Mechanistic Insights into Propolis in Targeting Type 2 Diabetes Mellitus: A Systematic Review

Abstract

Type 2 diabetes mellitus (T2DM) is a major global health concern characterized by insulin resistance and impaired glucose metabolism. Growing interest in natural therapies has led to the exploration of propolis, a resinous bee product, for its potential anti-diabetic effects. This review examines the mechanisms by which propolis may aid in T2DM management. A literature search was conducted in SCOPUS and PubMed using the terms (Propolis) AND (diabetes OR “insulin resistance” OR hyperglycemia), focusing on studies published from 2014 onwards. The search yielded 384 and 207 records in SCOPUS and PubMed, respectively. After screening and full-text review, 42 studies met the inclusion criteria. Key variables analyzed included the type and source of propolis, experimental models, dosage, treatment duration, and primary and secondary outcomes. Findings highlight multiple mechanisms through which propolis may benefit T2DM, including enhancing pancreatic β-cell function, improving insulin sensitivity, regulating glucose and lipid metabolism, modulating gut microbiota, and reducing oxidative stress and inflammation. Some studies also reported protective effects on renal and hepatic function. Overall, propolis exhibits promising potential as a complementary therapy for T2DM. However, further well-designed clinical trials are necessary to confirm its efficacy, determine optimal dosing, and identify key bioactive compounds responsible for its therapeutic effects. Future research should focus on optimizing its clinical application for diabetes management.

Keywords

Apiculture - propolis - bee glue - diabetes mellitus - hyperglycemia - insulin resistance

Abbreviations list

ACC: Acetyl-CoA carboxylase

ACOX: Acyl-CoA oxidase

ACSL1: Acyl-CoA synthetase long chain family member 1

ADMA: Asymmetric dimethylarginine

Akt: Protein kinase B

APC: Artepillin C

Arg: Arginine

CAPE: Caffeic acid phenethyl ester

CPT: Carnitine palmitoyltransferase

CREB: cAMP-response element binding protein

CRTC2: CREB-regulated transcription coactivator 2

DGAT1: Diacylglycerol O-acyltransferase 1

F/B: Firmicutes-to-Bacteroidetes

FASN: Fatty acid synthase

G6Pase: Glucose-6-phosphatase

Gln: Glutamine

GLUT4: Glucose transporter type 4

GPx: Glutathione peroxidase

HbA1C: Hemoglobin A1C

HMG-CoA: Hydroxymethylglutaryl-coenzyme A

HO-1: Heme oxygenase-1

IDF: International Diabetes Federation

IL: Interleukin

INSIG: Insulin-induced gene proteins

IRS: Insulin receptor substrate

JNK: c-Jun N-terminal kinase

LPL: Lipoprotein lipase

LPS: Lipopolysaccharide

LXR: Liver X receptor

NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B

NO: Nitric oxide

PGC-1α : Peroxisome proliferator-activated receptor-gamma coactivator-1alpha

Phe: Phenylalanine

PI3K: Phosphoinositide 3-kinase

PPAR: Peroxisome proliferator-activated receptor

ROS: Reactive oxygen species

SCD1: Stearoyl-CoA desaturase-1

Ser: Serine

Sirt1: Sirtuin 1

SOD: Superoxide dismutase

SREBF: Sterol regulatory element-binding transcription factor

SREBP: Sterol regulatory element-binding protein

T2DM: Type 2 diabetes mellitus

Thr: Threonine

Tyr: Tyrosine

UCP: Uncoupling protein

α : Alpha

β : Beta
 

Introduction

Diabetes mellitus, a chronic metabolic disorder characterized by persistent hyperglycemia, affects millions worldwide, with the incidence continuously rising. According to the International Diabetes Federation (IDF) Diabetes Atlas (2021), 10.5% of adults aged 20 – 79 are living with diabetes, with nearly half unaware of their condition. By 2045, IDF projections estimate a 46% increase, in which 1 in 8 adults–around 783 million people–will be affected [1]. Notably, type 2 diabetes mellitus (T2DM) accounts for 90 – 95% of all diabetes cases, making it the predominant and most widespread form of the disease worldwide [1]. Despite the development of numerous antidiabetic drugs, the global diabetic population continues to rise, indicating that current treatments and preventive measures may be inadequate. Increasing interest in natural therapies has led to the exploration of propolis, a resinous substance produced by bees, for its potential therapeutic effects in managing T2DM.

Propolis, often referred to as bee glue, is a resinous substance primarily produced by honeybees from plant exudates. Honeybees collect tree resin and mix it with beeswax and their saliva to create propolis, which they use to seal-protect their hives. Propolis has potent antimicrobial properties and helps to maintain hive hygiene, serving as a natural barrier against pathogens and parasites. Propolis contains a complex mixture of biologically active compounds, include flavonoids such as galangin, chrysin, pinocembrin, and kaempferol, along with phenolic acids like caffeic acid, p-coumaric acid, and ferulic acid, which vary depending on the geographical location, plant source, and bee species [2], [3]. Propolis has been utilized for centuries in traditional medicine due to its broad spectrum of biological activities, including anti-inflammatory, antioxidant, and antimicrobial effects [2], [4], [5].

Propolis has also been utilized in traditional medicine to manage various ailments, including blood sugar irregularities. In folk practices, it was commonly applied to wounds and consumed to alleviate symptoms associated with elevated blood glucose levels [6], [7]. In recent decades, scientific interest has surged, particularly regarding its potential to reduce the risk of developing T2DM and its role as an adjunctive therapy for diabetes management. Clinical studies have demonstrated that propolis supplementation can improve glycemic control in both healthy individuals and those with T2DM [8], [9]. A recent meta-analysis of 22 studies highlighted that dose-dependent propolis supplementation significantly reduced fasting plasma glucose, hemoglobin A1C (HbA1C), insulin resistance, and several key cardiometabolic parameters such as triglycerides, LDL-cholesterol, and systolic blood pressure in adults [10]. Although the observed reductions may not always reach clinical significance, these findings suggest that propolis could serve as a valuable adjunct therapy in managing chronic diseases and as a health-promoting supplement for improving overall well-being in healthy individuals. Another meta-analysis consisting of six randomized controlled trials concluded that propolis supplementation significantly lowers fasting blood glucose and HbA1C among T2DM patients. However, no significant effect was observed in fasting insulin and or in the homeostasis model assessment of insulin resistance in the same cohort [11].

Despite promising evidence, propolis does not consistently restore blood glucose levels to clinically significant thresholds (euglycemia) [12], [13], raising questions about its therapeutic efficacy in clinical settings. Moreover, the reported hypoglycemic effects of propolis vary significantly across studies, likely due to variations in its phytochemical composition, which is influenced by geographical and botanical factors. Heterogeneity in study designs–including differences in disease states, experimental models, dosages, and treatment durations–further contributes to the inconsistencies observed in the literature [14].

