Insulin resistance in health and disease: exploring the role of disuse skeletal muscle atrophy, testosterone and Beta-Hydroxy-Beta-Methylbutyrate (HMB) in young and older men

Background Combined exercise and nutraceutical interventions seems to have the potential to reverse some of the catabolic state associated with human skeletal muscle disuse atrophy and to positively influence glucose metabolism, however mechanisms underlying these processes are poorly defined and needs further exploration. Methods This thesis carried out a literature review of human skeletal muscle disuse atrophy and the effects on glucose metabolism before describing 3 randomised controlled trials to evaluate the effect of single leg immobilisation on muscle disuse in young men, effects of testosterone suppression (young men) and supplementation (old men) in addition to resistance exercise on glycaemic control and the role of Beta-Hydroxy-Beta-Methylbutyrate (HMB) supplementation on glucose metabolism in young and old men. Results Literature review revealed that immobilisation lowers fasted state muscle protein synthesis (MPS) and induces fed-state ‘anabolic resistance’ and induces muscle insulin resistance (IR). The randomised controlled trial described in this thesis showed that disuse atrophy acutely is driven by decline in MPS rather than increase in muscle protein breakdown (MPB) and seems to induce insulin resistance. Further, Testosterone (T) therapy and non-suppressed endogenous T, enhanced insulin sensitivity in older and young men, respectively, coupled with RET. Finally, HMB significantly reduced the insulin area-under-the-curve (AUC) with no difference in glucose AUC, resulting in a trend towards an increase in the Cederholm index of insulin sensitivity in younger men. Conclusions A multitudinous approach may be needed to overcome the increasing burden of persistent IR states such as Type 2 diabetes associated with loss of skeletal muscle: sarcopenia (disuse, disease, ageing etc.) and anabolic hormone resistance (ageing). So, our study tries to approach this complex area and it may be conceivable to address this issue by combining pre/re-habilitation (combined with RET) post muscle disuse, combined with anabolic hormone replacement (testosterone) and with nutraceuticals (HMB) supplementation