Skip to main content Accessibility help
×
Home

Food protein hydrolysates as a source of dipeptidyl peptidase IV inhibitory peptides for the management of type 2 diabetes

  • Orla Power (a1) (a2), A. B. Nongonierma (a1) (a2), P. Jakeman (a2) (a3) and R. J. FitzGerald (a1) (a2)

Abstract

The prevalence of type 2 diabetes mellitus (T2DM) is increasing and it is estimated that by 2030 approximately 366 million people will be diagnosed with this condition. The use of dipeptidyl peptidase IV (DPP-IV) inhibitors is an emerging strategy for the treatment of T2DM. DPP-IV is a ubiquitous aminodipeptidase that cleaves incretins such as glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), resulting in a loss in their insulinotropic activity. Synthetic DPP-IV drug inhibitors are being used to increase the half-life of the active GLP-1 and GIP. Dietary intervention is accepted as a key component in the prevention and management of T2DM. Therefore, identification of natural food protein-derived DPP-IV inhibitors is desirable. Peptides with DPP-IV inhibitory activity have been identified in a variety of food proteins. This review aims to provide an overview of food protein hydrolysates as a source of the DPP-IV inhibitory peptides with particular focus on milk proteins. In addition, the proposed modes of inhibition and structure–activity relationship of peptide inhibitors are discussed. Milk proteins and associated peptides also display insulinotropic activity and help regulate blood glucose in healthy and diabetic subjects. Therefore, milk protein derived peptide inhibitors may be a unique multifunctional peptide approach for the management of T2DM.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Food protein hydrolysates as a source of dipeptidyl peptidase IV inhibitory peptides for the management of type 2 diabetes
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Food protein hydrolysates as a source of dipeptidyl peptidase IV inhibitory peptides for the management of type 2 diabetes
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Food protein hydrolysates as a source of dipeptidyl peptidase IV inhibitory peptides for the management of type 2 diabetes
      Available formats
      ×

Copyright

Corresponding author

* Corresponding author: R. J. FitzGerald, fax 00353-61-331490, email dick.fitzgerald@ul.ie

