Functional Factors for Hypoglycemic Effects in Natural Products and Their Mechanisms of Action

Diabetes is a common clinical disease. With the improvement of living standards, the increase in the number of obese people, and the intensification of population aging, the incidence of diabetes has been rising year by year. Diabetes is diverse in types and requires long-term treatment, making hypoglycemic drugs an indispensable necessity for patients. Hypoglycemic drugs can be divided into insulin injections and oral hypoglycemic drugs. Clinically, commonly used oral hypoglycemic drugs include western medicine preparations and traditional Chinese medicine preparations. Western medicine preparations mainly include biguanides (such as metformin), sulfonylurea insulin secretagogues (such as glimepiride, glipizide, and gliclazide), non-sulfonylurea insulin secretagogues (such as repaglinide and nateglinide), α-glucosidase inhibitors (such as acarbose, voglibose, and miglitol), DPP-4 inhibitors (such as sitagliptin), and GLP-1 receptor agonists (such as exenatide and liraglutide). These oral hypoglycemic western medicines primarily achieve the goal of lowering blood sugar by increasing insulin sensitivity, delaying the metabolism of carbohydrates in the small intestine, repairing and improving the function of pancreatic β-cells, and promoting the secretion of insulin by pancreatic β-cells. However, these drugs have various side effects, such as adverse reactions in the gastrointestinal tract and skin, as well as upper respiratory tract and urinary tract infections.

Traditional Chinese Medicines (TCMs) are prepared from various Chinese herbal medicines through processing into different dosage forms. The plant-based ingredients of oral hypoglycemic TCMs mainly include astragalus, rehmannia glutinosa, radix pseudostellariae, trichosanthes root, ophiopogon japonicus, kudzu root, and salvia miltiorrhiza, among others. These ingredients primarily exert their therapeutic effects on type 2 diabetes by nourishing qi and yin, tonifying the kidney-yin, invigorating the spleen, and promoting the production of body fluids. Compared to western medicine preparations, TCMs generally have fewer toxic and side effects. However, traditional Chinese medicine therapy emphasizes individual differences among patients, and some TCMs may not be suitable for all populations. Additionally, long-term use of TCMs is not recommended, and their side effects are not always clearly defined. Currently, commonly used oral hypoglycemic TCMs include Jiangtang Jia Pian (Sugar-Lowering Tablet A), Jiangtang Shu Pian (Sugar-Lowering Comfort Tablet), Yuquan Wan (Jade Spring Pill), Shenqi Jiangtang Pian (Ginseng and Astragalus Sugar-Lowering Tablet), Ganlu Xiaoke Jiaonang (Manna Thirst-Quenching Capsule), Kele Ning Jiaonang (Thirst-Quenching and Tranquilizing Capsule), and Tangmaikang Keli (Sugar Vessel Health Granules). The ingredients, effects, and scopes of application of these TCMs are outlined in the following table (source: Reference [1]).

Polysaccharides, saponins, polyphenols, alkaloids, protein peptides, and plant essential oils serve as the material basis for the hypoglycemic effects derived from plants.

1. Polysaccharides

The hypoglycemic effects of polysaccharides encompass a wide range of mechanisms, which can be summarized as follows: ① Protecting pancreatic β-cells and promoting insulin release. ② Influencing the activity of enzymes involved in glucose metabolism, promoting glycogen synthesis or inhibiting glycogenolysis. ③ Antagonizing hyperglycemic hormones. ④ Enhancing glucose utilization by peripheral tissues and target organs. ⑤ Preventing lipid peroxidation. ⑥ Increasing insulin receptors or enhancing their affinity, thereby improving insulin sensitivity. ⑦ Improving microcirculation. Polysaccharides such as okra polysaccharides, gracilaria polysaccharides, and physalis pubescens polysaccharides exert hypoglycemic effects by regulating the activity of enzymes involved in glucose metabolism, including inhibiting α-glucosidase, α-amylase, and key enzymes in gluconeogenesis, while enhancing the activity of key enzymes in glycolysis and the pentose phosphate pathway. Polysaccharides like gracilaria polysaccharides, red bean polysaccharides, and tea polysaccharides promote the synthesis of liver glycogen from blood glucose and stimulate insulin secretion to control blood glucose levels in the body. Polysaccharides like cyclocarya paliurus polysaccharides, coptis chinensis polysaccharides, and sweet corncob polysaccharides can repair damaged pancreatic tissue, increase the number of pancreatic β-cells, elevate insulin levels, and regulate blood glucose to alleviate hyperglycemic symptoms. Additionally, polysaccharides such as astragalus polysaccharides, balsam pear polysaccharides, and sweet corncob polysaccharides can increase serum HDL-C levels, reduce LDL-C, TC, and TG levels, alleviate lipid metabolism disorders caused by hyperglycemia, and thereby improve hyperglycemic symptoms.

