Article

Antidiabetic activity of combined extracts of Hibiscus sabdariffa Linn.

and Stevia rebaudiana Bert. on streptozotocin-induced diabetes

Wistar rats

Ami Tjitraresmi^1,2*, Raden Maya Febriyanti^1,2, Daffa Anjabtsawa³, Yasmiwar Susilawati^1,2

Muhaimin^1,2

,

¹Department of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Indonesia

²Herbal Study Center, Universitas Padjadjaran, Indonesia

³Pharmacist Profession Study Program, Faculty of Pharmacy, Universitas Padjadjaran, Indonesia

Abstract

The increasing prevalence of diabetes mellitus and the limitation in its conventional therapies

underscores the need for alternative treatments. Hibiscus sabdariffa Linn. and Stevia rebaudiana Bert.

have demonstrated individual antidiabetic activities attributed to their secondary metabolites, including

flavonoid and phenolic compounds. This study employed an experimental in vivo design using rats

induced with STZ. Thirty rats were divided into five groups (n=6): normal control, negative control,

positive control (Glibenclamide), and two treatment groups receiving the combined aqueous extracts of

H.sabdariffa and S.rebaudiana (RSAE) at 500 and 1000 mg/kgBW. Diabetes was induced using STZ (50

mg/kgBW administered i.p). Blood glucose levels were measured fasting and 2 hr postprandial at days 0,

3, and 14 after administration of RSAE. Data were analyzed using One-Way ANOVA. RSAE exhibited

dose‐dependent hypoglycaemic activity in STZ‐induced diabetic rats, significantly reducing (p < .005)

fasting blood glucose by up to 50.7 % and two‐hour post‐prandial glucose by 44.97% at 1000

mg/kgBW.

Keywords: Blood glucose level, extract, herbal, medicinal plants, post-prandial glucose

Graphical Abstract

*

Corresponding author

Email addresses: ami.tjitraresmi@unpad.ac.id

DOI: https://doi.org/10.22437/chp.v9i2.46449

Received July 1^st2025; Accepted July 26^th2025; Available online August 01^st2025

(https://creativecommons.org/licenses/by/4.0 )

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Chempublish Journal, 9(2) 2025,167-182

Introduction

inhibit α-amylase and α-glucosidase and

preserve pancreatic β-cell integrity [17–22].

Despite these clear benefits, H. sabdariffa

has sour taste which resulting palatability

challenge. Therefore, it is necessary to pair

H. sabdariffa with a natural, non-caloric

sweetener that can both mask its acidity and

contribute its own antidiabetic properties.

Type 2 Diabetes mellitus (T2DM) is the

fastest-growing

worldwide.

metabolic

Approximately 589

disorder

million

adults worldwide are living with diabetes

and its prevalence is projected to rise to 853

million by 2050 [1]. Current pharmacological

management of T2DM typically begins with

metformin which frequently combined with

sulfonylureas such as glibenclamide when

metformin alone no longer maintains

glycaemic targets. Glibenclamide remains

one of the most widely prescribed second-

line agents because it is inexpensive, has a

rapid onset, and can lower HbA1c by 1–2 %

[2,3]. Although these agents generate

favourable outcomes for many patients,

their long‐term use is frequently limited by

adverse effects and increasing therapeutic

Leaves of Stevia rebaudiana Bert. are known

for its diterpene glycoside stevioside (4–13 %

w/w) and rebaudioside A (2–4 %), which are

200–300 times sweeter than sucrose [23,24].

It can mask the intrinsic sourness of H.

sabdariffa infusions, offering an organoleptic

advantage for patient compliance. Beyond

its sweetness, steviol glycosides stimulate

glucose-dependent insulin secretion via

TRPM5-mediated Ca²⁺ influx, up-regulate

GLUT-4 and down-regulate hepatic PEPCK,

producing fasting- and post-prandial glucose

reductions in STZ- and diet-induced rodent

models and improving weight maintenance

in small human trials [25,26]. S. rebaudiana

resistance

[4].

For

instance,

chronic

glibenclamide therapy is associated with

progressive β-cell exhaustion, weight gain,

and an increased risk of cardiovascular

events, while secondary failure rates can

exceed 40% within five years [5,6]. These

leaves

also

contains

polyphenols

(chlorogenic, ferulic, caffeic and gallic acids),

flavonoids (rutin, kaempferol-3-rutinoside)

and essential nutrients that collectively

endow strong antioxidant capacity (ORAC)

lipid peroxidation and advanced glycation

limitations,

together

with

the

rising

prevalence of drug-induced hypoglycaemia

and the economic burden of lifelong

pharmacotherapy,

leading

to

growing

interest in plant-derived antihyperglycaemic

agents that are affordable and well-tolerated

[7,8].

end-product

Furthermore, the review by Peteliuka et al.

