International Journal of Molecular Sciences Review Discovery of Food-Derived Dipeptidyl Peptidase IV Inhibitory Peptides: A Review Rui Liu 1,2,3,4 , Jianming Cheng 1,2,3,* and Hao Wu 1,2,3,* 1 Jiangsu Key Laboratory of Research and Development in Marine Bio-resource Pharmaceutics, Nanjing University of Chinese Medicine, Nanjing 210023, China; [email protected] 2 Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing 210023, China 3 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China 4 School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA * Correspondence: [email protected] (J.C.); [email protected] (H.W.); Tel.: +86-25-85811524 (J.C.); +86-25-85811206 (H.W.) Received: 21 December 2018; Accepted: 19 January 2019; Published: 22 January 2019 Abstract: Diabetes is a chronic metabolic disorder which leads to high blood sugar levels over a prolonged period. Type 2 diabetes mellitus (T2DM) is the most common form of diabetes and results from the body’s ineffective use of insulin. Over ten dipeptidyl peptidase IV (DPP-IV) inhibitory drugs have been developed and marketed around the world in the past decade. However, owing to the reported adverse effects of the synthetic DPP-IV inhibitors, attempts have been made to find DPP-IV inhibitors from natural sources. Food-derived components, such as protein hydrolysates (peptides), have been suggested as potential DPP-IV inhibitors which can help manage blood glucose levels. This review focuses on the methods of discovery of food-derived DPP-IV inhibitory peptides, including fractionation and purification approaches, in silico analysis methods, in vivo studies, and the bioavailability of these food-derived peptides. Moreover, food-derived DPP-IV inhibitory peptides discovered during this decade are listed and distributed in a 3D scatter plot graph based on their IC50, molecular weight, and grand average of hydropathicity values, which can help us to understand the relationship between the features of the peptides and their activities. Keywords: dipeptidyl-peptidase IV inhibition; food proteins; peptides; type 2 diabetes mellitus 1. Introduction Diabetes is a chronic metabolic disorder which leads to high blood sugar levels over a prolonged period. Type 2 diabetes mellitus (T2DM), type 1 diabetes mellitus (T1DM), and gestational diabetes mellitus are the most frequent forms; other specific types exist that are much less common [1,2]. In recent years, diabetes has become one of the leading causes of death worldwide. According to the International Diabetes Federation (IDF), it is estimated that about 425 million people were living with diabetes globally in 2017 and that the number will be 642 million by 2040 [3]. T2DM is the most common form of diabetes and results from the body’s ineffective use of insulin: it accounts for the vast majority of people with diabetes around the world. The World Health Organization (WHO) estimates that 90 percent of people living with diabetes have type 2 disease [4]. The exact cause of T2DM remains unclear [5]. The involvement of insulin resistance and pancreatic β-cell dysfunction in the pathogenesis of T2DM has been discussed for a long time [6]. Kahn et al. determined the relationship between insulin sensitivity and β-cell function, and pointed out that the relationship was similar to a feedback loop control system [7]. After insulin-sensitive tissues, such as skeletal muscle, adipose tissue, and liver, Int. J. Mol. Sci. 2019, 20, 463; doi:10.3390/ijms20030463 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 463 2 of 22 take up glucose, these tissues send a feedback signal to the β-cells that they need insulin. In order to maintain normal glucose homoeostasis, β-cells release a certain concentration of insulin. If insulin resistance occurs, the feedback signal from tissues causes the β-cells to increase insulin output to maintain normal glucose tolerance. However, under the situation of insulin resistance, and once the β-cells become unable to release sufficient insulin, glucose concentrations will increase [6]. Genetic and environmental factors are reported to be crucial determinants of insulin resistance and β-cell dysfunction. Genomic investigation has shown that more than 50 gene loci are associated with T2DM [8]. Environmental factors, including energy expenditure, caloric intake, nutrient composition, environmental chemicals, and even the gut environment and gut microbiome, are important as well [9,10]. Aside from those factors, the brain–gut axis also plays an important role in normal glucose homoeostasis. The gastrointestinal tract can release various peptides which are closely related to T2DM, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP are well known as incretins and can increase insulin secretion and suppress glucagon secretion [11]. GLP-1 and GIP are released into the small intestine and regulate glucose homoeostasis. The incretin effect, defined as the insulin secretory response of the incretins, accounts for at least 50% of the total insulin secreted after a meal [12]. However, both GLP-1 and GIP are rapidly deactivated by an enzyme: dipeptidyl peptidase IV (DPP-IV). DPP-IV can cleave the N-terminal dipeptide residues of GLP-1 and GIP and produce inactive incretins, which leads to GLP-1 and GIP losing their insulinotropic activity [13,14]. DPP-IV is a homodimeric serine peptidase, which consists of approximately 700 amino acids in each subunit. DPP-IV preferentially cleaves substrate peptides with Pro or Ala at the penultimate position of peptides. DPP-IV is responsible for the degradation of GLP-1 and GIP [15]. DPP-IV inhibition is a key target in the treatment of T2DM, and DPP-IV inhibitors were one of the first classes of oral antidiabetic drugs to be prospectively designed as anti-hyperglycemic agents [16]. To date, more than ten DPP-IV inhibitory drugs, which are classified as gliptins, have been developed and marketed around the world [17]. In 2006 Sitagliptin was the first gliptin to be approved by the United States Food and Drug Administration [18], and new members continue to be approved, such as Vildagliptin, Saxagliptin, Linagliptin, Gemigliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Omarigliptin, Evogliptin, and Gosogliptin [16]. However, these synthetic DPP-IV inhibitors are reported to have some adverse effects [19], such as gastrointestinal adverse effects [20], allergic reactions [21], skin-related side effects [22], and musculoskeletal disorders [23]. However, DPP-IV inhibitors have been discovered in foods, herbal preparations, natural sources, and traditional Chinese medicines, including phenolic compounds from blueberry–blackberry wine blends [24], alkaloids from seed extract of Castanospermum australe [25], and procyanidins from grape seed [26], all of which have shown good DPP-IV inhibitory activity. Various foods, including milk, fish, wheat gluten, beans, egg, and bivalve mollusks, are natural protein sources; after enzymatic hydrolysis, microbial fermentation, decoction, or some other physical and/or chemical processing, their proteins may be degraded and release various DPP-IV inhibitory peptides [27–32]. It has been reported different peptides showed different DPP-IV inhibitory modes, including competitive, uncompetitive, noncompetitive and mixed-type modes, which means those peptides might exert DPP-IV inhibitory activity by binding either at the active site and/or outside the catalytic site of DPP-IV [5]. It has been suggested that those natural food- or herb-derived constituents should be safer than synthetic forms, and could be used for glycemic management. Among the sources of DPP-IV inhibitors, food protein-derived DPP-IV inhibitory peptides have attracted the attention of more and more researchers, owing to their high efficacy and safety [33]. The purpose of this review is to describe the discovery of food-derived DPP-IV inhibitory peptides, and to provide information on their use in glycemic management and blood glucose regulation. Int. J. Mol. Sci. 2019, 20, 463 3 of 22 Int. J. Mol.2. Methods Sci. 2019, 20 for, 463 Discovering Food-Derived DPP-IV Inhibitory Peptides 3 of 23 2.1.Many Enzymatic bioactive Hydrolysates peptides have of Food been Proteins discovered in the enzymatic hydrolysates of various food proteins. 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