, Gannon MC, Nuttall FQ (2008) Leucine, when ingested with glucose, synergistically stimulates insulin secretion and lowers blood glucose. Metabolism 57:1747–1752

    Article  CAS  PubMed  Google Scholar 

  35. Xu G, Kwon G, Cruz WS, Marshall CA, McDaniel ML (2001) Metabolic regulation by leucine of translation initiation through the mTOR-signaling pathway by pancreatic beta-cells. Diabetes 50:353–360

    Article  CAS  PubMed  Google Scholar 

  36. Adeva MM, Calviño J, Souto G, Donapetry C (2012) Insulin resistance and the metabolism of branched-chain amino acids in humans. Amino Acids 43:171–181

    Article  CAS  PubMed  Google Scholar 

  37. Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, Rochon J, Gallup D, Ilkayeva O, Wenner BR, Yancy WS Jr, Eisenson H, Musante G, Surwit RS, Millington DS, Butler MD, Svetkey LP (2009) A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 9:311–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zheng Y, Li Y, Qi Q, Hruby A, Manson JE, Willett WC, Wolpin BM, Hu FB, Qi L (2016) Cumulative consumption of branched-chain amino acids and incidence of type 2 diabetes. Int J Epidemiol 45:1482–1492

    Article  PubMed  PubMed Central  Google Scholar 

  39. Giesbertz P, Padberg I, Rein D, Ecker J, Höfle AS, Spanier B, Daniel H (2015) Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes. Diabetologia 58:2133–2143

    Article  CAS  PubMed  Google Scholar 

  40. Lackey DE, Lynch CJ, Olson KC, Mostaedi R, Ali M, Smith WH, Karpe F, Humphreys S, Bedinger DH, Dunn TN, Thomas AP, Oort PJ, Kieffer DA, Amin R, Bettaieb A, Haj FG, Permana P, Anthony TG, Adams SH (2013) Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. Am J Physiol Endocrinol Metab 304:1175–1187

    Article  Google Scholar 

  41. She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ (2007) Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab 293:E1552–E1563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fu L, Bruckbauer A, Li F, Cao Q, Cui X, Wu R, Shi H, Zemel MB, Xue B (2015) Interaction between metformin and leucine in reducing hyperlipidemia and hepatic lipid accumulation in diet-induced obese mice. Metabolism 64:1426–1434

    Article  CAS  PubMed  Google Scholar 

  43. Begin-Heick N, Dalpe-Scott M, Rowe J, Heick HM (1985) Zinc supplementation attenuates insulin secretory activity in pancreatic islets of the ob/ob mouse. Diabetes 34:179–184

    Article  CAS  PubMed  Google Scholar 

  44. Wang X, Li H, Fan Z, Liu Y (2012) Effect of zinc supplementation on type 2 diabetes parameters and liver metallothionein expressions in Wistar rats. J Physiol Biochem 68:563–572

    Article  CAS  PubMed  Google Scholar 

  45. Vardatsikos G, Pandey NR, Srivastava AK (2013) Insulino-mimetic and anti-diabetic effects of zinc. J Inorg Biochem 120:8–17

    Article  CAS  PubMed  Google Scholar 

  46. Coulston L, Dandona P (1980) Insulin-like effect of zinc on adipocytes. Diabetes 29:665–667

    Article  CAS  PubMed  Google Scholar 

  47. Van Campen DR, Scaife PU (1967) Zinc interference with copper absorption in rats. J Nutr 91:473–476

    CAS  PubMed  Google Scholar 

  48. Condomina J, Zornoza-Sabina T, Granero L, Polache A (2002) Kinetics of zinc transport in vitro in rat small intestine and colon: interaction with copper. Eur J Pharm Sci 16:289–295

    Article  CAS  PubMed  Google Scholar 

  49. Sharonova IN, Vorobjev VS, Haas HL (2000) Interaction between copper and zinc at GABAA receptors in acutely isolated cerebellar Purkinje cells of the rat. Br J Pharmacol 130:851–856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Schwarz K, Mertz W (1959) Chromium (III) and the glucose tolerance factor. Arch Biochem Biophys 85:292–295

    Article  CAS  PubMed  Google Scholar 

  51. Clodfelder BJ, Emamaullee J, Hepburn DD, Chakov NE, Nettles H, Vincent JB (2000) The trail of chromium(III) from the blood to the urine: the roles of transferrin and chromodulin. J Biol Inorg Chem 6:608–617

    Article  Google Scholar 

  52. Vincent JB (2000) The biochemistry of chromium. J Nutr 130:715–718

    CAS  PubMed  Google Scholar 

  53. Moshtaghie AA, Ani M, Bazrafshan MR (1992) Comparative binding study of aluminum and chromium to human transferrin. Effect of iron. Biol Trace Elem Res 32:39–46

    Article  CAS  PubMed  Google Scholar 

  54. Sargent T, Lim TH, Jenson RL (1979) Reduced chromium retention in patients with hemochromatosis, a possible basis of hemochromatotic diabetes. Metabolism 28:70–79

    Article  PubMed  Google Scholar 

  55. Lim TH, Sargent T, Kusubov N (1983) Kinetics of trace element chromium (III) in the human body. Am J Phys 244:R445–R454

    CAS  Google Scholar 

  56. Sun Y, Ramirez J, Woski SA, Vincent JB (2000) The binding of trivalent chromium to low-molecular-weight chromiumbinding substance (LMWCr) and the transfer of chromium from transferrin and chromium picolinate to LMWCr. J Biol Inorg Chem 5:129–136

    Article  CAS  PubMed  Google Scholar 

  57. Krol E, Krejpcio Z (2011) Evaluation of anti-diabetic potential of chromium (III) propionate complex in high-fat diet fed and STZ injected rats. Food Chem Toxicol 49:3217–3123

    Article  CAS  PubMed  Google Scholar 

  58. Bailey CH (2014) Improved meta-analytic methods show no effect of chromium supplements on fasting glucose. Biol Trace Elem Res 157:1–8

    Article  CAS  PubMed  Google Scholar 

  59. Landman GW, Bilo HJ, Houweling ST, Kleefstra N (2014) Chromium does not belong in the diabetes treatment arsenal: current evidence and future perspectives. World J Diabetes 5:160–164

    PubMed  PubMed Central  Google Scholar 

  60. American Diabetes Association (2014) Clinical practice recommendations. Diabetes Care 37:S1–S155

    Article  Google Scholar 

  61. Kolahian S, Sadri H, Shahbazfar AA, Amani M, Mazadeh A, Mirani M (2015) The effects of leucine, zinc, and chromium supplements on inflammatory events of the respiratory system in type 2 diabetic rats. PLoS One. doi:10.1371/journal.pone.0133374

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was financially supported by the Research Council of University of Tabriz. The authors also express their appreciation to A. Sadeghi for his help in conducting this experiment.

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Authors and Affiliations

  1. Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, 516616471, Iran

    Hassan Sadri

  2. Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology and ICePhA, University of Tuebingen, 72074, Tuebingen, Germany

    Negar Nowroozi Larki & Saeed Kolahian

  3. Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, 516616471, Iran

    Negar Nowroozi Larki & Saeed Kolahian

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  1. Hassan Sadri
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Correspondence to Hassan Sadri.

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Sadri, H., Larki, N.N. & Kolahian, S. Hypoglycemic and Hypolipidemic Effects of Leucine, Zinc, and Chromium, Alone and in Combination, in Rats with Type 2 Diabetes. Biol Trace Elem Res 180, 246–254 (2017). https://doi.org/10.1007/s12011-017-1014-2

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