While numerous preclinical studies and human trials have primarily focused on the hypoglycemic effects of propolis and its ability to improve glucose metabolism, relatively few have investigated its underlying mechanisms of action. Therefore, this review aims to consolidate existing evidence on these mechanisms, providing a clearer understanding of how propolis exerts its antidiabetic effects. By integrating current knowledge, this study seeks to elucidate the therapeutic potential of propolis as a natural agent or functional food in T2DM management, as well as its role in reducing the risk of T2DM among at-risk individuals.

Methods

This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This review has not been registered in PROSPERO.

Search strategy

A literature search was conducted in the SCOPUS and PubMed databases using the search terms “propolis”, “diabetes”, “insulin resistance”, and “hyperglycemia”. The search was restricted to articles published from 2014 up to the last search date, 21 February 2025. The specific search strings utilized were as follows:

• SCOPUS: TITLE-ABS-KEY ([propolis] AND [diabet* OR “insulin resistance” OR hyperglyc*]) AND PUBYEAR > 2013 AND PUBYEAR < 2026 AND (LIMIT-TO [LANGUAGE, “English”])

• PubMed: (propolis) AND (diabet* OR “insulin resistance” OR hyperglyc*)[MeSH Terms]

Eligibility criteria

Inclusion criteria

Only peer-reviewed, full-text original articles published in English that specifically addressed the mechanisms by which propolis alleviates diabetes, using in vitro, ex vivo, and in vivo experimental models and human subjects were considered for the final review.

Exclusion criteria

Studies were excluded if they met any of the following conditions: (i) studies that focused on multiple experimental substances or compounds, making it challenging to isolate the effects of propolis, (ii) studies that focused on synthetic compounds or bioactive substances not derived from propolis, (iii) studies that did not provide clear descriptions of the mechanisms by which propolis exerts its effects on T2DM, (iv) retracted articles, review articles, non-peer-reviewed articles, or grey literature, for example, conference abstracts, editorials, letters, and commentaries, and book chapters or monographs.

Data extraction and variables of interest

Data extraction was performed independently by two investigators. The titles and abstracts of retrieved records were screened against the inclusion and exclusion criteria. Articles deemed potentially relevant were retrieved for full-text review. The accuracy of extracted data was cross-verified, and disagreements were resolved through discussion or by involving a third investigator. Data were extracted and tabulated in [Table 1], based on the following key variables:

• Propolis or propolis-derived compound–refers to the nature of the propolis used in the study, which may include either crude propolis extract or isolated bioactive compounds derived from propolis. The distinction is important as crude extracts contain a mixture of bioactive compounds, while isolated compounds focus on specific active constituents.

• Source of propolis–indicates the geographical origin of the propolis used in the study, specifying the country where it was collected. The chemical composition of propolis varies based on regional flora, climate, and bee species, influencing its biological activity.

• Experimental models–describes the type of model used to assess the effects of propolis, which can include in vitro models, cell cultures or isolated tissues (used for mechanistic studies), in vivo models, animal models, e.g., diabetic mice, rats used to evaluate physiological and biochemical responses to propolis treatment, or ex vivo models, experiments conducted on tissues, organs, or cells that have been isolated from a living organism, e.g. isolated pancreatic islet.

• Dosage–the amount of propolis or propolis-derived compound administered in the study, typically expressed in mg/kg.

• Route of administration–specifies how propolis was delivered to the experimental model.

• Treatment duration–the length of time the experimental model was exposed to propolis treatment.

• Primary outcomes: These outcomes may involve direct molecular, cellular, or biochemical changes that provide mechanistic insight into its biological activity, e.g., enhancement of pancreatic β-cell function, improved insulin sensitivity, regulation of glucose and lipid metabolism, modulation of gut microbiota, and attenuation of oxidative stress and inflammation. These effects collectively contribute to improved glycemic control and reduced insulin resistance.

• Secondary outcomes: Additional effects observed in the study that may support or complement the primary mechanistic findings. These outcomes may include broader metabolic changes, or functional improvements in the experimental model, e.g., changes in body weight, food/water intakes, and behavioral or symptomatic changes.

• Mechanistic classification of effects: The classification is primarily based on the pathophysiological defects contributing to the development of T2DM, i.e., Egregious Eleven, but it is not strictly limited. The key mechanisms considered include pancreatic β-cell dysfunction, insulin resistance in muscle, increased lipolysis in adipose tissue, reduced incretin effect, increased glucagon secretion from α-cells, increased renal glucose reabsorption, neurotransmitter dysfunction in the brain, mitochondrial dysfunction, inflammation, and gut microbiota dysbiosis.

Table 1 Mechanistic actions of propolis extracts or propolis-derived compounds in targeting key aspects in T2DM.

