Pharmacological and Clinical Studies of Medicinal Plants That Inhibit Dipeptidyl Peptidase-IV

Figures & data

Figure 1 Schematic on GLP-1 secretion in the L-cell. Glucose arising from carbohydrate metabolism is transported at the luminal face of the L-cell via sodium-glucose cotransporter-1 (SGLT-1), which is coupled with Na⁺ influx, depolarizing the cell membrane (ΔΨ), opening VDCC, increasing intracellular Ca²⁺ levels, and triggering exocytosis of GLP-1 containing granules at the L-cell’s basolateral face. Increased intracellular ATP from glucose metabolism closes K_ATP channels, potentiating GLP-1 release. Long-chain fatty acids interact with G protein-coupled receptors (GPR40 and GPR120), triggering intracellular Ca²⁺ release to prompt GLP-1 release. Amino acids affect the secretion of GLP-1 by a similar mechanism mediated by Na⁺ ions.

Abbreviations: GLUT2, glucose transporter 2; GLP-1, glucagon-like peptide-1; GLP-2, glucagon-like peptide-2; Trpc3, transient receptor potential channel 3, VDCC, voltage-dependent calcium channel; SGLT1, sodium/glucose co-transporter 1.

Figure 2 (a) 3D structure of human dipeptidyl peptidase-IV in complex with a potent selective inhibitor, alogliptin (indicated by red arrow) (PDB ID 2ONC; PDB DOI https://doi.org/10.2210/pdb2ONC/pdb; Resolution 2.55 Å; deposited by Feng et al, 2007. Total structure weight: 346.99 kDa); (b) DPP-IV binding subsites for the inhibitors which are numbered from the cleavage point to the S2, S1, S1’, S2’, and S2 extensive subsites. Class I inhibitors bind to S1 and S2 subsites; Class II inhibitors to S2’, S1’, and S2 subsites; Class III inhibitors to S1, S2, and S2 extensive subsites. Adapted from Biochem Biophys Res Commun, 434(2), Nabeno M, Akahoshi F, Kishida H, et al. A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site. 191–196, Copyright (2013), with permission from Elsevier.³⁵