(2021) summarizes the antidiabetic

mechanism of action of S. rebaudiana

including insulinotropic signalling and

carbohydrate-digestive enzyme blockade.

Stevioside, rebaudioside and steviol

potentiate TRPM5-dependent Ca²⁺

formation

[23,27].

Hibiscus sabdariffa Linn., widely consumed as

a herbal tea, has garnered considerable

attention for its ability to lower both fasting

and post-prandial blood glucose in a variety

of animal models and even preliminary

human trials [8–16]. These pharmacological

effects are attributed to its abundant

A

oscillations in β-cells, driving glucose-

regulated insulin release without stimulating

hypoglycaemia [24].

polyphenols

anthocyanins, quercetin and protocatechuic

acid. Anthocyanins (e.g., cyanidin-3-

content,

particularly

Our preliminary work demonstrated that a 3:

1 combination of H. sabdariffa and S.

glucoside), quercetin and protocatechuic

acid in H. sabdariffa are reported to scavenge

reactive oxygen species, up-regulate GLUT-4,

rebaudiana

mg/kg BW) demonstrated a 51 % fall in

fasting blood glucose in alloxan-induced

freeze-dried

powder

(1000

168

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Chempublish Journal, 9(2) 2025,167-182

hyperglycaemic rats [28]. These findings,

together with our previous literature review

of phytochemistry and pharmacology of H.

glycaemia in STZ-induced diabetic Wistar

rats

over

a

14-day

period,

using

glibenclamide as an active reference.

sabdariffa

complementary,

and

S.

rebaudiana,

multi-target

suggest

actions

Materials and Methods

including synergistic enzymatic blockade,

delaying carbohydrate absorption, β-cell

protection & insulinotropism. Antioxidant

properties of H. sabdariffa mitigate STZ-

Ethical approval

The study protocol was reviewed and

approved by the Health Research Ethics

induced

oxidative

stress

while

steviol

Commission

Kesehatan), Faculty of Medicine, Universitas

Padjadjaran (Ethical Approval No.

525/UN6.KEP/EC/2024), and was conducted

in accordance with the ARRIVE 2.0 guidelines

and the Guide for the Care and Use of

Laboratory Animals.

(Komisi

Etik

Penelitian

glycosides from S. rebaudiana directly

enhance insulin release [21,29].

A broad spectrum of diabetogenic protocols

has

been

reported,

including

single

diabetogenic agent induction such as alloxan

and streptozotocin (STZ), combination of STZ

and nicotinamide, high fat diet combining

with low-dose STZ, partial pancreatectomy,

and various genetic manipulations [30].

Plant Material and Extraction

Two thousand grams of a commercially

available 3:1 blend of H. sabdariffa calyces

and S. rebaudiana leaves (Rosvia™, 3Sadulur

Herbal, West Java, Indonesia) were infused in

5.000 mL of water heated to 73–74 °C with

continuous stirring for 5 min, then vacuum-

filtered through Whatman No. 1 paper. The

filtrate was then transferred into sealed

vessels and lyophilized at the Laboratory of

However,

chemically

induced

models

created with sub-diabetogenic doses of

alloxan or streptozotocin (STZ) remains the

most

widely

use

models

because

it

generates

hyperglycaemia

rapidly,

inexpensive and can be reproduced in most

standard rodent facilities [31,32]. Among the

chemical options, STZ has emerged as the

preferred

diabetogenic

agent.

Unlike

Agricultural

Industrial

Technology,

alloxan, whose narrow therapeutic window,

pronounced nephro- and hepatotoxicity and

erratic glycaemic response compromise

reproducibility, STZ enters β-cells via GLUT-2

transporters and produces a predictable

Universitas Padjadjaran (Indonesia). Freeze-

drying yielded a dry aqueous extract (RSAE)

with recovery 34.7%. Freeze-dried powder

was stored in -20°C for further analysis.

alkylation-mediated

precipitates oxidative stress, progressive

DNA

lesion

that

Animals and Experimental Design

insulin secretory failure and the mixed

Thirty male Wistar rats (3–4 months old, 120–

200 g) were obtained from the Animal

Breeding Facility, Institut Teknologi Bandung

and housed in groups of 10 per standard

cage on corn‐cob bedding. The animal room

was maintained at 22 ± 2 °C with 50–60 %

relative humidity and a 12 hr light and 12 hr

dark cycle. Rats had ad libitum access to

standard laboratory chow and filtered water.

