The regulation of muscle protein turnover in diabetes.

Diabetes cannot be considered simply a disease of glucose dysregulation; it is a chronic inflammatory disease that affects nearly every biological process, including protein metabolism. Diabetes is associated with disturbances in muscle protein metabolism that results in decreased muscle mass and in some cases, loss in the activities of daily living, decreased productivity and diminished quality of life. Alteration in protein metabolism and its effect on muscle mass and function is one of the most challenging and least understood issues in the management of diabetes. Central among insulin action in muscle is suppression of protein degradation pathways and up-regulation of anabolic pathways. In type 1 diabetes, muscle wasting essentially results from insulin deficiency and this induces of genes involved in the ubiquitin proteasome pathway. On the other hand, the chief defect that leads to muscle atrophy in type 2 diabetes is decreased insulin responsiveness primarily in muscle. Decreased insulin responsiveness has been attributed to defects in the insulin signaling pathways secondary to inflammation (e.g., NF-κB activation and elevated levels of TNF-α, IL-1 and IL-6), metabolic acidosis, increased circulating free fatty acids and glucotoxicity. Furthermore, emerging pathways, such as myostatin/activin A system are beginning to be uncovered. We conclude with a discussion of possible interventions to slow, mitigate or reverse muscle wasting associated with diabetes. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.