On the Need to Distinguish Between Insulin-Normal and Insulin-Resistant Patients in Testosterone Therapy

Male hypogonadism is a disorder characterized by low levels of the hormone testosterone and patients may also have insulin sensitivity (IS) or insulin resistance (IR), such that they show different clinical complications and different metabolic pathways. In this review, we compare metabonomic differences observed between these two groups before and after testosterone therapy (TRT) in order to obtain information on whether the two hormones testosterone and insulin are synergistic or antagonistic. IS hypogonadism uses glucose as the main biofuel, while IR activates gluconeogenesis by the degradation of branched-chain amino acids. The Krebs (TCA) cycle is active in IS but connected with glutaminolysis, while in IR the TCA cycle stops at citrate, which is used for lipogenesis. In both cases, the utilization of fatty acids for energy (β-oxidation) is hampered by lower amounts of acetylcarnitine, although it is favored by the absence of insulin in IR. Increased free fatty acids (FFAs) are free in the blood in IS, while they are partially incorporated in triglycerides in IR. Thus, upon TRT, the utilization of glucose is increased more in IS than in IR, revealing that in IR there is a switch from preferential glucose oxidation to lipid oxidation. However, in both cases, a high production of lactate and acetyl-CoA is the final result, with these levels being much higher in IR. Lactate is used in IS in the glucose-lactate cycle between the liver and muscle to produce energy, while in IR lactate and acetyl-CoA are biotransformed into ketone bodies, resulting in ketonuria. In conclusion, the restoration of testosterone values in hypogonadism gives better results in IS than in IR patients: in IS, TRT restores most of the metabolic pathways, while in IR TRT impairs insulin, and when insulin is inactive TRT activates an ancestral molecular mechanism to produce energy. This evidence supports the hypothesis that, over time, hypogonadism switches from IS to IR, and in the latter case most of the insulin-related metabolisms are not reactivated, at least within 60 days of TRT. However, testosterone therapy in both IS and IR might be of benefit given supplementation with metabolites that are not completely restored upon TRT, in order to help restore physiological metabolisms. This review underlines the importance of using a systems biology approach to shed light on the molecular mechanisms of related biochemical pathways involving insulin and testosterone.