Propolis/Propolis-derived compound	Source of propolis	Experimental Model	Dosage, route of administration, and duration	Primary outcomes	Secondary outcomes	Mechanistic classification of effects	Reference
Propolis	Taiwan	In vivo (High-fat and -fructose diet-fed and streptozotocin-injected Sprague–Dawley rats)	183.9 – 919.5 mg/kg/day, oral (8 weeks)	Increased β-cell mass and improved β-cell function Improved lipid profile Reduced pro-inflammatory cytokines and increased antioxidant factors Increased leptin and adiponectin	–	Safeguard pancreatic β-cell and insulin production	[15]
Propolis	Malaysia	In vitro (Alpha glucosidase inhibition assay) In vivo (Streptozotocin-injected Sprague–Dawley rats)	In vitro (10 mg/mL) In vivo [300 mg/kg/day, oral (4 weeks)]	Increased pancreatic islet area, β-cell number, and β-cell mass and improved pancreas morphology Inhibited α-glucosidase Preserved pancreatic cell integrity Reduced pro-inflammatory markers and increased anti-inflammatory marker	Reduced polyphagia, polydipsia, and weight loss	Safeguard pancreatic β-cell and insulin production Inhibit intestinal glucose digestion and absorption Mitigate oxidative stress and inflammation	[16]
Propolis	Indonesia	In vivo (Alloxan-injected Wistar rats)	50 – 200 mg/kg, oral (3 weeks)	Increased insulin production Preserved pancreatic cell integrity	–	Safeguard pancreatic β-cell and insulin production Mitigate oxidative stress and inflammation	[17]
Propolis	N/A	In vivo (Streptozotocin-induced Wister albino rats)	0.3 g/kg/day, oral (2 weeks)	Increased pancreatic islet area and β-cell number and improved pancreas morphology Reduced lipid peroxidation	–	Safeguard pancreatic β-cell and insulin production	[18]
Propolis	Nigeria	In vivo (Alloxan-injected Wistar rats)	200 – 300 mg/kg, oral (28 days)	Improved pancreas morphology Lower lipid levels Increased antioxidant levels	Increased body weight Improved liver profile Improved hepatic morphology	Safeguard pancreatic β-cell and insulin production	[19]
Propolis	N/A	In vivo (Streptozotocin-injected BALB/c mice) Ex vivo (Pancreatic beta cells isolated from mice)	In vivo [100 – 200 mg/kg, oral (7 weeks)] Ex vivo (100 – 200 mg/mL)	Increased insulin production	Prevented cisplatin-induced apoptosis	Safeguard pancreatic β-cell and insulin production	[20]
Propolis	Anatolia	In vitro (Alpha amylase and alpha glucosidase inhibition assays) In vivo (Streptozotocin-injected Wistar rats)	In vitro (N/A) In vivo [0.5 mL/100 g, oral (4 weeks)]	Improved pancreas morphology Ameliorated glomerular damage Inhibited α-amylase and α-glucosidase	Reduced polydipsia	Safeguard pancreatic β-cell and insulin production Preserve renal function Inhibit intestinal glucose digestion and absorption	[21]
Propolis	Malaysia	In vivo (Streptozotocin-injected Sprague–Dawley rats)	300 – 600 mg/kg, oral (4 weeks)	Improved pancreas morphology Exhibited antioxidant activity	Increased body weight Reduced polyphagia	Safeguard pancreatic β-cell and insulin production	[22]
Propolis	Turkey	In vivo (High-fat diet-fed and streptozotocin-injected Wistar albino rats)	250 mg/kg, oral (35 days)	Improved pancreas morphology Lower lipid levels Increased antioxidant levels	Increased body weight	Safeguard pancreatic β-cell and insulin production	[23]
Propolis-derived artepillin C	Brazil	In vitro (HEK293T cells) In vivo (High-fat diet-fed C57BL/6 mice)	In vitro (1 – 5 µM) In vivo (20 mg/kg, oral)	Reduced gluconeogenesis Reduced lipogenesis Increased insulin sensitivity Lower lipid levels	Reduced body weight	Regulate hepatic glucose metabolism Modulate lipid metabolism	[24]
Propolis-derived caffeic acid phenethyl ester	China	In vitro (Hepatoblastoma cells) In vivo (High-fat diet-fed and streptozotocin-injected C57BL/6 J mice)	In vitro (30 – 60 ng/mL) In vivo [15 – 30 mg/kg, oral (5 weeks)]	Reduced gluconeogenesis Enhanced insulin receptor substrate phosphorylation Lower hepatic oxidative stress and inflammation Reduced inflammation in adipose tissue Reduced pro-inflammatory cytokines Lower lipid levels	Reduced body weight and food intake	Regulate hepatic glucose metabolism Enhance insulin signaling pathway Mitigate oxidative stress and inflammation	[25]
Propolis	Brazil	In vivo (Periodontitis C57BL/6 mice)	200 mg/kg, oral (3 times/week for 5 weeks)	Reduced gluconeogenesis Reduced inflammation in adipose tissue	Reduced endotoxin level	Regulate hepatic glucose metabolism Mitigate oxidative stress and inflammation	[26]
Propolis-derived galangin and pinocembrin	N/A	In vitro (Insulin-resistant hepatoblastoma cells)	0 – 80 µmol/L	Increased glycolysis Increased insulin receptor sensitivity	–	Regulate hepatic glucose metabolism Enhance insulin signaling pathway	[27]
Propolis	Brazil	In vitro (Mouse skeletal muscle C2C12 cells) In vivo (Diabetic homozygous Db/Db mice)	In vitro (100 µg/mL) In vivo [2% w/w propolis in chow diet, oral (8 weeks)]	Modulated hepatic lipid metabolism Restored muscle impairment Reduced Firmicutes-to-Bacteroidetes (F/B) ratio	Reduced body weight Reduced pro-inflammatory macrophages and increased anti-inflammatory macrophages in the liver	Regulate hepatic lipid metabolism Enhance muscular glucose uptake Ameliorate gut dysbiosis	[32]
Propolis	China	In vivo (High-fat diet-fed C57BL/6 mice)	150 – 300 mg/kg, oral (9 weeks)	Enhanced fat breakdown and adipocytes browning Upregulated Lactobacillus level Lower lipid levels Reduced inflammation	Reduced body weight	Modulate lipid metabolism Ameliorate gut dysbiosis	[33]
Propolis-derived baccharin	Brazil	In vitro (Mouse 3 T3-L1 preadipocytes) In vivo (C57BL/6 J and C57BL/6 J-ob/ob mice)	In vitro (20 – 100 µM) In vivo [10 – 50 mg/kg, intraperitoneal (5 weeks)]	Reduced lipogenesis	–	Modulate lipid metabolism	[35]
Propolis-derived caffeic acid phenethyl ester	N/A	Ex vivo (Subcutaneous adipose tissue sample from a healthy human subject)	10 µM	Reduced lipogenesis Enhanced fat breakdown and adipocytes browning Reduced inflammation in adipose tissue	–	Modulate lipid metabolism Mitigate oxidative stress and inflammation	[37]
Propolis	Nigeria	In vivo (Streptozotocin-injected albino rats)	200 – 600 mg/kg, oral (3 and 6 weeks)	Reduced lipogenesis Reduced lipid levels and reduced lipotoxicity	–	Modulate lipid metabolism	[40]
Propolis	Taiwan	In vivo (High-fat diet-fed C57BL/6 J mice)	500 – 1000 ppm, drinking water (12 weeks)	Reduced lipogenesis Enhanced adipocytes browning Reduced Firmicutes-to-Bacteroidetes (F/B) ratio Reduced Verrucomicrobiota and Akkermansia levels Reduced Desulfovibrio level	Improved cold-induced non-shivering thermogenesis	Modulate lipid metabolism Ameliorate gut dysbiosis	[41]
Propolis	Brazil	In vitro (L6 myotubes) In vivo (ICR mice and Sprague–Dawley rats) Ex vivo (Skeletal muscles from Sprague–Dawley rats)	In vivo (50 – 250 mg/kg, oral) Ex vivo (1 – 10 µg/mL)	Enhanced GLUT4 translocation	–	Enhance muscular glucose uptake	[45]
Propolis	Iran	In vivo (Streptozotocin-injected Wistar rats)	100 – 200 mg/kg, oral (6 weeks)	Ameliorated glomerular damage Ameliorated renal damage Reduced lipid peroxidation Increased antioxidant levels	Increased body weight	Preserve renal function Mitigate oxidative stress and inflammation	[51]
Propolis	N/A	In vivo (High-fat diet-fed and streptozotocin-injected C57BL/6 mice)	600 mg/kg, oral (4 weeks)	Reduced Firmicutes-to-Bacteroidetes (F/B) ratio Increased Verrucomicrobiota and Akkermansia levels Reduced Tenericutes and Ruminococcus levels Reduced pro-inflammatory cytokines and increased anti-inflammatory cytokine	Increased body weight	Ameliorate gut dysbiosis	[52]
Propolis	China	In vivo (High-fat diet-fed C57BL/6 J mice)	200 – 400 mg/kg oral (12 weeks)	Reduced Firmicutes-to-Bacteroidetes (F/B) ratio Reduced Tenericutes and Ruminococcus levels Lower lipid levels Reduced pro-inflammatory cytokines and increased anti-inflammatory cytokine	Reduced body weight	Ameliorate gut dysbiosis	[55]
Propolis	China	In vivo (High-fat diet-fed and streptozotocin-injected Sprague-Dawley rats)	80 – 240 mg/kg, oral (4 weeks)	Increased Firmicutes-to-Bacteroidetes (F/B) ratio Upregulated Lactobacillus level Restored intestinal mucosal barrier	Increased body weight Reduced polydipsia	Ameliorate gut dysbiosis and intestinal mucosal barrier dysfunction	[56]
Propolis	China	In vitro (Alpha glucosidase, rat intestinal sucrase and intestinal maltase inhibition assays)	2 – 200 µg/mL	Inhibited α-glucosidase	Inhibited rat intestinal sucrase and maltase activities	Inhibit intestinal glucose digestion and absorption	[63]
Propolis	Morocco	In vitro (Alpha amylase and alpha glucosidase inhibition assays)	N/A	Inhibited α-amylase and α-glucosidase Exhibited antioxidant activity	–	Inhibit intestinal glucose digestion and absorption	[64]
Propolis	Australia	In vitro (Alpha amylase and alpha glucosidase inhibition assays)	2 mg/mL	Inhibited α-amylase and α-glucosidase Inhibited lipase	–	Inhibit intestinal glucose digestion and absorption	[65]
Propolis	Turkey	In vitro (Alpha amylase and alpha glucosidase inhibition assays)	N/A	Inhibited α-amylase and α-glucosidase Exhibited antioxidant activity	–	Inhibit intestinal glucose digestion and absorption	[66]
Propolis	Berdav	In vitro (Alpha glucosidase inhibition assays)	0 – 0.005 µg/µL	Inhibited α-glucosidase Exhibited antioxidant activity	–	Inhibit intestinal glucose digestion and absorption	[67]
Propolis	Okinawa	In vitro (Alpha glucosidase inhibition assays)	N/A	Inhibited α-glucosidase Exhibited anti-inflammatory activity	–	Inhibit intestinal glucose digestion and absorption	[68]
Propolis	East Asia	In vitro (Alpha amylase and alpha glucosidase inhibition assays)	62.5 – 50 000 µg/mL	Inhibited α-amylase and α-glucosidase Exhibited antioxidant activity	–	Inhibit intestinal glucose digestion and absorption	[69]
Cycloartane-type triterpenes	Indonesia	In vitro (Alpha glucosidase inhibition assays)	0.1 – 10 µg/mL or 0.2 – 23.5 µM	Inhibited α-glucosidase Exhibited antioxidant activity	–	Inhibit intestinal glucose digestion and absorption	[70]
Propolis	Mexico	In vitro (Alpha amylase and alpha glucosidase inhibition assays)	N/A	Inhibited α-amylase and α-glucosidase Exhibited antioxidant activity	–	Inhibit intestinal glucose digestion and absorption	[71]
Propolis	Bitlis	In vitro (Alpha glucosidase inhibition assays)	N/A	Inhibited α-glucosidase Exhibited antioxidant activity	–	Inhibit intestinal glucose digestion and absorption	[72]
Propolis	Ghana	In vitro (Alpha amylase inhibition assays)	200 – 1000 µg/mL	Inhibited α-amylase Exhibited antioxidant activity	–	Inhibit intestinal glucose digestion and absorption	[73]
Propolis	Iran	In vitro (Alpha amylase inhibition assays)	0.3 – 0.9 mg/mL	Inhibited α-amylase	–	Inhibit intestinal glucose digestion and absorption	[74]
Propolis	Indonesia	In vitro (Alpha glucosidase inhibition assays)	N/A	Inhibited α-glucosidase	–	Inhibit intestinal glucose digestion and absorption	[75]
Propolis	Egypt	In vitro (Alpha glucosidase inhibition assays)	N/A	Inhibited α-glucosidase	–	Inhibit intestinal glucose digestion and absorption	[76]
Propolis-derived caffeic acid phenethyl ester	N/A	In vivo (Streptozotocin-injected Wistar rats)	30 mg/kg, oral (21 days)	Preserved pancreatic cell integrity	Increased body weight Reduced polydipsia, polyphagia and polyuria	Mitigate oxidative stress and inflammation	[77]
Propolis	Brazil	In vivo (ob/ob mice and high-fat diet-fed C57BL/6 mice)	100 mg/kg, intraperitoneal (twice per week for one month)	Reduced inflammation in adipose tissue	–	Mitigate oxidative stress and inflammation	[81]
Propolis	Indonesia	In vivo (Streptozotocin-injected BALB/c mice)	50 – 200 mg/kg, oral (2 weeks)	Increased number of naïve T cells Reduced pro-inflammatory cytokines	–	Mitigate oxidative stress and inflammation	[83]
Propolis	Indonesia	In vivo (Peptide S961-injected BALB/c mice)	50 – 200 mg/kg, oral (14 days)	Increased number of naïve T cells	Prevented apoptosis of spleen cells in diabetic mouse	Mitigate oxidative stress and inflammation	[84]

