Table 3.

Molecular mechanisms of action of antidiabetic peptides isolated from various dietary sources.

Dietary protein source	Enzyme used to produce peptides	Peptide sequence or molecular weight	Object	IC50/EC50 values	Activity/mechanisms of action	Reference
Rice bran	Umamizyme G and bioprase SP	Dipeptides LP and IP	DPP-IV inhibition assay	DPP-IV IC502.3 ± 0.1 mg/mL	Peptides sowed strong DPP-IV inhibition activity	[130]
Egg white albumin	Alcalase	KLPGF	α-Glucosidase and α-amylase inhibitory assays	α-Glucosidase inhibitory IC5059.5 ± 5.7 μM and α-amylase inhibitory IC50 120 μM	KLPGF exhibited strong antidiabetic potential by inhibiting α-glucosidase and α-amylase activities	[66]
Casein	Prolyl oligopeptidase	FLQP	DPP-IV inhibition assay	DPP-IV IC5065.3 ± 3.5 μM	FLQP exhibited DPP-IV inhibition activity	[70]
Bovine and porcine meat proteins	Papain and pepsin	PPL	DPP-IV inhibition assay	DPP-IV IC50 390.14 μM	Peptides showed DPP-IV inhibition	[131]
Porcine skin	Alcalase and flavourzyme	—	Streptozotocin-induced diabetic rats	—	Peptides improved glucose tolerance and inhibited DPP-IV activity and enhanced GLP-1 and the insulin level	[132]
Egg yolk	Proteinase from Asian pumpkin	LAPSLPGKPKPD	DPP-IV and α-glucosidase assays	DPP-IV IC50 361.5 μmol/L and α-glucosidase IC50 1065.6 μmol/L	Peptides showed DPP-IV and α-glucosidase inhibitory activities	[67]
Halibut and tilapia skin gelatin	Flavourzyme	SPGSSGPQGFTG,GPVGPAGNPGANGLN, PPGPTGPRGQPGNIGF, IPGDPGPPGPPGP, LPGERGRPGAPGP, and GPKGDRGLPGPPGRDGM	Streptozotocin-induced diabetic rats	—	Peptides improved glucose tolerance through DPP-IV inhibition and GLP-1 secretion enhancement	[73]
Styela clava	Protamex	—	Patients with diabetes	—	Peptides exhibited a decreased hemoglobin A1c and plasma insulin levels	[78]
Black bean	Alcalase	AKSPLF, LSKSVL, FEELN, and PHL	Caco-2 cell and rats	—	Peptides showed antidiabetic effects by blocking GLUT2 and SGLT1 and reduced glucose absorption and postprandial glucose and blood glucose	[133]
Wheat	Bacterial protease	770–77740 Da	GLUTag cells and rats	—	Peptides improved hyperglycemia via activating GLP-1 secretion via stimulation of the calmodulin-dependent kinase II pathway mediated by G protein-coupled receptor family C group 6 subtype A	[134]
Atlantic cod (Gadus morhua) meat	Protamex	<2000 Da	41 healthy individuals	—	Peptides decreased the postprandial insulin	[77]
Oat globulin	Trypsin	OGb, LQAFEPLR, and EFLLAGNNK	Caco-2 cell	DPP-IV IC50 OGb 188.1 μg/mL and LQAFEPLR IC50 141.7 μM	Peptides showed potent inhibition on DPP4 and α-glucosidase activity and reduced DPP4 protein expression and upregulated the expressions of α-glucosidase, GLUT2, and GLUT5	[135]
Milk whey protein	Protease	<5000 Da	21 prediabetic humans	—	Peptides (1400 or 2800 mg/kg BW) decreased under glucose curve and showed a minor insulinotropic and reduced HbA1c	[76]
Egg white	Thermolysin and pepsin	IRW	TNF-α-treated L6 rat skeletal muscle cells	—	IRW reduced glucose uptake and enhanced insulin receptor activation and improved insulin sensitivity by inhibiting p38 and JNK1/2 activation	[23]
Boarfish (Capros aper) protein	Alcalase and flavourzyme	<2 kDa	BRIN-BD11 and GLUTag cells and mice	DPP-IV inhibitory activity IC50 1.18 mg/mL	Peptides increased insulin secretion and inhibited DPP-IV activity. Peptides increased insulin levels and reduced glucose concentration	[72]
Blue whiting (Micromesistius poutassou) muscle protein	Alcalase and flavourzyme	<5 kDa	GLUTag cells, BRIN-BD11 cells, 3T3-L1 adipocytes, DPP-IV assay, and mice	DPP-IV inhibitory activity IC501.28 ± 0.04 mg/mL	Peptides showed being antidiabetic via DPP-IV inhibitory activity, increasing insulin-stimulated glucose, stimulating insulin secretion and GLP-1, and decreasing glucose	[71]
Potato protein	Alcalase	DIKTNKPVIF	Diabetic mice	—	Peptides showed antidiabetic effects via regulation of blood glucose, plasma total glycerol, total cholesterol, insulin, and HbA1c	[6]
