Lipid accumulation in skeletal muscle and insulin sensitivity.

Plasma free fatty acid (FFA) levels, which are generally elevated in obese subjects, appear to be an important link between obesity and insulin resistance. Several studies have shown that acute raising of plasma free fatty acid levels, via infusion of lipid emulsions, causes profound insulin resistance in skeletal muscle of animals and human subjects. Remarkably, the insulin resistance that occurs during lipid infusion becomes apparent only after a delay of 3-4 hours, making a direct effect of FFA on insulin action unlikely. To this issue, FFA may need to accumulate first as triglycerides inside the muscle fibres to cause disturbances in the insulin signalling cascade. The metabolic characteristics of MCFA make them an interesting tool to study the involvement of long-chain fatty acids (and derived metabolites) in the development of insulin resistance. Since medium chain fatty acids cannot be converted to diacylglycerol and subsequently stored as triglycerides and are preferentially oxidised they may not interfere with insulin signalling.Therefore, by comparing the effect of medium-chain and long-chain fatty acids on insulin signalling, it can be directly tested that the accumulation of diacylglycerol is responsible for the impaired insulin signalling.

Administration of a lipid emulsion consisting of long-chain triglycerides will induce insulin resistance due to increased DAG mass and subsequent activation of the PKC pathway in skeletal muscle. Infusion of a lipid emulsion consisting of medium-chain triglycerides will not increase DAG mass and the PKC pathway will not be activated. Therefore, the induction of insulin resistance will be absent.

Before and after the 6h hyperinsulinemic-euglycemic clamps with simultaneous lipid/glycerol infusion, a muscle biopsiy will be obtained. Throughout each clamp, blood samples will be drawn every hour.

Ten healthy, lean, untrained male subjects (age 18-35; BMI ≤ 25 kg/m2) will undergo, in a randomized crossover design, a 6h-hyperinsulinemic euglycemic clamp (to assess insulin sensitivity) with simultaneous lipid infusion. In the first condition, the lipid infusion will consist of triglycerides containing long-chain fatty acids while in the second condition, fatty acids in the lipid emulsion will be mainly of medium-chain length. As a control condition, glycerol will be infused (to match the glycerol content of the other lipid emulsions). Before and after each glucose clamp, muscle biopsies will be obtained.