The potential application of L-leucine in the management of metabolic syndrome

L-leucine has potential benefits for improving core symptoms of metabolic syndrome (MS)—including insulin resistance, obesity, and dyslipidemia—by regulating insulin sensitivity, optimizing glucose-lipid metabolism, inhibiting inflammatory responses, and maintaining muscle mass. It can serve as an auxiliary dietary intervention, but its use must be rationalized with dose control and consideration of individual differences.

I. Core Mechanisms of Action

1. Improving Insulin Resistance and Regulating Blood Glucose

L-leucine activates the AMPK signaling pathway, promoting glucose uptake and utilization in skeletal muscle cells, thereby reducing fasting blood glucose and postprandial blood glucose fluctuations.

It enhances insulin signal transduction and alleviates insulin resistance by activating the mTORC1 pathway to increase the phosphorylation level of insulin receptor substrate-1 (IRS-1).

Clinical studies show that after 8 weeks of L-leucine supplementation, insulin sensitivity in MS patients improves by 15%–20%, and glycated hemoglobin (HbA1c) decreases by 0.3%–0.5%.

2. Optimizing Glucose-Lipid Metabolism and Reducing Fat Accumulation

L-leucine regulates the activity of key enzymes in hepatic gluconeogenesis, inhibiting excessive glucose production while promoting fat breakdown and β-oxidation.

It inhibits the activity of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), reducing hepatic and visceral fat deposition, and lowering triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels.

It increases high-density lipoprotein cholesterol (HDL-C) synthesis, improves lipid profiles, and reduces the risk of atherosclerosis.

3. Inhibiting Chronic Inflammation and Alleviating Metabolic Disorders

MS is often accompanied by low-grade chronic inflammation, which L-leucine mitigates by regulating the balance of inflammatory factors.

It decreases the levels of pro-inflammatory factors such as TNF-α and IL-6 in serum, increases the expression of anti-inflammatory factors such as IL-10, and reduces inflammatory interference with insulin signaling.

It inhibits the activation of the NF-κB inflammatory pathway, alleviates inflammatory infiltration in adipose tissue and the liver, and improves the function of metabolic organs.

4. Maintaining Muscle Mass and Improving Body Composition

MS patients are prone to "sarcopenic obesity" (coexisting muscle loss and fat accumulation), which L-leucine specifically targets.

As a key substrate for muscle protein synthesis, it activates the mTOR signaling pathway to promote myofiber regeneration and maintain muscle mass and strength.

Increased muscle mass raises basal metabolic rate, enhances energy expenditure, and aids in weight and body fat control, forming a positive "muscle gain-fat burning" cycle.

II. Potential Application Scenarios and Effects

1. Intervention for Insulin Resistance and Prediabetes

Target Population: Individuals with fasting blood glucose of 5.6–6.9 mmol/L and insulin resistance index (HOMA-IR) > 2.6.

Effect: Daily supplementation of 2–3g L-leucine for 12 weeks can reduce HOMA-IR by 25%–30% and lower the risk of progressing to type 2 diabetes.

2. Obesity and Body Composition Improvement

Target Population: MS patients with BMI ≥ 28 kg/m² and visceral fat area > 80 cm².

Effect: Combined with a low-calorie diet and moderate exercise, daily supplementation of 3–4g L-leucine can further reduce body fat percentage by 1.5%–2% within 16 weeks, increase muscle mass retention rate by 10%–15%, and reduce muscle loss during weight loss.

3. Regulation of Dyslipidemia

Target Population: Patients with triglycerides > 1.7 mmol/L and HDL-C < 1.04 mmol/L (males) or < 1.3 mmol/L (females).

Effect: Daily supplementation of 2–3g L-leucine for 8 weeks can reduce triglycerides by 10%–15%, increase HDL-C by 5%–8%, and slightly improve LDL-C levels.

III. Application Precautions and Limitations

1. Dose and Administration

Recommended Daily Dose: 2–4g, divided into 2 doses (1–2g after breakfast and dinner). Avoid single high doses (>5g) to prevent gastrointestinal discomfort.

Optimal Combination: Use synergistically with dietary fiber, complex carbohydrates, and other BCAAs (isoleucine, valine) to improve absorption efficiency and metabolic regulation effects.

2. Contraindications and Special Populations

Individuals with Impaired Liver or Kidney Function: L-leucine metabolism primarily occurs in skeletal muscle, but those with severe liver or kidney dysfunction should use it cautiously to avoid metabolite accumulation.

Diabetic Patients: Monitor blood glucose during supplementation to prevent hypoglycemia caused by synergistic effects with hypoglycemic drugs.

Pregnant Women, Lactating Women, and Children: Insufficient safety data are available; routine supplementation is not recommended.

3. Limitations

L-leucine is only an auxiliary intervention and cannot replace basic treatments such as diet control and exercise, nor can it substitute for hypoglycemic or lipid-lowering drugs.

Significant individual differences exist: effects are more pronounced in patients with obvious insulin resistance, but relatively limited in those with simple obesity without insulin resistance.

IV. Future Research Directions

Clarify the differential effects of different L-leucine doses on various MS subtypes and develop personalized supplementation plans.

Explore the synergistic mechanisms of L-leucine with other nutrients (e.g., dietary fiber, Omega-3 fatty acids) to optimize intervention strategies.

Conduct long-term follow-up studies to verify the preventive effects of L-leucine on MS complications (e.g., cardiovascular diseases, kidney diseases).