Molecular targets and mechanisms of bioactive peptides against metabolic syndromes

Abstract

Bioactive peptides are present in all living organisms and have critical roles ranging from protection against infection as the key element of innate immunity, regulating blood pressure and glucose levels, to reducing signs of ageing by killing senescent cells. Bioactive peptides are also encrypted within food protein sequences that can be released during proteolysis or food processing. These specific food protein fragments are reported to have potential for improving human health and preventing metabolic diseases through their impact on inflammation, blood pressure, obesity, and type-2 diabetes. This review mainly focuses on the molecular targets and the underlying mechanisms of bioactive peptides against various metabolic syndromes including inflammation, high blood pressure, obesity, and type-2 diabetes, to provide new insights and perspectives on the potential of bioactive peptides for management of metabolic syndromes.

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1. Introduction

The prevalence of various chronic diseases, such as cardiovascular disease, chronic inflammation disease, cancers, diabetes, osteoporosis, etc., is increasing at an alarming rate worldwide.¹ In addition to genetic factors, the onset and development of these chronic diseases are lifestyle-related, within which diet plays an important role.^2–5 Many bioactive food components such as dietary fiber, omega-3 fatty acids, phytochemicals, and others are thought to have health-promoting properties.⁶ Food protein-derived bioactive peptides are increasingly recognized for their vast potential to improve human health and prevent chronic diseases via their impacts on various biochemical pathways.⁷

Numerous bioactive peptides have been identified from various kinds of food sources (as summarized in Table 1); soy, egg, milk, and fish are the most extensively studied proteins for preparing bioactive peptides. In addition to proteolysis, bioactive peptides can also be formed during food processing, in particular fermentation (i.e. His-His-Leu from soy paste,⁸ Met-Ala-Pro and Met-Lys-Pro from cheese^9,10), or present naturally (i.e. lunasin, a 43-amino acid peptide identified from soy).^11–13 Their diversified structures¹⁴ give bioactive peptides a broad scope of functions ranging from protection against infection as the key element of innate immunity, regulating blood pressure and glucose levels (Fig. 1), to reducing signs of ageing via killing senescent cells.^15–17 The objective of this review is to provide an update on recent progress and perspectives regarding bioactive peptides against metabolic diseases and potential underlying mechanisms.

Fig. 1 Proposed mechanisms of bioactive peptides on anti-inflammatory, anti-obesity, and anti-diabetic activities. (A) Bioactive peptides exert their anti-diabetic activity mainly via promoting insulin signaling and AMPK signaling pathways. They may act as an insulin mimic to activate the insulin receptor (IR) and insulin receptor substrate (IRS), followed by recruitment of PI3K to IRS; subsequently, activation of PI3K phosphorylates PKB/AKT via PDK1, which in turn promote glycogen synthesis through GSK3, or promote glucose uptake through GLUT4, or inhibit gluconeogenesis through FOXO1. However, whether the feedback from excessive activation of mTORC1 signaling by over-nutrition in obesity could inhibit PI3K through PTEN or the interaction between IR and IRS or not requires further investigation. Bioactive peptides also may stimulate glucose uptake through activating the AMPK pathway and then promoting GLUT4 translocation to the cell membrane. (B) Bioactive peptides exert their anti-obesity activity via inhibiting expression of nuclear transcript factor PPARγ. (C) The anti-inflammatory activity of bioactive peptides is via inhibiting NF-κB, MAPK, and/or JAK-STAT pathways by inhibiting: (1) the stimulus (TNFα, IL-1, or LPS) and their corresponding receptor (TNFR, IL-1R, TLR)-mediated phosphorylation of MAPKKK and the downstream MAPK leading to inhibition of transcription factors (i.e. c-Myc, ATF-2 and c-Jun). (2) Activation of the IκB kinase (IKK) complex, which in turn limits phosphorylation of IκBα and its subsequent polyubiquitination, proteasomal degradation of IκBα as well as release of homo/heterodimers p50 and RelA (p65), resulting in inhibition of transcription of target genes for inflammatory response. (3) Cytokine-mediated phosphorylation of JAK and subsequent phosphorylation of STAT that in turn form the STAT-STAT dimer and translocation dimer to the nucleus, which need to be further validated. This figure was drawn using the Pathway Builder Tool (Version 2.0, http://www.proteinlounge.com). Abbreviations: AMPK, AMP-activated protein kinase; FOXO1, forkhead box O1; PTEN, phosphatase and tensin homologue; GLUT4, glucose transporter 4; GSK3, glycogen synthase kinase; IL-1, interleukin-1; LPS, lipopolysaccharides; IR, insulin receptor; IRS, IR substrate; JAK-STAT, janus kinase-signal transducer and activator of transcription; MAPK, mitogen activated protein kinase; MAPKKK, MAPK kinase kinase; PDK1, 3-phosphoinositide-dependent kinase; PI3K, phosphoinositide 3-kinase; PKB/AKT, protein kinase B; PPARγ, peroxisome proliferator-activated receptor γ; NF-κB, nuclear factor-kappa B; TNFα, tumor necrosis factor.

Table 1 Examples of food proteins derived bioactive peptides and their mechanisms of action

Bioactivities	Protein source	Peptide identifies	Mechanisms of action	Cells or animals	Ref.
Anti-inflammation peptides
Animal source	Bovine casein	Val-Pro-Pro (VPP); Ile-Pro-Pro (IPP)	• Inhibited NF-κB pathway	• 3T3-F442A preadipocytes	25 and 29
			• Reduced adipokine levels	• apolipoprotein E knockout mice
	Bovine casein	VPP	• Inhibited either MAPK-JNK pathway or renin–angiotensin system	• Leukocyte and endothelium	26 and 30
				• Adipocyte and macrophage interactions
	Egg	Ile-Arg-Trp (IRW)	• Inhibited NF-κB pathway	• Human endothelial cells	31 and 32
Botanical source	Marine algae	Peptide from P. yezoensis	• Inhibited MAPK pathways	• RAW 264.7	35
Plant source	Soy	Val-Pro-Tyr	• Reduced expression of TNF-α, IL-6, IL-1, and IL-17	• Caco-2	33
	Soy	lunasin	• Reduced expression of Th2 cytokine	• BALB/c mice	34
Anti-hypertensive peptides
Plant sources	Fermented soybean	His-His-Leu	• Decreased ACE activity in aorta	• SHRs	8
	Sour milk	VPP, IPP	• Increased Mas receptor/NO mediated vasodilation	• Endothelial cells	47 and 48
			• Reduced ACE activity	• Isolated aortic rings
Animal sources	Ovotransferrin	Ile-Gln-Trp, Leu-Lys-Pro	• Increased NO-mediated vasodilation	• Endothelial cells	49–52
			• Reduced vascular inflammation	• SHRs
	Ovotransferrin	IRW	• Increased NO-mediated vasodilation	• SHRs	56
			• Reduced vascular inflammation
			• Up-regulated ACE2 expression
	Bonito	Leu-Lys-Pro-Asn-Met	• A pro-type ACE inhibitory peptide	• SHRs	53
	Sardine muscle	Val-Tyr	• Blocked the angiotensin II type 1 (AT1) receptor	• Mild hypertensive subjects	55
	Lactoferrin	Leu-Ile-Trp-Lys-Leu, Arg-Pro-Tyr-Leu	• Ang II type 1 (AT1) receptor antagonist	• Rabbits	16
			• Inhibition of angiotensin II-induced vasoconstriction
			• ACE inhibition
Anti-obesity peptides
Animal sources	Cheese whey	Casein glycomacropeptides (GMP)	• Inhibited proliferation and differentiation	• Primary rat preadipocytes	72
	Tuna	Asp-Ile-Val-Asp-Lys-Ile-Glu-Ile	• Inhibited C/EBPs and PPARγ expression	• 3T3-L1 preadipocytes	73
			• Inhibited adipocyte differentiation
	Milk	IPP and VPP	• Upregulated PPARγ and adiponectin	• 3T3-F442A preadipocytes	25
			• Anti-inflammation
	milk κ-casein	Caseinomacropeptide	• Stimulated cholecystokinin release	• Male wistar rats	80
Plant sources	Black soy	Isoflavone-free peptide mixture (BSP)	• Decreased appetite	• Diet-induced obese (DIO) mice	77
			• Activated AMPK and STAT3 phosphorylation	• C2C12 myocytes
	Soy protein β-conglycinin	Val-Arg-Ile-Arg-Leu-Leu-Gln-Arg-Phe-Asn-Lys-Arg-Ser	• Suppressed appetite	• Male Sprague-Dawley rats	78
			• Stimulated cholecystokinin (CCK) release
Anti-type 2 diabetes peptides
Plant sources	Soybean	Aglycin	• Maintained IR and IRS1 expression	• Type 2 diabetic mice	106
			• Elevated phosphorylation of IR, IRS1, and AKT
			• Increased translocation of GLUT4 to cell membrane
	Soybean	Trp-His	• Activated AMPK in an insulin-independent way	• L6 muscle cells	118 and 119
			• Increased GLUT4 translocation to plasma membrane
Animal sources	Bovine milk casein glycomacropeptide	Ile-Pro-Pro-Lys-Lys-Asn-Gln-Asp-Lys-Thr-Glu	• Increased phosphorylation of Akt and AMPK	• HepG2 cells	117
			• Activated both insulin and AMPK signaling pathways

