initiation & elongation factors mRNA binding synthesis & assembly initiation & elongation factors mRNA binding synthesis & assembly blood amino acids Na+
FIGURE 14 Effects of insulin on protein turnover in muscle. Reactions stimulated by insulin are shown in blue. The dashed arrows indicate inhibition.
acids from blood by stimulating their transport across the plasma membrane. Insulin increases protein synthesis by promoting phosphorylation of the initiation factors (e.g., eIF-2 for eukaryotic initiation factor-2) that govern translation of mRNA. Under the influence of insulin, attachment of mRNA to ribosomes is enhanced, as reflected by the higher content of polysomes compared to monosomes. This effect of insulin appears to be selective for mRNAs for specific proteins. On a longer timescale, insulin increases total RNA in muscle by increasing synthesis of RNA and protein components of ribosomes. Understanding of how insulin decreases protein degradation is incomplete, but it appears that insulin decreases ATP-dependent protein degradation both by decreasing expression of various elements of the proteasomal protein degrading apparatus and by modulating the protease activity of its components.
Insulin reduces outflow of glucose from the liver and promotes storage of glycogen. It inhibits glycogenolysis, gluconeogenesis, ureogenesis, and ketogenesis, and it stimulates the synthesis of fatty acids and proteins. These effects are accomplished by a combination of actions that change the activity of some hepatic enzymes and rates of synthesis of other enzymes. Hence not all the effects of insulin occur on the same timescale. Although we use the terms block and inhibit to describe the actions of insulin, it is important to remember that these verbs are used in the relative and not the absolute sense. Rarely would inhibition of an enzymatic transformation be absolute. In addition, all ofthe hepatic effects ofinsulin are reinforced indirectly by actions of insulin on muscle and fat to reduce the influx of substrates for gluconeogenesis and ketogenesis. The actions of insulin on hepatic metabolism are always superimposed on a background of other regulatory influences exerted by metabolites, glucagon, and a variety of other regulatory agents. The magnitude of any change produced by insulin is thus determined not only by the concentration of insulin, but also by the strength of the opposing or cooperative actions of these other influences. Rates of secretion of both insulin and glucagon are dictated by physiologic demand. Because of their antagonistic influences on hepatic function, however, it is the ratio, rather than the absolute concentrations, of these two hormones that determines the overall hepatic response.
In general, liver takes up glucose when the circulating concentration is high and releases it when the blood level is low. Glucose transport into or out of hepatocytes depends on a high-capacity insulin-insensitive isoform of the glucose transporter GLUT 2. Because the movement of glucose is passive, net uptake or release depends on whether the concentration of free glucose is higher in extracellular or intracellular fluid. The intracellular concentration of free glucose depends on the balance between phosphorylation and dephosphorylation of glucose (Fig. 15, cycle II). The two enzymes that catalyze phosphorylation are hexokinase, which has a high affinity for glucose and other 6-carbon sugars, and glucokinase, which is specific for glucose. The kinetic properties of glucokinase are such that phosphorylation increases proportionately with glucose concentration over the entire physiologic range. In addition, glucokinase activity is regulated by glucose. When glucose concentrations are low, much of the glucokinase is bound to an inhibitory protein that sequesters it within the nucleus. An increase in glucose concentration releases glucokinase from its inhibitor and allows it to move into the cytosol where glucose phosphorylation can take place.
Phosphorylated glucose cannot pass across the hepa-tocyte membrane. Dephosphorylation of glucose requires the activity of glucose-6-phosphatase. Insulin suppresses synthesis of glucose-6-phosphatase and increases synthesis of glucokinase, thereby decreasing net output of glucose while promoting net uptake. This response to insulin is relatively sluggish and contributes to long-term adaptation rather than to minute-to-minute regulation. The rapid effects of insulin to suppress glucose release are exerted indirectly through decreasing the availability of glucose-6-phosphate, hence starving the phosphatase of substrate. Uptake and phosphorylation by glucokinase is only one source of glucose-6-P. Glucose-6-P is also produced by gluconeogenesis and glycogenolysis. Insulin not only inhibits these processes, but it also drives them in the opposite direction.
Most of the hepatic actions of insulin are opposite to those of glucagon, discussed earlier, and can be traced to inhibition of cyclic AMP accumulation. Rapid actions of insulin largely depend on changes in the phosphor-ylation state of enzymes already present in hepatocytes. Insulin decreases hepatic concentrations of cyclic AMP by accelerating its degradation by cyclic AMP phos-phodiesterase, and it may also interfere with cAMP formation and, perhaps, activation protein kinase A. The immediate consequences can be seen in Fig. 15 and are in sharp contrast to the changes in glucose metabolism produced by glucagon, as shown in Fig. 3. Insulin promotes glycogen synthesis and inhibits glycogen breakdown. These effects are accomplished by the combination of interference with cyclic AMP-dependent processes that drive these reactions in the opposite direction (see Fig. 4); by inhibition of glycogen synthase glycogen
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