Type 2 diabetic patients exhibit a decreased fat oxidative capacity and high levels of circulating free fatty acids (FFAs). This is a major cause for insulin resistance, in particularly in skeletal muscle, by reducing insulin stimulated glucose uptake, this likely occurs due to accumulation of lipid inside the muscle cell. A reduced skeletal muscle oxidative capacity can worsen this state. Type 2 diabetes mellitus also is associated with impaired metabolic flexibility, i.e. an impaired switching from fatty acid to glucose oxidation in response to insulin. Thus, a reduced fat oxidative capacity and metabolic inflexibility are important components of skeletal muscle insulin resistance. The cause of these derangements in skeletal muscle of type 2 diabetic patients remains to be elucidated. An impaired mitochondrial function is a likely candidate. Evidence from both in vivo and ex vivo studies supports the idea that an impaired skeletal muscle mitochondrial function is related to the development of insulin resistance and type 2 diabetes mellitus. Obesity plays a role not only for the functioning of the muscle but also for the functioning of adipose tissue. Adipose tissue regulates energy usage and food-uptake via a large number of adipokines and related factors, like for instance leptin, adiponectin, omentin, visfatin, resistin, tumor necrosis factor-a (TNF-alpha), interleukin-6 (IL-6), retinol-binding protein 4 (RBP4), and others. The regulation of these factor is malfunctioning in Type 2 Diabetics.