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2 Bioactive peptides on human health

2.1 Bioactive peptides against inflammation

Inflammation is one of the body's defensive responses to stimuli, such as pathogen invasion, injury, tissue damage, or infection.¹⁷ Controlled inflammation is essential for normal body function; however, persistent, chronic inflammation at a low intensity is a causative factor for a wide range of chronic diseases such as obesity, type 2 diabetes, asthma, osteoporosis, inflammatory bowel disease, cancer, central nervous system disease, and cardiovascular disease.^17,18 Chronic inflammation is mediated mainly by the nuclear factor-kappa B (NF-κB) pathway, the mitogen activated protein kinase-c-jun N-terminal kinase (MAPK-JNK) pathway, and the janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, usually under the stimuli of tumor necrosis factor α (TNFα), interleukin-1 (IL-1), and lipopolysaccharides (LPS).^19–21 In the canonical NF-κB signaling pathway, the stimulus (TNFα, IL-1, or LPS) binds to its respective receptor (tumor necrosis factor receptor, TNFR, interleukin-1 receptor, IL-1R, or Toll-like receptors, TLRs) leading to activation of the IκB kinase (IKK) complex in the cytoplasm, which in turn phosphorylates IκBα followed by its subsequent polyubiquitination, proteasomal degradation of IκBα, and then release of the homo/heterodimers p50 and RelA (also known asp65); after translocation to the nucleus, these dimers activate transcription of target genes for the inflammatory response.²² In the MAPK pathway, phosphorylation and activation of MAPK kinase kinase (MAPKKK) leads to phosphorylation of MAPK kinase (MAPKK), which in turn mediates phosphorylation of MAPKs (including extracellular signal-regulated kinase, ERK, JNK, and p38). Activated MAPKs then phosphorylate a variety of transcription factors (i.e. c-Myc, ATF-2, and c-Jun) leading to diverse cellular activities such as cell proliferation, migration, differentiation, and survival for the ERK1/2 signaling pathway; autophagy, apoptosis stress, and inflammation for the JNK and p38 signaling pathways.²³ Similarly, when cytokines bind to their corresponding receptors, JAKs are activated leading to phosphorylation of STAT and formation of STAT-STAT dimer. Subsequently, the dimer is translocated to the nucleus and regulates specific gene expression by directly binding to DNA resulting in the inflammatory response.²⁴

Several food-derived bioactive peptides are reported to have anti-inflammatory activities both in in vitro cellular systems and in in vivo animal models.^25–28 Milk-derived tripeptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) showed anti-inflammation activity through inhibition of the NF-κB pathway, as well as increased release of adiponectin in adipocytes,²⁵ contributing to their protective roles against atherosclerotic development in apolipoprotein E knockout mice.²⁹ Furthermore, VPP's anti-inflammatory effect was reported to be mediated through inhibition of either the MAPK-JNK pathway in leukocyte and endothelium or the renin–angiotensin system (RAS) in adipocyte and macrophage interactions.^26,30 Egg-derived tripeptide Ile-Arg-Trp (IRW)'s anti-inflammatory activity also acted through the NF-κB pathway.^31,32 Other anti-inflammatory peptides are Val-Pro-Tyr (VPY) and lunasin from soy, and peptide from P. yezoensis (PPY1, a marine algae).^33–35 Further information on anti-inflammatory peptides has been recently reviewed.^17,25 Given the underlying role of chronic inflammation in many types of chronic diseases, anti-inflammatory peptides identified from food proteins may have a potential role against a wide range of chronic diseases. A number of anti-inflammatory functional foods have been marketed successfully (i.e. lactoferrin from milk whey protein and sesquiterpenoid from Inula plants), providing insight into developing novel peptides against chronic diseases.^36–39 However, there is lack of understanding regarding specific peptide receptors and the associated signaling pathways that mediate their anti-inflammation activities; furthermore, crosstalk among RAS components and these signaling pathways requires further elucidation.

2.2 Bioactive peptides against high blood pressure

Most bioactive peptides have been characterized as inhibitors of angiotensin converting enzyme (ACE),^8,40–44 a key enzyme for regulation of blood pressure, water, and salt balance in RAS.⁴⁵ ACE is responsible for conversion of inactive decapeptide angiotensin I (Ang I) into a vasoconstrictive octapeptide, angiotensin II (Ang II), a major component in adverse blood pressure regulation. Ang II has two main receptors, angiotensin type 1 receptor (AT1) and angiotensin type 2 receptor (AT2).⁴⁶ Binding of angiotensin II to the AT1 receptor causes vasoconstriction and high blood pressure. RAS has been extensively explored as the target for development of antihypertensive drugs.

Well-studied ACE inhibitory peptides include Val-Pro-Pro and Ile-Pro-Pro from sour milk,^47–49 Ile-Arg-Trp, Ile-Gln-Trp, and Leu-Lys-Pro from egg protein ovotransferrin,^50–52 and Leu-Lys-Pro-Asn-Met and Val-Tyr from fish.^53–55 Although most of these peptides have been identified as ACE inhibitors, their mechanisms of action in vivo are more complicated than initially expected. It was revealed that lactoferrin-derived peptides Leu-Ile-Trp-Lys-Leu and Arg-Pro-Tyr-Leu can selectively inhibit angiotensin II-induced vasoconstriction by blocking AT1 receptors.¹⁶ Apart from binding to the AT1 receptor, Ang II can also be converted into Ang (1–7) by ACE2, a homologous enzyme to ACE; Ang-(1–7) binds to the G-protein-coupled receptor (GPCR)-MAS, showing a vasodilatory effect.⁴⁵ Our group demonstrated for the first time that ACE2 is involved with the blood pressure-lowering activity of the ovotransferrin-derived ACE inhibitory peptide Ile-Arg-Trp in SHRs through upregulation of ACE2 gene expression.⁵⁶ Molecular targets,⁵⁷ as well as progress on understanding the mechanisms of ACE inhibitory peptides, have been recently reviewed.^57,58 Given the complexity of the pathophysiology of hypertension, it seems that many ACE inhibitory peptides function beyond ACE inhibition in vivo.

