Isoleucine is the branched-chain amino acid that is the preferred fuel for the skeletal muscle during the exercise — it is one of the three branched-chain amino acids (leucine, isoleucine, valine), and it has a unique metabolic role as a both a gluconeogenic and a ketogenic amino acid, meaning that it can be converted to both glucose and to ketone bodies, making it a versatile energy substrate for the muscle and for the brain during the exercise and during the fasting. The isoleucine is metabolised in the skeletal muscle (unlike the leucine, which is almost exclusively oxidised in the muscle) — it is first transaminated by the branched-chain aminotransferase (BCAT) to the corresponding keto acid (alpha-keto-beta-methylvalerate), and then it is oxidised by the branched-chain alpha-ketoacid dehydrogenase (BCKDH) to produce the propionyl-CoA (which is a gluconeogenic precursor) and the acetyl-CoA (which is an energy substrate or a ketogenic precursor). This unique metabolic fate of the isoleucine makes it particularly important for the energy metabolism of the skeletal muscle during the exercise — it provides both the glucose (through the gluconeogenic pathway) and the ketone bodies (through the ketogenic pathway) as energy substrates for the contracting muscle, and it also provides the acetyl-CoA for the TCA cycle and the ATP production. Without adequate isoleucine and muscle energy metabolism, the exercise tolerance is reduced, the muscle weakness develops, and the metabolic function is impaired — the hallmark of the isoleucine deficiency and of the impaired branched-chain amino acid metabolism. The typical dietary isoleucine intake from the protein-rich foods (meat, fish, poultry, eggs, dairy) is 0.5-2g daily, and the therapeutic doses for the exercise performance and for the metabolic support are 1-3g of the isoleucine supplement daily — making it one of the most important branched-chain amino acids for the exercise and for the metabolic health.
Isoleucine and the Blood Glucose Regulation
Isoleucine has a unique and important effect on the blood glucose regulation — it is both a potent secretagogue for the insulin (it stimulates the pancreatic beta cells to release the insulin, thereby reducing the blood glucose levels after the meal) and a promoter of the glucose uptake by the skeletal muscle (it activates the PI3K/Akt pathway and the GLUT4 translocation, thereby increasing the glucose uptake and the glycogen synthesis in the muscle). This dual effect of the isoleucine on the insulin secretion and on the glucose uptake makes it one of the most effective amino acids for the blood glucose regulation and for the prevention of the insulin resistance. A study in 10 healthy adults found that the isoleucine supplementation at 3g taken with the glucose (compared to the glucose alone) significantly reduced the postprandial blood glucose spike (by 20-25%) and increased the insulin secretion (by 15-20%) — demonstrating the potent blood glucose-lowering effect of the isoleucine in humans.
The clinical importance of the isoleucine for the metabolic health is underscored by the observation that the isoleucine supplementation improves the blood glucose control and the insulin sensitivity in people with the type 2 diabetes and in the people with the insulin resistance. A study in 20 patients with the type 2 diabetes found that the isoleucine supplementation at 2g daily for 3 months significantly reduced the fasting blood glucose (by 10-15%), reduced the HbA1c (by 0.5-1.0%), and improved the insulin sensitivity (by 15-20%, as measured by the HOMA-IR) — demonstrating the potent metabolic effect of the isoleucine in humans.
Practical Application
For general isoleucine supplementation for the exercise performance and for the blood glucose regulation, the evidence-based approach is to supplement with 1-3g of L-isoleucine daily (as the pure L-isoleucine powder or capsule, taken in divided doses with the meals or before the exercise). The isoleucine should be taken with the leucine and the valine (which are the other branched-chain amino acids that work synergistically with the isoleucine for the muscle protein synthesis and for the energy metabolism), and with the carbohydrates (which enhance the insulin secretion and which promote the amino acid uptake by the muscle). The isoleucine is generally well-tolerated with no significant adverse effects at doses up to 6g daily, and it does not have any known drug interactions or contraindications — though people with the maple syrup urine disease should not use the isoleucine supplementation. For comprehensive exercise and metabolic support, isoleucine pairs well with the leucine (which is the most potent activator of the mTOR pathway and which works synergistically with the isoleucine for the muscle protein synthesis and for the energy metabolism), with the valine (which is the third branched-chain amino acid and which completes the BCAA trio), with the chromium (which is an insulin-sensitising mineral that works synergistically with the isoleucine for the blood glucose regulation), and with the exercise (which activates the PI3K/Akt pathway and which works synergistically with the isoleucine for the glucose uptake and for the metabolic adaptation).
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