Results

The identification phase of the study involved searching for records from two major databases: Scopus (n = 384) and PubMed (n = 207). A total of 285 records were excluded, comprising 75 records that did not meet the imposed document type criteria and 210 duplicates. During the screening phase, 306 records were reviewed. Of these, 15 records were excluded due to inaccessibility of the full text. In the eligibility assessment, 291 full-text articles were examined to determine their relevance. A total of 249 articles were excluded for various reasons, including involvement of more than one substance or co-delivery system (n = 29), using of synthetic compound or bioactive substance not derived from propolis (n = 33), lack of clarity regarding the mechanism of diabetes relief (n = 58), and irrelevant to the study focus of this review (n = 129). After applying the inclusion and exclusion criteria, 42 full-text articles were included in the final review ([Fig. 1]).

Fig. 1 PRISMA flow diagram.

The extracted data are summarized in [Table 1]. Additionally, the outcomes of the included studies were categorized and discussed based on their mechanistic actions and classification in targeting key aspects of T2DM, including insulin production, glucose and lipid metabolism, oxidative stress, and inflammation ([Fig. 2]).

Fig. 2 Propolis actions targeting pathophysiological aspects in T2DM.

Discussion

Propolis safeguards pancreatic β-cell and insulin production

Propolis enlarges the pancreatic islet area, improves pancreas morphology, increases β-cell number, restores diminished β-cell mass in diabetic condition, and normalizes insulin secretion, as evidenced by the improved homeostasis model assessment of β-cell function level, leading to a reduced blood glucose level and increased insulin production [15], [16], [17], [18], [19], [20], [21], [22], [23]. The decrease in the cleaved caspase-3 level suggests that propolis protects β-cells from apoptosis, while the increased expression of proliferating cell nuclear antigen, a key factor in nucleic acid metabolism involved in replication and repair, indicates enhanced β-cell regeneration [16].

Propolis/propolis-derived compounds regulate hepatic glucose and lipid metabolism

Gluconeogenesis

In T2DM, hepatic gluconeogenesis is abnormally elevated due to insulin resistance, dysregulated hormonal control, and increased activity of gluconeogenic enzymes. This contributes to hyperglycemia and the overall progression of the disease.