Group allocation was determined using

insulin-deficient/insulin-resistant

state

characteristic of late-stage T2DM [33,34].

Building on this preliminary evidence and

pathophysiological relevance of the STZ-

induced diabetes animal model, the present

study aims to characterise hypoglycaemic

potential of H. sabdariffa dan S. rebaudiana

combination. In this study we compared the

effects of two oral doses (500 and 1000

mg/kgBW) on fasting and post-prandial

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Federer’s formula for sample size is (t-1) (n-)

 15 where t is the number of groups (5) and

n the number of animals per group. To

ensure adequate power and allow for

potential attrition, we selected n = 6 animals

per group (total N = 30). After a 7-day

acclimatization, rats were randomized into

five groups (n = 6 each) including Normal

control (CN), Negative control (C-) given STZ

and 0.5 % of Na-CMC, Positive control (C+)

given STZ and glibenclamide 5 mg/kgBW,

Extracts, glibenclamide, and Na-CMC were

administered orally once daily for 14 days.

Blood glucose measurements

Fasting blood glucose (FBG) and 2 hours

post-prandial glucose (PPG) were measured

on days 0, 3, and 17 using Easy-Touch

glucometer (GlucoDr™). The hypoglycemic

effect of each treatment was expressed as

the percentage change in blood glucose

between Day 3 (D1’after STZ induction) and

Day 17 (D14’ after treament), calculated

using equation 1.

Test group I (Test I)

combination of H. sabdariffa

given STZ and

and S.

rebaudiana (RSAE) 500 mg/kgBW, and Test

group II (Test II) given STZ and RSAE 1000

mg/kgBW. Diabetes was induced by a single

intraperitoneal injection of STZ 50 mg/kgBW.

Blood glucose level was check after 72 hr of

STZ administration. Rats with fasting blood

glucose > 126 mg/dL were included in the

study and subjected to further treatments.

To calculate the percentage reduction in

blood glucose relative to the untreated

diabetic control at Day 14’ was calculated

using equation 2. Same formula is applied

for the 2 hr post-prandial glucose (PPG).

FBG Day 3−FBG Day 14

(

)

 Day 1′ − Day 14′ % =

푥 100%

(1)

(2)

FBG Day 3

FBG Negative control group−FBG Treated Group

푥 100%

FBG Negative control group

(GAE) per gram of freeze-dried aqueous

extract (mg GAE/g) and reported as the

Total Phenolic Content (TPC)

The TPC of each freeze-dried extract was

measured by the Folin–Ciocalteu method

following the Farmakope Herbal Indonesia

(FHI) monograph. Briefly, 0.5 mL of extract

solution (1 mg/mL in distilled water) was

mixed with 2.5 mL of ten-fold diluted Folin–

Ciocalteu reagent and allowed to react for 5

min at room temperature. Then, 2.0 mL of

7.5 % (w/v) sodium carbonate solution was

added, the mixture was vortexed, and

incubated in the dark for 60 min at 25 °C.

Absorbance was measured at 760 nm

against a reagent blank. Gallic acid standards

(0–200 µg/mL) were prepared in the same

manner to generate a calibration curve. TPC

was calculated as mg gallic acid equivalents

mean

±

SD

of

three

independent

determinations.

Total Flavonoid Content (TFC)

TFC was determined by the aluminum

chloride (AlCl₃) colorimetric method as

described

in

the

Farmakope

Herbal

Indonesia (FHI) monograph. Aliquots of 0.5

mL extract solution (1 mg/mL) were

transferred to 10 mL volumetric flasks. To

each flask were added 0.1 mL of 10 % (w/v)

AlCl₃ solution and 0.1 mL of 1 M potassium

acetate; the volume was adjusted to 10 mL

with distilled water. After gentle mixing, the

reaction mixtures were incubated at room

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Chempublish Journal, 9(2) 2025,167-182

temperature for 30 min. Absorbance was

recorded at 415 nm versus a blank

containing all reagents except extract.