References

Hide All
1. World Health Organisation (2012) Diabetes programme, country and regional data. http://www.who.int/diabetes/facts/world_figures/en/ (accessed 12 September 2012).
2. Ben-Avraham, S, Harman-Boehm, I, Schwarzfuchs, D et al. (2009) Dietary strategies for patients with type 2 diabetes in the era of multi-approaches; review and results from the dietary intervention randomized controlled trial (DIRECT). Diabetes Res Clin Pract 86, S41S48.
3. Drucker, DJ (2006) The biology of incretin hormones. Cell Metab 3, 153165.
4. Drucker, DJ (2007) Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes. Diabetes Care 30, 13351343.
5. Gupta, V & Kalra, S (2011) Choosing a gliptin. Indian J Endo Metab 15, 298308.
6. Krushner, P & Gorrell, M (2010) DPP-4 inhibitors in type 2 diabetes: importance of selective enzyme inhibition and implications for clinical use. J Fam Pract 59, 2.
7. American Diabetes Association (2009) Standards of medical care in diabetes—2009. Diabetes Care 32, S13S61.
8. FitzGerald, RJ & Meisel, H (2003) Milk protein hydrolysates and bioactive peptides. In Advanced Dairy Chemistry 1: Proteins, 3rd ed., pp. 675698 [Fox, PF & Mc Sweeney, PLH, editors]. New York: Kluwer Academic/Plenum Publishers.
9. Murray, BA & FitzGerald, RJ (2007) Angiotensin converting enzyme inhibitory peptides derived from food proteins: biochemistry, bioactivity and production. Curr Pharm Des 13, 773791.
10. Frid, AH, Nilsson, M, Holst, JJ et al. (2005) Effect of whey on blood glucose and insulin responses to composite breakfast and lunch meals in type 2 diabetic subjects. Am J Clin Nutr 82, 6975.
11. Manders, RJF, Wagenmakers, AJM, Koopman, R et al. (2005) Co-ingestion of a protein hydrolysate and amino acid mixture with carbohydrate improves plasma glucose disposal in patients with type 2 diabetes. Am J Clin Nutr 82, 7683.
12. Lacroix, IME & Li-Chan, ECY (2012) Dipeptidyl peptidase-IV inhibitory activity of dairy protein hydrolysates. Int Dairy J 25, 97102.
13. Nongonierma, AB & FitzGerald, RJ (2013a) Dipeptidyl peptidase IV inhibitory and antioxidative properties of milk protein-derived dipeptides and hydrolysates. Peptides 39, 157163.
14. Perley, MJ & Kipnis, DM (1967) Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J Clin Invest 46, 19541962.
15. Nauck, M, Homberger, E, Siegel, EG et al. (1986) Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocr Metab 63, 492498.
16. Kim, W & Egan, JM (2008) The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev 60, 470512.
17. Nauck, M, Stöckmann, F, Ebert, R et al. (1986) Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 29, 4652.
18. Vilsbøll, T, Krarup, T, Deacon, CF et al. (2001) Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 50, 609613.
19. Nauck, MA, Bartels, E, Orskov, C et al. (1993) Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7–36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocr Metab 76, 912917.
20. Drucker, D (2003) Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Inv Drug 12, 87100.
21. Reimann, F, Habib, AM, Tolhurst, G et al. (2008) Glucose sensing in L cells: a primary cell study. Cell Metab 8, 532539.
22. Hall, WL, Millward, DJ, Long, SJ et al. (2003) Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite. Br J Nutr 89, 239248.
23. Power, O, Conway, C, McCormack, W et al. (2011) A comparison of the insulinotropic and enterogastric response to ingestion of an equivalent quantity of maltodextran and whey protein. Proc Nutr Soc 70, E357.
24. Hira, T, Mochida, T, Miyashita, K et al. (2009) GLP-1 secretion is enhanced directly in the ileum but indirectly in the duodenum by a newly identified potent stimulator, zein hydrolysate, in rats. Am J Physiol Gastrointest Liver Physiol 297, G663G671.
25. Oya, M, Kitaguchi, T, Pais, R et al. (2012) The GPRC6A receptor is involved in amino acid-induced glucagon-like peptide-1 secretion from GLUTag cells. J Biol Chem 288, 45134521.
26. Reimann, F, Williams, L, Silva Xavier, G et al. (2004) Glutamine potently stimulates glucagon-like peptide-1 secretion from GLUTag cells. Diabetologia 47, 15921601.
27. Lindgren, O, Carr, RD, Deacon, CF et al. (2011) Incretin hormone and insulin responses to oral versus intravenous lipid administration in humans. J Clin Endocr Metab 96, 25192524.
28. Schirra, J, Katschinski, M, Weidmann, C et al. (1996) Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest 97, 92103.
29. Mentlein, R, Gallwitz, B & Schmidt, WE (1993) Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7–36) amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 214, 829835.
30. Holst, JJ (2007) The physiology of glucagon-like peptide 1. Physiol Rev 87, 14091439.
31. Kreymann, B, Ghatei, MA, Williams, G et al. (1987) Glucagon-like peptide 1 7–36: a physiological incretin in man. Lancet 330, 13001304.
