Background: Dietary dairy intake has been associated with a lower risk of developing type 2 diabetes mellitus. While the underlying mechanisms are not fully understood, recent studies suggest that this protective role is linked to the biological properties of dairy proteins.
Objective: Determine the viability of dairy as a dietary source of biopeptides with anti-diabetic properties.
Methodology: We analyzed the dairy proteins with the highest concentration in the milk of five species: bovine, sheep, goat, buffalo, and human. These were later subjected to simulated digestion in the BIOPEP-UWM platform, and subsequently to an in silico analysis of the percentage of gastrointestinal absorption, renal excretion, and mean effective concentration (EC50).
Results: A total of 51 di- and tripeptides with dipeptidyl peptidase-IV inhibitory bioactivity (iDPP-IV) were obtained. The 13 biopeptides with the highest gastrointestinal absorption probability were those dipeptides with leucine and tryptophan residues in the C-terminal position, being these the most frequent amino acids in the iDPP-IV compounds. Moreover, six of the thirteen highly absorbable biopeptides appeared to derive from the digestion of proteins present in the milk of the five species. The bioactive profile analysis revealed 12 high-affinity molecular targets, of which two, DPP-IV and calpain-I, are involved in diabetes pathophysiology.
Conclusions: This study outlines parameters such as the gastrointestinal absorption, theoretical renal excretion, and anti-diabetic biopeptides'EC50 of DPP-IV inhibition thereby contributing new insights into the nutraceutical properties of dairy products and stating the release of iDPP-IV biopeptides during gastrointestinal digestion as an underlying mechanism of dairy intake reduction of type 2 diabetes mellitus risk.
Liu Y, Wang K, Maisonet M, Wang L, Zheng S. Associations of lifestyle factors (smoking, alcohol consumption, diet and physical activity) with type 2 diabetes among American adults from National Health and Nutrition Examination Survey (NHANES) 2005-2014. J Diabetes 2017;9(9):846–54. DOI: 10.1111/1753-0407.12492
Gao D, Ning N, Wang C, Wang Y, Li Q, Meng Z, Liu Y, Li Q. Dairy products consumption and risk of type 2 diabetes: Systematic review and dose-response meta-analysis. PLoS ONE 2013;8(9):e73965. DOI: 10.1371/journal.pone.0073965
Fan M, Li Y, Wang C, Mao Z, Zhou W, Zhang L, Yang X, Cui S, Li L. Dietary protein consumption and the risk of type 2 diabetes: A dose-response meta-analysis of prospective studies. Nutrients 2019;11(11):2783. DOI: 10.1007/s00394-018-1737-7
Hidayat K, Du X, Shi B. Milk in the prevention and management of type 2 diabetes: The potential role of milk proteins. Diabetes Metab Res Rev 2019;35(8). DOI: 10.1002/dmrr.3187
Minkiewicz P, Iwaniak A, Darewicz M. BIOPEP-UWM database of bioactive peptides: Current opportunities. Int J Mol Sci 2019;20(23):5978. DOI: 10.3390/ijms20235978
Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017;7(1):42717. DOI: 10.1038/srep42717
Xiong G, Wu Z, Yi J, Fu L, Yang Z, Hsieh C, Yin M, Zeng X, Wu C, Lu A, Chen X, Hou T, Cao D. ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Res 2021;49(W1):W5–14. DOI: 10.1093/nar/gkab255
Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res 2019;47(W1):W357–64. DOI: 10.1093/nar/gkz382
Nongonierma AB, Mooney C, Shields DC, FitzGerald RJ. Inhibition of dipeptidyl peptidase IV and xanthine oxidase by amino acids and dipeptides. Food Chem 2013 Nov;141(1):644–53. DOI: 10.1016/j.foodchem.2013.02.115
Lan VTT, Ito K, Ohno M, Motoyama T, Ito S, Kawarasaki Y. Analyzing a dipeptide library to identify human dipeptidyl peptidase IV inhibitor. Food Chem 2015;175:66–73. DOI: 10.1016/j.foodchem.2014.11.131
Nongonierma AB, Mooney C, Shields DC, FitzGerald RJ. In silico approaches to predict the potential of milk protein-derived peptides as dipeptidyl peptidase IV (DPP-IV) inhibitors. Peptides 2014;57:43–51. DOI: 10.1016/j.peptides.2014.04.018
Sachdeva V, Roy A, Bharadvaja N. Current prospects of nutraceuticals: A review. CPB. 2020;21(10):884–96. DOI: 10.2174/1389201021666200130113441
Premi, M., Bansal, V. Nutraceuticals for management of metabolic disorders. In: Treating endocrine and metabolic disorders with herbal medicines. 2021. p. 298–320. DOI: 10.4018/978-1-7998-4808-0.ch013
