A review on selected herbal plants as alternative anti-diabetes drugs: chemical compositions, mechanisms of action, and clinical study

Figures & data

Figure 1. The putative metabolites have been reported as antidiabetes agents from selected herbal plants: a) phytosterol groups; b) alkaloid groups; c) triterpenoid groups; and d) phenolic groups.

Table 1. The putative active compound types from herbal plants play a significant role in treating diabetes.

Herbal plant sources	The putative active compounds				References
	Chemical compound names	Approaches Techniques used	Testing Evaluation	Biological Activities
Aloe vera	five phytosterol : Lophenol, 24-methyl-lophenol, 24-ethyl-lophenol, cycloartanol, and 24-methylene-cycloartanol	The isolated active compounds	In-vivo using mice	They can decrease blood glucose levels at long-term effects with decreased levels is approximately 64%, 28%, 47%, 51%, and 55% of control levels, respectively	[11]
Andrographis paniculata	Andrographolide	Isolated active compounds	In-vivo using rats	It decreased blood glucose levels and improved pancreatic organs (islet and beta cells)	[12]
Anredera cordifolia	8-Glucosylapigenin (vitexin)	Molecular docking (in silico)	The isolated compound and glibenclamide interact against the CYP3A4 receptor	The combination of vitexin with glibenclamide can increase binding energy stability up to -4.4 (kcal/mol). Thus, the addition vitexin increases its potency as anti-diabetes	[13]
		Isolated active compound	In-vitro (α-glucosidase inhibitory activity)	This isolate has IC50 of 20.23 μg/mL	[14]
Catharanthus roseus	4 alkaloids: vindoline, vindolidine, vindolicine and vindolinine	Isolated active compound	In-vitro (increase glucose uptake in β-TC6 and C2C12 skeletal muscle cells and inhibition activity of PTP-1B	Vindolicine is the best alkaloid reported can increase glucose uptake at a dose of 12.5 μg/mL and has IC50 of PTP-1B is 11.6 μg/mL	[15]
Centella asiatica	betulinic acid, centellasapogenol, and methyl brahmate	Molecular docking (in silico)	They inhibited Sodium-glucose co-transporter 2 (SGLT-2)	Strong binding energy and structural stability	[16]
	Asiaticoside	An Isolated active compound	In vivo using albino mice	It can reduce blood glucose levels at a dose of 5.6 mg/kg BW mice	[17]
Clitoria ternatea	triterpenoids, flavonol glycosides, anthocyanins, and steroids	Phytochemical screening	In vivo using albino mice	it significantly decreases the serum glucose contents of rat	[18]
Cosmos caudatus	Rutin, quercetin 3-O-glucoside, quercetin 3-O-xyloside, quercetin 3-O-arabinofuranoside and quercetin 3-O-rhamnoside	Metabolomic approaches	In vitro (α-glucosidase inhibitory activity)	IC50 of etanolic leaf extract: 12.6–40.9 μg/mL	[19]
Moringa oleifera	anthraquinone, 2-phenylchromenylium (Anthocyanins), and hemlock tannin	In silico Approaches	active binding of active compounds from Moringa oleifera with mutated protein of diabetes mellitus	They can interact strongly with targeted protein of diabetes mellitus	[20]
	Quinic acid, Caffeic acid, Chlorogenic acid, Gallic acid, Coumaroylquinic acid, Astragalin, Kaempferol-3-O-rutinoside, Vitexin, Rutin, Quercetin-acetyl-glucoside, Quercetin-malonyl-glucoside, Isoquercetin, Kaempferol acetyl glycoside, and Quercetin	In silico Approaches	Binding Interaction of active compounds with human pancreatic α-amylase	It has minimum docking scores and its binding affinity is high	[10]
	4-hydroxyphenylacetonitrite, fluoropyrazine, methyl-4-hydroxybenzoate, and vanillin	The Isolated compound	In-silico approaches, In Vitro using insulin secretion stimulators, and In vivo using mice and Wistar rats.	They can stimulate insulin secretion (in-vitro), and reduce blood glucose levels in diabetic rats (in vivo). Even, in silico approaches also showed hydrogen interaction with active site residue.	[21]
	Agnucastoside C	The Isolated compound	In vivo using female mice	It can change the serum thyroid hormones, insulin, glucose, different lipids; hepatic lipid peroxidation, and enzymatic antioxidants such as superoxide dismutase, catalase, and glutathione peroxidase of female mice	[22]
Orthosiphon stamineus	Sinensetin, salvigenin, tetramethylscutellarein, 3,7,4’-tri-O-methylkaempferol, and orthosiphol A	The Isolated compounds	In vitro (α-glucosidase inhibitory activity)	tetramethylscutellarein (3) and d 3,7,4’-tri-O-methyl kaempferol t α-glucosidase with IC50 values of 6.34 and 0.75 mM, respectively. While orthosiphol A (5) selectively inhibited intestinal maltase with an IC50 value of 6.54 mM.	[23]
Psidium guajava	lanost-7-en-3β-ol-26-oic acid, anost-7-en-3β, 12β-diol-26-oic acid, lanost-7- en-3β, 12β, 29-triol-26-oic acid, and lanost-7-en-3β-ol-26-oic acid-3β-D-glucopyranoside	The isolated compounds	In-vivo using rats	They significantly decrease blood glucose levels	[24]
	Dihydro-3,3,’4,’5,7 – pentahydroxyflavone glycoside and apigenin 7-O-glucoside	The isolated compounds	In vitro (α-glucosidase inhibitory activity)	-	[25]
Trigonella foenum-graecum	N-linoleoyl-2- amino – butyrolactone (N55)	an isolated compound	In vitro (as a modulatory GLP 1 activity)	It enhances GLP-1 signaling	[26]

