the pancreas gland. The entry of a water-soluble substrate such as glucose across an impermeable lipid bi-layer into a cell requires a speciﬁc transport mechanism. These protein carriers are known as glucose ‘transporters’ (GLUTs). In the case of glucose there are at least six types and they tend to be tissue-speciﬁc. In the case of muscle the transporter is called ‘Glut 4’. It is normally present in excess in the cell membrane even in the absence of insulin and is not rate limiting for glucose entry into the cell (Sonksen 2001). Insulin acts in a stimulatory and an inhibitory manner (Schafer 1916). It stimulates the translocation of ‘Glut 4’ from the cytoplasm of muscle and adipose tissue to the cell membrane. This increases the rate of glucose uptake to values greater than in the basal state without insulin, shown in isolated adipocytes from rats (Figure 3) (Thomas et al 1979). There are a sufﬁcient number of glucose transporters in all cell membranes at all times to ensure enough glucose uptake, to satisfy the cell’s respiration, even in the absence of insulin. Insulin increases the number of these transporters in some cells but glucose uptake is never truly insulin-dependent (Sonksen, 2001). In Figure 3, it can be seen that simultaneously with insulin’s excitatory action in stimulating lipogenesis, insu- lin also exhibits an inhibitory action in preventing glycerol release. It is this inhibitory action on lipolysis (and also glycolysis, gluconeogenesis, ketogenesis, and proteolysis) that accounts for most of insulin’s physiological actions in AAS, growth hormone, and insulin abuse man. The inhibitory actions are also responsible for insulin’s net anabolic actions. Insulin increases glucose metabolism more through reducing FFA and ketone levels than it does through recruit- ing more GLUTs into the muscle cell membrane. Insulin does, however, have a direct action recruiting more GLUTs into muscle cell membranes. This facilitates glucose uptake which is reﬂected as an increase in the metabolic clear- ance rate (MCR) of glucose, measured with isotope tracer technology and is a nonlinear function of blood glucose concentration, increasing as glucose concentration falls and insulin levels rise (Sonksen and Sonksen 2000). Glucose transport into the cell is mainly determined by the con- centration gradient between the extracellular ﬂuid and the intracellular ‘free’ glucose. ‘Free’ glucose is very low inside the cell as it is immediately phosphorylated. In uncontrolled diabetes, particularly where there is a high concentration of FFA and ketones, glycolysis is inhibited, phosphorylation of ‘free’ glucose stops and intracellular ‘free’ glucose rises. Insulin recruits more transporters into the cell membrane from an intracellular pool. This increases the rate of glucose entry for a given glucose concentration and this is reﬂected in vivo by an increase in the MCR of glucose, which is an in vivo measure of substrate transporter activity (Boroujerdi et al 1995). Experiments in normal subjects using hyperglycaemic and hyperinsulinaemic ‘clamps’ have shown the importance Figure 3 Insulin exhibits both inhibitory and excitatory actions via the same receptor. In these experiments carried out on rat adipose tissue, in vitro insulin simultaneously inhibits lipolysis (the release of glycerol from stored triglyceride) and stimulates lipogenesis (formation of stored triglyceride from glucose).Thus its anabolic action is due to two mechanisms working synergistically. Copyright © 1979 Royal Society of Medicine. Reproduced with permission from Thomas SHL,Wisher MH, Brandenburg D, et al. 1979. Insulin action on adipocytes. Evidence that the anti-lipolytic and lipogenic effects of insulin are medicated by the same receptor. Biochem J, 184:355–60. Therapeutics and Clinical Risk Management 2008:4(3) 593