In the presence of euglycemia, insulin displays a potent suppressive action on hepatic glucose production, such that portal insulin concentrations of less than 100 mU L−1 abolish glucose entry into the circulation. Figure 14.7 shows a typical time course for endogenous glucose production following an acute increase in plasma insulin to levels of 60 – 70 mU L−1 in a healthy subject. Dose – response curves relating calculated portal plasma insulin concentrations to suppression of glucose production (Figure 14.8) indicate a half maximal effect at 30 mU L−1 , corresponding to increments in portal insulin in the range of only 5 – 10 mU L−1 . Note that in its capacity of a glucose-producing organ the liver is very sensitive to insulin; physiologic hyperinsulinemia, on the other hand, does activate glucokinase, but the resulting increment in hepatic glucose uptake is very small . Hyperglycemia induced by intravenous glucose administration strongly synergizes this inhibitory action of insulin on hepatic glucose release (see Figure 14.4): in normal adults, a rise in arterial plasma glucose levels of only about 2 mmol L−1 is sufficient to reduce glucose output promptly by over 80% . Figure 14.8 also shows the dose – response of insulin-stimulated whole-body glucose disposal. The apparent maximum at euglycemia is in the order of 60 μmol min−1 kg−1 in healthy adult subjects, whereas the half-maximum lies around 70 – 110 mU L−1 of peripheral (systemic) plasma insulin concentrations . A dose – response curve of similar shape is derived when progressively higher insulin doses are applied locally in forearm tissues, about 70% of which consists of skeletal muscle . Extrapolating the latter data to total body muscle mass makes it possible to estimate that, with prevailing peripheral plasma insulin concentrations in the high physiologic range (60 – 90 mU L−1 ), 50 – 70% of a total glucose flux of 30 – 40 μmol min−1 kg−1 is disposed of in muscle tissue. Obviously, this percentage increases further at still higher insulin levels as the contribution of insulin-independent tissues declines. The control of glucose production and utilization by insulin is dependent on both concentration and time. At any given hormone concentration, there is a finite time before the effect sets in and reaches its maximum. Such onset time is the sum of a circulatory delay (from arterial blood to cell surface) and a cellular lag (intracellular diffusion and effector activation). Similarly, insulin’s effect is present for some time (offset) after the circulating concentration has returned to prestimulatory levels. Figure 14.9 shows the activation and deactivation times of insulin calculated at euglycemia over a wide range of plasma hormone levels (up to 1000 mU L−1) . With the reservations inherent in the analysis of non-steady-state tracer data, these results provide evidence that activation and deactivation are inversely related to one another; thus, at higher insulin doses the effect is more rapid and takes longer to wane. Further, the relationship between onset and offset time is different for the liver (suppression of glucose release) and for peripheral tissues (stimulation of glucose uptake): at any insulin dose, the liver is activated more rapidly and more persistently. The latter phenomenon may have to do with the shorter diffusion time of blood-borne substances into highly perfused organs (1 mL min−1 per gram of tissue in the liver versus a corresponding value of 0.04 mL min−1 g−1 in resting skeletal muscle; Table 14.1). The inter-individual variation of insulin-stimulated glucose disposal is large, covering a five- to sixfold span even in relatively homogeneous groups of healthy subjects. Adipose mass and degree of physical fitness are powerful determinants of insulin sensitivity, in that weight loss and regular aerobic training are associated with demonstrable gains in insulin sensitivity. On the other hand, age, gender, distribution of body fat, diet, and menstrual phase are general physiologic covariates of insulin sensitivity. Evidence obtained in Pima Indians  demonstrates that genetic factors are at work in the distribution of insulin sensitivity in the population. By combining indirect calorimetry with dose – response studies using the clamp technique, it has been possible to quantitate the two major components of whole-body glucose disposal, that is, glucose oxidation and nonoxidative glucose disposal — the latter consisting of glycogen synthesis for the most part (>90%) and the remainder being net lactate production via aerobic glycolysis [68,69]. Figure 14.10 shows that the two daughter curves retain the sigmoidal shape of the mother curve but with distinctly different dose kinetics. Thus, glucose oxidation is more sensitive (lower apparent half-maximum) but saturates earlier (lower maximum) than glycogen synthesis; the latter behaves as a pathway with low sensitivity and high capacity.
