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IntroductionType 2 diabetes mellitus (T2DM) is a heterogeneous disorder
characterized by a progressive decline in insulin action (insulin resistance [IR]) accompanied by the inability of β cells to compensate for IR (islet β cell dysfunction).
According to the latest Diabetes Atlas published by the International Diabetes Federation (IDF), in 2019, 463 million adults aged 20 to 79 years were living with diabetes globally (1 in 11 people), with 702 million
cases expected by 2045.
There is growing evidence that liver disease and gut flora may be strongly associated with
the development of metabolic diseases such as obesity, IR and T2DM.
Studies have shown that in addition to neutral lipids such as triglycerides (TG) or cholesterol lipids, other lipids, including diacylglycerol (DAG), ceramides, fatty acids, and their metabolites, have potential biological activity and may reach excessive levels
in the liver.
Therefore, their accumulation may interfere with the function of liver cells, especially their ability
to respond to changes in insulin levels.
In addition, studies have found that microbial targets may have the potential to reduce the incidence
of IR and common and cardiovascular diseases.
Due to the complex and diverse pathogenesis of T2DM, it has not been fully elucidated
.
Various interventions have been used to delay the progression
of T2DM.
Clinical drugs such as metformin, sulfonamides and the new drug thiazolidinedione (TZD) have therapeutic effects, but they also have some adverse side effects
on the body.
Most drugs are used only for single-channel therapy, not multi-target therapy
.
Therefore, there is a growing need to develop more effective anti-diabetic drugs
with fewer side effects.
As a natural product, more than 300 chemical components have been isolated and identified from propolis, including polyphenols, terpenes, quinones, esters, aldehydes, ketones and hydrocarbons, so it is called "natural purple gold"
.
In China, the main components of propolis are polyphenols, of which phenolic acids and flavonoids are the main functional components
.
Studies have shown that the flavonoids (such as sylin, kaempferol, quercetin and naringenin) and phenolic acids (such as caffeic acid, cinnamic acid, chlorogenic acid, phenethyl caffeate and atpilin C) in propolis have certain efficacy
on diabetes due to their antibacterial, anti-inflammatory and immunomodulatory functions.
A recent study showed that propolis not only lowered blood sugar in diabetic rats, but also repaired intestinal mucosal damage, favored intestinal flora, and improved short-chain fatty acid (SCFAs) levels
in diabetic rats.
Metabolomics is a discipline
that studies the variety, quantity and interrelationship of endogenous small molecule metabolites (molecular weight (mw)<1000 kDa) under the influence of internal and external factors such as disease invasion, drug intervention, and environmental changes.
At present, it has been widely used in the study of disease mechanisms, the discovery of biomarkers, the evaluation and prediction of clinical efficacy and other fields<b116>.
The objective of this study is to determine the fecal metabolic profiles of T2DM and normal mice based on the ultra-performance liquid chromatography-quadrupole - time-of-flight-mass spectrometry (UPLC-Q-TOF-MS) metabolomics strategy to screen for potential biomarkers of T2DM and to explore the effect
of propolis ethanol extract (EEP) on the pathogenesis of T2DM.
In conclusion, this study aims to further elucidate the pathogenesis of T2DM and provide new ideas
for the clinical application of EEP.
Results and DiscussionEEP Effects on body weight, blood glucose and serum insulin Effects of EEP on body weight, blood glucose and serum insulin Figure 1 shows that after EEP intervention, EEP slowed the decline of body mass in T2DM mice, was dose-dependent, and significantly reduced blood glucose levels (Figure 1A, B), a result that may be related to the potent compound caffeate phenethyl caffeate in EEP, but the exact mechanism needs further study
。 In addition, EEP improves insulin sensitivity, increases insulin levels in the body, and lowers HOMA-IR levels, which in turn regulates blood glucose homeostasis in the body (Figure 1C, D).
Fig.
1 Effects of EEP on (A) body weight, (B) blood glucose, (C) insulin and (D) insulin resistance in mice The effect of EEP on blood biochemical indexes was found in Figure 2, and it was found that after EEP intervention, lipid metabolism disorders could be improved, which may be related to
the abundance of phenolic substances in propolis.
In addition, studies on the active ingredients of propolis have shown that a large number of flavonoids and phenolics in propolis can directly scavenge free radicals and enhance the body's antioxidant capacity, thereby improving liver damage
.
The results of this study suggest that both doses of EEP intervention have varying degrees of restorative effect on liver function (Figure 2E, F), a result that may be related to
its antioxidant activity.
Fig.
2 Effects of EEP on mice (A)TC, (B)TG, (C) HDL-C, (D) LDL-C, (E) AST and (F)ALT The effect of EEP on liver injury in T2DM mice is described in Figures 3A-3D
.
Compared with liver tissue in the T2DM group, the hepatic lobular structure after EEP intervention was clearer, and only some hepatocytes had mild granular degeneration (black arrows) and no obvious inflammatory cell infiltration
.
Insulin resistance in patients with T2DM promotes the release of free fatty acids (FFAs) from adipose tissue, increases FFA in the liver, and promotes mitochondrial oxidative stress
.
Too much reactive oxygen species (ROS) induce inflammation and necrosis of liver cells, activating the liver to produce more collagen and connective tissue
.
Tissue growth factor accumulates in the extracellular matrix, which then develops into liver fibrosis and progresses to cirrhosis and hepatocellular carcinoma
.
The results of this study showed that EEP had a good recovery effect on liver tissue damage caused by T2DM, thereby reducing the occurrence
of chronic liver disease and its complications.
(A) Con group, (B) T2DM group, (C) EEP-L group, (D) EEP-H group
.
HE staining; ×400 Figure 3 Effect of EEP on liver injury in T2DM mice Metabolic profiling analysis used UPLC-Q-TOF-MS based metabolomics method to analyze the changes of metabolites in feces in four groups of mice, and multivariate statistical analysis combined with PCA and OPLS-DA to screen potential biomarkers
.
The PCA score plot (Figure 4A~C) shows the overall difference
between the groups.
To better distinguish between metabolites, the OPLS-DA model was established to maximize
the covariance between the data.
As shown in Figure 5A, C, and E, there was a significant separation between the EEP intervention groups (EEP-L group and EEP-H group) compared to the T2DM group, especially the difference between the T2DM group and the EEP-H group, and this result showed that propolis had a great effect
on fecal metabolites of T2DM 。 （A）Con vs.
T2DM； （B）T2DM vs.
EEP-L； (C) T2DM vs.
EEP-H Figure 4 Comparison of OPLS-DA in four groups of mouse fecal metabolic spectrum PCA score plot: (a) T2DM vs.
EEP-L; （B）T2DM vs.
EEP-L； （C）T2DM vs.
EEP-H； Displacement Test Chart: (D)Con vs.
T2DM； （E）T2DM vs.
EEP-L； T2DM vs.
EEP-H Figure 5 Comparison of OPLS-DA score and displacement test plot of fecal metabolic spectrum of four groups of mice LC-MS metabolic spectrum analysis and related pathway analysis obtained variable weight values (VIPs) according to the OPLS-DA model, and potential biomarkers were screened with VIP>1 and P<0.
05<b135>.
Twenty-seven potential biomarkers were screened, as shown in Table 1 and Figure 6, which are mainly involved in the metabolic pathways
of sterol lipids, fatty acids, glycerophospholipids, polyketones, prool lipids, glycerides, and sphingolipids.
After EEP intervention, compared with the T2DM group, 6 metabolites were significantly down-regulated, 12 metabolites were significantly up-regulated, and 9 metabolites were not significantly changed.
In the EEP-H group, 8 metabolites were significantly downregulated and 19 metabolites were significantly increased
.
EEP may effectively modulate T2DM-induced disruption of glycerides, sphingolipids, riboflavin, and steroid metabolic pathways by altering metabolic pathways of inflammation, oxidative stress, amino acids, and lipids (see text).
Table 1 Identification results of potential biomarkers Figure 6 Relative content of
27 metabolites in fecal samples Conclusion Propolis is a natural medicine with a wide range of biological activities and pharmacological effects, and has shown efficacy
in the treatment of T2DM 。 In this study, serum biochemistry, liver morphology, fecal metabolomics and other methods were used to detect the therapeutic effect and metabolic regulation
of EEP on HFD by STZ-induced T2DM mouse model.
The results clarify the potential mechanism of action of EEP in the treatment of T2DM, which provides a new direction
for the treatment of T2DM.
However, the study also had some limitations
.
The effect of propolis on T2DM was studied only from the perspective of overall metabolomics; The specific active ingredient in propolis that affects T2DM < b147 has not been identified>。 Based on this research, our research group will determine the active ingredients
in EEP that affect T2DM by analyzing the chemical composition of EEP.
Differential metabolites found in T2DM mice need to be validated
with samples from human patients.
First author
Wang Chunmei, female, preparatory member of the Communist Party of China, from Zhaotong, Yunnan Province, studied for a master's degree in animal husbandry at the College of Animal Science, Shanxi Agricultural University from 2018 to 2021, with the main research direction of biological functions
of bee products.
Participated in the "1331 Project" project of Shanxi Higher Education Revitalization Plan
.
He published a
paper in the domestic journal "Food Engineering".
Corresponding author
Jiang Yusuo, male, member of the Communist Party of China, born in October 1963, doctor, second-level professor, doctoral supervisor, from
Wanrong County, Shanxi Province.
He is currently the director of the Institute of Animal Production and a member of
the professors' committee.
He is also the executive director of the Chinese Beekeeping Society and the deputy director of the Bee Biology Professional Committee; President of
Shanxi Bee Association.
He has visited Japan twice for further study
.
He has presided over and completed 2 National Natural Science Foundation of China, 9 provincial and ministerial scientific research projects, won 1 second prize of Shanxi Science and Technology Progress Award, and 1 appraisal achievement award
.
He has published more than 80 papers in domestic and foreign academic journals such as Journal of Insect Science, Applied Entomology and Zoology, Chinese Agricultural Sciences, Journal of Entomology, and Journal of Zoology, including more than 20 papers indexed by SCI
.
Published 11 textbooks and books on apiology, including 3 chief editors and 5 deputy editors; Member of the editorial board of the Chinese agricultural encyclopedia "Bee Industry Volume" and the deputy editor
of the branch of "Bee Biology".
It has trained 8 doctoral students and 11 master's students, and currently has 4 doctoral students and 11 masters
.
He has won the second prize of "Shanxi Province College Young Teachers Teaching Basic Skills Competition", Shanxi Agricultural University "Three Education People" advanced individual and Shanxi Agricultural University "Excellent Teacher" and other honorary titles
.
In 2019 and 2020, he was a review expert
at the discipline review team meeting of the Department of Life Sciences, National Natural Science Foundation of China.
Chunmei Wanga, Huiting Zhaob, Kai Xuc, Yali Dud, Jinjia Liua, Jinfei Wanga, Yusuo Jianga
a College of Animal Science, Shanxi Agricultural University, Taigu 030801, China
b College of Life Sciences, Shanxi Agricultural University, Taigu 030801, China
c Jilin Province Institute of Apicultural Science, Jilin 132108, China
d College of Veterinary Medicine, Shanxi Agricultural University, Taigu 030801, China
*Corresponding author.
A large number of studies have shown that propolis has positive effects in the treatment of type 2 diabetes mellitus (T2DM).
However, there are have only been a few reports that are based on an ultra-high performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry (UPLC-Q-TOF-MS) analysis of the fecal metabolomics of ethanol extract of propolis (EEP) in the treatment of T2DM.
The present investigation was designed to screen potential biomarkers of T2DM by the metabonomic method and to explain the possible anti-diabetes mechanism of EEP according to the changes in the biomarkers.
The results showed that EEP improved the body weight (BW) of T2DM mice, lowered blood sugar levels, and significantly restored blood biochemical indicators related to T2DM, such as fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), aspartate transaminase (AST), and alanine aminotransferase (ALT).
Liver pathology showed that EEP reversed liver damage caused by T2DM.
Metabolomics data identified 27 potential biomarkers in fecal samples.
EEP effectively regulated the dysfunction in the metabolic pathways of glycerophospholipids, sphingolipids, riboflavins, and sterol lipids caused by T2DM.
In summary, our research results revealed positive effects of EEP in the treatment of T2DM and provided potential candidate markers for further research and in the clinical treatment of T2DM.
WANG C M, ZHAO H T, XU K, et al.
Fecal metabolomics reveals the positive effect of ethanol extract of propolis on T2DM mice[J].
Food Science and Human Wellness, 2023, 12(1): 161-172.
DOI:10.
1016/j.
fshw.
2022.
07.
034.
