Next Article in Journal
Therapeutic Effects of Live Lactobacillus plantarum GKD7 in a Rat Model of Knee Osteoarthritis
Previous Article in Journal
Validating Accuracy of an Internet-Based Application against USDA Computerized Nutrition Data System for Research on Essential Nutrients among Social-Ethnic Diets for the E-Health Era
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Nutrients
Volume 14
Issue 15
10.3390/nu14153169
nutrients-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Progress in Research on the Alleviation of Glucose Metabolism Disorders in Type 2 Diabetes Using Cyclocarya paliurus

by
Xue Wang
†,
Lu Tang
†,
Wenxin Ping
,
Qiaofen Su
,
Songying Ouyang
* and
Jingqian Su
*
Fujian Key Laboratory of Innate Immune Biology, Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation, Biomedical Research Center of South China, Key Laboratory of OptoElectronic Science and Technology for Medicine of the Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou 350117, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Nutrients 2022, 14(15), 3169; https://doi.org/10.3390/nu14153169
Submission received: 6 July 2022 / Revised: 26 July 2022 / Accepted: 28 July 2022 / Published: 31 July 2022
(This article belongs to the Section Nutrition and Diabetes)
Browse Figures
Versions Notes

Abstract

:
Globally, the incidence of diabetes is increasing annually, and China has the largest number of patients with diabetes. Patients with type 2 diabetes need lifelong medication, with severe cases requiring surgery. Diabetes treatment may cause complications, side-effects, and postoperative sequelae that could lead to adverse health problems and significant social and economic burdens; thus, more efficient hypoglycemic drugs have become a research hotspot. Glucose metabolism disorders can promote diabetes, a systemic metabolic disease that impairs the function of other organs, including the heart, liver, and kidneys. Cyclocarya paliurus leaves have gathered increasing interest among researchers because of their effectiveness in ameliorating glucose metabolism disorders. At present, various compounds have been isolated from C. paliurus, and the main active components include polysaccharides, triterpenes, flavonoids, and phenolic acids. C. paliurus mainly ameliorates glucose metabolism disorders by reducing glucose uptake, regulating blood lipid levels, regulating the insulin signaling pathway, reducing β-cell apoptosis, increasing insulin synthesis and secretion, regulating abundances of intestinal microorganisms, and exhibiting α-glucosidase inhibitor activity. In this paper, the mechanism of glucose metabolism regulation by C. paliurus was reviewed to provide a reference to prevent and treat diabetes, hyperlipidaemia, obesity, and other metabolic diseases.

1. Introduction

Type 2 diabetes mellitus (T2DM) is an expanding global health problem, with the number of affected individuals increasing over the past 35 years. In 2021, approximately 537 million people were found to be affected by diabetes globally, with a prevalence of 10.5%; the number of cases is expected to reach 783 million by 2045. Further, 6.7 million out of the 537 million patients died of diabetes and its complications, accounting for ~12.2% of the total global deaths due to all causes. The global health expenditure for diabetes was estimated to be USD 966 billion in 2021. Diabetes is not only a public health threat but also imposes a significant burden on the national economy [1]. Glucose metabolism disorders are characterized by chronic hyperglycaemia and are mainly caused by defects in insulin secretion, insulin action, or both [2]. These disorders can induce the onset of diabetes, and long-term hyperglycemia can induce the development of systemic metabolic disorders that impair the function of organs, including the heart, liver, and kidneys, leading to diabetes-associated complications [3]. A high-calorie diet increases the probability of developing T2DM, and diet is one of the foundations to treat and prevent diabetes [4]. Obesity leads to increased lipid storage in the adipose tissue, and when adipose tissue can no longer store lipids, free fatty acids (FFAs) are released through increased lipolysis. Increased FFA levels promote muscle and liver insulin resistance (IR), impair insulin secretion from pancreatic β cells, attenuate glucose uptake in skeletal muscle and liver cells, increase hepatic glucose production, and decrease hepatic glycogen synthesis, ultimately leading to chronic hyperglycaemia [5]. Long-term hyperglycemia and high concentrations of fatty acids are the major causes of pancreatic β-cell failure and death [6]. Therefore, reducing appetite, regulating blood lipid levels, relieving pathologic IR, and reducing islet β-cell apoptosis could be an effective way to treat T2DM glucose metabolism disorder.
Some components of natural plants with low toxicity effectively ameliorate glucose metabolism disorders. Cyclocarya paliurus is a plant of the dicotyledon class Jugaceae, which is unique to China. It is widely distributed in Anhui, Jiangsu, Zhejiang, Jiangxi, Fujian, Taiwan, Hubei, Hunan, Sichuan, Guizhou, Guangxi, Guangdong, and south-eastern Yunnan and often grows in mountainous and humid forests at an altitude of 500–2500 m [7]. It is named C. paliurus as the tree is shaped like a willow, and its fruits are green and shaped like copper coins. Since October 2013, the National Health and Family Planning Commission of the People’s Republic of China has approved the use of C. paliurus leaves as a new raw food material, which has increasingly become a research hotspot because of its effectiveness in treating glucose metabolism disorders. Wang et al. reviewed the positive regulation of C. paliurus extract on insulin resistance, inflammation, oxidative stress, intestinal microbiota, lipid metabolism, and the protection of islet cells in type 2 diabetes with different extraction methods [8]. In our previous study, we identified 46,292 haploid genes in C. paliurus leaves using whole-genome sequencing. Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes enrichment analysis showed that these genes are involved in polyketone biosynthesis, amino acid and nucleotide metabolism, and starch and sucrose metabolism [9]. C. paliurus contains various active ingredients, such as polysaccharides, triterpenes, flavonoids, and phenolic acids, present mainly in the leaves [10]. Our study revealed that the contents of polysaccharides, triterpenes, flavonoids, and phenolic acids in C. paliurus leaves differed in different months. Polysaccharides, triterpenes, and flavonoids were most abundant in October. In vitro studies have demonstrated that some C. paliurus phenolic acids, such as neochlorogenic acid and vanillic acid, exhibit α-amylase and potential hypoglycemic activities [11]. Its regulation of glucose metabolism has multiple components and targets and involves multiple channels.
This paper describes the current research status, summarizes the active components and action mechanism of C. paliurus in regulating glucose metabolism, and acts as a reference for resource development and the clinical application of C. paliurus.

2. Active Components of C. paliurus

2.1. C. paliurus Polysaccharide (CPP)

Polysaccharides are found in animals, plants, and the cell walls of microorganisms. They are safe and exhibit low toxicity when used as drugs. As an important part of our daily diet, polysaccharides are not directly digested by gastrointestinal enzymes [12]. They play a key role in maintaining human intestinal microbiota. Fermented polysaccharides produce important metabolites in the intestine, such as short-chain fatty acids (SCFAs) and succinic acid [13]. Increasing evidence has shown that polysaccharides are the main regulators of the function and composition of intestinal microbiota. Supplementing natural polysaccharides can effectively target metabolic disorders induced by a high-fat diet (HFD) by acting on the intestinal microbiota [14]. CPP, a natural macromolecule with various biological activities, is considered to be a highly effective component. As shown in Figure 1, CPP is a new pectin-like polysaccharide with high water solubility and high branching, composed of eight monosaccharides: galacturonic acid, glucose, galactose, arabinose, mannose, xylose, rhamnose, and glucuronic acid [15]. As shown in Table 1, in vivo experiments have shown that CPP can alleviate the symptoms of T2DM and ameliorate glucose and lipid metabolism disorders in T2DM rats by regulating intestinal microbiota and SCFA levels [8,16,17,18,19].

2.2. C. paliurus Flavonoids

Flavonoids are considered to be a class of biologically active plant secondary metabolites that have antiviral, anti-allergic, antibacterial, and anti-inflammatory functions [27]. Flavonoids are composed of 15 carbon skeletons and two aromatic rings (A and B), which are connected by a three-carbon chain [28]. Several studies have shown that flavonoids exert various positive effects on metabolic disorders. The regulatory functions of flavonoids in promoting carbohydrate digestion, insulin signal transduction, insulin secretion, glucose uptake, and fat deposition facilitate the potential anti-T2DM activity [29]. As described in Table 2, previous studies have shown that C. paliurus flavonoids ameliorate liver lipid deposition in rats [30], regulate intestinal microorganisms in obese mice [31], reduce blood glucose levels [32], and act as antioxidants [33].

2.3. C. paliurus Triterpenes

Triterpenes are mainly found on plant surfaces [42]. Pentacyclic triterpenoids and their derivatives inhibit α-glucosidase, α-amylase, and pancreatic lipase activity, regulating blood glucose levels and reducing insulin resistance. They have become one of the most widely studied anti-diabetic compounds [43]. The total triterpenoid content of C. paliurus has also been shown to ameliorate glucose and lipid metabolism disorders [20]. A total of 137 triterpenoids are found in C. paliurus leaves [10], as described in Table 2, many of which promote glucose uptake [21,44,45] and improve lipid metabolism [46,47].

