Carnosine supplementation reduces plasma soluble transferrin receptor in healthy overweight or obese individuals: a pilot randomised trial
- 58 Downloads
Abnormalities of iron homeostasis have been linked to insulin resistance, type 2 diabetes and cardiovascular disease. Carnosine, an over-the-counter food supplement with chelating properties, has been shown to decrease serum iron and improve glucose metabolism in diabetic rodents. We have previously demonstrated that carnosine supplementation prevented worsening of glucose metabolism in healthy overweight and obese middle-aged adults. Yet, the impact of carnosine on markers of iron metabolism in humans has not been investigated. We aimed to determine whether carnosine supplementation has an effect on iron parameters in overweight and obese, otherwise healthy adults. We included 26 participants, who were randomly allocated to receive 1 g carnosine (n = 14) or identical placebo (n = 12) twice daily for 12 weeks. Iron parameters including iron, ferritin, transferrin, soluble transferrin receptor, total iron binding capacity and iron saturation were measured in serum or plasma by standard commercial assays. Carnosine supplementation decreased plasma soluble transferrin receptor compared to placebo (mean change difference ± standard error: − 0.07 ± 0.03 mg/l, p = 0.04). None of the other iron parameters were different between carnosine and placebo groups. At follow-up, soluble transferrin receptor was associated inversely with urinary carnosine concentrations and positively with serum carnosinase-1 activity (both p < 0.02). Our findings suggest that carnosine may modulate iron metabolism in high-risk groups which could ameliorate insulin resistance and prevent type 2 diabetes. Larger human clinical trials are required to confirm our results.
KeywordsIron metabolism Soluble transferrin receptor Carnosine Insulin resistance Type 2 diabetes
We thank the volunteers for their participation in the trial. We also thank Professor Wim Derave for performing the carnosinase measurements. This study was supported by the Grant Agency of the Slovak Academy of Sciences VEGA 2/0107/18, Slovak Research and Development Agency SRDA (APVV) 15/0253, Royal Australasian College of Physicians, Diabetes Australia Research Trust and Foundation for High Blood Pressure Research. Carnosine supplement was received from Flamma SPa, Italy. EB is a recipient of the Monash Graduate and Monash International Postgraduate Scholarships. BdC is supported by a National Heart Foundation Future Leader Fellowship (100864).
EB conceived the study idea, performed data analysis and interpretation, wrote first draft of the manuscript and revised subsequent drafts until publication. BdC designed the study, contributed to the study idea and data analysis, and critically reviewed the manuscript. MPJdC co-designed the study with BdC and contributed to the review of the manuscript. JU & BU assisted with design of the study, performed all clinical measurement and contributed to review of the manuscript. TK & PK contributed to the clinical study performance and data collection. JMFR contributed to review of the manuscript. GA performed to laboratory measurement and reviewed the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Written informed consent was obtained from all individual participants included in the study.
- Adelmann K, Frey D, Riedl E, Koeppel H, Pfister F, Peters V, Schmitt CP, Sternik P, Hofmann S, Zentgraf HW, Navis G, van den Born J, Bakker SJ, Kramer BK, Yard BA, Hauske SJ (2012) Different conformational forms of serum carnosinase detected by a newly developed sandwich ELISA for the measurements of carnosinase concentrations. Amino Acids 43(1):143–151. https://doi.org/10.1007/s00726-012-1244-8 CrossRefPubMedGoogle Scholar
