Obesity is associated with an increased risk of several diseases and premature mortality. Although we are all aware that obesity increases the risk of type 2 diabetes and that losing weight by exercising is protective, what is less understood is that a single bout of exercise increases insulin sensitivity for 24-48 hours.  The major site of insulin resistance in type 2 diabetes is skeletal muscle.  This talk will discuss the regulation of skeletal muscle glucose uptake into skeletal muscle and compare and contrast the effects of exercise and insulin.  Although people with type 2 diabetes have reduced insulin-stimulated glucose uptake into skeletal muscle, importantly, during exercise their skeletal muscle glucose uptake is normal.  Therefore, if we can understand what regulates skeletal muscle glucose uptake during exercise agents may be able to be developed to mimic the exercise pathway in those that can not or will not exercise.  Although there are distinct pathways regulating skeletal muscle glucose uptake in response to exercise and insulin, exercise is able to increase insulin sensitivity in skeletal muscle.  The potential regulators of this beneficial effect of exercise will be discussed including recent work we have conducted examining the role of nitric oxide.  In addition, there will be discussion of the evidence that exercise early in life can attenuate the increased diabetes risk of being born small.