Table 1 In silico Study

Plant	Compound Name	Binding Energy (kcal/mol)	Amino Acid Residues Involved in the Interaction (Hydrogen Bond)	Amino Acid Residues Involved in the Interaction (Hydrophobic Bond)	Reference
Liliaceae family
Allium sativum	Caffeic acid 3-glucoside	−7.436	Asn711, Ser631, Glu203, Tyr548, Glu203, Tyr663, Arg123, His124, Tyr667	N/A	[44]
	Malonylgenistin	−7.438	Val207, Arg358, Ser630, Ser209, Phe357, Tyr662	Tyr662, His740, Tyr666, Val711
	Calenduloside E	−10.172	Glu204, Ile205, Trp630, Arg123, Tyr548	Phe355, Tyr548, Tyr667
Malvaceae family
Urena lobata	β-Sitosterol	−6.59	N/A	N/A	[45]
	Gossypetin	−5.20	N/A	N/A	[45]
	Chrysoeriol	−4.66	N/A	N/A	[45]
	Mangiferin	−7.66	N/A	N/A	[45]
	Stigmasterol	−7.42	N/A	N/A	[45]
Moringaceae family
Moringa oleifera	Urethane	−84.99	Asn710, Glu205, Glu206	Val656, His704	[46]
	Isothiocyanate	−81.10	His740, Arg125, Ser630, Asn710, Tyr662, Tyr547, Ser630	N/A	[46]
	Dipeptide	−47.36	Tyr547	N/A	[46]
Zingiberaceae family
Curcuma longa	Calebin A	−98.721	Glu206, Tyr662, Ser552, Cys551, Tyr585	N/A	[47]
	Curcumin	−66.765	N/A	N/A	[48]
Solanaceae family
Withania coagulans	Withasomnine	−6.6	N/A	N/A	[49]
	Withanolide E	−7.6	N/A	N/A	[49]
	Withanone	−7.9	N/A	N/A	[49]
	Withaferine A	−8.1	N/A	N/A	[49]
	Withangulatin A	−8.8	N/A	N/A	[49]
	Withacoagulin H	−8.9	N/A	N/A	[49]
	Withanolide D	−9.2	N/A	N/A	[49]
	Withanolide B	−9.5	N/A	N/A	[49]
	Sitoindoside IX	−9.8	N/A	N/A	[49]
Hypoxidaceae family
Curculigo latifolia	Phlorizin	−10.9	Arg125, Asp545, Asp454, Gln553, Lys554, Trp629	Tyr547	[50]
	Scandenin	−9.3	N/A	Trp629	[50]
	Pomiferin	−9.6	Asp556, Asp560	Trp629	[50]
	Berberine	−8.9	Gln553, Ser630	Tyr547	[50]
	Monobenzone	−7.4	Ser630	N/A	[50]
	Mundulone	−9.3	Ser630, His740	Trp629	[50]
	Dimethycaffeic acid	−7.1	Gln553, Ser630	Tyr547	[50]
Rutaceae family
Melicope latifolia	Methyl p-coumarate	−5.7	N/A	N/A	[51]
Melicope glabra	Trans-decursidinol	−7.7	Glu206, Arg125, Ser630, Glu205	Glu205, Tyr666	[52]
	Swermirin	−5.4	Lys122, Asp739	His740, Arg125	[52]
	Methyl 3,4,5- trimethoxycinnamate	−5.6	Arg125, Tyr547, Arg669, Val 207, Tyr662	Tyr666, Glu205	[52]
	Renifolin	−7.8	Glu206, Glu205, Asn710, Arg125, Ser630	Tyr547, Phe357	[52]
	4’,5,6,7- tetramethoxyflavone	−7.7	Arg125, Ser630, His740, Asn710, Tyr547, Val207	Glu205, Phe357	[52]
	Isorhamnetin	−7.8	Glu206, Arg358, Tyr547	Phe357, Tyr666	[52]
	Quercetagetin-3,4’- dimethyl ether	−7.9	Ser209, Arg125, Tyr631	Glu205, Glu206, Tyr666, Phe662	[52]
	5,3’,4’-trihydroxy-6,7-dimethoxyflavone	−8.1	Glu206, Arg125, Asn710, His740, Ser630	Glu205	[52]
	2-methoxy-5-acetoxyfruranogermacr-1(10)-en-6-one	−6.3	His126, Arg125	Glu205, Tyr666, Phe357	[52]
Apiaceae family
Angelica keiskei	4-hydroxyderricin	−7.42	Glu206	Phe357	[53]
	Xanthoangelol	−7.81	Glu205, Glu206	Phe357	[37]
Fabaceae family
Glycyrrhiza uralensis	Licochalcone A	−6.16	Glu203	N/A	[54]
	Licochalcone B	−6.29	Arg123, Ser631, Arg670, His741	N/A	[54]

Abbreviation: N/A, Not applicable.

Table 2 In vitro Study Using Human DPP-IV Inhibitory Screening Kit

Plant (Family)	Plant Part Used/ Compound Used	Solvent	IC50 in µg/mL or % Inhibitory	Reference
Allium sativum	Tubers	Methanol	70.88 µg/mL	[44]
Urena lobata	Roots and leaves	Ethanol	1.65 mg/mL	[45]
Momordica charantia	Fruits	Water	28.15%	[55]
Moringa oleifera	Isothiocyanate	N/A	157.694 µM	[46]
Camellia sinensis	Leaves	Water	59%	[56]
Curcuma longa	Calebin A	N/A	55.9%	[47]
	Curcumin	N/A	50%	[48]
Morus alba	Leaves	Water	480 μg/mL	[57]
Withania coagulans	Fruits	Ethanol	63.2%	[49]
Curculigo latifolia	Roots	Water	66.15%	[50]
	Fruits	Water	42.79%	[50]
Eugenia jambolana	Fruits	N/A	278.94 µg/mL	[58]
Gymnema sylvestre	Leaves	N/A	773.22 µg/mL	[58]
Pterocarpus marsupium	Bark	N/A	273.73 µg/mL	[58]
Glycyrrhiza uralensis	Licochalcone A	N/A	347.93	[54]
	Licochalcone B	N/A	797.84	[54]
Melicope latifolia	Bark	Chloroform	37.16 µg/mL	[51]
	Methyl p-coumarate	N/A	911.44 µM	[51]
Melicope glabra	Leaves	Chloroform	169.40 μg/mL	[52]
	Bark	Chloroform	332.31 μg/mL	[52]
Taraxacum officinale	Whole plant	Acetone	44.85%	[55]
	Whole plant	Ethanol	43.69%	[55]
Coptis chinensis	Berberine	N/A	13.3 μM	[59]
Angelica keiskei	Yellow sap	Ethanol	5.94 μg/mL	[37]
	Yellow sap	Ethyl acetate	34.03 μg/mL	[37]
	Xanthoangelol	N/A	10.49 μM	[37]
	4-hydroxyderricin	N/A	81.44 μM	[53]