Quercetin standards (0–100 µg/mL) were

disposing of post-absorptive glucose surges

[36–39]. By assessing both parameters, we

have been able to delineate the multifaceted

antihyperglycaemic

combination of

activity

sabdariffa

of

and

the

S.

treated

identically

to

construct

the

H.

calibration curve. TFC was expressed as mg

quercetin equivalents (QE) per gram of

aqueous extract (mg QE/g), reported as the

rebaudiana. These dual effects on fasting

and post-prandial glycaemia not only

underscore the therapeutic breadth of the

H.sabdariffa and S. rebaudiana but also align

with existing literature that has reported

mean

±

SD

of

three

independent

determinations.

both

insulin-sensitizing

and

digestive

Statistical Analysis

enzyme–modulatory properties for their

constituent phytochemicals [20,26,40–42].

Data are presented as mean ± SD. Normality

(Shapiro–Wilk) and homogeneity (Levene)

were verified, one-way ANOVA followed by

Newman–Keuls (homogeneous) or Games–

Howell (heterogeneous) post-hoc tests was

applied with α = 0.05 using IBM SPSS ver. 30.

Fasting Blood Glucose (FBG)

To evaluate the antihyperglycaemic efficacy

of the H. sabdariffa and S. rebaudiana

combination (RSAE), fasting blood glucose

(FBG) was measured at baseline (Day 0), 72

hr post–STZ induction (Day 1’) and after 14

days of treatment (Day 14’). All data are

presented as mean ± SD (n = 6 per group).

Statistical assumptions at Day 14’ (Shapiro–

Wilk, p > 0.05; Levene’s test, p > 0.05)

permitted one-way ANOVA followed by

Newman–Keuls post-hoc comparisons (α =

0.05).

Result and Discussion

The primary objectives of the management

of diabetes are to reduce the incidence and

burden of complications and to improve

quality of life. Historically, these objectives

were

pursued

through

control

of

hyperglycaemia [35]. In the present study,

fasting blood glucose (FBG) and post-

prandial blood glucose (PPG) measurements

were employed to capture distinct yet

At baseline, all groups were normoglycaemic

(63–85 mg/dL). By Day 3, STZ-treated groups

C(–), C(+), Test 1, Test 2 exhibited a marked

rise in FBG versus the normal control C(N),

confirming successful diabetes induction

(Table 1). After 14 days of treatment,

glibenclamide C(+) reduced FBG by 38.3%

and achieved a 54.5% decrease relative to

C(–). The 500 mg/kg extract (Test 1) elicited a

33.3% intra-treatment drop and a 39.1%

reduction versus C(–), while the 1000 mg/kg

dose (Test 2) produced a 28.2% intra-

treatment drop and the greatest relative

improvement, 57.4% lower than C(–) (Table

1).

complementary

aspects

of

glycaemic

control. FBG levels primarily reflect the

balance between hepatic glucose production

and peripheral insulin sensitivity during

periods without nutrient intake. Therefore,

an elevated FBG is indicative of heightened

gluconeogenesis

and

impaired

insulin

action, hallmark features of early type 2

diabetes pathogenesis. In contrast, PPG

profiles reveal the capacity of pancreatic β-

cells to mount a rapid secretory response to

carbohydrate

effectiveness

ingestion

peripheral

and

tissues

the

in

of

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Chempublish Journal, 9(2) 2025,167-182

Table 1. Fasting blood glucose level measurement

Day 3

(D1’)

(mg/dL)

Day 17

(D14’)

(mg/dL)

 D1’ –

D14’

(%)*

 vs C (-)

Group

Day 0

(%)

C(N)

71.83 ± 9.68

72.50 ± 5.99

73.17 ± 5,98

86.17 ± 7.05

–17.8

n/a

C(–)

370.33 ± 46.86

409.17 ± 48.72

–10.4

Reference

Glibenclamide

5 mg/kgBW

Test 1

84.83 ± 14.05

79.83 ± 9.11

301.50 ± 60.30

374.33 ± 47.00

186.00 ± 36.09

249.50 ± 39.16

38.3

33.3

54.5

39.1

500 mg/kgBW

Test 2

1000

63.67 ± 7.42

242.50 ± 11.65

174.00 ± 35.59

28.2

57.4

mg/kgBW

*Negative value shows an increase

Figure 1 shown the significance result based

on statistical analysis. Untreated group C (-)

maintained markedly elevated fasting blood

glucose levels at Day 14’ (409.2 ± 48.7

mg/dL). Administration of glibenclamide 5

mg/kgBW (C+) produced antihyperglycaemic

effect, lowering FBG to 186.0 ± 36.1 mg/dL (p

< 0.001 vs. C(–). The RSAE combination

extract at 500 mg/kg (Test 1) reduced FBG to

249.5 ± 39.2 mg/dL (p < .001), while the 1000

mg/kg dose (Test 2) achieved the greatest

decrease, reaching 174.0 ± 35.6 mg/dL (p <

.001).