- Aldini G, Orioli M, Rossoni G, Savi F, Braidotti P, Vistoli G, Yeum KJ, Negrisoli G, Carini M (2011) The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats. J Cell Mol Med 15(6):1339–1354. https://doi.org/10.1111/j.1582-4934.2010.01101.x CrossRefPubMedGoogle Scholar
- Aldini G, Carini M, Yeum KJ, Vistoli G (2014) Novel molecular approaches for improving enzymatic and nonenzymatic detoxification of 4-hydroxynonenal: toward the discovery of a novel class of bioactive compounds. Free Radic Biol Med 69:145–156. https://doi.org/10.1016/j.freeradbiomed.2014.01.017 CrossRefPubMedGoogle Scholar
- Baye E, Ukropec J, de Courten MPJ, Vallova S, Krumpolec P, Kurdiova T, Aldini G, Ukropcova B, de Courten B (2017) Effect of carnosine supplementation on the plasma lipidome in overweight and obese adults: a pilot randomised controlled trial. Sci Rep 7(1):17458. https://doi.org/10.1038/s41598-017-17577-7 CrossRefPubMedPubMedCentralGoogle Scholar
- Choudhuri S, Dutta D, Sen A, Chowdhury IH, Mitra B, Mondal LK, Saha A, Bhadhuri G, Bhattacharya B (2013) Role of N-epsilon- carboxy methyl lysine, advanced glycation end products and reactive oxygen species for the development of nonproliferative and proliferative retinopathy in type 2 diabetes mellitus. Mol Vis 19:100–113PubMedPubMedCentralGoogle Scholar
- Coimbra S, Catarino C, Nascimento H, Ines Alves A, Filipa Medeiros A, Bronze-da-Rocha E, Costa E, Rocha-Pereira P, Aires L, Seabra A, Mota J, Ferreira Mansilha H, Rego C, Santos-Silva A, Belo L (2017) Physical exercise intervention at school improved hepcidin, inflammation, and iron metabolism in overweight and obese children and adolescents. Pediatr Res 82(5):781–788. https://doi.org/10.1038/pr.2017.139 CrossRefPubMedGoogle Scholar
- Cooksey RC, Jones D, Gabrielsen S, Huang J, Simcox JA, Luo B, Soesanto Y, Rienhoff H, Abel ED, McClain DA (2010) Dietary iron restriction or iron chelation protects from diabetes and loss of beta-cell function in the obese (ob/ob lep-/-) mouse. Am J Physiol Endocrinol Metab 298(6):E1236–E1243. https://doi.org/10.1152/ajpendo.00022.2010 CrossRefPubMedPubMedCentralGoogle Scholar
- de Courten B, Jakubova M, de Courten MP, Kukurova IJ, Vallova S, Krumpolec P, Valkovic L, Kurdiova T, Garzon D, Barbaresi S, Teede HJ, Derave W, Krssak M, Aldini G, Ukropec J, Ukropcova B (2016) Effects of carnosine supplementation on glucose metabolism: pilot clinical trial. Obesity (Silver Spring) 24(5):1027–1034. https://doi.org/10.1002/oby.21434 CrossRefGoogle Scholar
- Elbarbary NS, Ismail EAR, El-Naggar AR, Hamouda MH, El-Hamamsy M (2017) The effect of 12 weeks carnosine supplementation on renal functional integrity and oxidative stress in pediatric patients with diabetic nephropathy: a randomized placebo-controlled trial. Pediatr Diabetes. https://doi.org/10.1111/pedi.12564 PubMedCrossRefGoogle Scholar
- Everaert I, Taes Y, De Heer E, Baelde H, Zutinic A, Yard B, Sauerhofer S, Vanhee L, Delanghe J, Aldini G, Derave W (2012) Low plasma carnosinase activity promotes carnosinemia after carnosine ingestion in humans. Am J Physiol Renal Physiol 302(12):F1537–F1544. https://doi.org/10.1152/ajprenal.00084.2012 CrossRefPubMedGoogle Scholar
- Fernandez-Real JM, Izquierdo M, Moreno-Navarrete JM, Gorostiaga E, Ortega F, Martinez C, Idoate F, Ricart W, Ibanez J (2009) Circulating soluble transferrin receptor concentration decreases after exercise-induced improvement of insulin sensitivity in obese individuals. Int J Obes (Lond) 33(7):768–774. https://doi.org/10.1038/ijo.2009.99 CrossRefGoogle Scholar
