The correlation between L-leucine and insulin secretion

L-leucine has a dual connection with insulin secretion—"direct stimulation + indirect regulation." It not only directly promotes insulin secretion from pancreatic β-cells as a nutritional signal but also indirectly optimizes insulin action efficiency by improving insulin sensitivity and regulating metabolic pathways. Relevant studies have confirmed its key role in blood glucose regulation.

I. Mechanisms of Directly Stimulating Insulin Secretion

1. Metabolite-Mediated Signal Activation

In pancreatic β-cells, L-leucine is metabolized by branched-chain amino acid transaminase (BCAT) to form α-ketoisocaproate (KIC), which is further catalyzed by dehydrogenase to produce acetyl-CoA. Acetyl-CoA enters the tricarboxylic acid (TCA) cycle to generate ATP, closing the ATP-sensitive potassium channels (KATP) on the pancreatic β-cell membrane. Membrane depolarization opens calcium channels, and calcium influx triggers the release of insulin granules. Meanwhile, KIC can activate intracellular glutamate dehydrogenase (GDH), promoting glutamate metabolism to generate additional ATP and enhancing the insulin secretion signal.

2. Mammalian Target of Rapamycin (mTOR) Pathway Regulation

L-leucine can directly activate the mTOR signaling pathway in pancreatic β-cells, phosphorylating the downstream ribosomal protein S6 kinase (p70S6K), thereby regulating the synthesis and secretion of insulin granules. This pathway also upregulates insulin gene transcription, increasing proinsulin production and providing sufficient substrates for secretion.

3. Activation of Amino Acid-Sensing Receptors

G protein-coupled receptors 40 (GPR40) and GPR120 on the pancreatic β-cell membrane can sense branched-chain amino acids such as L-leucine. Their activation enhances calcium signaling through second messenger pathways, synergistically promoting insulin secretion. Studies have shown that L-leucine has a higher binding affinity for GPR40 than other BCAAs, which is its unique advantage in stimulating secretion.

II. Associated Mechanisms of Indirectly Regulating Insulin Action

1. Improving Insulin Sensitivity

L-leucine promotes the expression and membrane localization of GLUT4 glucose transporters in skeletal muscle cells, enhancing the response of skeletal muscle to insulin, increasing glucose uptake and utilization, and indirectly reducing the secretory pressure on pancreatic β-cells. In adipose tissue, L-leucine can inhibit the expression of inflammatory factors (e.g., TNF-α, IL-6), reduce adipocyte insulin resistance, and optimize systemic insulin sensitivity.

2. Regulating Hepatic Glucose Metabolism to Indirectly Affect Insulin Demand

L-leucine inhibits the activity of key hepatic gluconeogenic enzymes (e.g., phosphoenolpyruvate carboxykinase, glucose-6-phosphatase), reducing hepatic glucose output and lowering blood glucose levels, thereby decreasing the body’s demand for insulin. Meanwhile, its metabolite acetoacetate can serve as an energy substrate for the liver, replacing glucose for energy supply and further reducing the stimulation of insulin secretion caused by blood glucose fluctuations.

III. Key Research Evidence and Conclusions

1. Human Clinical Trials

In healthy individuals, oral administration of 2–5 g L-leucine significantly increases plasma insulin levels within 30–60 minutes, with the peak value 30%–50% higher than the baseline, and blood glucose levels decrease by 10%–15% simultaneously.

In patients with type 2 diabetes, supplementation of L-leucine (3–7 g/day for 12 weeks) does not significantly increase fasting insulin levels, but the insulin resistance index (HOMA-IR) improves by 20%–30%, and the postprandial blood glucose peak decreases.

2. Cell and Animal Experiments

In in vitro culture of pancreatic β-cells, adding 1–5 mmol/L L-leucine increases insulin secretion by 2–3 times, while BCAT or mTOR inhibitors can block this effect, confirming the key roles of metabolic pathways and the mTOR pathway.

In diabetic mouse models, supplementation of L-leucine restores pancreatic β-cell function, increases insulin secretion, reduces blood glucose and glycated hemoglobin levels, and delays the progression of diabetes.

3. Dose-Dependence and Synergistic Effect Studies

The stimulation of insulin secretion by L-leucine is dose-dependent, with an effective daily dose of 2–10 g in humans. Excess intake (>15 g/day) may reduce the stimulation effect due to metabolic burden.

Synergistic supplementation with glucose, other BCAAs (e.g., L-isoleucine, L-valine), or dietary fiber leads to a more significant promotion of insulin secretion, reflecting nutritional synergy advantages.

IV. Research Controversies and Future Directions

1. Potential Controversies

Some studies have found that long-term high-dose supplementation of L-leucine may cause imbalance in BCAAs metabolism, increase the pressure on pancreatic β-cells in obese individuals, and even exacerbate insulin resistance, indicating the importance of dose control.

There are individual differences in the response to L-leucine among different populations (e.g., healthy people, diabetic patients, the elderly), and precise supplementation schemes need to be further clarified.

2. Future Research Directions

Further explore the synergistic regulatory mechanisms between L-leucine and other nutrients (e.g., probiotics, vitamin D) to optimize blood glucose management strategies.

Conduct long-term intervention studies in individuals with prediabetes to verify the role of L-leucine in protecting insulin secretion function.

Develop drugs or functional foods targeting the L-leucine metabolic pathway to provide new directions for diabetes treatment.