These results confirm

a

dose-

dependent antihyperglycaemic activity of

the combined extract.

Figure 1. Fasting Blood Glucose at Day 14’ (Mean ± SD). Error bars represent ±SD. Asterisks

denote values significantly different from the negative control (C(–), p < 0.001).

Post-prandial Blood Glucose (PPG)

mean ± SD (n = 6); statistical assumptions at

Day 14’ (Shapiro–Wilk: W = .92–.98, p > .05;

Levene’s test: p = .003) dictated one-way

ANOVA followed by Games–Howell post-hoc

analysis (α = .05). At Day 0, all groups

exhibited comparable PPG values (79.7–

Two-hour post-prandial glucose (PPG) levels

were measured at baseline (Day 0), 72 hr

post–STZ (Day 1’) and after 14 days of

treatment (Day 14’). Data is presented as

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Chempublish Journal, 9(2) 2025,167-182

100.5 mg/dL). By Day 3 (D1’), STZ-treated

group (C(–), C(+), Test 1, and Test 2) displayed

pronounced hyperglycaemia (401.7–425.7

mg/dL) relative to the normal control (86.8

Figure

2

then

further

ilustrated

the

signficance of blood glucose reduction of the

treated group at Day 14’ compare to the

negative control (C-) group. Glibenclamide

(significantly reduced PPG to 226.3 ± 30.2

mg/dL (p < 0.001 vs. C(–)), corresponding to

a 50.0 % reduction. The RSAE combination at

500 mg/kg (Test 1) lowered PPG to 283.5 ±

26.4 mg/dL (37.4 % reduction, p < 0.001),

while the 1000 mg/kg dose (Test 2) achieved

a PPG of 243.5 ± 28.3 mg/dL—46.2 % lower

than C (–) (p < 0.001).

mg/dL),

confirming

successful

hyperglycemic induction. After 14 days of

treatment (Day 14’), glibenclamide achieved

a 35.9 % reduction from the Day 1’, the 500

mg/kg RSAE combination (Test 1) decreased

PPG by 33.4 %, while the 1000 mg/kg dose

(Test 2) produced the greatest effect, a 41.4

% drop compare to Day 1’ and 46.2%

reduction vs C(-) (Table 2).

Table 2. Post-prandial glucose level measurement

Day 3

(D1’)

(mg/dL)

Day 17

(D14’)

(mg/dL)

 D1’ –

14’

(%)*

 vs C (-)

Group

Day 0

(%)

C(N)

79.67ꢀ±ꢀ12.94 86.83ꢀ±ꢀ10.80

87.67ꢀ±ꢀ9.05

103.00ꢀ±ꢀ6.63

-18.6 %

-12.7 %

n/a

C(–)

401.67ꢀ±ꢀ38.40 452.83ꢀ±ꢀ51.04

Reference

Glibenclamide

5 mg/kgBW

100.50ꢀ±ꢀ10.84 353.33ꢀ±ꢀ17.13 226.33ꢀ±ꢀ30.22

35.9 %

33.4 %

50.0 %

37.4 %

Test 1

500 mg/kgBW

82.67ꢀ±ꢀ5.61

425.67ꢀ±ꢀ45.45 283.50ꢀ±ꢀ26.40

Test 2

1000

86.83ꢀ±ꢀ7.03

415.83ꢀ±ꢀ21.57 243.50ꢀ±ꢀ28.26

41.4 %

46.2 %

mg/kgBW

*Negative value shows an increase

Figure 2. Two-Hour Post-Prandial Blood Glucose at Day 14’ (Mean ± SD). Error bars represent

±SD. Asterisks denote values significantly different from the negative control (C(–), p

< 0.001).

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Chempublish Journal, 9(2) 2025,167-182

Epidemiological data indicated there have

associated increased postprandial glucose

(PPG) with a higher risk of macrovascular

events, and long-term high fasting blood

substances in this extract, particularly the

flavonoids and polyphenols, may reduce

basal

hyperglycemia.