2.4. C. paliurus Phenolic Acids

Phenolic acids are widely found in fruits, vegetables, grains, beans, wine, and dairy foods, which have been shown to increase glucose intake and glycogen synthesis and ameliorate glucose and lipid metabolism disorders in obesity, cardiovascular disease, and diabetes and its complications [48]. As described in Table 2, C. paliurus phenolic acids also have a certain antioxidant activity shown by both in vivo and in vitro studies [49].

3. Mechanism of Regulating Glucose Metabolism

3.1. Reduction of Glucose Intake

Excessive nutritional intake is closely associated with insulin resistance [50], which can cause a series of pathological reactions, including hyperinsulinemia, β-cell apoptosis, and oxidative stress, finally leading to T2DM. The hypothalamus is the main center in the brain that regulates appetite and plays an essential role in regulating energy intake [51]. The hypothalamic insulin signaling pathway is also involved in the regulation of appetite [52]. The hypothalamic expression levels of proopiomelanocortin (POMC) and neuropeptide Y (NPY) are closely associated with the control of food intake. The upregulation of POMC reduces appetite, as does the downregulation of NPY [53]. The phosphoinositide 3-kinase (PI3K)-dependent activation of protein kinase B (Akt) can inhibit the activity of Forkhead box 1 (FOXO1) [54], which stimulates NPY transcription and inhibits POMC transcription [55].
As shown in Figure 2, C. paliurus flavonoids have been demonstrated to reduce food intake, body weight, serum insulin level, and insulin resistance in SHR/CP rats. this may be due to the increased phosphorylation of the insulin receptor (INSR)/insulin receptor substrate-1 (IRS1)/PI3K/Akt/FOXO1 pathway, thereby stimulating the hypothalamic insulin signal, which, in turn, regulates appetite and reduces food intake by regulating the expression of NPY and POMC [24].

3.2. Blood Lipid Level Reduction

Obesity induces increased lipid storage in adipose tissues. When the adipose tissues no longer have the capacity to store lipids, FFAs are released through increased lipolysis. Once the FFAs enter the blood, they are deposited on the lining of blood vessels, leading to increased blood lipid levels. Increased FFA levels promote muscle and liver IR [5]. Long-term hyperglycaemia and high FFA levels are major causes of pancreatic β-cell failure and death [6]; thus, regulating blood lipid levels is of great significance in glucose metabolism.

3.2.1. Inhibition of Fatty Acid Synthesis or Lipogenesis

Tumor necrosis factor-α (TNF-α) stimulates hepatic lipid deposition by enhancing the expression of the sterol regulatory element-binding protein 1c (SREBP-1c) gene [56]. SREBP-1c plays an important role in hepatic lipogenesis by regulating the expression of its downstream genes, such as fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC-1) [57]. Lin et al. induced hepatic steatosis in Sprague–Dawley rats by feeding them an HFD. They found that C. paliurus triterpenoids decreased mRNA expression levels; blood lipid levels; TNF-α, SREBP1, ACC1, and FAS protein levels in the HFD-fed Sprague–Dawley rats. Moreover, hepatic fat deposition improved, and hepatic fat content reduced (Figure 3) [23].

3.2.2. Inhibition of Exogenous Lipid Uptake

Apolipoprotein B48 (apoB48) is a component protein of chylomicrons and participates in dietary lipid absorption [58]. ApoB48 promotes the absorption of exogenous lipids in the intestine, and, thus, apoB48 overexpression may lead to hyperlipidaemia [59]. TNF-α, a major pro-inflammatory cytokine, also plays a key role in lipid metabolism, especially lipid absorption [60]. TNF-α stimulates the activation of the p38 mitogen-activated protein kinase (MAPK) pathway and promotes the production of lipoproteins that contain the apoB48 protein in the intestine [61]. Ethanolic extracts and triterpenes from C. paliurus inhibit TNF-α-induced MAPK phosphorylation and apoB48 production and reduce the levels of triacylglycerol (TG), total cholesterol (TC), high-density lipoprotein-C (HDL-C), and low-density lipoprotein-C (LDL-C) in the blood, thereby conferring an anti-hyperlipidemic effect (Figure 4) [22,62].

3.3. Regulation of the Insulin Signaling Pathway

The insulin signaling pathway can be roughly summarized as follows: insulin binds to the INSR and activates the IRS by increasing its tyrosine residue phosphorylation. The IRS then regulates PI3K/Akt phosphorylation, which, in turn, regulates blood glucose. A defect in the pathway can produce pathologic IR [63]. IR is a systemic metabolic disorder characterized by hypoinsulinemia in the skeletal muscle, liver, and adipocytes [64]. IR and the consequent hyperinsulinemia lead to increased pancreatic β-cell apoptosis and decreased β-cell mass [65]. Obesity-related IR is closely associated with overnutrition, which overdrives the processes of nutrient utilization (endoplasmic reticulum (ER) stress and oxidative stress) or cytotoxic response (inflammation) mediated by nutritional stress [48]. Based on current research, various active components in C. paliurus improve insulin signal transduction in multiple tissues and cells, such as muscle tissue, adipocytes, and liver cells. As shown in Figure 5, Fang et al. found that C. paliurus triterpenoids enhance the phosphorylation of key proteins (IRS-1, Akt, and glycogen synthase kinase β (GSK-3β)) in the insulin signaling pathway and that insulin stimulates glucose uptake in fully differentiated 3T3-L1 adipocytes [21]. C. paliurus flavonoids activate insulin signaling in an insulin-independent manner (IRS1-PI3K-Akt-AS160 (Tbc1d family Rab GTPase activator)), which brings about increased glucose uptake by inducing the translocation of glucose transporter 4 (GLUT4) in C2C12 cells. The plasma glucose levels of streptozocin (STZ)-induced hyperglycemic mice were moderately reduced 1 h after a single administration of C. paliurus flavonoids, with increased AS160 and Akt phosphorylation in skeletal muscles (Figure 5) [66].
Zheng et al. found that C. paliurus triterpenoids remarkably reduced the levels of serum and liver TG and TC in C57BL/6J mice that were fed an HFD. Furthermore, they significantly reduced blood glucose and insulin levels, reduced the IR index (HOMA-IR), increased the tyrosine residue phosphorylation level of IRS and 2-deoxyglucose (2DG) uptake in palmitic acid-induced HepG2 cells and primary hepatocyte fatty liver models, and reduced the number of lipid droplets and intracellular TG content. A mechanistic study showed that C. paliurus triterpenoids increased the phosphorylation of PI3K, Akt, and GSK-3β (Figure 3) [20].