2.3 Bioactive peptides against obesity

According to the World Health Organization (WHO), an individual with a body mass index (BMI, weight divided by height square) of 30.0 kg m⁻² or greater is obese;⁵⁹ BMI ranging from 25.0 to 29.9 kg m⁻² is classified as overweight. Obese individuals often exhibit abdominal and upper body obesity and have larger waist circumferences (men ≥102 cm, women ≥88 cm); abdominal obesity is closely associated with disorders such as hyperglycemia, type 2 diabetes, hypertension, dyslipidemia, gallbladder disease, coronary heart disease (CHD), and cancer.^60–62 Obesity develops when energy intake exceeds energy expenditure resulting from reduced physical exercise and sedentary lifestyle. The energy imbalance contributes to adipose dysfunction and development of obesity and relevant complications. Adipocyte dysfunction is manifest by an excessively increased number and size of adipocytes (hyperplasia and hypertrophy).⁶³ Adipogenesis is regulated by peroxisome proliferator-activated receptor γ (PPARγ) (encoded by PPARG) and CCAAT/enhancer-binding protein α/β/δ (C/EBPα/β/δ);⁶⁴ activation of PPARγ promotes differentiation of preadipocytes into mature adipocytes.⁶⁵ Therefore, a potential target for obesity control is reducing adipogenesis by inhibiting the activity of PPARγ or reducing preadipocyte differentiation.⁶⁶ A synthetic PPARγ antagonist, bisphenol A diglycidyl ether, has been demonstrated to inhibit adipogenesis in preadipocytes 3T3-L1 and 3T3-F442A, which may exert some positive effects in treatment of obesity.⁶⁷ Other synthetic PPARγ antagonists, such as HX531,⁶⁸ GW-9962, and LG100641,⁶⁹ have also been investigated for their potential uses against diet-induced obesity.

There is interest in exploring food components such as peptides or protein hydrolysates as potential alternatives for prevention of obesity. Whey protein isolate has been reported to inhibit expression of PPARγ and lipid accumulation in 3T3-L1 preadipocytes, and also to significantly reduce weight gain in rats fed high-fat diets.⁷⁰ A soy protein hydrolysate⁷¹ and milk casein glycomacropeptides (GMP)⁷² have also been demonstrated to inhibit fat accumulation in primary and 3T3-L1 adipocytes, respectively. Recently, a peptide Asp-Ile-Val-Asp-Lys-Ile-Glu-Ile derived from boiled tuna was found to decrease glucose uptake and triglyceride (TG) levels, and inhibit C/EBPs and PPARγ levels in 3T3-L1 cells, indicating its potential use against obesity.⁷³

As an endocrine agent, adipocytes secrete a variety of adipocytokines such as leptin, resistin, and adiponectin, which are important regulators of relevant metabolism.⁶⁵ It has been reported that the plasma concentration of adiponectin in both men and women correlates negatively with BMI⁷⁴ and visceral adiposity.⁷⁵ Even though the specific modes of action for PPARγ activator thiazolidinediones (TZDs) such as rosiglitazone to elicit insulin sensitivity and weight gain remain under debate, moderate activation of PPARγ leading to increased adiponectin is considered to be a potential strategy for treating excessive visceral adiposity.⁶¹ Accordingly, the aforementioned lactotripeptides Val-Pro-Pro and Ile-Pro-Pro can also induce beneficial adipocyte differentiation, proper upregulation of PPARγ, and secretion of the protective lipid adipokine adiponectin in 3T3-F442A cells,²⁵ indicating their potential role against obesity. A soy protein diet has been reported to increase adiponectin mRNA level in adipose tissue and adiponectin plasma concentration in obese mice,⁷⁶ which may exert some positive effects to improve obesity. Yamauchi et al.⁶⁸ indicated that either by reducing adipocyte differentiation and apoptosis or by upregulation of adiponectin, both moderate reduction of PPARγ activity and PPARγ activation could ameliorate insulin resistance, associated with decreased triglyceride content in muscle or liver and prevention of adipocyte hypertrophy. Thus, a crosstalk and coordinated role may exist between PPARγ and the various adipocytokines such as adiponectin to promote insulin sensitivity.

Apart from modulation of adipose biology to lower adiposity, bioactive peptides could also regulate energy balance via increasing satiety, reducing appetite, and increasing energy expenditure to lower food intake and weight gain. A black soybean protein-derived isoflavone-free peptide mixture was reported to reduce body weight and ameliorate hypercholesterolemia in high fat diet-induced obese rats via decreasing appetite and regulating whole-body energy balance.⁷⁷ A peptide Val-Arg-Ile-Arg-Leu-Leu-Gln-Arg-Phe-Asn-Lys-Arg-Ser derived from soy protein β-conglycinin was demonstrated to decrease body fat and food intake via stimulated release of cholecystokinin (CCK) and thus suppression of appetite.⁷⁸ Milk casein-derived casomorphins with opioid-like activities can interact with gastric opioid receptors to slow gastrointestinal motility to regulate appetite.⁷⁹ Other milk proteins such as caseinoglycomacropeptide⁸⁰ and whey protein⁸¹ also have been found to stimulate CCK release and activate the glucagon-like peptide-1(GLP-1) pathway, respectively, to increase satiety while suppressing appetite. Protein is the most satiating macronutrient. A high-protein diet particularly enriched with β-lactoglobulin has been reported to reduce body weight;⁸² it is not known, however, whether peptides released during gastrointestinal digestion might be responsible for the benefit.

2.4 Bioactive peptides against type-2 diabetes (T2D)

According to Diabetes Canada, “Type 2 diabetes is a disease in which your pancreas does not produce enough insulin, or your body does not properly use the insulin it makes” (http://www.diabetes.ca). Type 2 diabetes (T2D) affects 422 million adults worldwide and this number is expected to reach 592 million by 2035.^83,84 In addition to genetic factors, modern sedentary lifestyle and overnutrition are closely associated with the onset and development of T2D.⁸⁵ As discussed above, obesity is a key contributor to the development of T2D because of prolonged and chronic exposure to excessive nutrition.⁸⁵ In normal glucose homeostasis, an increase in plasma glucose concentration after a meal stimulates insulin release, thus enhancing uptake of glucose by the liver, gut, and peripheral tissues (i.e. muscle), and also suppressing hepatic glucose production; however, this dynamic balance is disturbed in T2D.⁸⁶ Pathogenesis of T2D is characterized by impaired insulin secretion and/or insulin resistance.⁸⁷ Impaired insulin secretion resulting from β-cell loss and dysfunction may occur because of amyloid deposition in pancreatic islets, β-cell differentiation, glucotoxicity, and lipotoxicity,⁸⁷ while insulin resistance is an impaired response of target organs (adipose tissue, skeletal muscle, and liver) to insulin-mediated actions, such as inadequate suppression of hepatic glucose production, and reduced insulin-mediated glucose uptake and utilization in skeletal muscle and adipose tissue.^88,89