This

could

be

accomplished by improving insulin receptor

glucose

complications [43–45]. Therefore, a drug

that can simultaneously reduce basal

hepatic glucose output and suppress

(FBG)

with

microvascular

signaling

gluconeogenic

Simultaneously, the significant suppression

in postprandial glucose spikes (PPG)

and

blocking

enzymes

the

hepatic

[46,47].

postprandial glucose spikes would be highly

desirable. Our findings thus support the

potential of this herbal combination as a

suggests a different mode of action that

involves the inhibition of the small intestine's

α-amylase and α-glucosidase enzymes. The

holistic

comparable

sulfonylurea

glycemic

modulator,

providing

carbohydrate

absorption are slowed as a result [48,49]

hydrolysis

and

glucose

efficacy

therapy

to

in

conventional

streptozotocin-

Total phenolic content (TPC)

induced diabetic rats while reducing the

inherent risk of hypoglycemia. In general,

the measurement of both FBG and PPG has

offered a comprehensive evaluation of the

antidiabetic mechanisms at work and

highlights the potential of H. sabdariffa

sepals and S. rebaudiana leaves extract as an

adjunct or alternative to conventional

hypoglycaemic medications.

The total phenolic content was determined

using gallic acid as the reference standard.

The gallic acid standard curve exhibited

linearity with the linear regression equation

A=0.0030C−0.0115 with R² = 0.9993 (Figure 3).

Table 3 presents the mean absorbance at

760 nm and the corresponding total

phenolic content (TPC) expressed as mg

gallic acid equivalents per gram of dry

extract (mg GAE/g).

After 14 days of treatment, there was a

decrease in fasting blood glucose (FBG)

levels, which implies that the bioactive

Figure 3. Gallic-acid standard curve

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Table 3. Total Phenolic Content of H. sabdariffa, S. rebaudiana, and Their Combination

Absorbance

(mean ± SD)

Samples

TPC (mgGAE/g)

102.75 ± 0.06

RSD (%)

0.57

H. sabdariffa extract

S. rebaudiana extract

RSAE combination (3:1)

0.174 ± 0.001

0.215 ± 0.001

0.203 ± 0.001

188.33 ± 0.05

118.85 ± 0.09

0.24

0.49

Total flavonoid content (TFC)

A=0.0075C−0.0705 with R² = 0.9985 (Figure

4).

Table

4

summarizes

415 nm

the

and

mean

the

The total flavonoid content was determined

using quercetin as the reference standard.

The quercetin standard curve exhibited

linearity with the linear regression equation

absorbance

at

corresponding total flavonoid content (TFC),

expressed as mg quercetin equivalents per

gram of dry extract (mg QE/g).

Figure 4. Quercetin standard curve

The H. sabdariffa sepals and S. rebaudiana

leaves combination's rich complement of

their phenolic and flavonoid constituents,

the quantitative distribution in our extracts

total phenolics and 3.10 mgQE/g of total

flavonoids.

The

combination

of

3:1

H.sabdariffa sepals and S.rebaudiana leaves

extract yielded intermediate values (118.85

mgGAE/g of total phenolics and 4.79 mgQE/g

refflect

the

glycaemic

improvements

observed in vivo [47]. The test results

showed the stevia leaves extract had a

significantly higher phenolic content at

188.33 mg gallic-acid-equivalent (GAE) per g

along with 6.99 mg quercetin-equivalent (QE)

per g of total flavonoid content, whereas the

rosella extract alone had 102.75 mgGAE/g of

of

flavonoids),

reflecting

the

additive

contributions of both plants.

H. sabdariffa phenolic groups is dominated

by

sabdariffoside

sabdariffoside—and protocatechuic acid,

anthocyanins—mostly

and

delphinidin-3-

cyanidin-3-

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Chempublish Journal, 9(2) 2025,167-182

which together represent over 60ꢀ% of its

total phenolics [50,51]. These compounds

demonstrated potent in vitro inhibition of α-

amylase and α-glucosidase (IC₅₀ꢀ=ꢀ50–120 μg

mL⁻¹) and have been shown to delay post-

prandial glycaemic peaks in human bread-

feeding trials [51,52]. Moreover, rosella

anthocyanins promote GLUT-4 translocation

and upregulate PPAR-γ expression in 3T3-L1

only counter systemic hyperglycaemia but

also

protect

highly

oxidative-sensitive

tissues such as the testes by integrating

antioxidant, anti-inflammatory, metabolic

and gene-regulatory mechanisms.

Limitation

Despite its promising findings, this study has

several important limitations. First, the use

of a single, chemically induced model of

diabetes (STZ-induced Wistar rats) captures

primarily the insulin-deficient and oxidative-

stress aspects of type 2 diabetes but does

adipocytes,

which

facilitates

greater

peripheral glucose uptake [53]. By reducing

reactive oxygen species and NF-κB signaling,

protocatechuic acid further shields β-cells,

promoting endogenous insulin secretion

and increased cell viability [54].

not

fully

replicate

the

multifactorial

pathogenesis seen in humans, such as diet-

induced insulin resistance or the chronic

inflammatory milieu. Second, our 14-day

Hepatic AMPK has been shown to be

activated by the phenolic content of S.

rebaudiana, which is high in caffeic, ferulic,

and chlorogenic acids[55]. This activation

increases GLUT-2 phosphorylation while

treatment

demonstrate

period,

acute

while

sufficient

to

antihyperglycaemic

effects, does not address long-term efficacy,

safety, or the risk of tolerance development.

Third, although we quantified total phenolic

and flavonoid content and correlated these

broad classes with glycaemic improvements,

we did not isolate or bio-assay individual

compounds thus, the precise bioactive

constituents remain undefined. Fourth, we

suppressing

important

gluconeogenic

enzymes like PEPCK. Rat models fed a high-

fat diet and STZ have shown these effects

[55–57]. Rutin and kaempferol-3-rutinoside

are part of the flavonoid subfraction of S.

rebaudiana, which inhibits intestinal starch

hydrolysis by acting as a competitive α-

focused

exclusively

on

blood

glucose

glucosidase

(stevioside) potentiates glucose-stimulated

insulin secretion via TRPM5-mediated

inhibitor.

Steviol

glycoside

measurements and did not assess insulin

levels, pancreatic histopathology, or markers

of β-cell mass and function, which would

calcium influx in beta cells [57]. Recent work

by Ajiboye et al. (2025) has extended the

antidiabetic profile of Hibiscus sabdariffa

beyond systemic glycaemic control to the

male reproductive system as complication of

T2DM. Flavonoid-enriched H. sabdariffa

extract at 150 and 300 mg/kgBW markedly

improved testicular redox status including

decrease in malondialdehyde, increase in

GSH, SOD, CAT, GPx and GST activities,

more

directly

confirm

protective

or

regenerative effects on pancreatic islets.

Conclusion

In conclusion, the combined aqueous

extracts of H. sabdariffa and S. rebaudiana

exhibited

antihyperglycaemic activity in STZ‐induced

diabetic Wistar rats, significantly reducing

fasting blood glucose and two‐hour post‐

dose‐dependent

accompanied

by

restoration

of

steroidogenesis and by normalisation of

cholesterol turnover through up-regulation

prandial

administration.

favorably with

glucose

These

glibenclamide

over

effects

14

compare

and

days

of

3β-

and

17β-hydroxysteroid

are

dehydrogenases [58]. Collectively, these

data show that H. sabdariffa flavonoids not

underpinned by the high phenolic and

flavonoid contents of the extracts, which

176

A.Tjiraresmi et al.

Chempublish Journal, 9(2) 2025,167-182

mechanistic evidence suggests act through

complementary pathways.

[5].

[6].

Padhi, S., Nayak, A.K., Behera, A. Type II

Diabetes Mellitus: A Review on Recent

Drug Based Therapeutics. Biomedicine

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110708 .

Acknowledgement

This research is supported Fundamental

Research Grant by the Ministry of Higher

Education, Science, and Technology Republic

of Indonesia awarded to RMF.

Ling, Z., Wang, Q., Stangé, G., In’t Veld,

P.,

Pipeleers,

D.

Recruits

into

Glibenclamide

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Treatment

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Author Contributions

and

Sustained Basal Insulin

Conceptualization,

AT

and

RMF;

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Methodology, AT and YS; Formal Analysis,

DA, AT, and RMF; Investigation, AT and DA;

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MM; Funding Acquisition, RMF. All authors

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version of the manuscript.

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Jacob, B.; Narendhirakannan, R.T. Role

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The authors declare no conflict of interest.

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