Acquah C, Dzuvor CKO, Tosh S, Agyei D. Anti-diabetic effects of bioactive peptides: recent advances and clinical implications. Crit Rev Food Sci Nutr 2020;1–14. DOI: 10.1080/10408398.2020.1851168
Andrade EL, Bento AF, Cavalli J, Oliveira SK, Freitas CS, Marcon R, Schwanke RC, Siquiera JM, Calixto JB. Non-clinical studies required for new drug development - Part I: early in silico and in vitro studies, new target discovery and validation, proof of principles and robustness of animal studies. Braz J Med Biol Res 2016;49(11):e5644. DOI: 10.1590/1414-431X20165644
Acquah C, Chan YW, Pan S, Agyei D, Udenigwe CC. Structure-informed separation of bioactive peptides. J Food Biochem 2019;43(1):e12765. DOI: 10.1111/jfbc.12765
Agyei D, Pan S, Acquah C, Danquah MK. Bioactivity profiling of peptides from food proteins. In: Soft Chemistry and Food Fermentation. Elsevier; 2017. p. 49–77. DOI: 10.1016/B978-0-12-811412-4.00003-5
Sun X, Udenigwe CC. Chemistry and biofunctional significance of bioactive peptide interactions with food and gut components. J Agric Food Chem 2020;68(46):12972–7. DOI: 10.1021/acs.jafc.9b07559
Patil P, Mandal S, Tomar SK, Anand S. Food protein-derived bioactive peptides in management of type 2 diabetes. Eur J Nutr 2015;54(6):863–80. DOI: 10.1007/s00394-015-0974-2
Barrero JA, Cruz CM, Casallas J, Vásquez JS. Evaluación in silico de péptidos bioactivos derivados de la digestión de proteínas presentes en la leche de bovino (B.taurus), oveja (O.aries), cabra (C.hircus) y búfalo (B.bubalis). TecnoLógicas 2020;50(24). DOI: 10.22430/22565337.1731
Keller F, Hartmann B, Czock D. Time of effect duration and administration interval for sitagliptin in patients with kidney failure. Eur J Drug Metab Pharmacokinet 2014;39(2):77–85. DOI: 10.1007/s13318-013-0164-7
Richter B. Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes. VHRM 2008;Volume 4:753–68. DOI: 10.2147/vhrm.s1707
Herman G, Stevens C, Vandyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: Results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther 2005;78(6):675–88. DOI: 10.1016/j.clpt.2005.09.002
Iwaniak A, Minkiewicz P, Darewicz M, Hrynkiewicz M. Food protein-originating peptides as tastants - Physiological, technological, sensory, and bioinformatic approaches. Food Res Int 2016;89:27–38. DOI: 10.1016/j.foodres.2016.08.010
Wan TT, Li X, Sun Y-M, Li Y-B, Su Y. Role of the calpain on the development of diabetes mellitus and its chronic complications. Biomed Pharmacother 2015;74:187–90. DOI: 10.1016/j.biopha.2015.08.008
Covington MD, Schnellmann RG. Chronic high glucose downregulates mitochondrial calpain 10 and contributes to renal cell death and diabetes-induced renal injury. Kidney Int 2012;81(4):391–400. DOI: 10.1038/ki.2011.356
Dókus LE, Yousef M, Bánóczi Z. Modulators of calpain activity: inhibitors and activators as potential drugs. Expert Opin Drug Discov. 2020;15(4):471–86. DOI: 10.1080/17460441.2020.1722638
Wang TY, Hsieh CH, Hung CC, Jao CL, Lin PY, Hsieh YL, Hsu KC. A study to evaluate the potential of an in silico approach for predicting dipeptidyl peptidase-IV inhibitory activity in vitro of protein hydrolysates. Food Chem 2017;234:431–8. DOI: 10.1016/j.foodchem.2017.05.035
Hsieh CH, Wang TY, Hung CC, Jao CL, Hsieh YL, Wu SX, Hsu KC. In silico, in vitro and in vivo analyses of dipeptidyl peptidase IV inhibitory activity and the antidiabetic effect of sodium caseinate hydrolysate. Food Funct 2016;7(2):1122–8. DOI: 10.1039/c5fo01324k
Nongonierma AB, Lalmahomed M, Paolella S, FitzGerald RJ. Milk protein isolate (MPI) as a source of dipeptidyl peptidase IV (DPP-IV) inhibitory peptides. Food Chem 2017;231:202–11. DOI: 10.1016/j.foodchem.2017.03.123
Uchida M, Ohshiba Y, Mogami O. Novel dipeptidyl peptidase-4–inhibiting peptide derived from ?-lactoglobulin. J Pharmacol Sci 2011;117(1):63–6. DOI: 10.1254/jphs.11089sc
Uenishi H, Kabuki T, Seto Y, Serizawa A, Nakajima H. Isolation and identification of casein-derived dipeptidyl-peptidase 4 (DPP-4)-inhibitory peptide LPQNIPPL from gouda-type cheese and its effect on plasma glucose in rats. Int Dairy J 2012;22(1):24–30. DOI: 10.1016/j.idairyj.2011.08.002
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Copyright (c) 2022 Revista Colombiana de Endocrinología, Diabetes & Metabolismo