32. Wettergren, A, Schjoldager, B, Mortensen, PE et al. (1993) Truncated GLP-1 (proglucagon 78–107-amide) inhibits gastric and pancreatic functions in man. Digest Dis Sci 38, 665673.
33. Näslund, E, Bogefors, J, Skogar, S et al. (1999) GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans. Am J Physiol Regul Integr Comp Physiol 277, R910R916.
34. Flint, A, Raben, A, Astrup, A et al. (1998) Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 101, 515520.
35. Rijkelijkhuizen, JM, McQuarrie, K, Girman, CJ et al. (2010) Effects of meal size and composition on incretin, α-cell, and β-cell responses. Metabolis 59, 502511.
36. Kim, S-J, Nian, C & McIntosh, CHS (2007) Activation of lipoprotein lipase by glucose-dependent insulinotropic polypeptide in adipocytes. J Biol Chem 282, 85578567.
37. Vilsbøll, T, Krarup, T, Madsbad, S et al. (2003) Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept 114, 115121.
38. Holst, JJ & Gromada, J (2004) Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endo M 287, E199E206.
39. Marguet, D, Baggio, L, Kobayashi, T et al. (2000) Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci USA 97, 68746879.
40. Nagakura, T, Yasuda, N, Yamazaki, K et al. (2003) Enteroinsular axis of db/db mice and efficacy of dipeptidyl peptidase IV inhibition. Metabolis 52, 8186.
41. Conarello, SL, Li, Z, Ronan, J et al. (2003) Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc Natl Acad Sci USA 100, 68256830.
42. Hu, P, Yin, Q, Deckert, F et al. (2009) Pharmacokinetics and pharmacodynamics of vildagliptin in healthy chinese volunteers. J Clin Pharmacol 49, 3949.
43. Ahrén, B, Landin-Olsson, M, Jansson, P-A et al. (2004) Inhibition of dipeptidyl peptidase-IV reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocr Metab 89, 20782084.
44. Yu, DMT, Yao, T-W, Chowdhury, S et al. (2010) The dipeptidyl peptidase IV family in cancer and cell biology. FEBS J 277, 11261144.
45. Mentlein, R (1999) Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides. Regul Pept 85, 924.
46. Gorrell, MD (2005) Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clin Sci 108, 277292.
47. Aertgeerts, K, Ye, S, Tennant, MG et al. (2004) Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation. Protein Sci 13, 412421.
48. Rasmussen, HB, Branner, S, Wiberg, FC et al. (2003) Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat Struct Mol Biol 10, 1925.
49. Kühn-Wache, K, Bär, JW, Hoffmann, T et al. (2011) Selective inhibition of dipeptidyl peptidase 4 by targeting a substrate-specific secondary binding site. Biol Chem 392, 223231.
50. Lambeir, A-M, Durinx, C, Scharpé, S et al. (2003) Dipeptidyl-Peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci 40, 209.
51. Ahrén, B, Schweizer, A, Dejager, S et al. (2011) Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans. Diabetes Obes Metab 13, 775783.
52. Rahfeld, J, Schierborn, M, Hartrodt, B et al. (1991) Are diprotin A (Ile-Pro-Ile) and diprotin B (Val–Pro–Leu) inhibitors or substrates of dipeptidyl peptidase IV? BBA-Protein Struct M 1076, 314316.
53. Hatanaka, T, Inoue, Y, Arima, J et al. (2012) Production of dipeptidyl peptidase IV inhibitory peptides from defatted rice bran. Food Chem 134, 797802.
54. Potashman, MH & Duggan, ME (2009) Covalent modifiers: an orthogonal approach to drug design. J Med Chem 52, 12311246.
55. Hoffmann, T, Kuehn-Wache, K, Demuth, H-U et al. (2002) inventors; OSI Pharmaceuticals, Inc., assignee. The present application relates to the secondary binding site of dipeptidyl peptidase IV, its relationship amongst substrates and to the modulation of substrate specificity of dipeptidyl peptidase IV. United States US 2004/0058876 A1 (Patent).
56. Velarde-Salcedo, AJ, Barrera-Pacheco, A, Lara-González, S et al. (2013) In vitro inhibition of dipeptidyl peptidase IV by peptides derived from the hydrolysis of amaranth (Amaranthus hypochondriacus L.) proteins. Food Chem 136, 758764.
57. Lorey, S, Stöckel-Maschek, A, Faust, J et al. (2003) Different modes of dipeptidyl peptidase IV (CD26) inhibition by oligopeptides derived from the N-terminus of HIV-1 Tat indicate at least two inhibitor binding sites. Eur J Biochem 270, 21472156.
58. Haque, E, Chand, R & Kapila, S (2009) Biofunctional properties of bioactive peptides of milk origin. Food Revs Int 25, 2843.
59. Korhonen, H (2009) Milk-derived bioactive peptides: From science to applications. J Funct Food 1, 177187.
60. Lacroix, IME & Li-Chan, ECY (2012) Evaluation of the potential of dietary proteins as precursors of dipeptidyl peptidase (DPP)-IV inhibitors by an in silico approach. J Funct Food 4, 403422.
61. Li-Chan, ECY, Hunag, S-L, Jao, C-L et al. (2012) Peptides derived from atlantic salmon skin gelatin as dipeptidyl-peptidase IV inhibitors. J Agric Food Chem 60, 973978.
