Intracellular Mechanisms of Metabolism Regulation: The Role of Signaling via the Mammalian Target of Rapamycin Pathway and Other Routes

The development of diabetes mellitus is the consequence of defects in the action of insulin in skeletal muscles and adipose tissue other than pancreas and liver defects. Insulin action defects are mostly the results of defects of the insulin intracellular signaling transduction pathway. This review summarizes the main mechanisms involved in insulin signaling and possible intracellular defects that lead to insulin resistance. We also report preliminary experimental data that suggest the existence of intracellular alternatives to insulin metabolic pathways stimulated by nutrients such as amino acids (AAs). Indeed, we found that oral supplements with AAs stimulated both glucose transporter–4 and protein synthesis through independent insulin signals in rat hearts. Evidence suggests that the mammalian target of rapamycin and/or other molecules could be involved in this insulin-independent metabolic pathway.This hypothesis suggests the presence of an ancestral metabolic pathway in eukaryotic cells that is not active when insulin intracellular signaling is efficient but can be activated by alternative stimuli, such as AAs, when insulin signaling is impaired. Our observations provide molecular evidence that supports the use of anabolic nutrients such as AAs, together with standard therapies, to overcome insulin resistance syndrome.