Skeletal muscle insulin resistance is a predictor of the development of type 2 diabetes and maintenance of adequate muscle glucose disposal in muscle may help to prevent diabetes. Lipodystrophy is a type of diabetes caused by a reduction of white adipose tissue and the adipokine leptin. Lipidemia, insulin resistance and hyperphagia develop as a consequence. In a recent study, we showed that increasing skeletal muscle mass by inhibiting signaling of myostatin, a transforming growth factor β (TGFβ) family member that negatively regulates muscle growth, prevents the development of diabetes in a mouse model of lipodystrophy. Muscle-specific myostatin inhibition also prevented hyperphagia suggesting muscle may regulate food intake. Here we discuss these results in the context of strategies to increase muscle insulin sensitivity as well as new findings about the effects of myostatin and other TGFβ family members on similar metabolic processes.