The cellular and molecular mechanisms of T2D are associated with insulin signaling, mammalian target of rapamycin (mTOR), and AMP-activated protein kinase (AMPK) signaling pathways.^90,91 Under physiological conditions, insulin stimulates phosphorylation of the insulin receptor (IR) and IR substrate (IRS), followed by recruitment of phosphoinositide 3-kinase (PI3K) to IRS. Subsequently, activation of PI3K phosphorylates protein kinase B (PKB/AKT) and atypical protein kinase C isoforms (aPKCs) via 3-phosphoinositide-dependent kinase (PDK1).⁹² However, in a state of chronic hyperglycemia, a defect of IR or post-receptor (i.e. IRS1, IRS2, and PI3K) may lead to a series of metabolic disorders including (1) decreased glucose transporter 4 (GLUT4)-dependent glucose uptake,⁹⁰ (2) reduced glycogen synthesis through glycogen synthase kinase (GSK3) or salt-inducible kinase 2 (SIK2),⁹⁰ (3) increased gluconeogenesis through forkhead box O1 (FOXO1),⁹⁰ and (4) limited protein synthesis through mTORC1-S6K1 axis in diabetes.⁹⁰ Furthermore, increased activity of extracellular signal-regulated kinase (ERK) in adipocytes and adipose tissue is associated with T2D pathogenesis.⁹³ Feedback to the insulin pathway also contributes to regulation of glucose homeostasis. Albeit AKT-mTORC1 signaling is limited in diabetes, excessive activation of mTORC1 signaling by over-supplied nutrients in obesity could (1) inhibit IRS and its interaction with IR through growth factor receptor-bound protein 10 (GRB10) phosphorylation;^90,94,95 and (2) inhibit phosphatidylinositol 3,4,5-trisphosphate (PIP3) via hypoxia inducible factor 1α (HIF1α) and phosphatase and tensin homologue (PTEN).^90,96

It appears that a number of peptides (including proteins) and phytochemicals can enhance insulin sensitivity via multiple signaling pathways.^97,98 For instance, Momordica charantia (bitter melon, a traditional medicine used for treatment of T2D) alone and in its powder form can reduce insulin resistance through suppression of NF-κB and JNK/p38 MAPKs pathways in liver, muscle, and adipose tissues in obese and diabetic rats.^99,100 A cucurbitane-type triterpenoid enhanced the insulin signaling pathway, GLUT4 expression, and MAPK activation.¹⁰¹ Momordicosides increase glucose uptake through stimulating translocation of GLUT4 to the cell membrane.¹⁰²Momordica charantia insulin receptor-binding protein (mcIRBP)-derived peptides, mcIRBP-19 and mcIRBP-68, enhance insulin binding to IR, stimulating phosphorylation of AKT and expression of GLUT4, resulting in increased glucose uptake in adipocytes and glucose clearance in diabetic mice.^103–105 Soy protein also shows anti-diabetic activities. Aglycin isolated from soybean can improve glucose uptake via elevated phosphorylation of IR, IRS1, and AKT, as well as translocation of GLUT4 to cell membrane.¹⁰⁶ Recent progress has been reviewed on the potential of anti-diabetic plants on improving insulin sensitivities.¹⁰⁷ However, the link between food-derived bioactive peptides and mTOR signaling, as well as their feedback to insulin signaling, has not been explored.

In addition, AMPK activation was recently proposed as a potential therapeutic target for prevention and amelioration of insulin resistance and T2D.^91,108 A Ca²⁺-dependent pathway mediated by Ca²⁺/calmodulin-dependent protein kinase kinase β (CaMKKβ) and a low energy level (high AMP/ATP or ADP/ATP ratio) mediated by serine/threonine kinase II (LKB1), phosphorylated and then activated AMPK.^109–111 Activation of AMPK phosphorylates AS160 (a 160 kDa Akt substrate), resulting in reduced activity of Rab guanosine triphosphatase (GTPase) but increased GTP load on the storage sites of GLUT4, therefore promoting GLUT4 translocation to cell membrane, which ultimately stimulates glucose uptake in skeletal muscle and adipocytes.^112–116 Some bioactive peptides or protein hydrolysates have been demonstrated to improve insulin sensitivity through activating insulin and/or AMPK signaling pathways. For instance, a peptide Ile-Pro-Pro-Lys-Lys-Asn-Gln-Asp-Lys-Thr-Glu derived from casein glycomacropeptide prevented high glucose-induced insulin resistance in hepG2 cells by activating both insulin and AMPK signaling pathways via phosphorylation of Akt and AMPK.¹¹⁷ A dipeptide Trp-His (WH) and a soybean hydrolysate fraction prepared by electrodialysis enhanced glucose uptake in L6 muscle cells through activation of AMPK in an insulin-independent way and enhanced GLUT4 translocation to the plasma membrane, respectively.^118,119 Soy β-conglycinin and soybean peptides improved glucose uptake and insulin sensitivity through activation of AMPK in skeletal muscle in Goto-Kakizaki rats.^118,120,121

For T2D patients, a normal plasma glucose level either in the fasting or postprandial states is of great importance. Postprandial plasma glucose level is considered to be a better marker of glycemic control than fasting plasma glucose levels.¹²² Postprandial plasma level is regulated mainly by α-glucosidase and ubiquitous enzyme dipeptidyl peptidase (DPP)-IV. Inhibitors of α-glucosidase and DPP-IV have been explored extensively for potential for management of T2D.¹²² Research progress in this field has been reviewed.¹²³

Given the complex pathophysiology of T2D, there are multiple targets for bioactive peptides, such as enhancing insulin secretion, potentiating insulin and/or AMPK signaling, and/or inhibiting inflammation, and improved GLUT4 expression and translocation to membrane.^{87,93,117,124–127} In addition to these targets, the crosstalk among insulin, AMPK, and mTOR signaling pathway is also a key treatment aspect for T2D management in response to anti-diabetes peptides.

3 Conclusions

Bioactive peptides have beneficial effects on blood pressure, inflammation, obesity, and T2D, indicating great promise as functional foods/nutraceuticals against metabolic syndromes. Bioactive peptides such as Leu-Lys-Pro-Asn-Met and Val-Tyr have been commercialized.⁵⁴ However, use of bioactive peptides has been criticized because their susceptibility to gastrointestinal proteases and peptidase could render them inactive prior to reaching sites of action, despite many bioactive peptides being proved bioavailable and bioactive in vivo. Recent progress on characterization of various target pathways indicates that bioactive peptides might function locally through receptors on cell membranes. This signifies the importance of further research to explore their mechanisms of action in vivo. Integration of advanced omics technologies with bioinformatic analysis is expected to shed light on the novel pathways of action of the peptides in vivo. It would also be worthwhile studying the effects of bioactive peptides on “master regulators” or “central targets” (i.e. MAPK) and “specific targets” (i.e. IR for T2D, PPAR for obesity) to understand the multifunctional nature of many bioactive peptides and the crosstalk that may be involved. There is an urgent need for translational research so that beneficial bioactive peptides can be made commercially available.

Conflicts of interest

No conflicts of interest.

Acknowledgements

This work was supported by National Key R&D Program of China (2017YFD0400600) and Natural Sciences and Engineering Research Council of Canada.