Table 3 In vivo Study

Plant	Model Category	Dose	Duration of Treatment (Days)	Result	Reference
Liliaceae family
Allium sativum	STZ-induced SD rats	500 mg/kg BW	56	↓Blood glucose, ↑ insulin serum, ↓ HbA1C	[60]
Malvaceae family
Urena lobata	High fructose diet-induced Sprague-Dawley rats	1000 mg/kg	28	↑GLP-1 bioavailability, ↓blood glucose, ↑insulin serum	[61]
Cucurbitaceae family
Momordica charantia	STZ-induced Wistar rats	10%	84	↓Fasting blood glucose, ↑insulin-positive pancreatic beta cells	[62]
Moringaceae family
Moringa oleifera	Alloxan-induced Sprague-Dawley rats	50 mg/day	56	↓Blood glucose	[63]
Theaceae family
Camellia sinensis	High fat diet Sprague-Dawley rats	250 mg/5 mL per kg	9	↑Oral glucose tolerance, ↑insulin serum, ↑β-cell mass	[56]
Moraceae family
Morus alba	STZ-induced Wistar rats	0.5 g/kg/day	28	↓Blood glucose, ↑insulin serum	[64]
Solanaceae family
Withania coagulans	High sucrose-induced Wistar rats	400 mg/kg	28	↑β-cell mass, ↓blood glucose, ↑insulin serum, ↑% insulin sensitivity	[49]
Hypoxidaceae family
Curculigo latifolia	High fat diet and STZ-induced Sprague-Dawley rats	200 mg/kg	28	↑Insulin serum, ↓plasma glucose	[61]
Myrtaceae family
Eugenia jambolana	STZ-induced Wistar albino rats	15 mg/kg	56	↓Fasting blood glucose	[58]
Apocynaceae family
Gymnema sylvestre	STZ-induced Wistar rats	120 mg/kg	21	↑Insulin serum, ↓blood glucose	[65]
Fabaceae family
Pterocarpus marsupium	STZ-induced Wistar rats	1%	60	↑Insulin serum, ↓blood glucose	[66]
Asteraceae family
Taraxacum officinale	STZ and nicotinamide-induced Wistar rat	1000 mg/kg polyherbal with Momordica charantia extract	28	↓Blood glucose	[55]
Ranunculaceae family
Coptis chinensis	STZ and high glucose-induced Wistar rats	180 mg/kg	168	↓Fasting blood glucose, ↓glycosylated hemoglobin	[67]
Apiaceae family
Angelica keiskei	STZ-induced mice	800 mg/kg	28	↓Fasting blood glucose	[68]

Notes: ↓ = Decrease; ↑ = Increase.

Abbreviation: STZ, Streptozotocin.