3.4. Reduction of β-Cell Islet Apoptosis

Studies have shown that both high glucose levels and high concentrations of FFAs induce a stress response in pancreatic β cells, including ER stress and mitochondrial dysfunction caused by oxidative stress secondary to excessive reactive oxygen species (ROS) production and inflammation. Crosstalk between these pathways may induce a feed-forward mechanism and aggravate toxic glycolipid stress, which could eventually lead to β-cell dysfunction, apoptosis, and possible dedifferentiation [67].
β cells are predisposed to ER stress because of the high demands on the ER incurred by insulin synthesis, especially during IR, which requires large amounts of insulin to be produced. This leads to an increased expression of ER stress markers and β-cell ER expansion in patients with T2DM. The ER plays a critical role in lipid biosynthesis, Ca2+ storage, and synthesis and folding of secreted proteins. The accumulation of unfolded or misfolded proteins in the ER results in ER stress, which activates the unfolded protein response [68].
This set of intracellular signaling pathways is initiated by three ER stress sensors and transducers, specifically, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor-6 (ATF6), and inositol requiring enzyme-1 (IRE1). The purpose of signal transduction is to restore ER homeostasis by deadening overall protein translation, upregulating ER folding capacity, and reducing misfolded proteins [68,69]. The apoptosis will be triggered if the goal is not achieved [70].
β cells are also highly sensitive to oxidative stress. ROS, which act as important signaling messengers, are generated in these cells during glucose metabolism to trigger insulin secretion and β-cell expansion in response to elevated glucose levels. However, prolonged exposure to ROS under hyperglycemic conditions results in cellular damage, impaired glucose-stimulated insulin secretion, and ultimately, β-cell death [71]. The ROS produced by β cells in response to metabolic stress affect mitochondrial structure and function. Specifically, ROS oxidize mitochondrial membrane phospholipids such as cardiolipin and impair membrane integrity, which results in the release of cytochrome c, thereby triggering apoptosis [70]. In a study that combined STZ with HFD-induced diabetic mice and high-sugar-fed and HFD-fed mice, treatment with C. paliurus triterpenoids significantly reduced the serum malondialdehyde content (MDA), reduced oxidative stress, and enhanced the activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). In the STZ-induced NIT-1 cell injury model, C. paliurus triterpenoids significantly reduced ROS production and cell apoptosis, promoted cell proliferation, and alleviated STZ-induced damage to NIT-1 cells [72].
Akt kinases and kinases in the MAPK superfamily play important roles in regulating pancreatic β-cell apoptosis [6]. Activation of the PI3K/AKT pathway upregulates the expression of the Bax/Bcl-2 complex [73], while activation of the MAPK pathway downregulates the expression of the same complex [74], and apoptosis can be invited by intrinsic or extrinsic pathways. The intrinsic pathway activates internal signals through Bax, Bcl-2, cytochrome c, and caspase-9. The Bax protein also has an inhibitory effect on Bcl-2, an antiapoptotic protein. Endogenous apoptosis occurs when the Bax protein is stimulated to move to and from an opening in the outer membrane. Cytochrome c migrates from the mitochondrial membrane into the cytoplasm to trigger the formation of apoptotic bodies, which activates caspase-9 and ultimately promotes cell death; the activation of caspase-8 in the exogenous pathway leads to apoptosis [75]. Xiao et al. found that the aqueous extract of C. paliurus increased the number of pancreatic β cells by decreasing β-cell apoptosis in mice in which diabetes was induced by feeding an HFD combined with STZ treatment. Using STZ to induce NIT-1 cells to establish an in vitro apoptosis model of pancreatic β cells, they found that the aqueous extract of C. paliurus inhibits NIT-1-cell apoptosis. Studies have shown that the aqueous extract of C. paliurus downregulates the phosphorylation of p38, ERK, and c-Jun N-terminal kinase (JNK). It can also upregulate Akt phosphorylation; inhibit the expression of caspase-8, caspase-9, and cleaved caspase-3; decrease the Bax/Bcl-2 ratio, all of which significantly inhibit pancreatic β-cell apoptosis (Figure 6) [25].
The abovementioned stress pathways interact with each other. Glucose metabolism produces excess ROS in a high-glucose environment, which induces Ca2+ consumption in the ER, bringing about ER stress [76]. ER stress induces the expression of pro-inflammatory genes by activating transcription factors such as NF-κB and JNK [77]. Mild ER stress sensitizes β cells to the IL-1β and TNF-α cytokines, which amplify the inflammatory response [78]. At present, only a few studies have reported the inhibition of β-cell apoptosis by C. paliurus through the above stress pathways.

3.5. Promotion of Synthesis and Secretion of Insulin

Insulin release from pancreatic β cells is a highly coordinated process involving insulin gene transcription, proinsulin biosynthesis, and insulin secretion. As the major insulin secretagogue, glucose actively regulates the insulin release to ensure adequate intracellular stores and fulfill the secretion demands [79,80,81]. Lipotoxicity and glucolipotoxicity have been exhibited to alter several key functions of insulin secretion. High glucose and FFA palmitate levels stimulate ceramide production [3,4] and activate the stress kinases JNK [82], extracellular regulated protein kinases (ERK1/2), and PAS domain-containing serine/threonine kinase (PASK) [83], partly through the activity of the transcription factor peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and CCAAT enhancer-binding proteins (C-EBPβ) (Figure 6). These proteins inhibit the binding of the transcriptional regulators musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), insulin promoting factor-1 (PDX-1), and neurogenic differentiation (NeuroD) to the insulin promoter [84,85], which ultimately brings about decreased insulin transcription levels. Glucose triggers insulin secretion by producing numerous coupling factors, including changes in the adenosine triphosphate (ATP)/adenosine triphosphate (ADP) ratio, closure of the ATP-sensitive potassium channels, and depolarization of cell membranes. Calcium influx stimulates insulin exocytosis, and insulin secretion is affected, to varying degrees, by exposure to chronic FFA environments [70].
A few studies have reported the induction of insulin synthesis and secretion by C. paliurus extract. Feng et al. found that the flavonoids in C. paliurus enhances insulin secretion stimulated by glucose in normal MIN6 cells [86]; nevertheless, the specific mechanism has not yet been elucidated.

3.6. Regulation of Intestinal Microorganisms

The 16S rRNA high-throughput sequencing technology and bioinformatic analysis has developed by leaps and bounds, and scientists have realized that the intestinal microbiota is essential to human health. Recent studies have found that imbalances in the composition of intestinal microbiota are critical for metabolic diseases [87] and that the intestinal microbiota plays a critical role in metabolic diseases, notably those combined with low-grade chronic inflammation [88].
The intestinal microbiota both affects the digestion and absorption of food and energy supply and regulates the physiology of the host and development of diseases. The physiological metabolism of the body is regulated by genes and intestinal microbiota [89]. Daily diet can influence host susceptibility to most chronic diseases by altering intestinal microbiota composition, metabolites, and metabolic functions [90]. As shown in Figure 4, Wu et al. found that CPPs increased the number of SCFAs (acetic acid, propionic acid, butyric acid, and valeric acid) in the feces of healthy mice in a dose-dependent manner. Sequencing of 16S rRNA showed that the administration of 200 mg/kg of CPPs effectively increased intestinal microbiota diversity in healthy mice as well as affected the relative abundance of Spirillum and Clostridium sp., enhancing the metabolic function of the intestinal microbiota [18]. Obesity and metabolic syndrome are associated with a decrease in the abundance of Clostridium. The presence of Clostridium brings about reduced lipid absorption and body emaciation by downregulating expression of CD36, a receptor that mediates the binding and uptake of long-chain fatty acids [91]. Meehan et al. found that Lachnospiraceae, a member of the order Clostridiales, can protect against obesity and colon cancer in humans by producing butyrate [92]. Yao et al. found that CPPs can alleviate the symptoms of T2DM by increasing the abundance of SCFA-producing bacteria, promoting SCFA production, and increasing the production of SCFA-GLP1/PYY-related sensory mediators in STZ- and HFD-induced diabetic rats [17]. Li et al. found that the intragastric administration of CPPs increased the abundance of Ruminococcus UCG-005, a beneficial bacterium, in STZ- and HFD-fed diabetic rats, increase the level of serum GLP1 and the content of intestinal SCFAs, and reduce the blood glucose, serum insulin and Bax/Bcl-2 ratio of rats. UCG-005 is the key bacterium that prevents the onset of diabetes by promoting fecal SCFA production. The analysis of urine metabolites showed that CPP treatment helped protect against diabetes by significantly enhancing the activity of several pathways closely associated with nutritional (amino acid and purine) and energy metabolism (tricarboxylic acid cycle) [16].

3.7. Inhibition of α-Glucosidase Activity

α-Glucosidase is a glycoside hydrolase that is responsible for hydrolyzing disaccharides. It is essential for absorbing starch, dextrin, and disaccharides. Inhibition of α-glucosidase causes malabsorption and slower carbohydrate absorption, which attenuates the increase in postprandial blood glucose levels. α-Glucosidase inhibitors may also increase the release of glucagon-like peptide-1 (GLP-1), contributing to the hypoglycemic effect. α-Glucosidase inhibitors effectively improve glycemic control in T2DM [93]. Li et al. extracted more than 20 triterpenoids from the aqueous extract of C. paliurus, of which cyclocarioside Z9 and cyclocarioside Z10 strongly inhibited the α-glucosidase activity with IC50 values of 257.74 μM and 282.23 μM, respectively. The IC50 value of acarbose, a positive control drug, was 359.36 μM [46]. Ning et al. found that the aqueous extract of C. paliurus had a significant α-glucosidase inhibitory activity, with an IC50 value of 31.5 ± 1.05 μg/mL, which was much lower than that of the positive control acarbose (IC50 = 296.6 ± 1.06 μg/mL). Ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry and an in vitro α-glucosidase inhibition test were used to identify and confirm that kaempferol-3-o-rhamnoside, quercetin, kaempferol, asiatic acid, and genistein were the main components that inhibited α-glucosidase activity in the C. paliurus extract. In vitro experiments also confirmed that these α-glucosidase inhibitors reduce postprandial hyperglycaemia in C57BL/6J mice (Figure 4) [26].