Propolis-derived Artepillin C (APC) has shown potential in mitigating the hyperglycemia seen T2DM by targeting key pathways associated with hepatic gluconeogenesis. It reduces fasting blood glucose levels in obese mice by disrupting the formation of the cAMP-response element binding protein (CREB)/CREB-regulated transcription coactivator 2 (CRTC2) transcription complex, leading to decreased expression of glucose-6-phosphatase (G6Pase), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and phosphoenolpyruvate carboxykinase 1, key regulators of gluconeogenesis, thereby lowering glucose output. The same research team has also concluded that APC improves insulin sensitivity and ameliorates hyperlipidemia in obese mice [24], while another study demonstrated that propolis-derived caffeic acid phenethyl ester (CAPE) significantly ameliorates insulin resistance through modulation of c-Jun N-terminal kinase (JNK) and the nuclear factor kappa-B (NF-κB) signaling pathway in mice and hepatoblastoma cells [25]. Propolis administration has been shown to downregulate glucose-6-phosphatase catalytic subunit expression, which encodes G6Pase [26].

Glycolysis

Galangin and pinocembrin enhance the activities of hexokinase [27], which catalyzes the phosphorylation of glucose to glucose-6-phosphate [28], and pyruvate kinase, which facilitates the conversion of phosphoenolpyruvate into pyruvate during glycolysis [29]. Galangin and pinocembrin enhance insulin receptor phosphorylation, improving its sensitivity. They also reduce serine (Ser)/threonine phosphorylation of insulin receptor substrate (IRS), leading to increased tyrosine (Tyr) phosphorylation and improved insulin signaling [30]. Tyrosine protein kinase phosphorylates the tyrosine residues of IRS, activating it and promoting downstream protein kinase B (Akt) phosphorylation. Activated Akt increases glycogen synthesis and glucose utilization by promoting the phosphorylation of glycogen synthase kinases 3α and 3β [31]. Additionally, galangin and pinocembrin deactivate the mammalian target of rapamycin, reducing the phosphorylation of ribosomal protein S6 kinase beta-1 and ribosomal protein S6, which alleviates insulin resistance and enhances glycometabolic enzyme synthesis, thereby boosting glucose consumption [27].

Lipid metabolism

Fat accumulation around the liver leads to steatosis, potentially contributing to diabetes progression. APC treatment suppresses the hepatic expression of sterol regulatory element binding protein (SREBP) cleavage-activating protein while increasing the levels of insulin-induced gene proteins (INSIG) 1 and 2b. These INSIG proteins inhibit the translocation and cleavage of SREBPs, leading to lower levels of hepatic SREBP-1a, SREBP-1c, and SREBP-2 and subsequently reducing cholesterol synthesis. As a result, the messenger ribonucleic acid (mRNA) levels of SREBP target genes involved in cholesterol synthesis (such as HMG-CoA lyase and HMG-CoA synthase), cholesterol uptake (including low-density lipoprotein receptor and proprotein convertase subtilisin/Kexin Type 9), and fatty acid syntheses (such as acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and acyl-CoA synthetase long-chain family member 1 (ACSL1)) are downregulated. In addition to reducing hepatic nonesterified fatty acids and glycerol levels, APC treatment has upregulated expression of triglyceride hydrolysis-related enzymes, including macrophage galactose-type lectin-1, carboxyl ester lipase, and endothelial lipase. APC reduces the recruitment of liver X receptor (LXR) α and retinoid X receptor α, key lipid metabolism regulators, to the LXR response element of the sterol regulatory element-binding transcription factor (SREBF) 1 promoter, thereby suppressing its expression. Notably, APC does not reduce LXRα, SREBP1, and SREBP2 expressions in the liver of CRTC2-knockout mice, suggesting dependency of APC inhibition on the CRE-driven mechanism. Thus, it can be concluded that APC inhibits the transcription of SREBF1 and SREBF2 through a CREB/CRTC2-mediated pathway [24].

Propolis has been shown to prevent lipid buildup in liver tissue, resulting in reduced liver weight and triglyceride levels. Propolis reduces inflammation, fibrosis, and fatty acid metabolism-related genes, such as tumor necrosis factor-α (TNF-α), CC motif chemokine ligand 2, collagen type I alpha 1 chain, FASN, stearoyl-CoA desaturase-1 (SCD1), and ELOVL fatty acid elongase 6, in the liver of diabetic mice [32]. Additionally, propolis regulates the hepatic lipid metabolism-related gene, including an increase in PGC-1 expression, which is reduced in the diabetic group [33]. Propolis enhances the expressions of peroxisome proliferator-activated receptor (PPAR) α, which stimulates lipolysis, and cholesterol 7 alpha-hydroxylase, responsible for converting cholesterol into bile acids. As a result, the propolis-treated group shows reduced levels of triacylglycerol, total cholesterol, and low-density lipoprotein, along with an increase in high-density lipoprotein [15]. Propolis reduces the expression of perilipin 2, a protein that enhances hepatic lipid accumulation [26]. In the insulin-resistant model, the expression of acyl-CoA oxidase (ACOX), a key enzyme in peroxisomal fatty acid oxidation, is elevated. Production of abundant acetyl-carnitine by excess peroxisomal oxidation raises the mitochondrial acetyl-CoA/CoA ratio, which inhibits mitochondrial β-oxidation and leads to hyperglycemia-induced hepatic lipid accumulation [34]. By decreasing ACOX expression, propolis helps suppress peroxisomal β-oxidation, which may improve insulin sensitivity and reduce the plasma glucose level [26].

Propolis/propolis-derived compounds modulate lipid metabolism

Lipogenesis

APC modulates lipid metabolism in adipose tissue by simultaneously reducing the expression of genes involved in lipogenesis and enhancing those related to lipolysis and fatty acid consumption. This is evidenced by the downregulation of key players in fatty acid and cholesterol synthesis, such as SREBP-1c, SREBP-2, FASN, ACC, SCD1, and ACSL1. Additionally, APC suppresses apolipoprotein B, a fatty acid-binding protein, lipoprotein lipase (LPL), a triglyceride-releasing enzyme, and resistin, an insulin-resistant hormone. On the other hand, APC enhances the expression of carnitine palmitoyltransferase (CPT) 1, which drives fatty acid β-oxidation, as well as hormone-sensitive lipase and adipose triglyceride lipase 1, both of which are vital for lipolysis. Furthermore, APC promotes the expression of glucose transporter type 4 (GLUT4), facilitating glucose uptake, and upregulates uncoupling protein (UCP) 2 and UCP3, which are essential regulators of thermogenesis [24].

