Clinical Note

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Optimal management of IDDM (type I) strives to match insulin dosage with food intake and physical activity. Many patients are able to receive their insulin from a small infusion pump that delivers the hormone subcutaneously throughout the day. They are taught to adjust the rate of hormone delivery upward or downward to match their circulating insulin concentrations to physiologic circumstances. Tight control of blood glucose concentration decreases the incidence of such long-term complications of diabetes as atherosclerosis, kidney failure, and blindness.

kinase, which, like protein kinase A, inactivates glyco-gen synthase; and by activation of the phosphatase that dephosphorylates both glycogen synthase and phos-phorylase. The net effect is that glucose-6-P is incorporated into glycogen.

By lowering cAMP concentrations, insulin decreases the breakdown and increases the formation of fructose-2,6-phosphate, which potently stimulates phosphofruc-tokinase and promotes the conversion of glucose to pyruvate. Insulin affects several enzymes in the PEP substrate cycle (see Fig. 15, cycle IV) and in so doing directs substrate flow away from gluconeogenesis and toward lipogenesis (Fig. 16). With relief of inhibition of pyruvate kinase, PEP can be converted to pyruvate, which then enters mitochondria. Insulin activates the mitochondrial enzyme that catalyzes decarboxylation of pyruvate to acetyl CoA and indirectly accelerates this reaction by decreasing the inhibition imposed by fatty long chain 4/—fatty acids long chain 4/—fatty acids

FIGURE 16 Effects of insulin on lipogenesis in hepatocytes. Blue arrows indicate reactions that are increased, and broken arrow indicates reaction that is decreased. (1) Pyruvate kinase, (2) pyruvate dehydro-genase, (3) acetyl CoA carboxylase, and (4) fatty acid synthase.

acid oxidation. Decarboxylation of pyruvate to acetyl coenzyme A irreversibly removes these carbons from the gluconeogenic pathway and makes them available for fatty acid synthesis. The roundabout process that transfers acetyl carbons across the mitochondrial membrane to the cytoplasm, where lipogenesis occurs, requires condensation with oxaloacetate to form citrate. Citrate is transported to the cytosol and cleaved to release acetyl CoA and oxaloacetate. Recall from earlier discussion that oxaloacetate is a crucial intermediate in gluconeo-genesis and is converted to PEP by PEP carboxykinase. Insulin bars the flow of this lipogenic substrate into the gluconeogenic pool by inhibiting synthesis of PEP carboxykinase. The only fate left to cytosolic oxalo-acetate is decarboxylation to pyruvate.

Finally, insulin increases the activity of acetyl CoA carboxylase, which catalyzes the rate-determining reaction in fatty acid synthesis. Activation is accomplished in part by relieving cyclic AMP-dependent inhibition and in part by promoting the polymerization of inactive subu-nits of the enzyme into an active complex. The resulting malonyl CoA not only condenses to form long-chain fatty acids but also prevents oxidation of newly formed fatty acids by blocking their entry into mitochondria (see Fig. 7). On a longer timescale, insulin increases the synthesis of acetyl CoA carboxylase.

Note that hepatic oxidation of either glucose or fatty acids increases delivery of acetyl CoA to the cytosol, but ketogenesis results only from oxidation of fatty acids. The primary reason is that lipogenesis usually accompanies glucose utilization and provides an alternate pathway for disposal of acetyl CoA. There is also a quantitative difference in the rate of acetyl CoA production from the two substrates: 1 mol of glucose yields only 2 mol of acetyl CoA compared to 8 or 9 mol for each mole of fatty acids.

Mechanism of Insulin Action

The many changes that insulin produces at the molecular level—membrane transport, enzyme activation, gene transcription, and protein synthesis—have been described. The molecular events that link these changes with the interaction of insulin and its receptor are still incompletely understood but are the subjects of intense investigation. Many of the intermediate steps in the action of insulin have been uncovered, but others remain to be identified. It is clear that transduction of the insulin signal is not accomplished by a linear series of biochemical changes, but rather that multiple intracel-lular signaling pathways are activated simultaneously and may intersect at one or more points before the final result is expressed (Fig. 17).

The insulin receptor is a tetramer composed of two a and two p glycoprotein subunits that are held together by disulfide bonds that link the a-subunits to the p-subunits and the a-subunits to each other (Fig. 18). The a- and p-subunits of insulin are encoded in a single gene. The a-subunits are completely extracellular and contain the insulin-binding domain. The p-subunits span the plasma membrane and contain tyrosine kinase activity in the cytosolic domain. Binding to insulin is thought to produce a conformational change that relieves insulin receptor

insulin receptor

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