62. Huang, S-L, Jao, C-L, Ho, K-P et al. (2012) Dipeptidyl-peptidase IV inhibitory activity of peptides derived from tuna cooking juice hydrolysates. Peptides 35, 114121.
63. Uenishi, H, Kabuki, T, Seto, Y et al. (2012) 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 22, 2430.
64. Uchida, M, Ohshiba, Y & Mogami, O (2011) Novel dipeptidyl peptidase-4 inhibiting peptide derived from beta-lactoglobulin. J Pharmacol Sci 117, 6366.
65. Tulipano, G, Sibilia, V, Caroli, AM et al. (2011) Whey proteins as source of dipeptidyl dipeptidase IV (dipeptidyl peptidase-4) inhibitors. Peptides 32, 835838.
66. Silveira, ST, Martínez-Maqueda, D, Recio, I et al. (2013) Dipeptidyl peptidase-IV inhibitory peptides generated by tryptic hydrolysis of a whey protein concentrate rich in β-lactoglobulin. Food Chem 141, 10721077.
67. Tominaga, Y, Yokota, S, Tanaka, H et al. (2012) inventors; Kaneka Corporation, assignee. Dipeptidyl peptidase-4 inhibitor. United States US 2012 0189611 (Patent).
68. Silva-Sánchez, C, de la Rosa, APB, León-Galván, MF et al. (2008) Bioactive peptides in amaranth (Amaranthus hypochondriacus) seed. J Agric Food Chem 56, 12331240.
69. Aart, V, Catharina, M, Zeeland-Wolbers, V et al. (2009) inventors; Newtricous B.V. , assignee. Egg protein hydrolysates. WO 2009/128713 (Patent).
70. Foltz, M, Van Buren, L, Klaffke, W et al. (2009) Modeling of the relationship between dipeptide structure and dipeptide stability, permeability, and ACE inhibitory activity. J Food Sci 74, H243H251.
71. Nongonierma, AB, Mooney, C, Shields, DC et al. (2013b) Inhibition of dipeptidyl peptidase IV and xanthine oxidase by amino acids and dipeptides. Food Chem 141, 644653.
72. Fox, P, McSweeney, P (2003) Proteins. In Advanced Dairy Chemistry, 3rd ed., pp. 146238 [Fox, P & McSweeney, P, editors]. New York: Kluwer Academic/Plenum Publishers.
73. Boots, J (2006) inventor Campina Nederland Holding B.V., assignee. Protein hydrolysates enriched in peptides inhibiting DPP IV and thier use. WO 2006/068480 200 (Patent).
74. Maritim, AC, Sanders, RA & Watkins, JB (2003) Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxic 17, 2438.
75. Abubakar, A, Saito, T, Kitazawa, H et al. (1998) Structural analysis of new antihypertensive peptides derived from cheese whey protein by proteinase K digestion. J Diary Sci 81, 31313138.
76. Durrant, J & McCammon, JA (2011) Molecular dynamics simulations and drug discovery. BMC Bio 9, 71.
77. Pripp, A (2007) Docking and virtual screening of ACE inhibitory dipeptides. Eur Food Res Technol 225, 589592.
78. Norris, R, Casey, F, FitzGerald, RJ et al. (2012) Predictive modelling of angiotensin converting enzyme inhibitory dipeptides. Food Chem 133, 13491354.
79. Tanaka-Amino, K, Matsumoto, K, Hatakeyama, Y et al. (2008) ASP4000, a novel, selective, dipeptidyl peptidase 4 inhibitor with antihyperglycemic activity. Eur J Pharmacol 590, 444449.
80. Mochida, T, Hira, T & Hara, H (2010) The corn protein, zein hydrolysate, administered into the ileum attenuates hyperglycemia via its dual action on glucagon-like peptide-1 secretion and dipeptidyl peptidase-IV activity in rats. Endocrinology 151, 30953104.
81. Ahrén, B, Simonsson, E, Larsson, H et al. (2002) Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes. Diabetes Care 25, 869875.
82. Ahrén, B, Gomis, R, Standl, E et al. (2004) Twelve- and 52-week efficacy of the dipeptidyl peptidase IV Inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 27, 28742880.
83. Lindsay, JR, Duffy, NA, McKillop, AM et al. (2005) Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes. Diabetic Med 22, 654657.
84. Nilsson, M, Holst, JJ & Bjorck, IME (2007) Metabolic effects of amino acid mixtures and whey protein in healthy subjects: studies using glucose-equivalent drinks. Am J Clin Nutr 85, 9961004.
85. Power, O, Hallihan, A & Jakeman, P (2009) Human insulinotropic response to oral ingestion of native and hydrolysed whey protein. Amino Acids 37, 333339.
86. van Loon, L, Saris, W, Verhagen, H et al. (2000) Plasma insulin response after ingestion of different amino acid or protein mixtures with carbohydrate. Am J Clin Nutr 72, 96105.
87. Nongonierma, AB & FitzGerald, RJ (2013c) Dipeptidyl peptidase IV inhibitory properties of a whey protein hydrolysate: influence of fractionation, stability to simulated gastrointestinal digestion and food-drug interaction. Int Dairy J 32, 3339.

Keywords

Food protein hydrolysates as a source of dipeptidyl peptidase IV inhibitory peptides for the management of type 2 diabetes

  • Orla Power (a1) (a2), A. B. Nongonierma (a1) (a2), P. Jakeman (a2) (a3) and R. J. FitzGerald (a1) (a2)

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed