The hypoglycemic efficacy of 1-DNJ in mulberry leaf extract

1. Introduction

The maintenance of glucose homeostasis is crucial for human health. Chronic hyperglycemia is not only a core characteristic of diabetes but also triggers various chronic complications, such as cardiovascular diseases, kidney damage, neuropathy, and retinopathy, which severely impair patients' quality of life and overall health. Currently, clinical drugs for treating diabetes have certain efficacy, yet they are associated with side effects like the risk of hypoglycemia and gastrointestinal discomfort. Therefore, it is of great significance to explore safe and effective hypoglycemic components from natural products. Mulberry leaves, as a traditional Chinese medicinal herb, have a long history of medicinal use in China. Modern studies have shown that mulberry leaves contain a variety of bioactive components, such as flavonoids, polysaccharides, and alkaloids, which exhibit multiple pharmacological activities including hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory effects. Among them, 1-Deoxynojirimycin (1-DNJ), a unique alkaloid specific to mulberry leaves, has attracted much attention due to its significant hypoglycemic activity. 1-DNJ has a relatively high content in mulberry leaves and possesses a unique chemical structure and mechanism of action. In recent years, it has become one of the key focuses in research on the hypoglycemic mechanism of mulberry leaves.

2. Plant Sources and Physicochemical Properties of 1-DNJ

1-Deoxynojirimycin (1-DNJ) is a naturally occurring pyrrolidine alkaloid, primarily distributed in the leaves of Morus plants, and can also be detected in a few other plant species. The content of 1-DNJ in mulberry leaves varies with factors such as variety, harvest season, and processing method, with generally higher levels in young leaves. In terms of physicochemical properties, 1-DNJ is a white or pale yellow crystalline solid with good water solubility, and is either tasteless or slightly sweet. Its chemical structure contains multiple hydroxyl and amino groups, which endow it with strong hydrophilicity and bioactivity. 1-DNJ has good stability; it is not easily degraded when stored at room temperature but may undergo partial decomposition under high temperature or strong acid-base conditions. As an α-glucosidase inhibitor, 1-DNJ exerts its effects in the body mainly through intestinal absorption, and its physicochemical properties provide a material basis for subsequent extraction, separation, development of functional foods, and pharmaceutical formulations.

3. Mechanism of Action of 1-DNJ's Hypoglycemic Activity

3.1 Inhibition of α-glucosidase activity

α-glucosidases are a class of enzymes present in the brush border of the small intestinal mucosa. They can break down carbohydrates into glucose, which is then absorbed by the intestines into the bloodstream, leading to elevated blood glucose levels. 1-DNJ has a molecular structure similar to glucose, enabling it to competitively bind to the active site of α-glucosidase. This inhibits the enzyme's hydrolysis of carbohydrates, delays glucose absorption, and thereby reduces postprandial blood glucose peaks.

3.2 Regulation of gut microbiota

Gut microbiota plays an important role in human metabolism and is closely linked to the development of diabetes. 1-DNJ can improve blood glucose by regulating gut microbiota. On one hand, it inhibits the growth of harmful bacteria and reduces the microbiota that may contribute to obesity and insulin resistance. On the other hand, it promotes the proliferation of beneficial bacteria, such as increasing the number of butyrate-producing bacteria. Improvement of gut microbiota can elevate the levels of short-chain fatty acids (SCFAs) like acetic acid and propionic acid in serum, which helps activate the secretion of glucagon-like peptide-1 (GLP-1) by intestinal cells. GLP-1 can promote insulin secretion, suppress appetite, and thereby regulate blood glucose levels.

3.3 Enhancement of insulin sensitivity

Insulin resistance is a key cause of type 2 diabetes, characterized by a reduced bodily response to insulin and decreased efficiency in glucose utilization. Studies have shown that 1-DNJ can improve insulin resistance through multiple pathways. On one hand, it can activate energy metabolism regulatory pathways, promoting glucose uptake by muscle and adipose cells; on the other hand, it can inhibit key enzymes involved in hepatic glucose production, thereby reducing blood glucose synthesis.

3.4 Protection of pancreatic β-cells

Impaired function and reduced number of pancreatic β-cells are key factors contributing to diabetes. Studies have shown that 1-DNJ can protect pancreatic β-cells, reduce their death, and maintain normal insulin secretion. In a hyperglycemic environment, β-cells tend to produce excessive reactive oxygen species (ROS), leading to cellular damage and apoptosis. 1-DNJ can enhance intracellular antioxidant capacity and reduce ROS levels, thereby alleviating oxidative stress. Meanwhile, it can also regulate cellular signaling pathways, inhibit stress responses, and further reduce β-cell death.

3.5 Enhancement of anti-inflammatory and antioxidant activities

Multiple animal and cell experiments suggest that 1-DNJ may also involve the regulation of anti-inflammatory and antioxidant signaling pathways in the prevention and treatment of diabetes. On one hand, 1-DNJ can alleviate the chronic low-grade inflammation in diabetic conditions by inhibiting the activation of signaling pathways and reducing the expression of pro-inflammatory cytokines. On the other hand, it can enhance antioxidant activity, including increasing the levels of antioxidant enzymes and reducing the production of lipid peroxidation products, thereby alleviating oxidative stress damage induced by hyperglycemia.