4. Conclusions

C. paliurus is a healthy food resource that is unique to China. It has a significant hypoglycemic effect, high economic value, and great development and application potential. The causes of diabetes are complex, and a single preventive and treatment approach has limited effects and does not provide an effective therapeutic outcome. The main functional components of C. paliurus involved in glucose metabolism regulation are polysaccharides, triterpenes, and flavonoids, which can be used to treat glucose metabolism disorder in diabetes by reducing glucose uptake, regulating blood lipids, regulating insulin signaling pathways, and reducing β-cell apoptosis. Furthermore, these components increase insulin synthesis and secretion, regulate the abundance of intestinal microorganisms, and inhibit α-glucosidase activity.
C. paliurus is widely distributed, and the main components vary greatly with the areas of production, solvent polarity, or extraction methods. As a new raw food material, the composition and content of its active components need to be further elucidated. However, C. paliurus components are complex and diverse, and the regulation of glucose metabolism involves multiple targets and channels. Moreover, most of the mechanistic studies in this review were conducted using extracts, while few studies were conducted on monomeric components. Therefore, animal experiments or clinical verification is in urgent need to explore the specific molecular mechanisms of the C. paliurus components. In addition, although many animal experiments have shown that the C. paliurus extract ameliorates effects of glucose metabolism disorders, there is a lack of clinical trial data to support the findings.
Further studies are recommended on the following aspects. First, the number of population samples for food test research should be increased to the maximum to guide the development and utilization of C. paliurus as a functional food. Second, using advanced technologies such as transcriptomics and metabolomics, the specific mechanism of C. paliurus in regulating glucose and lipid metabolism should be further explored. Lastly, the material basis of the function of C. paliurus should be studied in detail to develop products with a controllable and standardized composition and content, to determine the optimal dose for biological activity.
In this review, the mechanism of action of the C. paliurus extract in treating glucose metabolism disorders in diabetes was reviewed. With more in-depth studies on the chemical constituents of C. paliurus, new pharmacological effects will be discovered. With the aid of developments in science and technology, we will further study the complete mechanistic network of C. paliurus in diabetes treatment with attention to the relationship between its efficacy and side effects.

Author Contributions

Conceptualization and design, J.S. and S.O.; analysis of the data and writing of the manuscript, J.S., X.W., L.T., W.P. and Q.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 31770948, 31570875, and 81803547), the Natural Science Foundation of Fujian Province, China (Grant No. 2021J01204), the Fujian Provincial Regional Development Project (2021N3005), and the Special Sci-tech Team Commissioner of Fujian province (T202005007; T202005013).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Acknowledgments

We would like to thank Qi Chen who provided suggestions regarding the manuscript.

Conflicts of Interest

The authors have declared no conflict of interest.

Abbreviations

2-DG: 2-deoxyglucose; ACC-1, acetyl-CoA carboxylase 1; ATF6, activating transcription factor-6; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BW, body weight; CAT, catalase; ERK, extracellular regulated protein kinases; FAS, fatty acid synthase; FBG, fasting blood glucose; FFA, free fatty acids; GSH-Px, glutathione peroxidase; HDL-C, high-density lipoprotein-C; HFD, high-fat diet; HOMA-IR, IRE1, inositol requiring enzyme-1; insulin resistance index; INSR, insulin receptor; IR, insulin resistance; IRS1, insulin receptor substrate-1; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein-C; MDA, malondialdehyde; NeuroD, neurogenic differentiation; NPY, neuropeptide Y; OGTT, oral glucose tolerance test; PASK, PAS domain-containing serine/threonine kinase; PBC, pancreatic β cells; POMC, proopiomelanocortin; PERK, protein kinase RNA-like endoplasmic reticulum kinase; ROS, reactive oxygen species; SCFAs, short-chain fatty acids; SD, Sprague–Dawley; SREBP-1c, sterol regulatory element-binding protein 1c gene; SOD, superoxide dismutase; STZ, streptozocin; TC, total cholesterol; TG, triacylglycerol.