2.Saponins

Saponins, also known as saponosides, are composed of sapogenins and sugars, uronic acids, or other organic acids. They are primarily found in terrestrial higher plants, with many traditional Chinese medicinal herbs such as ginseng, polygala, platycodon, licorice, anemarrhena, and bupleurum containing saponins as their main active ingredients. Saponins can be divided into two categories: steroidal saponins and triterpenoid saponins. They exhibit various biological activities including expectorant, antitussive, hemolytic, antibacterial, antipyretic, sedative, and anticancer effects.

Saponins can control blood glucose levels by stimulating glycogen synthesis through mechanisms such as utilizing the AMPK/NF-κB signaling pathway, activating the PI3K/AKT pathway, and causing the phosphorylation and inactivation of glycogen synthase kinase-3α/β (GSK-3α/β), thereby improving glucose tolerance. For instance, chaenomeles speciosa saponins can promote glucose uptake and utilization by cells, controlling serum glucose levels, through activating the AMPK/ACC signaling pathway and the GLUT4 pathway regulated by IRS-1/PI3K/AKT. Protecting and repairing pancreatic β-cells damaged by high glucose concentrations, enabling them to function normally, is also a primary method for saponins to lower blood glucose. Plant saponins like ginsenosides can alleviate insulin resistance and regulate blood glucose levels by activating the IRS1/PI3K/AKT/GSK3β-GS signaling pathway, reducing the Bax/Bcl-xL ratio, JNK phosphorylation levels, and Caspase-3 activity.

3.Polyphenols

Plant polyphenols, also known as plant tannins, primarily encompass phenolic acids, flavonols, flavanols, anthocyanins, and flavones. They possess potent antioxidant properties, effectively preventing chronic diseases such as hyperglycemia, hyperlipidemia, and cardiovascular and cerebrovascular diseases.

Research has shown that polyphenols like those found in the stems and leaves of 'Simon No. 1' sweet potato can upregulate the PI3K/AKT/GSK-3β signaling pathway in the liver and the PI3K/AKT/GLUT-4 pathway in muscle, enhancing glycogen synthesis and the activity of enzymes related to glucose metabolism, thereby regulating blood glucose homeostasis. Polyphenols such as sea-buckthorns' proanthocyanidins can regulate blood glucose levels by inhibiting the mRNA expression of G-6-P, GSK-3β, CPT1-α, and GP. Rose polyphenols, tea polyphenols from large-leaved yellow tea, and anthocyanins from black beans can reduce glucose production in the body by inhibiting the activities of α-glucosidase and α-amylase, contributing to hypoglycemic effects. Curcumin, cocoa proanthocyanidins, and european water chestnut tannin can regulate the AMPK signaling pathway, increase GLUT4 protein expression, and promote glucose transport into cells to lower blood glucose levels. Ginkgo flavone, sea-buckthorns' proanthocyanidins, and total flavonoids from loranthus can regulate blood lipid balance by reducing serum levels of TG, TC, and LDL-C and increasing HDL-C levels, thereby alleviating hyperglycemia.

