Recent research suggests that amino acids, such as leucine and isoleucine, can improve glucose tolerance in vivo and in vitro animal models by accelerating glucose uptake in peripheral tissues and stimulate glycogen synthesis in vitro in the absence of insulin. Our laboratory recently found that gavaging normal Sprague-Dawley rats with an amino acid mixture, composed of isoleucine, leucine, cystine, methionine, and valine, improved blood glucose response during an oral glucose challenge without an increase in the plasma insulin response. The blood glucose-lowering effect of the amino acid mixture was due to an increase in skeletal muscle glucose uptake. These results suggest that this amino acid supplement acutely improves muscle insulin sensitivity and blood glucose homeostasis. However, the effect of this amino acid mixture on glucose tolerance and muscle glycogen synthesis in humans has not been investigated. Some studies have also shown that daily supplementation or acute ingestion of amino acids may prevent muscle damage that occurs as a result of a prolonged, intense endurance exercise or strength training and therefore improves force production and exercise performance. However, the effects of the addition of an amino acid mixture to carbohydrate supplement on muscle damage after a prolonged endurance exercise, as well as on the subsequent anaerobic exercise performance, have not been characterized. Therefore, in this series of two studies, the effects of an amino acid mixture, composed of isoleucine, leucine, cyctine, methionine, and valine, on glucose tolerance, muscle glycogen resynthesis, muscle damage, and anaerobic exercise performance were investigated. Study 1 demonstrated that our amino acid mixture lowered the glucose response to an OGTT in healthy overweight/obese subjects in an insulin-independent manner. Study 2 demonstrated that both high and low dosages of amino acid mixture were effective in lowering blood glucose response to a carbohydrate bolus in athletes postexercise. High dosage of amino acid mixture was more potent in glucose regulation by providing a higher insulin response and amino acid effect. However, our amino acid mixture had no effects on post exercise muscle glycogen synthesis, exercise-induced muscle damage or subsequent anaerobic performance. Taken together, the results of this research series suggest that an amino acid mixture, composed of isoleucine and 4 additional amino acids, attenuates the glucose response to a glucose bolus in an insulin-independent manner, but does not enhance muscle glycogen restoration following exercise or prevent exercise-induced muscle damage. / text

The traditional treatment for phenylketonuria (PKU) is a phenylalanine (Phe)-restricted diet, supplemented with a Phe-free/low-Phe protein substitute. Pharmaceutical treatment with synthetic tetrahydrobiopterin (BH4), an enzyme cofactor, allows a patient subgroup to relax their diet. However, dietary protocols guiding the adjustments of protein equivalent intake from protein substitute with BH4 treatment are lacking. We systematically reviewed protein substitute usage with long-term BH4 therapy. Electronic databases were searched for articles published between January 2000 and March 2020. Eighteen studies (306 PKU patients) were eligible. Meta-analyses demonstrated a significant increase in Phe and natural protein intakes and a significant decrease in protein equivalent intake from protein substitute with cofactor therapy. Protein substitute could be discontinued in 51% of responsive patients, but was still required in 49%, despite improvement in Phe tolerance. Normal growth was maintained, but micronutrient deficiency was observed with BH4 treatment. A systematic protocol to increase natural protein intake while reducing protein substitute dose should be followed to ensure protein and micronutrient requirements are met and sustained. We propose recommendations to guide healthcare professionals when adjusting dietary prescriptions of PKU patients on BH4. Studies investigating new therapeutic options in PKU should systematically collect data on protein substitute and natural protein intakes, as well as other nutritional factors.