Table 4 Studies in Human

Plant	Dosage Form	Sample Size	Gender	Clinical Conditions	Standard Drug	Design of the Study	Length of Therapy (Days)	Efficacy or Clinical Outcomes	Adverse Effect	Reference
		(Patients)	Male (%)
Liliaceae family
Allium sativum	Garlic tablets	60	55%	T2DM with fasting blood sugar level between 100 to 130 mg/dL.	Metformin	Single-blind and placebo-controlled study. Intervention group (n=30) garlic tablet 300 mg three times daily and metformin 500 mg twice daily. Control group (n=30) placebo and metformin 500 mg twice daily	168	Reduction in fasting blood sugar, total cholesterol, LDL-C, triglycerides.	No AE and SAE was observed	[69]
Cucurbitaceae family
Momordica charantia	Bitter melon capsules	90	55.6%	T2DM diabetes, a glycosylated hemoglobin (HbA1c) level no greater than 7.5%	N/A	Single-center, randomized, double blind, placebo-controlled study. Intervention group (n=62) bitter melon capsules 2380 mg/day. Control group (n=28) placebo	84	Reduction in fasting blood sugar	Gastrointestinal symptoms, including anorexia, nausea, abdominal discomfort, and soreness; foamy urine; and skin rashes. No clinically SAE was observed	[70]
Moringaceae family
Moringa oleifera	Leaf powder	27	N/A	T2DM for at least 1 year	N/A	Intervention group (n=14) meal supplemented with 20 g of Moringa oleifera leaf. Control group (n=13) placebo	180	Reduction in blood glucose level	N/A	[71]
Moraceae family
Morus Alba	1-deoxynojirimycin (DNJ) in mulberry leaves powder	85	20%	Obese persons (BMI ≥ 25 kg/m2) aged 20–65 years, who had FPG of 100–140 mg/dL and/or 2 -h PPG following a 75 g oral glucose tolerance test (OGTT) of 140–199 mg/dL	N/A	Randomized controlled clinical study. Intervention group (n=64) 3 groups, single dose of 50 g sucrose solution (150 mL), mixed with mulberry leaf powder at weights 2.3; 4.6; 6.9 g. Control group (n=21) 1 group of placebo.	84	Reduction in fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c)	Gastrointestinal symptoms including bloating, flatulence, and loose stools, did not cause alteration in hepatic and renal function, no SAE was observed.	[72]
Myrtaceae family
Eugenia jambolana	Fruits tablet (GlycaCare-II^® polyherbal supplement)	69	47.8%	Prediabetes and newly diagnosed T2DM. Prediabetes was classified as per American diabetes association criteria HbA1c 5.7–6.4% and FBS between 100 mg/ dL to 125 mg/dL. Newly diagnosed T2DM patients had an HbA1c value of 6.5–7.5% and FBS>125 mg/dL	Metformin	Randomized, double-blind, active-controlled clinical trial. Intervention group prediabetic (n= 17) GlycaCare-II 522.5 mg twice daily, newly diagnosed T2DM (n= 24) GlycaCare-II 522.5 mg twice daily. Control group prediabetic (n=17) metformin 500 mg a day, newly diagnosed T2DM (n=16) metformin 500 mg a day	120	Reduction in Fasting blood glucose, HbA1C, and Postprandial blood glucose	No AE and SAE was observed	[73]
Fabaceae family
Pterocarpus marsupium	Bark tablet (GlycaCare-II^® polyherbal supplement)	69	47.8%	Prediabetes and newly diagnosed T2DM. Prediabetes was classified as per American diabetes association criteria HbA1c 5.7–6.4% and FBS between 100 mg/ dL to 125 mg/dL. Newly diagnosed T2DM patients had an HbA1c value of 6.5–7.5% and FBS>125 mg/dL	Metformin	Randomized, double-blind, active-controlled clinical trial. Intervention group prediabetic (n= 17) GlycaCare-II 522.5 mg twice daily, newly diagnosed T2DM (n= 24) GlycaCare-II 522.5 mg twice daily. Control group prediabetic (n=17) metformin 500 mg a day, newly diagnosed T2DM (n=16) metformin 500 mg a day	120	Reduction in Fasting blood glucose, HbA1C, and Postprandial blood glucose	No AE and SAE was observed	[73]
Apocynaceae family
Gymnema sylvestre	Leaves capsules	16	N/A	T2DM with fasting blood sugar level was 125 mg/dL or above	N/A	Intervention group (n=8) 1 g/day dosage (in two divided doses 12 hourly). Control group (n=8) placebo	30	Reduction in fasting blood glucose	No AE and SAE was observed	[74]
Asteraceae family
Taraxacum officinale	Root capsules (SR2004 polyherbal supplement)	119	58.2%	T2DM and any combination of oral hypoglycemics and/or insulin with a HbA1c 7.1–10% in the last 6 months, body mass index (BMI) < 45 kg/m^2	N/A	Single center, unblinded, prospective interventional study. Intervention group (n=119) 10% Taraxacum, 2 capsules three times a day, 30 minutes before meals taken with water.	84	Reduction in blood glucose and HbA1C	Minor abdominal symptoms reported in sixteen patients (16%), no SAE was observed.
Zingiberaceae family
Curcuma longa	Curcumin capsules	53	39.6%	T2DM, noninsulin dependent diabetic, aged between 40 and 70 years old and BMI 18.5–35 kg/ m^2 with a diagnose of 1 to 10 years	N/A	Randomized, double-blind, placebo-controlled trial. Intervention group (n=25) three capsules of 500 mg curcumin. Control group (n=28) placebo	70	Reduction in fasting blood glucose	No AE and SAE was observed	[75]
Ranunculaceae family
Coptis chinensis	Berberine pills	201	61.7%	Newly diagnosed T2DM	N/A	Randomized, double-blind, placebo-controlled trial. Intervention group (n=98) Berberine 0.6 g per 6 pills, twice daily before meal. Control group (n=103) placebo	336	Reduction in fasting blood glucose and HbA1C	Gastrointestinal symptoms, no SAE was observed	[76]

Abbreviations: AE, Adverse effect; N/A, Not applicable; SAE, Serious adverse effect; T2DMm, Type 2 diabetes mellitus.

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