References

  1. International Diabetes Federation. IDF Diabetes Atlas, 10th ed.; International Diabetes Federation: Brussels, Belgium, 2021. [Google Scholar]
  2. Poznyak, A.; Grechko, A.V.; Poggio, P.; Myasoedova, V.A.; Alfieri, V.; Orekhov, A.N. The Diabetes mellitus-atherosclerosis connection: The role of lipid and glucose metabolism and chronic inflammation. Int. J. Mol. Sci. 2020, 21, 1835. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Du, H.; Zhao, Y.; Yin, Z.; Wang, D.W.; Chen, C. The role of miR-320 in glucose and lipid metabolism disorder-associated diseases. Int. J. Biol. Sci. 2021, 17, 402–416. [Google Scholar] [CrossRef] [PubMed]
  4. Mozaffarian, D. Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: A comprehensive review. Circulation 2016, 133, 187–225. [Google Scholar] [CrossRef]
  5. Veit, M.; van Asten, R.; Olie, A.; Prinz, P. The role of dietary sugars, overweight, and obesity in type 2 diabetes mellitus: A narrative review. Eur. J. Clin. Nutr. 2022. [Google Scholar] [CrossRef]
  6. Šrámek, J.; Němcová-Fürstová, V.; Kovář, J. Kinase signaling in apoptosis induced by saturated fatty acids in pancreatic β-cells. Int. J. Mol. Sci. 2016, 17, 1400. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Chinese Academy of Sciences. Flora of China; Science Press: Beijing, China, 1979; pp. 18–19. [Google Scholar]
  8. Wang, H.; Tang, C.; Gao, Z.; Huang, Y.; Zhang, B.; Wei, J.; Zhao, L.; Tong, X. Potential role of natural plant medicine Cyclocarya paliurus in the treatment of type 2 diabetes mellitus. J. Diabetes Res. 2021, 2021, 1655336. [Google Scholar] [CrossRef] [PubMed]
  9. Zheng, X.; Xiao, H.; Su, J.; Chen, D.; Chen, J.; Chen, B.; He, W.; Chen, Y.; Zhu, J.; Fu, Y.; et al. Insights into the evolution and hypoglycemic metabolite biosynthesis of autotetraploid Cyclocarya paliurus by combining genomic, transcriptomic and metabolomic analyses. Ind. Crops Prod. 2021, 173, 114154. [Google Scholar] [CrossRef]
  10. Chen, Z.; Jian, Y.; Wu, Q.; Wu, J.; Sheng, W.; Jiang, S.; Shehla, N.; Aman, S.; Wang, W. Cyclocarya paliurus (Batalin) Iljinskaja: Botany, Ethnopharmacology, phytochemistry and pharmacology. J. Ethnopharmacol. 2022, 285, 114912. [Google Scholar] [CrossRef]
  11. Zheng, X.; Xiao, H.; Chen, J.; Zhu, J.; Fu, Y.; Ouyang, S.; Chen, Y.; Chen, D.; Su, J.; Xue, T. Metabolome and whole-transcriptome analyses reveal the molecular mechanisms underlying hypoglycemic nutrient metabolites biosynthesis in Cyclocarya paliurus leaves during different harvest stages. Front. Nutr. 2022, 9, 851569. [Google Scholar] [CrossRef]
  12. Shang, Q.; Jiang, H.; Cai, C.; Hao, J.; Li, G.; Yu, G. Gut microbiota fermentation of marine polysaccharides and its effects on intestinal ecology: An overview. Carbohydr. Polym. 2018, 179, 173–185. [Google Scholar] [CrossRef]
  13. Canfora, E.E.; Meex, R.C.R.; Venema, K.; Blaak, E.E. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat. Rev. Endocrinol. 2019, 15, 261–273. [Google Scholar] [CrossRef]
  14. Li, F.; Li, Q.; Zhang, Y.; Zhou, X.; Yi, R.; Zhao, X. Effects of Xylooligosaccharides on lipid metabolism, inflammation, and gut microbiota in C57BL/6J mice fed a high-fat diet. Front. Pharmacol. 2021, 12, 791614. [Google Scholar] [CrossRef] [PubMed]
  15. Wang, X.; Zhao, X.; Lv, Y.; Hu, M.; Fan, L.; Li, Q.; Cai, C.; Li, G.; Yu, G. Extraction, isolation and structural characterization of a novel polysaccharide from Cyclocarya paliurus. Int. J. Biol. Macromol. 2019, 132, 864–870. [Google Scholar] [CrossRef]
  16. Li, Q.; Hu, J.; Nie, Q.; Chang, X.; Fang, Q.; Xie, J.; Li, H.; Nie, S. Hypoglycemic mechanism of polysaccharide from Cyclocarya paliurus leaves in type 2 diabetic rats by gut microbiota and host metabolism alteration. Sci. China Life Sci. 2021, 64, 117–132. [Google Scholar] [CrossRef] [PubMed]
  17. Yao, Y.; Yan, L.; Chen, H.; Wu, N.; Wang, W.; Wang, D. Cyclocarya paliurus polysaccharides alleviate type 2 diabetic symptoms by modulating gut microbiota and short-chain fatty acids. Phytomedicine 2020, 77, 153268. [Google Scholar] [CrossRef] [PubMed]
  18. Wu, T.; Shen, M.; Yu, Q.; Chen, Y.; Chen, X.; Yang, J.; Huang, L.; Guo, X.; Xie, J. Cyclocarya paliurus polysaccharide improves metabolic function of gut microbiota by regulating short-chain fatty acids and gut microbiota composition. Food Res. Int. 2021, 141, 110119. [Google Scholar] [CrossRef] [PubMed]
  19. Wu, T.; Shen, M.; Guo, X.; Huang, L.; Yang, J.; Yu, Q.; Chen, Y.; Xie, J. Cyclocarya paliurus polysaccharide alleviates liver inflammation in mice via beneficial regulation of gut microbiota and TLR4/MAPK signaling pathways. Int. J. Biol. Macromol. 2020, 160, 164–174. [Google Scholar] [CrossRef]
  20. Zheng, X.; Zhao, M.G.; Jiang, C.H.; Sheng, X.P.; Yang, H.M.; Liu, Y.; Yao, X.M.; Zhang, J.; Yin, Z.Q. Triterpenic acids-enriched fraction from Cyclocarya paliurus attenuates insulin resistance and hepatic steatosis via PI3K/Akt/GSK3β pathway. Phytomedicine 2020, 66, 153130. [Google Scholar] [CrossRef]
  21. Fang, Z.J.; Shen, S.N.; Wang, J.M.; Wu, Y.J.; Zhou, C.X.; Mo, J.X.; Lin, L.G.; Gan, L.S. Triterpenoids from Cyclocarya paliurus that enhance glucose uptake in 3T3-L1 adipocytes. Molecules 2019, 24, 187. [Google Scholar] [CrossRef] [Green Version]
  22. Wu, Z.; Gao, T.; Zhong, R.; Lin, Z.; Jiang, C.; Ouyang, S.; Zhao, M.; Che, C.; Zhang, J.; Yin, Z. Antihyperlipidaemic effect of triterpenic acid-enriched fraction from Cyclocarya paliurus leaves in hyperlipidaemic rats. Pharm. Biol. 2017, 55, 712–721. [Google Scholar] [CrossRef] [Green Version]
  23. Lin, Z.; Wu, Z.F.; Jiang, C.H.; Zhang, Q.W.; Ouyang, S.; Che, C.T.; Zhang, J.; Yin, Z.Q. The chloroform extract of Cyclocarya paliurus attenuates high-fat diet induced non-alcoholic hepatic steatosis in Sprague Dawley rats. Phytomedicine 2016, 23, 1475–1483. [Google Scholar] [CrossRef] [PubMed]
  24. Xu, G.; Yoshitomi, H.; Sun, W.; Guo, X.; Wu, L.; Guo, X.; Qin, L.; Fan, Y.; Xu, T.; Liu, T.; et al. Cyclocarya paliurus (Batal.) Ijinskaja aqueous extract (CPAE) ameliorates obesity by improving insulin signaling in the hypothalamus of a metabolic syndrome rat model. Evid.-Based Complement. Altern. Med. 2017, 2017, 4602153. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Xiao, H.T.; Wen, B.; Ning, Z.W.; Zhai, L.X.; Liao, C.H.; Lin, C.Y.; Mu, H.X.; Bian, Z.X. Cyclocarya paliurus tea leaves enhances pancreatic β cell preservation through inhibition of apoptosis. Sci. Rep. 2017, 7, 9155. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Ning, Z.W.; Zhai, L.X.; Huang, T.; Peng, J.; Hu, D.; Xiao, H.T.; Wen, B.; Lin, C.Y.; Zhao, L.; Bian, Z.X. Identification of α-glucosidase inhibitors from Cyclocarya paliurus tea leaves using UF-UPLC-Q/TOF-MS/MS and molecular docking. Food Funct. 2019, 10, 1893–1902. [Google Scholar] [CrossRef]
  27. Abotaleb, M.; Samuel, S.M.; Varghese, E.; Varghese, S.; Kubatka, P.; Liskova, A.; Büsselberg, D. Flavonoids in cancer and apoptosis. Cancers 2018, 11, 28. [Google Scholar] [CrossRef] [Green Version]
  28. Maleki, S.J.; Crespo, J.F.; Cabanillas, B. Anti-inflammatory effects of flavonoids. Food Chem. 2019, 299, 125124. [Google Scholar] [CrossRef] [PubMed]
  29. Vinayagam, R.; Xu, B. Antidiabetic properties of dietary flavonoids: A cellular mechanism review. Nutr. Metab. 2015, 12, 60. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Hu, W.B.; Ouyang, K.H.; Wu, G.Q.; Chen, H.; Xiong, L.; Liu, X.; Wang, N.; Wang, W.J. Hepatoprotective effect of flavonoid-enriched fraction from Cyclocarya paliurus leaves on LPS/D-GalN-induced acute liver failure. J. Funct. Foods 2018, 48, 337–350. [Google Scholar] [CrossRef]
  31. Cheng, L.; Chen, Y.; Zhang, X.; Zheng, X.; Cao, J.; Wu, Z.; Qin, W.; Cheng, K. A metagenomic analysis of the modulatory effect of Cyclocarya paliurus flavonoids on the intestinal microbiome in a high-fat diet-induced obesity mouse model. J. Sci. Food Agric. 2019, 99, 3967–3975. [Google Scholar] [CrossRef] [PubMed]