PTP-1B: protein tyrosine phosphatase-1B

GLP 1: Glucagon-like Peptide-1

Figure 2. General pathways of mechanism of actions of anti-diabetic drugs.

Figure 3. Mechanism of actions from herbal plants in reducing blood glucose levels using in-vitro-based evaluation.

Table 2. The Reported Clinical Study of the Selected Herbal as antidiabetic agents.

Herbal plants		Clinical Studies				References
	Herb form	Participants	Study Evidence levels	Parameters	Effects and Doses
Aloe vera	Aloe vera juice 80%	50 participants (age: 35–60)	Level 7	Blood sugar levels	It can reduce blood glucose levels at least 2 weeks after treatment (twice/day)	[40]
Andrographis paniculata	Andrographis paniculata extract	73 participants (age: 18–60)	Level 7	GLP-1, DPP-4 enzyme, Fasting Plasma Insulin, Insulin concentrations measured	It will affect these parameters at a dose of 550 mg extract for 14 days (twice/day)	[41]
Centella asiatica	Centella asiatica	43 participants (age: 18–55)	Level 7	HbA1c level, TSS	The reductions of TSS from baseline using 240 mg per day for 1 year and not affect to HbA1c level	[42]
Clitoria ternatea	Clitoria ternatea water extract	15 participants (age: 20–40)	Level 7	Plasma glucose, insulin, and uric acid	It significantly decreased plasma glucose at a dose of 1 g or 2 g for 30–60 min after consumption	[43]
Cosmos caudatus	Fresh leaves	100 participants (age: 30–65)	Level 7	HbA1C, fasting glucose, insulin	the consumption of 15 g of fresh leaves reduced blood glucose levels for 8 weeks	[44]
Moringa oleifera	Moringa oleifera tea	103 participants (age: 18–65)	Level 7	blood glucose level	It will be evaluated the change in blood glucose levels at a dose of 4 grams of Moringa oleifera tea (twice/day) for 4 weeks	NCT04314258
Orthosiphon stamineus	Orthosiphon stamineus extract (NuvastaticTM 1000 mg)	100 participants (age: 18–65)	Level 7	Retinal Thickness	It will be observed thickness of DR patients who consume Nuvastatic products three times per day for 12 months	NCT04552600
Psidium guajava	Psidium guajava (PG) leaf extract and capsule of PG fruit	50 participants (mean age: 59)	Level 7	Blood glucose levels	A dose of 500 mg PG leaf extract is less effective compared with metformin, but a capsule of PG (same dose) fruit reduced blood glucose levels in 5 weeks	[45]
Trigonella foenum-graecum	Trigonella foenum-graecum extract and capsule form	100 participants (age: 22–55), meta-analysis	Level 2	HbA1c levels, Fasting blood glucose	The consumption of its seed extract in the dose range of 5–25 g and recommended at least 5 g per day in capsule form	[35]

^*TSS: total symptom score

DPP-4: dipeptidyl peptidase-4

HbA1C: hemoglobin A1c

DR: Diabetic Retinopathy

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