Propolis-derived baccharin has been shown to be effective in regulating lipid and glucose metabolism. Treatment with baccharin increases lipid accumulation in preadipocytes, enhances the activity of glycerol-3-phosphate dehydrogenase, an enzyme that catalyzes the conversion of dihydroxyacetone phosphate to glycerol-3-phosphate, and raises triglyceride levels, indicating its role in promoting preadipocyte differentiation into adipocytes. Baccharin also upregulates the mRNA expression of PPARγ, a key transcription factor in adipogenesis, along with its target genes, adipocyte fatty acid-binding protein, GLUT4 and adiponectin, and C1Q and collagen-domain-containing gene [35]. The increase in PPARγ-dependent luciferase activity, along with suppression of baccharin-induced lipid accumulation in the presence of the PPARγ antagonist GW9662, suggests that baccharin promotes adipocyte differentiation via a PPARγ-dependent pathway [35]. Due to these effects on adipocyte differentiation, the baccharin-administered diabetic model shows comparable value in body weight, liver weight, and white adipose tissue weight with those untreated diabetic controls. While this makes it challenging to conclude that baccharin modulates obesity in diabetic models, the observed improvements in non-fasting and fasting blood glucose levels suggest it may alleviate diabetes through an alternate pathway [35].

An elevated reactive oxygen species (ROS) level has been associated with lipid droplet accumulation, suggesting the negative regulatory role of ROS in mediating lipid metabolism [36]. CAPE treatment results in a decrease in lipid droplets, supported by a significant reduction in ROS formation and increased expression of the antioxidant enzyme, heme oxygenase-1 (HO-1). Additionally, it enhances the levels of PPARγ and CCAAT-enhancer binding protein α in adipocytes, leading to an upregulated level of adiponectin, a hormone that promotes insulin sensitivity. CAPE administration also downregulates diacylglycerol O-acyltransferase 1 (DGAT1) expression, a triglyceride-synthesis enzyme. At the same time, it increases preadipocyte factor-1 level, which inhibits preadipocyte differentiation [37].

While this might seem to contradict the earlier paragraph, which focuses on CAPEʼs effects on healthy adipocytes, this paragraph addresses hypertrophic adipocytes. Hypertrophic adipocyte, which is enlarged adipocyte due to excess triglyceride accumulation, is linked to increased inflammation and insulin resistance [38]. CAPE restores the function of hypertrophic adipocytes, evidenced by increased levels of PPARγ, adiponectin, and IRS1, alongside a decrease in leptin, TNF-α, interleukin (IL)-6, intercellular adhesion molecule-1, and NF-κB. These changes are important because proinflammatory environments inhibit adipogenesis and the insulin response in adipocytes. Restored lipogenesis activity, as seen in the increased levels of SREBP-1c and FASN, demonstrates ameliorated insulin resistance by CAPE treatment [37].

The hepatic hydroxymethylglutaryl-coenzyme A (HMG-CoA)-to-mevalonate ratio serves as a marker for cholesterol synthesis. In this process, the enzyme HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate [39]. An increased HMG-CoA-to-mevalonate ratio in the propolis-treated group suggests its potential to inhibit cholesterogenesis, as evidenced by significant reductions in hepatic cholesterol, triacylglycerol, and phospholipid levels [40]. In addition, decreased lipid accumulation in epidermal white adipocytes by propolis administration results in smaller cell size, along with significant reductions in triglyceride and cholesterol levels [41].

β-oxidation

β-oxidation refers to the breakdown of fatty acid molecules into acetyl-coenzyme A, playing a crucial role in obesity regulation and diabetes management [42]. CAPE treatment upregulates Sirtuin 1 (Sirt1) expression, which in turn activates its downstream targets, PPARα and PPARδ, leading to enhanced β-oxidation [37].

Browning of adipocytes

Lowered levels of glycosylated hemoglobin and plasma glucose associate browning of adipocyte with improved glucose metabolism [43], [44]. Propolis treatment has been shown to increase the level of PGC-1α, a crucial regulator of thermogenesis in brown adipocytes. This, in turn, stimulates the expression of UCP1 and UCP3 and promotes mitochondrial biogenesis, which enhances energy expenditure and glucose metabolism. Additionally, propolis treatment leads to increased expressions of thermogenesis- and browning-related adipose genes, such as cell death inducing DFFA like effector A, PPARα, PPARγ, type II iodothyronine deiodinase, cluster of differentiation 36, CPT1β, and fatty acid-binding protein [33], [41].

Propolis enhances glucose uptake in muscles and restores muscle impairment

Propolis enhances translocation of GLUT4 to the plasma membrane by stimulating phosphorylation of phosphoinositide 3-kinase (PI3K) and adenosine monophosphate-activated protein kinase, two pivotal regulators of glucose metabolism. This activation boosts glucose uptake into skeletal muscles, lowering blood glucose level and alleviating hyperglycemia [45]. Consistent with these findings, two additional studies have corroborated the role of propolis in facilitating muscular glucose uptake, further emphasizing its potential in managing blood sugar level [46], [47].

Propolis helps restore muscle mass and alleviates palmitic-acid-induced muscle atrophy and mitochondrial dysfunction. This is evidenced by the downregulation of muscle atrophy-related genes, including Forkhead box O1 transcription factor, myostatin, histone deacetylase 4, muscle atrophy F-box, and muscle-specific RING finger protein 1, in diabetic mice, along with increased adenosine triphosphate production and normalized mitochondrial function in C2C12 myotube cells. Additionally, propolis reverses the reduced concentration of amino acids involved in protein synthesis in the plantaris muscle of diabetic mice. Consequently, propolis administration improves glucose intolerance in these diabetic models [32].

Propolis preserves renal function

Glomerular damage

In diabetic kidneys, oxidative stress-induced expression of growth factors results in a significant increase in glomerular area and basement membrane thickening [48]. These factors promote extracellular matrix accumulation, increasing collagen and fibronectin, which leads to glomerular hypertension and capillary damage [49], [50]. Propolis treatment is beneficial in reducing the glomerular area and glomerular basement membrane thickness in the diabetic group, thereby mitigating these damaging processes [51]. The glomerulosclerosis and mesangial expansion observed in the diabetic group have also been greatly improved by propolis administration [21]. Preserved renal function leads to suppressed blood glucose levels in the propolis-treated group compared to the diabetic group.

Lipid metabolism

Propolis treatment alleviates the elevated levels of cholesterol, triacylglycerol, and phospholipids in the kidney of a diabetic model, leading to improved insulin resistance as indicated by reduction in blood glucose levels [40].

Propolis ameliorates gut dysbiosis and intestinal mucosal barrier dysfunction

Gut dysbiosis, an imbalance in the composition of gut microbiota, is often observed in individuals with T2DM. This dysbiosis leads to the overgrowth of harmful bacteria and a reduction in beneficial microbial populations. Such an imbalance triggers low-grade chronic inflammation, also known as metabolic inflammation, which plays a pivotal role in the onset of insulin resistance, a hallmark of T2DM. Propolis has been shown to positively influence gut microbiota composition, which is associated with its antidiabetic effects.