  32. Liu, Y.; Cao, Y.; Fang, S.; Wang, T.; Yin, Z.; Shang, X.; Yang, W.; Fu, X. Antidiabetic effect of Cyclocarya paliurus leaves depends on the contents of antihyperglycemic flavonoids and antihyperlipidemic triterpenoids. Molecules 2018, 23, 1042. [Google Scholar] [CrossRef] [Green Version]
  33. Shang, X.; Tan, J.N.; Du, Y.; Liu, X.; Zhang, Z. Environmentally-friendly extraction of flavonoids from Cyclocarya paliurus (Batal.) Iljinskaja leaves with deep eutectic solvents and evaluation of their antioxidant activities. Molecules 2018, 23, 2110. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Prasath, G.S.; Subramanian, S.P. Modulatory effects of fisetin, a bioflavonoid, on hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in hepatic and renal tissues in streptozotocin-induced diabetic rats. Eur. J. Pharmacol. 2011, 668, 492–496. [Google Scholar] [CrossRef]
  35. Alkhalidy, H.; Moore, W.; Wang, Y.; Luo, J.; McMillan, R.P.; Zhen, W.; Zhou, K.; Liu, D. The flavonoid kaempferol ameliorates streptozotocin-induced diabetes by suppressing hepatic glucose production. Molecules 2018, 23, 2338. [Google Scholar] [CrossRef] [Green Version]
  36. Li, D.; Jiang, C.; Mei, G.; Zhao, Y.; Chen, L.; Liu, J.; Tang, Y.; Gao, C.; Yao, P. Quercetin alleviates ferroptosis of pancreatic β cells in Type 2 diabetes. Nutrients 2020, 12, 2954. [Google Scholar] [CrossRef]
  37. Matboli, M.; Saad, M.; Hasanin, A.H.; Saleh, L.A.; Baher, W.; Bekhet, M.M.; Eissa, S. New insight into the role of isorhamnetin as a regulator of insulin signaling pathway in type 2 diabetes mellitus rat model: Molecular and computational approach. Biomed. Pharmacother. 2021, 135, 111176. [Google Scholar] [CrossRef] [PubMed]
  38. Li, S.; Zhang, Y.; Sun, Y.; Zhang, G.; Wang, T. Naringenin improves insulin sensitivity in gestational diabetes mellitus mice through AMPK. Nutr. Diabetes 2019, 9, 28. [Google Scholar] [CrossRef] [Green Version]
  39. Ogura, Y.; Kitada, M.; Xu, J.; Monno, I.; Koya, D. CD38 inhibition by apigenin ameliorates mitochondrial oxidative stress through restoration of the intracellular NAD+/NADH ratio and Sirt3 activity in renal tubular cells in diabetic rats. Aging 2020, 12, 11325–11336. [Google Scholar] [CrossRef] [PubMed]
  40. Gamede, M.; Mabuza, L.; Ngubane, P.; Khathi, A. Plant-derived oleanolic acid ameliorates markers associated with non-alcoholic fatty liver disease in a diet-induced pre-diabetes rat model. Diabetes Metab. Syndr. Obes. 2019, 12, 1953–1962. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  41. Gao, H.; Wu, H. Maslinic acid activates renal AMPK/SIRT1 signaling pathway and protects against diabetic nephropathy in mice. BMC Endocr. Disord. 2022, 22, 25. [Google Scholar] [CrossRef] [PubMed]
  42. Jäger, S.; Trojan, H.; Kopp, T.; Laszczyk, M.N.; Scheffler, A. Pentacyclic triterpene distribution in various plants—Rich sources for a new group of multi-potent plant extracts. Molecules 2009, 14, 2016–2031. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Oboh, M.; Govender, L.; Siwela, M.; Mkhwanazi, B.N. Anti-diabetic potential of plant-based pentacyclic triterpene derivatives: Progress made to improve efficacy and bioavailability. Molecules 2021, 26, 7243. [Google Scholar] [CrossRef] [PubMed]
  44. Sun, H.; Tan, J.; Lv, W.; Li, J.; Wu, J.; Xu, J.; Zhu, H.; Yang, Z.; Wang, W.; Ye, Z.; et al. Hypoglycemic triterpenoid glycosides from Cyclocarya paliurus (Sweet Tea Tree). Bioorg. Chem. 2020, 95, 103493. [Google Scholar] [CrossRef] [PubMed]
  45. Li, C.; Deng, S.; Liu, W.; Zhou, D.; Huang, Y.; Liang, C.Q.; Hao, L.; Zhang, G.; Su, S.; Xu, X.; et al. α-Glucosidase inhibitory and anti-inflammatory activities of dammarane triterpenoids from the leaves of Cyclocarya paliurus. Bioorg. Chem. 2021, 111, 104847. [Google Scholar] [CrossRef]
  46. Wu, Z.F.; Meng, F.C.; Cao, L.J.; Jiang, C.H.; Zhao, M.G.; Shang, X.L.; Fang, S.Z.; Ye, W.C.; Zhang, Q.W.; Zhang, J.; et al. Triterpenoids from Cyclocarya paliurus and their inhibitory effect on the secretion of apoliprotein B48 in Caco-2 cells. Phytochemistry 2017, 142, 76–84. [Google Scholar] [CrossRef] [PubMed]
  47. Yang, H.M.; Yin, Z.Q.; Zhao, M.G.; Jiang, C.H.; Zhang, J.; Pan, K. Pentacyclic triterpenoids from Cyclocarya paliurus and their antioxidant activities in FFA-induced HepG2 steatosis cells. Phytochemistry 2018, 151, 119–127. [Google Scholar] [CrossRef]
  48. Vinayagam, R.; Jayachandran, M.; Xu, B. Antidiabetic effects of simple phenolic acids: A comprehensive review. Phytother. Res. 2016, 30, 184–199. [Google Scholar] [CrossRef]
  49. Liu, Y.; Chen, P.; Zhou, M.; Wang, T.; Fang, S.; Shang, X.; Fu, X. Geographic variation in the chemical composition and antioxidant properties of phenolic compounds from Cyclocarya paliurus (Batal) Iljinskaja leaves. Molecules 2018, 23, 2440. [Google Scholar] [CrossRef] [Green Version]
  50. Petersen, M.C.; Shulman, G.I. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 2018, 98, 2133–2223. [Google Scholar] [CrossRef] [Green Version]
  51. Morton, G.J.; Cummings, D.E.; Baskin, D.G.; Barsh, G.S.; Schwartz, M.W. Central nervous system control of food intake and body weight. Nature 2006, 443, 289–295. [Google Scholar] [CrossRef]
  52. Thon, M.; Hosoi, T.; Ozawa, K. Possible integrative actions of leptin and insulin signaling in the hypothalamus targeting energy homeostasis. Front. Endocrinol. 2016, 7, 138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Kim, D.H.; Woods, S.C.; Seeley, R.J. Hypothalamic Akt/PKB signaling in regulation of food intake. Front. Biosci. 2012, 4, 953–966. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Guan, X. The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014, 307, R585–R596. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Kim, M.S.; Pak, Y.K.; Jang, P.G.; Namkoong, C.; Choi, Y.S.; Won, J.C.; Kim, K.S.; Kim, S.W.; Kim, H.S.; Park, J.Y.; et al. Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis. Nat. Neurosci. 2006, 9, 901–906. [Google Scholar] [CrossRef] [PubMed]
  56. Pang, J.L.; Wang, J.W.; Hu, P.Y.; Jiang, J.S.; Yu, C. HOTAIR alleviates ox-LDL-induced inflammatory response in Raw264.7 cells via inhibiting NF-κB pathway. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 6991–6998. [Google Scholar] [CrossRef] [PubMed]
  57. Horton, J.D.; Goldstein, J.L.; Brown, M.S. SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Investig. 2002, 109, 1125–1131. [Google Scholar] [CrossRef]
  58. Ros, E. Intestinal absorption of triglyceride and cholesterol. Dietary and pharmacological inhibition to reduce cardiovascular risk. Atherosclerosis 2000, 151, 357–379. [Google Scholar] [CrossRef]
  59. Cohn, J.S.; Johnson, E.J.; Millar, J.S.; Cohn, S.D.; Milne, R.W.; Marcel, Y.L.; Russell, R.M.; Schaefer, E.J. Contribution of apoB-48 and apoB-100 triglyceride-rich lipoproteins (TRL) to postprandial increases in the plasma concentration of TRL triglycerides and retinyl esters. J. Lipid Res. 1993, 34, 2033–2040. [Google Scholar] [CrossRef]
  60. Chen, X.; Xun, K.; Chen, L.; Wang, Y. TNF-alpha, a potent lipid metabolism regulator. Cell Biochem. Funct. 2009, 27, 407–416. [Google Scholar] [CrossRef] [PubMed]
  61. Qin, B.; Dawson, H.; Anderson, R.A. Elevation of tumor necrosis factor-alpha induces the overproduction of postprandial intestinal apolipoprotein B48-containing very low-density lipoprotein particles: Evidence for related gene expression of inflammatory, insulin and lipoprotein signaling in enterocytes. Exp. Biol. Med. 2010, 235, 199–205. [Google Scholar] [CrossRef]
  62. Ma, Y.; Jiang, C.; Yao, N.; Li, Y.; Wang, Q.; Fang, S.; Shang, X.; Zhao, M.; Che, C.; Ni, Y.; et al. Antihyperlipidemic effect of Cyclocarya paliurus (Batal.) Iljinskaja extract and inhibition of apolipoprotein B48 overproduction in hyperlipidemic mice. J. Ethnopharmacol. 2015, 166, 286–296. [Google Scholar] [CrossRef] [PubMed]
  63. Thirone, A.C.; Huang, C.; Klip, A. Tissue-specific roles of IRS proteins in insulin signaling and glucose transport. Trends Endocrinol. Metab. 2006, 17, 72–78. [Google Scholar] [CrossRef] [PubMed]
