Smith et al. (1) discussed the resistance to insulin properties of protein ingestion, focusing on the possible role of leucine as a master regulator of mTOR activation. But, finding leucine not guilty of insulin resistance is not a surprise as biochemistry indicates other amino acids as possible offenders.
As already described (2,3), some amino acids could be peculiarly and directly implicated in insulin resistance. Most suspect is alanine (which due to a low molecular weight is an amino acid whose number of molecules is extremely elevated in food proteins but also in plasma in absorptive and postabsorptive states) because it is derived by rapid metabolism of amino acids and one-step transamination of pyruvate molecules derived by glucose oxidation.
Alanine competes with pyruvate for receptors, thus creating a bottleneck for mitochondrial uptake of pyruvate that prevents full oxidation and also inhibits pyruvate kinase and the most upstream controller of glucose oxidation phosphofructokinase, mimicking the effects of citrate or glucagon. An accomplice in those actions may be arginine, abundantly present in food proteins, has a well-known liability in glucagon secretion (4), and this further implements circumstantial evidences of being implicated in the impairment of insulin-mediated glucose disposal.
Noticeably, long-term supplementation with all essential amino acids (containing leucine) by increasing the expression of PGC-1α, and consequently of PPAR-γ, promotes glucose homeostasis by mitochondrial biogenesis (5). Thus, I may agree with Smith et al. (1), leucine, although a ketogenic amino acid, is innocent of impairing insulin-stimulated glucose disposal. But, mTOR is not guilty, it is just a passive witness of a most complex signaling transduction.
Duality of Interest. F.S.D. is the inventor and licenser to Helsinn Healthcare SA of U.S. patents: US6218420 B1 (compositions based on amino acids for preventing and treating alimentary overloads in conditions of elevated body nitrogen requirements, without causing calcium losses) and US7973077 B2 (amino acid–based compositions for the treatment of pathological conditions distinguished by insufficient mitochondrial function). No other potential conflicts of interest relevant to this article were reported.