Propolis has been shown to decrease the proportion of Firmicutes [52], a Gram-positive bacterium involved in short-chain fatty acid synthesis, which negatively affects glucose and fat metabolism [53], [54]. The Firmicutes-to-Bacteroidetes (F/B) ratio is a common marker in microbiota studies. While the Bacteroidetes level is not reported in the previous study, several studies find that propolis supplementation lowers the F/B ratio [32], [41], [55]. This reduction is associated with decreased obesity. However, to fully evaluate the F/B ratio, it would be important to establish a reference for a balanced F/B ratio (non-obese group) and make the comparison. This is crucial, as a lower F/B ratio is also linked with inflammatory bowel disease [54]. The F/B ratio in two studies [32], [55] is comparable to that of a healthy, non-obese group, suggesting that this reduction may be beneficial. Another study presents a contrasting observation, where propolis administration increases the F/B ratio in the diabetic group compared to the control group. Although a high F/B ratio is typically associated with obesity, this finding is unexpected, as the body weight of the propolis-treated group appears lower than that of the control group [56]. The reason for this discrepancy remains unclear, but factors such as differences in experimental models, propolis dosage, or other underlying causes should be explored to better understand this variation.

Propolis increases the levels of Verrucomicrobiota and its genus Akkermansia [52], both of which are associated with improved glucose metabolism [57]. Interestingly, in another study, both levels are found to be decreased in the propolis-treated high-fat diet group, while they are undetectable in the control diet group [41]. This finding contradicts the results of the previous study. A low level of Tenericutes has been implicated in increased inflammation and impaired β-cell secretion [58], [59]. Propolis administration has been shown to decrease Tenericutes levels; however, the observed reduction in inflammation and improvement in glucose metabolism seem to contradict the earlier statement [55], suggesting a controversial relationship. Propolis treatment also increases the abundance of the Lachnospiraceae NK4A136 group, which is negatively correlated with serum triglyceride and total cholesterol levels. Increased Lachnospiraceae NK4A136 upregulates short-chain fatty acids production, which may help alleviate obesity in high-fat-diet-fed mice. Additionally, Desulfovibrio, a hydrogen sulfide–producing bacterium, which is observable in obese and diabetic patients, has been reduced in the propolis-treated group [41].

The propolis-treated group shows a reduction in Ruminococcus, a genus responsible for breaking down carbohydrates into glucose [60], and hence, its decrement may help reduce glucose formation and alleviate hyperglycemia [52]. Propolis also restores the reduced Lactobacillus level [33], [56], which plays a crucial role in glucose and lipid metabolism, thereby mitigating hyperglycemia and insulin resistance [61].

The hyperglycemic group exhibits a weakened intestinal mucosal barrier, allowing bacteria and toxin leakage into the bloodstream, further contributing to inflammation and diabetic complications. Propolis treatment helps restore the intestinal mucosal barrier, as evidenced by increased expression of tight junction proteins (claudin, occludin, and zonula occludens protein 1), improved tight and gap junctions in the intestinal epithelium, and reduced intercellular spaces. These effects contribute to a lowered blood glucose level and improved glucose tolerance in diabetic rats [56].

Propolis inhibits intestinal glucose digestion and absorption

The antidiabetic effect of propolis is further demonstrated by its ability to inhibit α-amylase and α-glucosidase, enzymes bound to the membrane of the small intestineʼs brush border. Carbohydrate digestion begins with alpha-amylase breaking down long-chain polysaccharides into short-chain oligosaccharides, followed by α-glucosidase that hydrolyzes disaccharides into monosaccharides like glucose, allowing for easy absorption by intestinal cells [62]. Propolis has been shown to exhibit comparable half-maximal inhibitory concentration to acarbose, a common antidiabetic drug, indicating its ability to slow down the catalytic activities of α-amylase and α-glucosidase during starch hydrolysis [16], [21], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76]. As a result, monosaccharide absorption is delayed, leading to a lower blood glucose level.

Propolis-derived compounds enhance insulin signaling pathway

CAPE enhances the phosphorylation of IRS1 (Tyr612) and Akt (Ser473) while reducing the phosphorylation of JNK and NF-κB in muscle tissue. This leads to a decrease in NF-κB nuclear translocation, preventing induction of pro-inflammatory factors [25].

Enhanced insulin receptor sensitivity, resulting from a modified conformation, is achieved through the binding of galangin and pinocembrin to the insulin receptor. The phenyl groups of both compounds establish hydrophobic interactions with the residues leucine-62, phenylalanine (Phe)-64, Phe-88, Valine-94, and Phe-96, as well as CH-π interactions with Phe-64, Phe-88, and Phe-96. Additionally, a cation-π interaction occurs between the arginine (Arg)-14 residue of the insulin receptor and the 4H-chromen-4-one scaffold of galangin or chroman-4-one scaffold of pinocembrin. Hydrogen bonding is observed between carbonyl oxygen of galangin and both Arg-14 and glutamine (Gln)-34 and between carbonyl oxygen of pinocembrin and Gln-34 [27].

Propolis/propolis-derived compounds mitigate oxidative stress and inflammation

Preserved pancreatic cell integrity

Oxidative stress plays a key role in the development of diabetes by damaging pancreatic cells and contributing to hyperglycemia. CAPE administration combats oxidative stress by upregulating the content of non-proteic thiol groups, which act as antioxidant by stabilizing free radicals. It also reduces the level of lipid hydroperoxide, a reactive oxygen species. Additionally, CAPE boosts the expressions of HO-1 antioxidant and gamma-Glutamyl-cysteine ligase, which is critical for glutathione synthesis [77].

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, causes nitric oxide synthase uncoupling, leading to the production of superoxide anion instead of nitric oxide (NO). This process reduces NO levels, resulting in endothelial dysfunction and increased oxidative stress [78]. CAPE administration lowers ADMA levels and increases the expression of dimethylarginine dimethylaminohydrolase-1, the enzyme responsible for breaking down ADMA, thereby restoring normal NO production and reducing oxidative damage. Additionally, CAPE treatment reduces the overexpression of inducible nitric oxide synthase, which is associated with inflammation and excessive NO production [79], as evidenced by normalized nitrite/nitrate levels in the CAPE-treated diabetic model [77]. Another study highlights the protective effects of propolis against oxidative stress by boosting the levels of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione-S-transferase, and glutathione reductase, while reducing ROS levels [16], [17].

Propolis treatment lowers the expression of pro-inflammatory markers like NF-κB (p65), TNF-α, and IL-1β while increasing the level of the anti-inflammatory cytokine IL-10 [16].

Alleviated hepatic oxidative stress and inflammation

Hepatic oxidative stress is alleviated by CAPE treatment, as evidenced by a reduction in ROS production [25]. CAPE enhances the phosphorylation of IRS1 (Tyr612), a key signaling protein for activating the downstream PI3K pathway, which in turn leads to the phosphorylation of Akt. CAPE treatment significantly increases phosphorylated Akt (Ser473) levels. Additionally, CAPE reduces the phosphorylation of JNK (Threonine (Thr) 183/Tyr185) and NF-κB p65 (Ser536), thereby inhibiting the nuclear translocation of NF-κB and the subsequent induction of pro-inflammatory cytokines. As a result, TNF-α expression is significantly lowered in the liver [25].