4. Research evidence for blood glucose regulation of 1-DNJ

4.1 Preclinical pharmacodynamic studies

In animal experiments, researchers mainly used diabetic or prediabetic models to observe the effects of oral administration of 1-DNJ or mulberry leaf extract on postprandial blood glucose and glucose tolerance. The results showed that after administration of 1-DNJ to diabetic mice, the magnitude of postprandial blood glucose elevation was significantly reduced, and the time to reach the blood glucose peak was delayed. In addition, after 1-DNJ intervention, the morphology and function of β cells in diabetic mice were restored, and insulin secretion was increased. In experiments with insulin-resistant rats, after 4 weeks of 1-DNJ intervention, fasting blood glucose decreased by approximately 18% and insulin sensitivity increased by about 32%, indicating its ability to effectively improve insulin resistance. In vitro experiments have demonstrated that 1-DNJ exerts significant inhibitory effects on α-glucosidases such as maltase and sucrase, and the inhibition is in a dose-dependent manner. For example, at a concentration of 10μM, 1-DNJ can achieve an inhibition rate of 65% on maltase, which is comparable to the inhibitory effect of acarbose, a commonly used clinical hypoglycemic drug, at the same concentration. Furthermore, 1-DNJ treatment can reduce the apoptosis rate of β cells by approximately 55% and improve insulin secretion.

4.2 Preliminary clinical observations and analysis

Currently, clinical research on 1-DNJ in blood glucose regulation is still in the preliminary stage, but existing studies have preliminarily demonstrated its potential. A small-scale clinical trial evaluated the effects of hydroalcoholic extract of black mulberry leaves on diabetic patients. The results showed that after three months of intervention, the patients' fasting blood glucose and glycated hemoglobin decreased significantly.

Another study found that after intake of mulberry leaf extract containing 1-DNJ, the subjects' 2-hour postprandial blood glucose levels decreased significantly, while the amplitude of postprandial blood glucose fluctuations was reduced, and the insulin secretion response was improved to some extent. This indicates that 1-DNJ can effectively delay the digestion and absorption of carbohydrates and help maintain postprandial blood glucose stability by improving insulin regulatory mechanisms.

5. Pharmacokinetics and Safety of 1-DNJ

Pharmacokinetic studies have shown that 1-DNJ is rapidly absorbed in the upper small intestine after oral administration. The peak plasma concentration typically occurs within 0.5–1.5 hours, with a relatively short plasma half-life (approximately 2–3 hours). It is primarily excreted in urine in its unchanged form, with minimal metabolic transformation. These pharmacokinetic characteristics indicate that administration during or before meals can maximize its effect in inhibiting postprandial blood glucose elevation. In terms of safety, within the recommended dose range (approximately 3–6 mg/day), evidence from both human and animal studies generally shows that 1-DNJ has high safety and good tolerability. Common adverse reactions are mild gastrointestinal discomfort, which are mostly transient—consistent with other α-glucosidase inhibitors of the same class—and can be alleviated through gradual dose escalation or administration with meals. Existing clinical and animal data do not indicate significant hepatotoxicity, nephrotoxicity, or systemic adverse effects. However, the safety of long-term high-dose administration and its use in special populations still require further research and verification.

6. Application Prospects and Challenges of 1-DNJ

1-DNJ shows significant application potential in the field of health, with notable advantages particularly in the development of products related to blood glucose regulation and metabolic health. For populations with elevated blood glucose levels, blood sugar-regulating beverages with 1-DNJ as the core ingredient can be developed to help stabilize blood glucose levels; for those at risk of metabolic abnormalities, it can be formulated into dietary supplements to assist in improving metabolic status. Its natural origin ensures product safety, making it suitable for long-term use, which also constitutes its unique advantage over chemically synthesized regulatory ingredients. However, its clinical promotion still faces several challenges, including limited in vivo bioavailability, variations in responses among different populations, lack of large-scale clinical evidence for long-term safety and efficacy, and unclear synergistic effects with other interventions. Future research should focus on optimizing formulations and administration methods, conducting systematic clinical validation, clarifying target populations and dosages, and further elucidating its mechanism of action, so as to promote the widespread application of 1-DNJ in the fields of blood glucose management and metabolic health.

7. Conclusion

Previous studies have confirmed that 1-DNJ, as the key hypoglycemic active component in mulberry leaves, not only delays carbohydrate absorption by inhibiting α-glucosidase but also regulates glucose homeostasis through multiple pathways, such as improving insulin signaling, modulating gut microbiota, and exerting anti-inflammatory and antioxidant effects. Compared with single drugs, its natural origin, component synergy, and good tolerability lay a solid foundation for its application in functional foods and auxiliary hypoglycemic fields. Future research should focus on long-term clinical validation and refined analysis of its mechanisms to promote its translation into clinical practice and public health domains.

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