References

1. P. Nichols, A. Ussery-Hall, S. Griffin-Blake and A. Easton, The evolution of the steps program, 2003–2010: transforming the federal public health practice of chronic disease prevention, Prev. Chronic Dis., 2012, 9, E50.
2. X. Y. Xu, J. Hall, J. Byles and Z. M. Shi, Dietary Pattern Is Associated with Obesity in Older People in China: Data from China Health and Nutrition Survey (CHNS), Nutrients, 2015, 7, 8170–8188.
3. E. P. Lopez, C. Rice, D. O. Weddle and G. J. Rahill, The relationship among cardiovascular risk factors, diet patterns, alcohol consumption, and ethnicity among women aged 50 years and older, J. Am. Diet. Assoc., 2008, 108, 248–256.
4. X. Y. Zhang, L. Shu, C. J. Si, X. L. Yu, W. Gao, D. Liao, L. Zhang, X. L. Liu and P. F. Zheng, Dietary Patterns and Risk of Stroke in Adults: A Systematic Review and Meta-analysis of Prospective Cohort Studies, J. Stroke Cerebrovasc. Dis., 2015, 24, 2173–2182.
5. D. M. A. McCartney, D. G. Byrne and M. J. Turner, Dietary contributors to hypertension in adults reviewed, Ir. J. Med. Sci., 2015, 184, 81–90.
6. P. Zimmet, K. G. Alberti and J. Shaw, Global and societal implications of the diabetes epidemic, Nature, 2001, 414, 782–787.
7. K. Majumder, Y. Mine and J. P. Wu, The potential of food protein-derived anti-inflammatory peptides against various chronic inflammatory diseases, J. Sci. Food Agric., 2016, 96, 2303–2311.
8. Z. I. Shin, R. Yu, S. A. Park, D. K. Chung, C. W. Ahn, H. S. Nam, K. S. Kim and H. J. Lee, His-His-Leu, an angiotensin I converting enzyme inhibitory peptide derived from Korean soybean paste, exerts antihypertensive activity in vivo, J. Agric. Food Chem., 2001, 49, 3004–3009.
9. H. Tonouchi, M. Suzuki, M. Uchida and M. Oda, Antihypertensive effect of an angiotensin converting enzyme inhibitory peptide from enzyme modified cheese, J. Dairy Res., 2008, 75, 284–290.
10. A. Yamada, T. Sakurai, D. Ochi, E. Mitsuyama, K. Yamauchi and F. Abe, Novel angiotensin I-converting enzyme inhibitory peptide derived from bovine casein, Food Chem., 2013, 141, 3781–3789.
11. V. P. Dia, W. Wang, V. L. Oh, B. O. de Lumen and E. G. de Mejia, Isolation, purification and characterisation of lunasin from defatted soybean flour and in vitro evaluation of its anti-inflammatory activity, Food Chem., 2009, 114, 108–115.
12. E. G. de Mejia and V. P. Dia, Lunasin and lunasin-like peptides inhibit inflammation through suppression of NF-kappa B pathway in the macrophage, Peptides, 2009, 30, 2388–2398.
13. A. Cam and E. G. de Mejia, RGD-peptide lunasin inhibits Akt-mediated NF-κB activation in human macrophages through interaction with the alpha V beta 3 integrin, Mol. Nutr. Food Res., 2012, 56, 1569–1581.
14. C. Udenigwe and R. E. Aluko, Food protein-derived bioactive peptides: production, processing, and potential health benefits, J. Food Sci., 2012, 77, R11–R24.
15. J. Y. Lee, Y. S. Choi, S. J. Lee, C. P. Chung and Y. J. Park, Bioactive peptide-modified biomaterials for bone regeneration, Curr. Pharm. Des., 2011, 17, 2663–2676.
16. R. Fernandez-Musoles, M. Castello-Ruiz, C. Arce, P. Manzanares, M. D. Ivorra and J. B. Salom, Antihypertensive Mechanism of Lactoferrin-Derived Peptides: Angiotensin Receptor Blocking Effect, J. Agric. Food Chem., 2014, 62, 173–181.
17. K. Majumder, Y. Mine and J. P. Wu, The potential of food protein-derived anti-inflammatory peptides against various chronic inflammatory diseases, J. Sci. Food Agric., 2016, 96, 2303–2311.
18. C. Nathan and A. Ding, Nonresolving inflammation, Cell, 2010, 140, 871–882.
19. D. Laveti, M. Kumar, R. Hemalatha, R. Sistla, V. G. Naidu, V. Talla, V. Verma, N. Kaur and R. Nagpal, Anti-inflammatory treatments for chronic diseases: a review, Inflammation Allergy: Drug Targets, 2013, 12, 349–361.
20. J. M. Kyriakis and J. Avruch, Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update, Physiol. Rev., 2012, 92, 689–737.
21. M. H. Kaplan, STAT signaling in inflammation, Jak-Stat, 2013, 2, e24198.
22. B. Hoesel and J. A. Schmid, The complexity of NF-kappaB signaling in inflammation and cancer, Mol. Cancer, 2013, 12, 86.
23. E. K. Kim and E. J. Choi, Compromised MAPK signaling in human diseases: an update, Arch. Toxicol., 2015, 89, 867–882.
24. J. J. O'Shea, D. M. Schwartz, A. V. Villarino, M. Gadina, I. B. McInnes and A. Laurence, The JAK-STAT pathway: impact on human disease and therapeutic intervention, Annu. Rev. Med., 2015, 66, 311–328.
25. S. Chakrabarti and J. P. Wu, Milk-Derived Tripeptides IPP (Ile-Pro-Pro) and VPP (Val-Pro-Pro) Promote Adipocyte Differentiation and Inhibit Inflammation in 3T3-F442A Cells, PLoS One, 2015, 10, e0117492.
26. Y. Sawada, Y. Sakamoto, M. Toh, N. Ohara, Y. Hatanaka, A. Naka, Y. Kishimoto, K. Kondo and K. Iida, Milk-derived peptide Val-Pro-Pro (VPP) inhibits obesity-induced adipose inflammation via an angiotensin-converting enzyme (ACE) dependent cascade, Mol. Nutr. Food Res., 2015, 59, 2502–2510.
27. D. P. Mohanty, S. Mohapatra, S. Misra and P. S. Sahu, Milk derived bioactive peptides and their impact on human health - A review, Saudi J. Biol. Sci., 2016, 23, 577–583.
28. S. Marcone, O. Belton and D. J. Fitzgerald, Milk-derived bioactive peptides and their health promoting effects: a potential role in atherosclerosis, Br. J. Clin. Pharmacol., 2017, 83, 152–162.
29. T. Nakamura, T. Hirota, K. Mizushima, K. Ohki, Y. Naito, N. Yamamoto and T. Yoshikawa, Milk-Derived Peptides, Val-Pro-Pro and Ile-Pro-Pro, Attenuate Atherosclerosis Development in Apolipoprotein E-Deficient Mice: A Preliminary Study, J. Med. Food, 2013, 16, 396–403.
30. K. Aihara, H. Ishii and M. Yoshida, Casein-Derived Tripeptide, Val-Pro-Pro (VPP), Modulates Monocyte Adhesion to Vascular Endothelium, J. Atheroscler. Thromb., 2009, 16, 594–603.
31. K. Majumder, S. Chakrabarti, S. T. Davidge and J. Wu, Structure and activity study of egg protein ovotransferrin derived peptides (IRW and IQW) on endothelial inflammatory response and oxidative stress, J. Agric. Food Chem., 2013, 61, 2120–2129.
32. W. Y. Huang, S. Chakrabarti, K. Majumder, Y. Y. Jiang, S. T. Davidge and J. P. Wu, Egg-Derived Peptide IRW Inhibits TNF-alpha-Induced Inflammatory Response and Oxidative Stress in Endothelial Cells, J. Agric. Food Chem., 2010, 58, 10840–10846.
33. J. Kovacs-Nolan, H. Zhang, M. Ibuki, T. Nakamori, K. Yoshiura, P. V. Turner, T. Matsui and Y. Mine, The PepT1-transportable soy tripeptide VPY reduces intestinal inflammation, Biochim. Biophys. Acta, Gen. Subj., 2012, 1820, 1753–1763.