- Freixenet N, Remacha A, Berlanga E, Caixas A, Gimenez-Palop O, Blanco-Vaca F, Bach V, Baiget M, Sanchez Y, Felez J, Gonzalez-Clemente JM (2009) Serum soluble transferrin receptor concentrations are increased in central obesity. Results from a screening programme for hereditary hemochromatosis in men with hyperferritinemia. Clin Chim Acta 400(1–2):111–116. https://doi.org/10.1016/j.cca.2008.10.019 CrossRefPubMedGoogle Scholar
- Houjeghani S, Kheirouri S, Faraji E, Jafarabadi MA (2017) l-carnosine supplementation attenuated fasting glucose, triglycerides, advanced glycation end products and tumor necrosis factor alpha levels in patients with type 2 diabetes: a double-blind placebo-controlled randomized clinical trial. Nutr Res. https://doi.org/10.1016/j.nutres.2017.11.003 PubMedCrossRefGoogle Scholar
- Meng G, Yang H, Bao X, Zhang Q, Liu L, Wu H, Du H, Xia Y, Shi H, Guo X, Liu X, Li C, Su Q, Gu Y, Fang L, Yu F, Sun S, Wang X, Zhou M, Jia Q, Guo Q, Song K, Huang G, Wang G, Wu Y, Niu K (2017) Increased serum ferritin levels are independently related to incidence of prediabetes in adult populations. Diabetes Metab 43(2):146–153. https://doi.org/10.1016/j.diabet.2016.07.028 CrossRefPubMedGoogle Scholar
- Montonen J, Boeing H, Steffen A, Lehmann R, Fritsche A, Joost HG, Schulze MB, Pischon T (2012) Body iron stores and risk of type 2 diabetes: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. Diabetologia 55(10):2613–2621. https://doi.org/10.1007/s00125-012-2633-y CrossRefPubMedPubMedCentralGoogle Scholar
- Peters V, Schmitt CP, Weigand T, Klingbeil K, Thiel C, van den Berg A, Calabrese V, Nawroth P, Fleming T, Forsberg E, Wagner AH, Hecker M, Vistoli G (2017) Allosteric inhibition of carnosinase (CN1) by inducing a conformational shift. J Enzyme Inhib Med Chem 32(1):1102–1110. https://doi.org/10.1080/14756366.2017.1355793 CrossRefPubMedPubMedCentralGoogle Scholar
- Podmore C, Meidtner K, Schulze MB, Scott RA, Ramond A, Butterworth AS, Di Angelantonio E, Danesh J, Arriola L, Barricarte A, Boeing H, Clavel-Chapelon F, Cross AJ, Dahm CC, Fagherazzi G, Franks PW, Gavrila D, Grioni S, Gunter MJ, Gusto G, Jakszyn P, Katzke V, Key TJ, Kuhn T, Mattiello A, Nilsson PM, Olsen A, Overvad K, Palli D, Quiros JR, Rolandsson O, Sacerdote C, Sanchez-Cantalejo E, Slimani N, Sluijs I, Spijkerman AM, Tjonneland A, Tumino R, van der DL A, van der Schouw YT, Feskens EJ, Forouhi NG, Sharp SJ, Riboli E, Langenberg C, Wareham NJ (2016) Association of multiple biomarkers of iron metabolism and type 2 diabetes: the EPIC-interact study. Diabetes Care 39(4):572–581. https://doi.org/10.2337/dc15-0257 CrossRefPubMedPubMedCentralGoogle Scholar
- Rajpathak SN, Negassa A, Kabat GC, Wylie-Rosett J, Rohan TE, Crandall J, Diabetes Prevention Program Research G (2009b) Elevated body iron stores predict the conversion from impaired glucose tolerance to type 2 diabetes. Diabetes Obes Metab 11(5):472–479. https://doi.org/10.1111/j.1463-1326.2008.00985.x CrossRefPubMedPubMedCentralGoogle Scholar
- Regazzoni L, de Courten B, Garzon D, Altomare A, Marinello C, Jakubova M, Vallova S, Krumpolec P, Carini M, Ukropec J, Ukropcova B, Aldini G (2016) A carnosine intervention study in overweight human volunteers: bioavailability and reactive carbonyl species sequestering effect. Sci Rep 6:27224. https://doi.org/10.1038/srep27224 CrossRefPubMedPubMedCentralGoogle Scholar
- Zhang S, Ntasis E, Kabtni S, van den Born J, Navis G, Bakker SJ, Kramer BK, Yard BA, Hauske SJ (2016) Hyperglycemia does not affect iron mediated toxicity of cultured endothelial and renal tubular epithelial cells: influence of l-carnosine. J Diabetes Res 2016:8710432. https://doi.org/10.1155/2016/8710432 PubMedCrossRefGoogle Scholar