  64. Haag, M.; Dippenaar, N.G. Dietary fats, fatty acids and insulin resistance: Short review of a multifaceted connection. Med. Sci. Monit. 2005, 11, RA359–RA367. [Google Scholar] [PubMed]
  65. Butler, A.E.; Janson, J.; Bonner-Weir, S.; Ritzel, R.; Rizza, R.A.; Butler, P.C. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003, 52, 102–110. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Yoshitomi, H.; Tsuru, R.; Li, L.; Zhou, J.; Kudo, M.; Liu, T.; Gao, M. Cyclocarya paliurus extract activates insulin signaling via Sirtuin1 in C2C12 myotubes and decreases blood glucose level in mice with impaired insulin secretion. PLoS ONE 2017, 12, e0183988. [Google Scholar] [CrossRef] [PubMed]
  67. Lytrivi, M.; Castell, A.L.; Poitout, V.; Cnop, M. Recent insights into mechanisms of β-cell lipo- and glucolipotoxicity in Type 2 diabetes. J. Mol. Biol. 2020, 432, 1514–1534. [Google Scholar] [CrossRef] [PubMed]
  68. Yong, J.; Johnson, J.D.; Arvan, P.; Han, J.; Kaufman, R.J. Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus. Nat. Rev. Endocrinol. 2021, 17, 455–467. [Google Scholar] [CrossRef]
  69. Marzban, L. New insights into the mechanisms of islet inflammation in type 2 diabetes. Diabetes 2015, 64, 1094–1096. [Google Scholar] [CrossRef] [Green Version]
  70. Marchetti, P.; Bugliani, M.; Lupi, R.; Marselli, L.; Masini, M.; Boggi, U.; Filipponi, F.; Weir, G.C.; Eizirik, D.L.; Cnop, M. The endoplasmic reticulum in pancreatic beta cells of Type 2 diabetes patients. Diabetologia 2007, 50, 2486–2494. [Google Scholar] [CrossRef]
  71. Cnop, M.; Toivonen, S.; Igoillo-Esteve, M.; Salpea, P. Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells. Mol. Metab. 2017, 6, 1024–1039. [Google Scholar] [CrossRef]
  72. Zhao, L.; Wang, X.; Li, J.; Tan, X.; Fan, L.; Zhang, Z.; Leng, J. Effect of Cyclocarya Paliurus on Hypoglycemic Effect in Type 2 Diabetic Mice. Med. Sci. Monit. 2019, 25, 2976–2983. [Google Scholar] [CrossRef]
  73. Liu, R.; Chen, Y.; Liu, G.; Li, C.; Song, Y.; Cao, Z.; Li, W.; Hu, J.; Lu, C.; Liu, Y. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis. 2020, 11, 797. [Google Scholar] [CrossRef] [PubMed]
  74. Yue, J.; López, J.M. Understanding MAPK signaling pathways in apoptosis. Int. J. Mol. Sci. 2020, 21, 2346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Wang, H.; Ren, R.; Yang, Z.; Cai, J.; Du, S.; Shen, X. The COL11A1/Akt/CREB signaling axis enables mitochondrial-mediated apoptotic evasion to promote chemoresistance in pancreatic cancer cells through modulating BAX/BCL-2 function. J. Cancer 2021, 12, 1406–1420. [Google Scholar] [CrossRef]
  76. Meyerovich, T.K.; Ortis, F.; Allagnat, F.; Cardozo, A.K. Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. J. Mol. Endocrinol. 2016, 57, R1–R17. [Google Scholar] [CrossRef] [Green Version]
  77. Hara, T.; Mahadevan, J.; Kanekura, K.; Hara, M.; Lu, S.; Urano, F. Calcium efflux from the endoplasmic reticulum leads to β-cell death. Endocrinology 2014, 155, 758–768. [Google Scholar] [CrossRef] [Green Version]
  78. Miani, M.; Colli, M.L.; Ladrière, L.; Cnop, M.; Eizirik, D.L. Mild endoplasmic reticulum stress augments the proinflammatory effect of IL-1β in pancreatic rat β-cells via the IRE1α/XBP1s pathway. Endocrinology 2012, 153, 3017–3028. [Google Scholar] [CrossRef] [PubMed]
  79. Fontés, G.; Zarrouki, B.; Hagman, D.K.; Latour, M.G.; Semache, M.; Roskens, V.; Moore, P.C.; Prentki, M.; Rhodes, C.J.; Jetton, T.L.; et al. Glucolipotoxicity age-dependently impairs beta cell function in rats despite a marked increase in beta cell mass. Diabetologia 2010, 53, 2369–2379. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Manukyan, L.; Ubhayasekera, S.J.; Bergquist, J.; Sargsyan, E.; Bergsten, P. Palmitate-induced impairments of β-cell function are linked with generation of specific ceramide species via acylation of sphingosine. Endocrinology 2015, 156, 802–812. [Google Scholar] [CrossRef] [Green Version]
  81. Morigny, P.; Boucher, J.; Arner, P.; Langin, D. Lipid and glucose metabolism in white adipocytes: Pathways, dysfunction and therapeutics. Nat. Rev. Endocrinol. 2021, 17, 276–295. [Google Scholar] [CrossRef]
  82. Solinas, G.; Naugler, W.; Galimi, F.; Lee, M.S.; Karin, M. Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proc. Natl. Acad. Sci. USA 2006, 103, 16454–16459. [Google Scholar] [CrossRef] [Green Version]
  83. Fontés, G.; Semache, M.; Hagman, D.K.; Tremblay, C.; Shah, R.; Rhodes, C.J.; Rutter, J.; Poitout, V. Involvement of Per-Arnt-Sim Kinase and extracellular-regulated kinases-1/2 in palmitate inhibition of insulin gene expression in pancreatic beta-cells. Diabetes 2009, 58, 2048–2058. [Google Scholar] [CrossRef] [Green Version]
  84. Hagman, D.K.; Hays, L.B.; Parazzoli, S.D.; Poitout, V. Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing MafA expression in isolated rat islets of Langerhans. J. Biol. Chem. 2005, 280, 32413–32418. [Google Scholar] [CrossRef] [Green Version]
  85. Kim, J.W.; You, Y.H.; Ham, D.S.; Cho, J.H.; Ko, S.H.; Song, K.H.; Son, H.Y.; Suh-Kim, H.; Lee, I.K.; Yoon, K.H. Suppression of peroxisome proliferator-activated receptor gamma-coactivator-1alpha normalizes the glucolipotoxicity-induced decreased BETA2/NeuroD gene transcription and improved glucose tolerance in diabetic rats. Endocrinology 2009, 150, 4074–4083. [Google Scholar] [CrossRef] [PubMed]
  86. Feng, A.; Fang, Z.; Chen, C.; Vong, C.T.; Chen, J.; Lou, R.; Hoi, M.P.M.; Gan, L.; Lin, L. Anti-hyperglycemic effects of refined fractions from Cyclocarya paliurus leaves on streptozotocin-induced diabetic mice. Molecules 2021, 26, 6886. [Google Scholar] [CrossRef] [PubMed]
  87. Zhang, Y.J.; Li, S.; Gan, R.Y.; Zhou, T.; Xu, D.P.; Li, H.B. Impacts of gut bacteria on human health and diseases. Int. J. Mol. Sci. 2015, 16, 7493–7519. [Google Scholar] [CrossRef] [PubMed]
  88. Hann, M.; Zeng, Y.; Zong, L.; Sakurai, T.; Taniguchi, Y.; Takagaki, R.; Watanabe, H.; Mitsuzumi, H.; Mine, Y. Anti-inflammatory activity of isomaltodextrin in a C57BL/6NCrl mouse model with lipopolysaccharide-induced low-grade chronici. Nutrients 2019, 11, 2791. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Li, H.Y.; Zhou, D.D.; Gan, R.Y.; Huang, S.Y.; Zhao, C.N.; Shang, A.; Xu, X.Y.; Li, H.B. Effects and mechanisms of probiotics, prebiotics, synbiotics, and postbiotics on metabolic diseases targeting gut microbiota: A narrative review. Nutrients 2021, 13, 3211. [Google Scholar] [CrossRef]
  90. Etxeberria, U.; Fernández-Quintela, A.; Milagro, F.I.; Aguirre, L.; Martínez, J.A.; Portillo, M.P. Impact of polyphenols and polyphenol-rich dietary sources on gut microbiota composition. J. Agric. Food Chem. 2013, 61, 9517–9533. [Google Scholar] [CrossRef]
  91. Huang, F.; Zheng, X.; Ma, X.; Jiang, R.; Zhou, W.; Zhou, S.; Zhang, Y.; Lei, S.; Wang, S.; Kuang, J.; et al. Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism. Nat. Commun. 2019, 10, 4971. [Google Scholar] [CrossRef] [Green Version]
  92. Meehan, C.J.; Beiko, R.G. A phylogenomic view of ecological specialization in the Lachnospiraceae, a family of digestive tract-associated bacteria. Genome Biol. Evol. 2014, 6, 703–713. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Proença, C.; Ribeiro, D.; Freitas, M.; Fernandes, E. Flavonoids as potential agents in the management of type 2 diabetes through the modulation of α-amylase and α-glucosidase activity: A review. Crit. Rev. Food Sci. Nutr. 2022, 62, 3137–3207. [Google Scholar] [CrossRef] [PubMed]
Nutrients 14 03169 g001 550
Figure 1. Chemical and structural formula of the Cyclocarya paliurus polysaccharide.
Figure 1. Chemical and structural formula of the Cyclocarya paliurus polysaccharide.
Nutrients 14 03169 g001
Nutrients 14 03169 g002 550
Figure 2. The mechanism of action of Cyclocarya paliurus flavonoids with respect to decreasing appetite. ↑: increase; ↓: decline.
Figure 2. The mechanism of action of Cyclocarya paliurus flavonoids with respect to decreasing appetite. ↑: increase; ↓: decline.
Nutrients 14 03169 g002
Nutrients 14 03169 g003 550