Reduced inflammation in adipose tissue

An elevated lipopolysaccharide (LPS) level in adipose tissue has been implicated in diabetes. Inhibited PPARγ activity and enhanced lipolysis by LPS treatment contributes to high fatty acid levels and dyslipidemia-associated insulin resistance. CAPE helps restore PPARγ and DGAT1 levels while reducing IL-6 (pro-inflammatory cytokine) expression [37]. CAPE has also been shown to reduce the expression of TNF-α, a pro-inflammatory cytokine, in the adipose tissue of a diabetic model. The reduction in TNF-α deactivates the JNK and NF-κB signaling pathways, as evidenced by decreased phosphorylation of JNK (Thr183/Tyr185) and NF-κB p65 (Ser536) in adipose tissue after CAPE treatment. By inhibiting NF-κB nuclear translocation, CAPE prevents the transcription of pro-inflammatory factors. This suppression of the JNK and NF-κB pathways enhances insulin signaling by increasing the phosphorylation of IRS-1 at Tyr612 and Akt at Ser473. As a result, insulin resistance is improved, and the blood glucose level is lowered [25].

Another study demonstrates that propolis administration reduces inflammation by lowering pro-inflammatory cytokines such as IL-6 and TNF-α. It also increases the expression of the C1q/tumor necrosis factor-related protein-9 gene, which promotes insulin sensitivity. Additionally, propolis upregulates IRS-1 and Sirt1, both of which are involved in insulin signaling and glucose metabolism. Furthermore, propolis lowers the expression of angiopoietin-like 4, an LPL inhibitor [80], which is linked to obesity-induced diabetes [26].

Propolis has been shown to induce the differentiation of myeloid-derived suppressor cells from M1 macrophages, playing a crucial role in immune modulation within adipose tissue. Notably, high-dose propolis upregulates the expressions of lymphocyte antigen 6 complex locus G and IL-10, key markers of myeloid-derived suppressor cells. This upregulation has been associated with an increased number of CD11b⁺ and Gr-1⁺ myeloid-derived suppressor cells and a reduction in CD11b⁺ and Gr-1^- macrophages, thereby alleviating adipose tissue inflammation [81].

Ameliorated renal damage

Propolis alleviates oxidative stress in kidneys, as indicated by lower malondialdehyde levels and enhanced activity of SOD and GPx and of the ferric-reducing ability of plasma [51].

Increased number of naïve T cells

Induction of pro-inflammatory cytokines by T cell activation drives inflammation and contributes to insulin resistance in metabolic organs [82]. Propolis has been shown to reduce the population of activated CD4⁺CD62 L T cells in a diabetic model [83]. Another study supports this, demonstrating that propolis increases the number of naïve CD8⁺CD62 L T cells [84]. This aligns with the finding that propolis administration results in a dominance of naïve T cells, suggesting that immune homeostasis is well-maintained, without activation of mature T cells upon migration from thymus to peripheral lymphoid tissues. Additionally, interferon-γ, a key immunomodulatory cytokine in T cell activation, is reduced in a diabetic model after propolis administration, leading to the downregulation of TNF-α expression [83], [84]. This reflects propolisʼs role in modulating the immune response and reducing inflammation in diabetes.

Conclusion and Future Perspective

In this paper, the hypoglycemic effects of propolis and propolis-derived compounds have been gathered and analyzed from the available literature. A range of mechanisms through which propolis targets various metabolic dysfunctions has been identified, primarily through enhancing insulin secretion, reducing hepatic glucose production, and inhibiting lipolysis. i) Propolis exerts protection against pancreatic β-cells, preserving insulin secretion. ii) Propolis effectively inhibits gluconeogenic enzyme activity, leading to reduced glucagon secretion. iii) Inhibited lipogenesis along with promoted β-oxidation and browning of adipocytes by propolis results in improved lipid metabolism and lowered blood glucose level. iv) Enhanced glucose uptake in skeletal muscles by propolis helps alleviate hyperglycemia. v) Propolis has been proven to alleviate glomerular damage, normalizing kidney function and mitigating the impact of renal damage on glucose metabolism. vi) Propolis helps restore the gut microbiota balance, improving glucose and lipid metabolism. vii) A postprandial blood glucose spike has been targeted by propolis via inhibition on α-amylase and α-glucosidase enzymes activity. viii) Propolis enhances insulin receptor sensitivity, promoting the insulin signaling pathway.

Throughout this review, oxidative stress and inflammation have frequently been discussed in relation to different organ systems, highlighting their roles in the development of diabetes. The hypoglycemic effect of propolis can largely be attributed to its diverse biological activities, particularly its strong antioxidant and anti-inflammatory properties, positioning propolis as a promising natural hypoglycemic agent. The antioxidant capacity of propolis, primarily due to its flavonoid content, helps alleviate oxidative stress. By reducing oxidative damage, particularly in the pancreas and other affected organs, propolis may offer protective effects that support insulin production and secretion. Simultaneously, the anti-inflammatory effect of propolis addresses chronic inflammation, another major contributor to the onset and complications of diabetes. This combination of antioxidant and anti-inflammatory actions enables propolis to target multiple underlying mechanisms involved in diabetes pathogenesis.

Despite these encouraging findings, several limitations must be addressed before propolis can be widely recommended as an adjunct therapy for diabetes management. One major challenge is the variability in propolis composition, as propolis from different regions contains distinct combination of bioactive compounds. Future research should prioritize standardizing propolis extracts to ensure consistency and reproducibility across studies. Additionally, more in-depth mechanistic studies are required to uncover the exact pathways through which propolis exerts its hypoglycemic effects, potentially leading to the identification of key bioactive compounds.

Overall, this review consolidates evidence on how propolis exerts its anti-diabetic effects and highlights its potential as a therapeutic agent for T2DM management. It identifies knowledge gaps and offers valuable insights into the translational potential of preclinical findings, guiding the design of future experiments and clinical trials on propolis for T2DM management. However, the findings in this review are based on qualitative interpretation, which may introduce bias or subjectivity in deriving conclusions. Future research incorporating meta-analysis and statistical synthesis could yield stronger quantitative conclusions, enhancing the reliability and generalizability of the findings.

Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Contributorsʼ Statement

Data collection: C. N. Wong, S-K. Lee, K. B. Liew, Y-L. Chew, A – L. Chua; design of the study: C. N. Wong, S-K. Lee, K. B. Liew, Y-L. Chew, A – L. Chua; analysis and interpretation of the data: C. N. Wong, S-K. Lee, K. B. Liew, Y-L. Chew, A – L. Chua; drafting the manuscript: C. N. Wong, S-K. Lee, K. B. Liew, Y-L. Chew, A – L. Chua, critical revision of the manuscript: C. N. Wong, S-K. Lee, K. B. Liew, Y-L. Chew, A – L. Chua; visualization: C. N. Wong, S-K. Lee. All data were generated in-house, and no paper mill was used. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 05 November 2024

Accepted after revision: 22 April 2025

Accepted Manuscript online:
28 April 2025

Article published online:
12 May 2025