34. E. J. McConnell, B. Devapatla, K. Yaddanapudi and K. R. Davis, The soybean-derived peptide lunasin inhibits non-small cell lung cancer cell proliferation by suppressing phosphorylation of the retinoblastoma protein, Oncotarget, 2015, 6, 4649–4662.
35. H. A. Lee, I. H. Kim and T. J. Nam, Bioactive peptide from Pyropia yezoensis and its anti-inflammatory activities, Int. J. Mol. Med., 2015, 36, 1701–1706.
36. B. I. Brown, Nutritional Management of Metabolic Endotoxemia: A Clinical Review, Altern. Ther. Health Med., 2017, 23, 42–54.
37. N. A. Hering, J. Luettig, S. M. Krug, S. Wiegand, G. Gross, E. A. van Tol, J. D. Schulzke and R. Rosenthal, Lactoferrin protects against intestinal inflammation and bacteria-induced barrier dysfunction in vitro, Ann. N. Y. Acad. Sci, 2017, 1405, 177–188.
38. J. Qin, W. Wang and R. Zhang, Novel natural product therapeutics targeting both inflammation and cancer, Chin. J. Nat. Med., 2017, 15, 401–416.
39. D. J. Newman and G. M. Cragg, Natural Products as Sources of New Drugs from 1981 to 2014, J. Nat. Prod., 2016, 79, 629–661.
40. K. G. Mallikarjun Gouda, L. R. Gowda, A. G. Rao and V. Prakash, Angiotensin I-converting enzyme inhibitory peptide derived from glycinin, the 11S globulin of soybean (Glycine max), J. Agric. Food Chem., 2006, 54, 4568–4573.
41. T. Kodera and N. Nio, Identification of an Angiotensin I-converting Enzyme Inhibitory Peptides from Protein Hydrolysates by a Soybean Protease and the Antihypertensive Effects of Hydrolysates in 4 Spontaneously Hypertensive Model Rats, J. Food Sci., 2006, 71, C164–C173.
42. D. D. Kitts and K. Weiler, Bioactive proteins and peptides from food sources. Applications of bioprocesses used in isolation and recovery, Curr. Pharm. Des., 2003, 9, 1309–1323.
43. R. Kumar, A. Kumar, R. Sharma and A. Baruwa, Pharmacological review on natural ACE inhibitors, Pharm. Lett., 2010, 2, 286.
44. J. R. Chen, T. Okada, K. Muramoto, K. Suetsuna and S. C. Yang, Identification of angiotensin I-converting enzyme inhibitory peptides derived from the peptic digest of soybean protein, J. Food Biochem., 2002, 26, 543–554.
45. J. L. Zhuo, F. M. Ferrao, Y. Zheng and X. C. Li, New frontiers in the intrarenal Renin-Angiotensin system: a critical review of classical and new paradigms, Front. Endocrinol., 2013, 4, 166.
46. M. Bader and D. Ganten, Update on tissue renin-angiotensin systems, J. Mol. Med., 2008, 86, 615–621.
47. T. Hirota, A. Nonaka, A. Matsushita, N. Uchida, K. Ohki, M. Asakura and M. Kitakaze, Milk casein-derived tripeptides, VPP and IPP induced NO production in cultured endothelial cells and endothelium-dependent relaxation of isolated aortic rings, Heart Vessels, 2011, 26, 549–556.
48. Y. Nakamura, N. Yamamoto, K. Sakai and T. Takano, Antihypertensive Effect of Sour Milk and Peptides Isolated from It That Are Inhibitors to Angiotensin I-Converting Enzyme, J. Dairy Sci., 1995, 78, 1253–1257.
49. G. S. Rutella, L. Solieri, S. Martini and D. Tagliazucchi, Release of the Antihypertensive Tripeptides Valine-Proline-Proline and Isoleucine-Proline-Proline from Bovine Milk Caseins during in Vitro Gastrointestinal Digestion, J. Agric. Food Chem., 2016, 64, 8509–8515.
50. K. Majumder and J. Wu, Purification and characterisation of angiotensin I converting enzyme (ACE) inhibitory peptides derived from enzymatic hydrolysate of ovotransferrin, Food Chem., 2011, 126, 1614–1619.
51. K. Majumder, S. Chakrabarti, J. S. Morton, S. Panahi, S. Kaufman, S. T. Davidge and J. Wu, Egg-derived tri-peptide IRW exerts antihypertensive effects in spontaneously hypertensive rats, PLoS One, 2013, 8, e82829.
52. K. Majumder, S. Chakrabarti, J. S. Morton, S. Panahi, S. Kaufman, S. T. Davidge and J. Wu, Egg-derived ACE-inhibitory peptides IQW and LKP reduce blood pressure in spontaneously hypertensive rats, J. Funct. Foods, 2015, 13, 50–60.
53. H. Fujita and M. Yoshikawa, LKPNM: a prodrug-type ACE-inhibitory peptide derived from fish protein, Immunopharmacol., 1999, 44, 123–127.
54. T. Lafarga and M. Hayes, Bioactive protein hydrolysates in the functional food ingredient industry: Overcoming current challenges, Food Rev. Int., 2017, 33, 217–246.
55. T. Kawasaki, E. Seki, K. Osajima, M. Yoshida, K. Asada, T. Matsui and Y. Osajima, Antihypertensive effect of Valyl-Tyrosine, a short chain peptide derived from sardine muscle hydrolyzate, on mild hypertensive subjects, J. Hum. Hypertens., 2000, 14, 519–523.
56. K. Majumder, G. X. Liang, Y. H. Chen, L. L. Guan, S. T. Davidge and J. Wu, Egg ovotransferrin-derived ACE inhibitory peptide IRW increases ACE2 but decreases proinflammatory genes expression in mesenteric artery of spontaneously hypertensive rats, Mol. Nutr. Food Res., 2015, 59, 1735–1744.
57. K. Majumder and J. Wu, Molecular targets of antihypertensive peptides: Understanding the mechanisms of action based on the pathophysiology of hypertension, Int. J. Mol. Sci., 2014, 16, 256–283.
58. J. Wu, W. Liao and C. Udenigwe, Revisiting the mechanisms of ACE inhibitory peptides from food proteins, Trends Food Sci. Technol., 2017, 69, 214–219.
59. P. G. Kopelman, Obesity as a medical problem, Nature, 2000, 404, 635.
60. Y. Okamoto, S. Kihara, T. Funahashi, Y. Matsuzawa and P. Libby, Adiponectin: a key adipocytokine in metabolic syndrome, Clin. Sci., 2006, 110, 267–278.
61. M. Ahmadian, J. M. Suh, N. Hah, C. Liddle, A. R. Atkins, M. Downes and R. M. Evans, PPAR [gamma] signaling and metabolism: the good, the bad and the future, Nat. Med., 2013, 99, 557–566.
62. K. L. Spalding, E. Arner, P. O. Westermark, S. Bernard, B. A. Buchholz, O. Bergmann, L. Blomqvist, J. Hoffstedt, E. Näslund and T. Britton, Dynamics of fat cell turnover in humans, Nature, 2008, 453, 783–787.
63. H. S. Camp, D. Ren and T. Leff, Adipogenesis and fat-cell function in obesity and diabetes, Trends Mol. Med., 2002, 8, 442–447.
64. E. D. Rosen and B. M. Spiegelman, Molecular regulation of adipogenesis, Annu. Rev. Cell Dev. Biol., 2000, 16, 145–171.
65. P. Tontonoz, E. Hu and B. M. Spiegelman, Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor γ, Curr. Opin. Genet. Dev., 1995, 5, 571–576.
66. H. Park, U. Ju, J. Park, J. Song, D. Shin, K. Lee, L. Jeong, J. Yu, H. Lee and J. Cho, PPARγ neddylation essential for adipogenesis is a potential target for treating obesity, Cell Death Differ., 2016, 23, 1296–1311.
67. H. M. Wright, C. B. Clish, T. Mikami, S. Hauser, K. Yanagi, R. Hiramatsu, C. N. Serhan and B. M. Spiegelman, A synthetic antagonist for the peroxisome proliferator-activated receptor γ inhibits adipocyte differentiation, J. Biol. Chem., 2000, 275, 1873–1877.