Figure 3. The mechanism of action of Cyclocarya paliurus extract with respect to inhibiting lipid synthesis and alleviating pathological insulin resistance in liver cells.
Figure 3. The mechanism of action of Cyclocarya paliurus extract with respect to inhibiting lipid synthesis and alleviating pathological insulin resistance in liver cells.
Nutrients 14 03169 g003
Nutrients 14 03169 g004 550
Figure 4. The mechanism of action of Cyclocarya paliurus extract with respect to lowering blood glucose and lipid levels through intestinal metabolism. ↑: increase; ↓: decline.
Figure 4. The mechanism of action of Cyclocarya paliurus extract with respect to lowering blood glucose and lipid levels through intestinal metabolism. ↑: increase; ↓: decline.
Nutrients 14 03169 g004
Nutrients 14 03169 g005 550
Figure 5. The mechanism of action of Cyclocarya paliurus extract with respect to inhibiting pathological insulin resistance in white adipocytes and muscle cells.
Figure 5. The mechanism of action of Cyclocarya paliurus extract with respect to inhibiting pathological insulin resistance in white adipocytes and muscle cells.
Nutrients 14 03169 g005
Nutrients 14 03169 g006 550
Figure 6. The mechanism of action of Cyclocarya paliurus flavone with respect to alleviating islet cell apoptosis and relatively insufficient insulin secretion caused by glycolipid toxicity.
Figure 6. The mechanism of action of Cyclocarya paliurus flavone with respect to alleviating islet cell apoptosis and relatively insufficient insulin secretion caused by glycolipid toxicity.
Nutrients 14 03169 g006
Table
Table 1. The mechanism of action of the different Cyclocarya paliurus extracts on type 2 diabetes mellitus.
Table 1. The mechanism of action of the different Cyclocarya paliurus extracts on type 2 diabetes mellitus.
Active IngredientExtraction MethodExtraction ConditionsBiological FunctionPossible MechanismModelReference
In VivoIn Vitro
PolysaccharideWater extraction
  • Dry leaves powder;
  • Solid residue (hot water);
  • Crude polysaccharide (dialysis, protein removal, decolorization chromatographic column);
  • Purified polysaccharide.
Regulation of intestinal microorganismsSCFAs→GLP-1→Insulin signaling pathwayWistar rats
High-fat feed + 30 mg/kg STZ		 [16]
PolysaccharideAlcohol extraction
  • Dry leaves with 80% ethanol for 24 h;
  • Residue (dry, soak in distilled water, filter);
  • Filtrate (decompression, concentration);
  • Filtrate (add anhydrous ethanol, centrifuged);
  • C. paliurus polysaccharide.
Regulation of intestinal microorganismsSCFAs→SCFAs-GLP1/PYYSD rats
High-fat feed + 35 mg/kg STZ		 [17]
TriterpeneAlcohol extraction
  • Dry leaves with 80% ethanol for 24 h;
  • Extractive (decompression, concentration, degreased with petroleum ether, partitioned with chloroform);
  • Triterpenic acid-rich fraction.
Improvement of insulin resistancePI3K→Akt→
GSK3β		C57BL/6J mice
High-fat feed		HepG2 cells induced by 100 mM PA[20]
TriterpeneAlcohol extraction
  • Dry leaves with 70% EtOH at room temperature;
  • Crude extract suspended in H2O, successively partitioned with petroleum ether, EtoAc, and n-BuOH.
Improvement of islet resistanceAMPK→P38→
PI3K→Akt→
GSK3β		 C2C12 cells
1% P/S, differentiation induced by 2% heat-inactivated HS 3T3-L1 cells
Differentiation was induced by 1 µM dexamethasone, 0.5 mM 3-isobutyl-1-methylxanthine, and 5 µg/mL insulin		[21]
TriterpeneAlcohol extraction
  • Dry leaves with 80% alcohol;
  • Extractive (decompression, concentration, degreased with petroleum ether, partitioned with chloroform);
  • Chloroform fraction (dissolved in chloroform, partitioned with NaOH, neutralizing the aqueous phase with HCl, re-extracted with chloroform);
  • Triterpenic acid-rich fraction.
HypolipidemiaTNF-α→MAPK→apoB48SD rats
High-fat feed		 [22]
TriterpeneAlcohol extraction + chloroform extraction
  • Dry leaves with 80% ethanol;
  • Extractive (decompression, concentration, partitioned with chloroform);
  • C. paliurus chloroform extract.
HypolipidemiaSREBP→ACC1/
FAS→Lipid synthesis		SD rats
High-fat feed		 [23]
FlavoneWater extraction
  • Dry leaves with 80% ethanol;
  • Extractive (decompression, concentration, degreased with petroleum ether);
  • Freeze-dried after decompression and concentration.
  • Crude extract.
Reduction in appetitePI3K/Akt→
FOXO1t→POMC/NPY		SHR/cp rats [24]
FlavoneWater extraction
  • Dry leaves boiled with water;
  • Aqueous extract (concentrated and dried under reduced pressure);
  • Crude extract.
Inhibition of islet cell apoptosisp38→ERK→JNK→AktC57BL/6J mice
High-fat feed + 25 mg/kg (3 day)		NIT-1 cells
11.1 mM glucose		 [25]
FlavoneWater extraction
  • Dry leaves boiled with water;
  • Aqueous extract (concentrated and dried under reduced pressure);
  • Crude extract.
Inhibition of the α-glucosidase activity C57BL/6J mice [26]
Abbreviations: NPY, neuropeptide Y; POMC, proopiomelanocortin; SCFAs, short-chain fatty acids.
Table
Table 2. Therapeutic effects of small molecules in Cyclocarya paliurus on type 2 diabetes mellitus.
Table 2. Therapeutic effects of small molecules in Cyclocarya paliurus on type 2 diabetes mellitus.
ClassificationName (9)Structure (9)Relevant IndicatorsModelReference
In VivoIn Vitro
FlavoneFisetin Nutrients 14 03169 i001FBG, Serum insulin, Glycosylation of red cellsWistar rats
50 mg/kg STZ		 [34]
Kaempferol Nutrients 14 03169 i002FBG, GSK3β phosphorylation, Liver pyruvate carboxylase activity, gluconeogenesisC57BL/6 mice
40 mg/kg STZ (3 days) 		[35]
Quercetin Nutrients 14 03169 i003FBG, Pancreatic iron deposition, Pancreatic PBC iron death, ROS, Serum insulinC57BL/6 mice
High-fat feed + 50 mg/kg STZ		 [36]
Isorhamnetin Nutrients 14 03169 i004FBG, Serum insulin, HOMA-IR, BW, blood fat, LncRNA-RP11-773H22.4Wistar rats
High-fat feed + 30 mg/kg STZ 		[37]
Naringenin Nutrients 14 03169 i005FBG, BW, Impaired glucose tolerance, Serum insulin, HOMA-IR, ROSC57BLKsJ db/+ mice [38]
Apigenin Nutrients 14 03169 i006Renal injury, Pro-inflammatory gene expression, CD38, Sirt3, ROSZucker rats [39]
TriterpeneOleanolic acid Nutrients 14 03169 i007BW, Liver weight, LDL, TG, SREBP, total bilirubin, Liver injurySD rats
High-sugar and high-fat feed		 [40]
Maslinic acid Nutrients 14 03169 i008BW, FBG, food intake, urinary albumin, Renal injury, kidney ROSC57BL/6 mice
50 mg/kg STZ		 [41]
(20S,24R)-20,24-Epoxy-25-hydroxy-12β-(α- l -arabinopyranosyloxy)-3,4-seco-dammara-4(28)-en-3-oic acid Nutrients 14 03169 i009AMP (AMPK)-p38 access, Glucose uptake C2C12 cells
differentiation induced by 1% P/s and 2% heat-inactivated horse serum
3T3-L1 cells
differentiation was induced by 1 µM dexamethasone, 0.5 mM 3-isobutyl-1-methylxanthine, and 5 µg/mL of insulin		[21]
Abbreviations: BW, body weight; FBG, fasting blood glucose; HOMA-IR, insulin resistance index; LDL, low-density lipoprotein; PBC, pancreatic β cells; ROS, reactive oxygen species; SD, Sprague–Dawley; STZ, streptozocin; TG, triacylglycerol.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Wang, X.; Tang, L.; Ping, W.; Su, Q.; Ouyang, S.; Su, J. Progress in Research on the Alleviation of Glucose Metabolism Disorders in Type 2 Diabetes Using Cyclocarya paliurus. Nutrients 2022, 14, 3169. https://doi.org/10.3390/nu14153169

AMA Style

Wang X, Tang L, Ping W, Su Q, Ouyang S, Su J. Progress in Research on the Alleviation of Glucose Metabolism Disorders in Type 2 Diabetes Using Cyclocarya paliurus. Nutrients. 2022; 14(15):3169. https://doi.org/10.3390/nu14153169

Chicago/Turabian Style

Wang, Xue, Lu Tang, Wenxin Ping, Qiaofen Su, Songying Ouyang, and Jingqian Su. 2022. "Progress in Research on the Alleviation of Glucose Metabolism Disorders in Type 2 Diabetes Using Cyclocarya paliurus" Nutrients 14, no. 15: 3169. https://doi.org/10.3390/nu14153169

APA Style

Wang, X., Tang, L., Ping, W., Su, Q., Ouyang, S., & Su, J. (2022). Progress in Research on the Alleviation of Glucose Metabolism Disorders in Type 2 Diabetes Using Cyclocarya paliurus. Nutrients, 14(15), 3169. https://doi.org/10.3390/nu14153169

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop