Saturday , August 19 2017
Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #78: Insulin Actions In Vivo: Glucose Metabolism Part 4 of 9

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #78: Insulin Actions In Vivo: Glucose Metabolism Part 4 of 9

Glucose disposal

In the basal state, steady/near steady-state conditions prevail and whole-body glucose disposal equals endogenous (hepatic) plus renal glucose production. Data on the individual contribution of organs and tissues to total glucose uptake have been obtained in regional catheterization studies. In the case of the splanchnic area, in which glucose uptake and production both occur simultaneously, such data have been derived from the combined use of glucose tracers and indwelling catheters, as diagrammatically shown in Figure 14.1. By collating the available information, the organ-circulation model of Figure 14.5 can be drawn, in which steady-state inter-organ exchanges of blood and glucose, and regional glucose gradients, are calibrated at a rate of endogenous glucose release of 840 μmol min−1 (or 12 μmol min−1 kg−1 or 1.2 mol day−1 ). In this model, it is seen that roughly 70% of basal glucose disposal takes place in insulin-independent tissues (brain, liver, kidney, intestine, erythrocytes). It can also be appreciated that the fractional extraction of glucose is quite low everywhere in the body (ranging from 1.7 to 2.8%) except in the brain (9%). If it is assumed that skeletal muscle (40% of body weight) receives 16% of cardiac output and is responsible for one quarter of overall glucose disposal (∼245μmolmin−1; Figure 14.5), then muscle glucose clearance averages 1.3 mL min−1 kg−1 of tissue.

Chapter14Fig14.5

This value can be compared with those of other organs and tissues (Table 14.1) similarly obtained by dividing the organ glucose clearance by the estimated organ weight. In the rank of efficiency of glucose utilization in the basal state, resting muscle is last, being 10 times less active than the liver, and 50 times less avid than the brain. In tissues in which specific glucose clearance is already high (brain, liver, kidneys), the effect on glucose uptake of acutely raising plasma insulin levels above fasting values is small or absent, while in muscle glucose clearance can increase by a factor of 10 over the physiologic range of insulin concentrations. The intermediate position of heart muscle in the list is likely accounted for by its working state. As reviewed earlier, these characteristics can now be seen as the physiologic equivalent of the type and abundance of specific glucose transporters with which the various tissues are endowed. They also narrow the concept of an insulin-independent tissue: thus, raising the plasma insulin concentration does not accelerate glucose clearance. However, lowering insulin may reduce the efficiency of glucose removal, and even non-insulin-regulatable glucose transporters are subject to chronic regulation. In humans this has been verified for at least two insulin-independent tissues: the liver and the brain. For the former, selective hypoinsulinemia (induced with somatostatin and glucagon replacement) lowers splanchnic glucose uptake below the basal value in healthy volunteers [32] (Figure 14.4).

Chapter14Fig14.4For the latter, indirect calculations indicate that brain glucose clearance is reduced in type 2 diabetic patients with moderate fasting hyperglycemia [52]. The intracellular disposition of transported glucose can be studied by using glucose tracers, and then tracking down the appearance of the label in specific metabolic products, such as lactate (i.e., anaerobic glycolysis) or carbon dioxide (i.e., complete oxidation) (see earlier discussion). It should be noted that these techniques, even when correctly applied, provide estimates of the metabolic fate of plasma glucose, which is the labeled pool. If, for example, there should be direct oxidation of glycogen in muscle, the plasma glucose specific activity would miss it (because of the lack of G6Pase in muscle tissue). However, total carbon dioxide production, measured with indirect calorimetry, would include the oxidized glycogen together with all the other oxidized substrates. In general, measuring the exchange of oxygen and carbon dioxide with indirect calorimetry makes it possible to obtain estimates of net rates of substrate oxidation and also provides a close estimate of the rate of energy expenditure [53]. In the basal state and under ordinary nutritional circumstances, oxygen consumption averages ∼250 mL min−1 , while carbon dioxide production is ∼200 mL min−1 , that is, a whole body respiratory quotient of 0.8 (RQ = carbon dioxide production/oxygen consumption). Simple calculations [54] thus estimate whole-body net carbohydrate oxidation at about 60% of total glucose uptake. As the brain uses 46% of glucose turnover (Table 14.1) and readily oxidizes the transported sugar, it follows that three quarters (i.e., 46/60 = 77%) of basal glucose oxidation occurs in the brain. Little is left for other tissues, which preferentially derive their metabolic energy from the oxidation of fatty substrates and return most of the glucose to the liver after conversion into lactate (Cori cycle). Skeletal muscle, for example, has a respiratory quotient of 0.75 and relies on fat oxidation for the production of 80% of the energy it needs in the resting state [55]. Thus, the basal state is characterized by parsimonious usage of glucose as fuel, which is selectively channeled to organs that cannot rely on alternative energy sources. Altogether over one half of total energy production (5 kJ min−1 ) is generated via oxidation of fat, of which there are plentiful (∼500MJ) and almost unlimited stores (e.g. obesity). The role of insulin in maintaining this metabolic setup is permissive rather than determinant. Through a loose brake on lipolysis, insulin lets FFA override glucose in the competition between the two chief substrates, keeps glucose transport and metabolism in its own target tissues at a minimum, and restrains protein breakdown (which contributes only about 15% to energy metabolism). The part that counterregulation plays in basal glucose uptake is less well defined, but probably is centered upon maintenance of lipolysis, since all the anti-insulin hormones are more or less potent lipolytic stimuli.

Glucose cycles

After transport through the plasma membrane, glucose does not necessarily follow a straight path to its eventual fate — be it glycogen, pyruvate, or pentoses — but may go around in what are known as futile cycles. A metabolic futile cycle is one in which a precursor is converted into a product by a forward reaction, which is then reversed to resynthesize the precursor. In this way, no net product accumulates, but energy (ATP) is used. One example of a futile cycle, G6P to fructose-6-phosphate and back through the phosphoglucoisomerase reaction, has been discussed previously and can be measured as the difference between the turnover rate as estimated by 2H and 3H isotopes of glucose. Another example is glucose to G6P via glucokinase and back via G6Pase. In general terms, whenever bidirectional flux through a metabolic pathway is simultaneously operative, there exists a cycle, regardless of the number of intermediate reactions and regardless of whether one or more tissues are involved. In this sense, lipolysis in adipose tissue, followed by partial re-esterification of FFA in the liver, is a complete cycle. Another one is protein breakdown in skeletal muscle with reincorporation of amino acids into proteins in the liver. The negative connotation of futility has traditionally been reserved for those cycles that go on in the same cell. They are, however, anything but futile. As discussed by Newsholme [56], a metabolic cycle with an internal loop is the best kinetic stratagem to keep the enzymes of a dormant pathway at a minimum of activity, and to ensure a sensitivity gain for ready amplification of incoming signals. The ATP cost of these cycles is itself a means of increasing the efficiency of energy dissipation. The fact that the activity of these cycles is under hormonal control (e.g. catecholamines and thyroid hormones enhance the cycling rate) makes room for modulation; in this way, these cycles become components of facultative thermogenesis.

Click here to view all Chapter 14 references.