68. T. Yamauchi, J. Kamon, H. Waki, K. Murakami, K. Motojima, K. Komeda, T. Ide, N. Kubota, Y. Terauchi and K. Tobe, The mechanisms by which both heterozygous peroxisome proliferator-activated receptor γ (PPARγ) deficiency and PPARγ agonist improve insulin resistance, J. Biol. Chem., 2001, 276, 41245–41254.
69. T. Leff and J. E. Reed, The antidiabetic PPARγ ligands: an update on compounds in development, Curr. Med. Chem.: Immunol., Endocr. Metab. Agents, 2002, 2, 33–47.
70. A. Rajic, J. Dhulia, C. G. Hosking and D. J. Autelitano, A novel dairy-derived isolate that inhibits adipogenesis and significantly reduces weight gain in a high fat animal model, Int. Dairy J., 2010, 20, 480–486.
71. C. Martinez-Villaluenga, V. P. Dia, M. Berhow, N. A. Bringe and E. Gonzalez de Mejia, Protein hydrolysates from β-conglycinin enriched soybean genotypes inhibit lipid accumulation and inflammation in vitro, Mol. Nutr. Food Res., 2009, 53, 1007–1018.
72. S. Xu, X. Mao, F. Ren and H. Che, Attenuating effect of casein glycomacropeptide on proliferation, differentiation, and lipid accumulation of in vitro Sprague-Dawley rat preadipocytes, J. Dairy Sci., 2011, 94, 676–683.
73. Y. M. Kim, I. H. Kim, J. W. Choi, M. K. Lee and T. J. Nam, The anti-obesity effects of a tuna peptide on 3T3-L1 adipocytes are mediated by the inhibition of the expression of lipogenic and adipogenic genes and by the activation of the Wnt/β-catenin signaling pathway, Int. J. Mol. Med., 2015, 36, 327–334.
74. Y. Arita, S. Kihara, N. Ouchi, M. Takahashi, K. Maeda, J. Miyagawa, K. Hotta, I. Shimomura, T. Nakamura, K. Miyaoka, H. Kuriyama, M. Nishida, S. Yamashita, K. Okubo, K. Matsubara, M. Muraguchi, Y. Ohmoto, T. Funahashi and Y. Matsuzawa, Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity, Biochem. Biophys. Res. Commun., 1999, 257, 79–83.
75. M. Ryo, T. Nakamura, S. Kihara, M. Kumada, S. Shibazaki, M. Takahashi, M. Nagai, Y. Matsuzawa and T. Funahashi, Adiponectin as a biomarker of the metabolic syndrome, Circ. J., 2004, 68, 975–981.
76. A. Nagasawa, K. Fukui, M. Kojima, K. Kishida, N. Maeda, H. Nagaretani, T. Hibuse, H. Nishizawa, S. Kihara and M. Waki, Divergent effects of soy protein diet on the expression of adipocytokines, Biochem. Biophys. Res. Commun., 2003, 311, 909–914.
77. E. Jang, J. Moon, J. Ko, C. Ahn, H. Lee, J. Shin, C. Park and J. Kang, Novel black soy peptides with antiobesity effects: activation of leptin-like signaling and AMP-activated protein kinase, Int. J. Obes., 2008, 32, 1161.
78. T. Nishi, H. Hara, K. Asano and F. Tomita, The soybean β-conglycinin β 51–63 fragment suppresses appetite by stimulating cholecystokinin release in rats, J. Nutr., 2003, 133, 2537–2542.
79. K. Erdmann, B. W. Cheung and H. Schröder, The possible roles of food-derived bioactive peptides in reducing the risk of cardiovascular disease, J. Nutr. Biochem., 2008, 19, 643–654.
80. N. L.-R. Pedersen, C. Nagain-Domaine, S. Mahé, J. Chariot, C. Rozé and D. Tomé, Caseinomacropeptide specifically stimulates exocrine pancreatic secretion in the anesthetized rat, Peptides, 2000, 21, 1527–1535.
81. W. Hall, D. Millward, S. Long and L. Morgan, Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite, Br. J. Nutr., 2003, 89, 239–248.
82. L. Pichon, M. Potier, D. Tome, T. Mikogami, B. Laplaize, C. Martin-Rouas and G. Fromentin, High-protein diets containing different milk protein fractions differently influence energy intake and adiposity in the rat, Br. J. Nutr., 2008, 99, 739–748.
83. L. Guariguata, D. R. Whiting, I. Hambleton, J. Beagley, U. Linnenkamp and J. E. Shaw, Global estimates of diabetes prevalence for 2013 and projections for 2035, Diabetes Res. Clin. Pract., 2014, 103, 137–149.
84. World Health Organization, Global report on diabetes, 2016, http://www.who.int/mediacentre/factsheets/fs312/en/ (accessed on July 25, 2017).
85. K. A. Coughlan, R. J. Valentine, N. B. Ruderman and A. K. Saha, AMPK activation: a therapeutic target for type 2 diabetes?, Diabetes, Metab. Syndr. Obes.: Targets Ther., 2014, 7, 241–253.
86. R. A. DeFronzo, Pathogenesis of type 2 diabetes mellitus, Med. Clin. North Am., 2004, 88, 787–835.
87. M. F. Kalin, M. Goncalves, J. John-Kalarickal and V. Fonseca, Pathogenesis of type 2 diabetes mellitus, in Principles of diabetes mellitus, ed. L. Poretsky, Springer international publishing, 2017, pp. 267–277.
88. J. L. Leahy, Pathogenesis of type 2 diabetes mellitus, Arch. Med. Res., 2005, 36, 197–209.
89. J. Lu, G. Xie, W. Jia and W. Jia, Insulin resistance and the metabolism of branched-chain amino acids, Front. Med., 2013, 7, 53–59.
90. K. D. Copps and M. F. White, Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2, Diabetologia, 2012, 55, 2565–2582.
91. R. W. Mackenzie and B. T. Elliott, Akt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes, Diabetes, Metab. Syndr. Obes.: Targets Ther., 2014, 7, 55–64.
92. T. F. Franke, D. R. Kaplan, L. C. Cantley and A. Toker, Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate, Science, 1997, 275, 665–668.
93. K. Ozaki, M. Awazu, M. Tamiya, Y. Iwasaki, A. Harada, S. Kugisaki, S. Tanimura and M. Kohno, Targeting the ERK signaling pathway as a potential treatment for insulin resistance and type 2 diabetes, Am. J. Physiol.: Endocrinol. Metab., 2016, 310, E643–E651.
94. K. R. Wick, E. D. Werner, P. Langlais, F. J. Ramos, L. Q. Dong, S. E. Shoelson and F. Liu, Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor, J. Biol. Chem., 2003, 278, 8460–8467.
95. P. P. Hsu, S. A. Kang, J. Rameseder, Y. Zhang, K. A. Ottina, D. Lim, T. R. Peterson, Y. M. Choi, N. S. Gray, M. B. Yaffe, J. A. Marto and D. M. Sabatini, The mTOR-Regulated Phosphoproteome Reveals a Mechanism of mTORC1-Mediated Inhibition of Growth Factor Signaling, Science, 2011, 332, 1317–1322.
96. F. Das, N. Ghosh-Choudhury, N. Dey, C. C. Mandal, L. Mahimainathan, B. S. Kasinath, H. E. Abboud and G. G. Choudhury, Unrestrained Mammalian Target of Rapamycin Complexes 1 and 2 Increase Expression of Phosphatase and Tensin Homolog Deleted on Chromosome 10 to Regulate Phosphorylation of Akt Kinase, J. Biol. Chem., 2012, 287, 3808–3822.
97. M. F. Bachok, B. N. M. Yusof, A. Ismail and A. A. Hamid, Effectiveness of traditional Malaysian vegetables (ulam) in modulating blood glucose levels, Asia Pac. J. Clin. Nutr., 2014, 23, 369–376.
98. J. Singh, E. Cumming, G. Manoharan, H. Kalasz and E. Adeghate, Medicinal chemistry of the anti-diabetic effects of momordica charantia: active constituents and modes of actions, Open Med. Chem. J., 2011, 5, 70–77.
99. S. J. Yang, J. M. Choi, S. E. Park, E. J. Rhee, W. Y. Lee, K. W. Oh, S. W. Park and C. Y. Park, Preventive effects of bitter melon (Momordica charantia) against insulin resistance and diabetes are associated with the inhibition of NF-kappaB and JNK pathways in high-fat-fed OLETF rats, J. Nutr. Biochem., 2015, 26, 234–240.
100. J. Bai, Y. Zhu and Y. Dong, Response of gut microbiota and inflammatory status to bitter melon (Momordica charantia L.) in high fat diet induced obese rats, J. Ethnopharmacol., 2016, 194, 717–726.
101. B. Jiang, M. Ji, W. Liu, L. Chen, Z. Cai, Y. Zhao and X. Bi, Antidiabetic activities of a cucurbitanetype triterpenoid compound from Momordica charantia in alloxaninduced diabetic mice, Mol. Med. Rep., 2016, 14, 4865–4872.
102. M. J. Tan, J. M. Ye, N. Turner, C. Hohnen-Behrens, C. Q. Ke, C. P. Tang, T. Chen, H. C. Weiss, E. R. Gesing, A. Rowland, D. E. James and Y. Ye, Antidiabetic activities of triterpenoids isolated from bitter melon associated with activation of the AMPK pathway, Chem. Biol., 2008, 15, 263–273.
103. H. Y. Lo, C. C. Li, T. Y. Ho and C. Y. Hsiang, Identification of the bioactive and consensus peptide motif from Momordica charantia insulin receptor-binding protein, Food Chem., 2016, 204, 298–305.
104. H. Y. Lo, T. Y. Ho, C. C. Li, J. C. Chen, J. J. Liu and C. Y. Hsiang, A novel insulin receptor-binding protein from Momordica charantia enhances glucose uptake and glucose clearance in vitro and in vivo through triggering insulin receptor signaling pathway, J. Agric. Food Chem., 2014, 62, 8952–8961.
105. H. Y. Lo, T. Y. Ho, C. Lin, C. C. Li and C. Y. Hsiang, Momordica charantia and its novel polypeptide regulate glucose homeostasis in mice via binding to insulin receptor, J. Agric. Food Chem., 2013, 61, 2461–2468.
106. J. Lu, Y. Zeng, W. Hou, S. Zhang, L. Li, X. Luo, W. Xi, Z. Chen and M. Xiang, The soybean peptide aglycin regulates glucose homeostasis in type 2 diabetic mice via IR/IRS1 pathway, J. Nutr. Biochem., 2012, 23, 1449–1457.
107. M. Eddouks, A. Bidi, B. El Bouhali, L. Hajji and N. A. Zeggwagh, Antidiabetic plants improving insulin sensitivity, J. Pharm. Pharmacol., 2014, 66, 1197–1214.
108. N. B. Ruderman, D. Carling, M. Prentki and J. M. Cacicedo, AMPK, insulin resistance, and the metabolic syndrome, J. Clin. Invest., 2013, 123, 2764–2772.
109. M. J. Sanders, P. O. Grondin, B. D. Hegarty, M. A. Snowden and D. Carling, Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade, Biochem. J., 2007, 403, 139–148.
110. M. C. Towler and D. G. Hardie, AMP-activated protein kinase in metabolic control and insulin signaling, Circ. Res., 2007, 100, 328–341.
111. K. A. Coughlan, R. J. Valentine, N. B. Ruderman and A. K. Saha, Nutrient Excess in AMPK Downregulation and Insulin Resistance, J. Endocrinol. Diabetes Obes., 2013, 1, 1008.
112. H. Sano, S. Kane, E. Sano, C. P. Miinea, J. M. Asara, W. S. Lane, C. W. Garner and G. E. Lienhard, Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation, J. Boil. Chem., 2003, 278, 14599–14602.
113. G. Ramm, M. Larance, M. Guilhaus and D. E. James, A role for 14–3–3 in insulin-stimulated GLUT4 translocation through its interaction with the RabGAP AS160, J. Boil. Chem., 2006, 281, 29174–29180.
114. K. Sakamoto and G. D. Holman, Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic, Am. J. Physiol.: Endocrinol. Metab., 2008, 295, E29–E37.
115. D. Carling, AMPK signalling in health and disease, Curr. Opin. Cell Biol., 2017, 45, 31–37.
116. S. Chen, D. H. Wasserman, C. MacKintosh and K. Sakamoto, Mice with AS160/TBC1D4-Thr649Ala knockin mutation are glucose intolerant with reduced insulin sensitivity and altered GLUT4 trafficking, Cell Metab., 2011, 13, 68–79.
117. J. J. Song, Q. Wang, M. Du, T. G. Li, B. Chen and X. Y. Mao, Casein glycomacropeptide-derived peptide IPPKKNQDKTE ameliorates high glucose-induced insulin resistance in HepG2 cells via activation of AMPK signaling, Mol. Nutr. Food Res., 2017, 61, 1600301.
118. C. Roblet, A. Doyen, J. Amiot, G. Pilon, A. Marette and L. Bazinet, Enhancement of glucose uptake in muscular cell by soybean charged peptides isolated by electrodialysis with ultrafiltration membranes (EDUF): activation of the AMPK pathway, Food Chem., 2014, 147, 124–130.
119. M. Soga, A. Ohashi, M. Taniguchi, T. Matsui and T. Tsuda, The di-peptide Trp-His activates AMP-activated protein kinase and enhances glucose uptake independently of insulin in L6 myotubes, FEBS Open Bio, 2014, 4, 898–904.
120. W. J. Yeh, H. Y. Yang and J. R. Chen, Soy beta-conglycinin retards progression of diabetic nephropathy via modulating the insulin sensitivity and angiotensin-converting enzyme activity in rats fed with high salt diet, Food Funct., 2014, 5, 2898–2904.
121. N. Tachibana, Y. Yamashita, M. Nagata, S. Wanezaki, H. Ashida, F. Horio and M. Kohno, Soy beta-conglycinin improves glucose uptake in skeletal muscle and ameliorates hepatic insulin resistance in Goto-Kakizaki rats, Nutr. Res., 2014, 34, 160–167.
122. A. Avignon, A. Radauceanu and L. Monnier, Nonfasting plasma glucose is a better marker of diabetic control than fasting plasma glucose in type 2 diabetes, Diabetes Care, 1997, 20, 1822–1826.
123. P. Patil, S. Mandal, S. K. Tomar and S. Anand, Food protein-derived bioactive peptides in management of type 2 diabetes, Eur. J. Nutr., 2015, 54, 863–880.
124. J. Caron, B. Cudennec, D. Domenger, Y. Belguesmia, C. Flahaut, M. Kouach, J. Lesage, J. F. Goossens, P. Dhulster and R. Ravallec, Simulated GI digestion of dietary protein: Release of new bioactive peptides involved in gut hormone secretion, Food Res. Int., 2016, 89, 382–390.
125. A. Zambrowicz, M. Pokora, B. Setner, A. Dabrowska, M. Szoltysik, K. Babij, Z. Szewczuk, T. Trziszka, G. Lubec and J. Chrzanowska, Multifunctional peptides derived from an egg yolk protein hydrolysate: isolation and characterization, Amino Acids, 2015, 47, 369–380.
126. B. Konrad, D. Anna, S. Marek, P. Marta, Z. Aleksandra and C. Jozefa, The Evaluation of Dipeptidyl Peptidase (DPP)-IV, alpha-Glucosidase and Angiotensin Converting Enzyme (ACE) Inhibitory Activities of Whey Proteins Hydrolyzed with Serine Protease Isolated from Asian Pumpkin (Cucurbita ficifolia), Int. J. Pept. Res. Ther., 2014, 20, 483–491.
127. S. L. Huang, C. L. Jao, K. P. Ho and K. C. Hsu, Dipeptidyl-peptidase IV inhibitory activity of peptides derived from tuna cooking juice hydrolysates, Peptides, 2012, 35, 114–121.

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