Spirulina platensis	—	GVPMPNK, RNPFVFAPTLLTVAAR, and LRSELAAWSR	α-Amylase, α-glucosidase, and DPP-IV assay	α-Amylase IC50 313.6 μg/mL, α-glucosidase IC50 134.2 μg/mL, and DPP-IV IC50 167.3 μg/mL	LRSELAAWSR exhibited strong inhibitory activity on α-amylase, α-glucosidase, and DPP-IV	[68]
Beans (Phaseolus vulgaris L.)	Pepsin and pancreatin	<3 kDa	Wistar rats and mice and in vitro assays	α-Amylase 16.9–89.1% and α-glucosidase inhibition 34.4–89.2%	Fractions inhibited α-amylase and α-glucosidase. Fractions showed both hypoglycemic and antihyperglycemic activities	[136]
Soy protein	Papain, trypsin, and alkaline proteinase	LLPLPVL, SWLRL, and WLRL	α-Glucosidase inhibitory assay	α-Glucosidase IC50 162.2–237.4 μmol/L	Peptides showed strong α-glucosidase inhibitory activity	[63]
Sea cucumber (Holothuria nobilis)	Mixture of papain and protamex	203–1907 Da	Type II diabetic rats induced by streptozotocin	—	Peptides (200 and 400 mg/kg BW) decreased fasting blood glucose. Peptides showed antidiabetic effects by increasing the expressions of PI3K, p-Akt, p-GSK-3β, and GLUT2/4 signaling pathways and decreasing the expression of p-IRS1	[73]
Largemouth bass (Micropterus salmoides)	Pepsin, trypsin, and chymotrypsin	ICY	DPP-IV inhibitory assay	DPP-IV IC50 0.73 mM	ICY had strong DPP4 inhibitory activities	[137]
Zebra blenny (Salaria basilisca) protein	Crude alkaline protease extract from zebra blenny	>30 kDa	DPP-IV inhibitory assay	DPP-IV IC50 71 μg/mL	Fraction showed α-amylase inhibitory activity	[64]
Walnut (Juglans mandshurica Maxim)	Alcalase	LPLLR	Hepatic HepG2 cells and in vitro assays	Inhibiting α-glucosidase 50.12% and α-amylase 39.08% at 2000 μM	LPLLR inhibited α-glucosidase and α-amylase and improved hepatic insulin resistance via enhancing glycogen synthesis and glucose uptake and reduced gluconeogenesis via activating the IRS-1/PI3K/Akt and AMPK pathways	[75]
Quinoa protein	Bromelain, chymotrypsin, and Pronase E	QHPHGLGALCAAPPST	α-Glucosidase and DPP-IV inhibitory assays	DPP-IV IC50 0.72–1.12 mg/mL and α-glucosidase IC50 1.0–1.45 mg/mL	Peptides showed antidiabetic effects by inhibiting DPP-IV and α-glucosidase	[62]
Corn germ protein	Alcalase, trypsin, and flavourzyme	<2–10 kDa	In vitro assays	Inhibiting α-amylase 71.3%, α-glucosidase 37.1%, and DPP-IV 45.9%	Peptides showed strong α-amylase, α-glucosidase, and DPP-IV inhibition	[61]
Sea cucumber (Stichopus japonicus)	Pepsin, trypsin, and chymotrypsin	<3 kDa	3T3-L1 and Hep G2 cells	DPP-IV IC50 0.51–0.52 mg/mL	Peptides improved glucose uptake and DPP-IV inhibitory activity	[7]
α-Lactalbumin-rich whey proteins	Trypsin	LDQWLCEKL	DPP-IV inhibitory activity	DPP-IV inhibition IC50 131 μM	LDQWLCEKL exhibited DPP-IV inhibition with a noncompetition	[138]
Palmaria palmata	Alcalase and flavourzyme	<1–5 kDa	Streptozotocin-induced diabetic mice	—	Peptides showed antidiabetic effects by reducing blood glucose and increasing insulin and improved terminal oral glucose tolerance and fasting blood glucose	[139]
Atlantic salmon (Salmo salar) skin	Trypsin	LDKVFR	DPP-IV inhibitory activity assay	DPP-IV inhibition IC50 128.7 μM	LDKVFR showed DPP-IV inhibition	[14]
Millet proteins	Papain	NDWHTGPLS and TYPHQQPPILT	DPP-IV inhibition assay	DPP-IV inhibition 75.72%	Peptides inhibited DPP-IV and occupied DPP-IV active center (S1 and S2 subsites) via H-bond and π − π	[21]

Akt: protein kinase B; AMPK: AMP-activated protein kinase; DPP-IV: dipeptidyl peptidase-IV; GLP-1: glucagon-like peptide-1; GLUT: glucose transporter; HbA1c: glycosylated hemoglobin; IC₅₀: 50% inhibitory concentration; STZ: streptozotocin; PI3K: phosphatidylinositol 3-kinase; p-Akt: phosphorylated protein kinase B; p-IRS1: phosphorylated insulin receptor substrate-1; IRS-1: insulin receptor substrate-1; JNK: c-Jun N-terminal kinase.