Obesity and type 2 diabetes frequently occur together, indicating that these conditions may share common pathological mechanisms. Increased circulating free fatty acid (FFA) concentrations have been indicated as an important risk factor in the etiology of both conditions and in the predisposition towards other chronic diseases like cardiovascular disease. An increased delivery of FFA to the liver may underlie many metabolic disturbances in obesity and type 2 diabetes like a decreased insulin binding to hepatocytes, a diminished insulin clearance, an impaired insulin-mediated suppression of hepatic glucose output and an increased very low density lipoprotein (VLDL)-triacylglycerol output. Additionally, it has been proposed that chronically elevated FFA concentrations may reduce insulin secretion in type 2 diabetes.

On one hand, the elevated FFA concentrations may result from an increased release from the expanded adipose tissue stores. There are indications that a decreased β-adrenergically mediated lipolysis may play an important role in the development or maintenance of increased triacylglycerol stores within (subcutaneous) adipose tissue (Blaak et al. 1994). This catecholamine resistance may be related to a decreased number or function of β₂-adrenoceptors, a dysbalance between α₂ and β-adrenoceptor function or a defect in the action of hormone-sensitive lipase. Additionally, it is hypothesized that defects in HSL translocation or perilipin function (proteins that coat the lipid droplet) may contribute to an impaired lipolytic response.

On the other hand, defects in skeletal muscle FFA uptake and oxidation exist in obesity and type 2 diabetes mellitus. Previously, we have shown a diminished skeletal muscle uptake of FFA in abdominally obese subjects during β-adrenergic stimulation (Blaak et al. 1994). Additionally, using the forearm balance technque in combination with infusion of the stable isotope tracer [U-¹³C]-palmitate, it was shown that the uptake and oxidation of FFA were diminished in skeletal muscle of type 2 diabetic subjects during postabsorptive conditions and during β-adrenergic stimulation (Blaak et al. 2000; Fig. 1). The impairments in FFA utilization also extended to a condition of moderate intensity exercise (at 50 % of V_O2,max), where it was shown (using the stable isotope tracer [U-¹³C]-palmitate) that the oxidation of plasma-derived fatty acids was significantly lower in type 2 diabetic subjects compared with controls, matched for body composition and maximal aerobic capacity (Mensink et al. 2001). This impaired capacity to take up and oxidize FFA during exercise persisted after weight reduction in type 2 diabetic subjects (Blaak et al. 2001) and was already present in obese subjects with impaired glucose tolerance (prediabetic state; Mensink et al. 2001; Fig. 2), indicating that these defects may play a primary role in the development of type 2 diabetes mellitus. We showed in a recent study that lifestyle intervention (a combined diet-physical activity intervention) can prevent a further deterioration of disturbances in (plasma free) fatty acid oxidation in subjects with IGT, which may be one of the mechanisms underlying the beneficial effect of a lifestyle-intervention programme on glucose tolerance and insulin resistance.

Several mechanisms may be responsible for the impaired capacity of skeletal muscle to take up or to oxidize plasma fatty acids. There are indications that muscle lipolysis may be increased in type 2 diabetic subjects (Blaak et al. 2000). An increased lipolysis may flood the muscle with FFA, thereby decreasing the blood-tissue concentration gradient, which is one of the primary determinants of plasma fatty acid uptake and oxidation. Furthermore, the biochemical characteristics of skeletal muscle for the capacity to take up or utilize FFA, like fibre type, oxidative enzyme capacity, the activity of carnitine palmitoyl transferease and the expression of various fatty acid binding proteins, may be altered in obese or obese type 2 diabetic subjects (Simoneau et al. 1999; Blaak et al. 2000). Further studies are required to elucidate the role of the disturbances in fatty acid metabolism in insulin resistance in obesity and type 2 diabetes mellitus and to obtain more information on the underlying mechanisms.