4.Alkaloids

Alkaloids are a diverse group of compounds with complex structures, primarily categorized into organic amines (e.g., ephedrine, leonurine), isoquinolines (e.g., berberine, morphine), pyrrolidines (e.g., hygrine, senecionine), and pyridines (e.g., nicotine, arecoline). Their hypoglycemic mechanism primarily involves inhibiting the activity of α-glucosidase. As the structure of alkaloids resembles that of sugars, they can competitively replace the position of sugars in the human body and bind with α-glucosidase. The presence of nitrogen elements strengthens this binding, resulting in a competitive inhibition of α-glucosidase activity, which further affects the metabolism of carbohydrate compounds. Mulberry twig alkaloids can competitively inhibit disaccharidases, reducing glucose production in the body. Berberine can control gluconeogenesis by inhibiting PEPCK1 activity, thereby lowering blood glucose concentrations. Nigella sativa seed alkaloids can promote glycogen synthesis through AKT-mediated GSK3 phosphorylation, improving glucose metabolism. Some alkaloids can also activate the AMPK signaling pathway, promoting glucose uptake by cells and reducing serum glucose levels. Additionally, alkaloids can regulate blood lipid balance by lowering serum TG and TC levels, alleviating hyperglycemic symptoms. They can also protect the liver from damage under hyperglycemic conditions, improve insulin receptor signaling pathways, and modulate the TGF-β/Smads signaling pathway.

5.Protein and Peptides

Plant proteins and peptides play a vital and irreplaceable regulatory role in human health, often utilized in the development of pharmaceuticals and health foods. Research has shown that momordicin and peptides found in bitter gourd exhibit significant hypoglycemic activity. By hydrolyzing bitter gourd with pectinase and cellulase, a bitter gourd polypeptide solution was prepared, which was found to have a hypoglycemic effect in diabetic mice models induced by alloxan through oral administration. Almond peptides effectively regulate blood glucose and blood lipid biochemical indicators in diabetic rats, demonstrating an auxiliary therapeutic effect on hyperlipidemia-induced diabetes. A polysaccharide-peptide complex isolated from mulberry leaves was found to reduce blood glucose levels in streptozotocin-induced diabetic mice through oral administration. Additionally, it reduced plasma triglycerides and cholesterol. The hypoglycemic mechanism of mulberry leaf peptides may involve stimulating insulin secretion and mitigating insulin degradation and inactivation in peripheral tissues, thereby increasing serum insulin concentrations and lowering blood glucose levels.

6.Plant Essential Oils

The chemical composition of plant essential oils is extremely complex, primarily consisting of terpene derivatives, aromatic compounds, aliphatic compounds, nitrogen- and sulfur-containing compounds, among others. Among these, terpenes are the most common and abundant components in essential oils, such as sabinene, myrcene, and pinene. Aromatic compounds constitute the second largest group in plant essential oils, primarily comprising phenols, aldehydes, ketones, esters, terpenoid derivatives, and phenylpropanoid derivatives, like cinnamaldehyde, eugenol, and cuminic aldehyde. Aliphatic compounds are present in small amounts in plant essential oils, while nitrogen- and sulfur-containing compounds are primarily found in spices.

Research reports indicate that active ingredients in plant essential oils, such as cinnamaldehyde, thymol, and honokiol, exhibit favorable hypoglycemic effects. Active components of plant essential oils (e.g., isoeugenol) can inhibit the activity of α-amylase and α-glucosidase, reducing glucose production in the body. Thymol and honokiol can lower serum TC, TG, and LDL-C levels while elevating HDL-C levels, maintaining lipid metabolism balance. Cinnamaldehyde upregulates the endothelial nitric oxide synthases (eNOS) and IRS1/PI3K/AKT2 signaling pathways, reduces AGEs, RAGE, and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) levels, improving insulin resistance. It also protects liver function by reducing serum AST and ALT activities, thereby alleviating hyperglycemic symptoms. Furthermore, active substances like thymol and cinnamaldehyde can regulate the activity of antioxidant enzymes (SOD, CAT) in the liver, kidneys, or aorta to protect these organs from the stress of hyperglycemia.

References

[1] Jin Fei, Zhu Liyun, Gao Yongsheng, et al. Research Progress on Hypoglycemic Effects and Mechanisms of Plant-Derived Active Ingredients [J]. Food Science, 2021, 42(21): 322-330.

[2] Wang Nan, Shi Guoying, Zhao Tingting, et al. Research Progress on Hypoglycemic Active Factors in Functional Foods [J]. Journal of Anhui Agricultural Sciences, 2017, 45(04): 75-77.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.