Skeletal muscle is the predominant site of insulin-mediated net glycogen synthesis; insulin also has a potent effect to augment hepatic glycogen synthesis although its contribution to total body glycogen synthesis is small compared to skeletal muscle. The increment in carbohydrate oxidation that follows systemic insulin administration occurs in muscle as well as other tissues including liver and adipocytes. Insulin inhibits lipolysis, reduces plasma FFA levels, and decreases and lipid utilization very effectively . As shown in Figure 14.11 (top), plasma FFA concentrations decline steeply in response to small increments in circulating insulin levels at euglycemia; this results from a drastic reduction in the rate of FFA appearance into the circulation. The consequence of the reduced availability of FFA is a parallel reduction in both FFA oxidation and nonoxidative FFA disposal, that is, reesterification (Figure 14.11, bottom). The reciprocal pattern of changes of glucose disposal/oxidation on the one hand, and lipid oxidation/utilization on the other, introduces the concept of substrate competition [70,71]. Glucose and long-chain FFA are the first and best-known example of substrates in mutual competition for use by insulin-dependent tissues as fuels. Physiologically, a rise in plasma glucose concentration increases the rate of glucose uptake into cells by mass action; the resulting increase in the generation of α-glycerolphosphate during anaerobic glycolysis supplies the substrate for augmented reesterification of tissue FFA, thereby limiting their release into the bloodstream. This effect is reinforced by the glucose-induced rise in insulin, which further reduces the supply of lipid substrates by directly inhibiting lipolysis. This glucose-on-FFA feedback is balanced by an FFA-on-glucose negative feedback. A rise in FFA availability enhances lipid oxidation and restrains pyruvate oxidation (at the pyruvate dehydrogenase step). This sequence of biochemical events and the intracellular signals that trigger it were elucidated by Randle and coworkers in an elegant series of experiments in rat hearts and diaphragms . In the human, experimental elevations in FFA concentrations inhibit insulin-mediated glucose disposal in a fashion that is both dose-dependent  and time-dependent . The insulin dose–response curves for glucose oxidation and glycogen synthesis are both shifted downwards during concomitant administration of an intravenous lipid load (Figure 14.12), providing evidence that an excess of lipid (FFA) supply inhibits not only glucose oxidation but also glycogen synthase  and glucose transport . The extent to which insulin action in target tissues is direct rather than mediated by shifts in substrate supply can be appreciated by comparing systemic with local insulin administration. When infused intra-arterially into the forearm, insulin does not alter the circulating substrate supply, in that neither FFA nor glucose levels change in the arterial blood re-circulating to the forearm tissues. Under these conditions, insulin stimulates forearm glucose uptake and lactate release, but induces only minimal changes in the local respiratory quotient (0.76). This indicates that the forearm tissues continue to rely mostly on lipid oxidation for energy production, and that the vast majority of insulin-stimulated glucose uptake is channeled to glycogen . In contrast, when comparable hyperinsulinemia is created by systemic insulin administration (with maintenance of euglycemia), the leg respiratory quotient increases from 0.74 to almost 1.00, that is, glucose oxidation increases while lipid oxidation is markedly depressed . In addition to substrate competition (Randle cycle), it is now recognized that FFA inhibit insulin-stimulated glucose metabolism by multiple other mechanisms. Following their entry into the cell, FFA are converted to their FACoA derivative. Long-chain FACoA inhibits the insulin-signal transduction system by causing serine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1 (see subsequent discussion) . LC-FACoA also have independent effects to inhibit the glucose transport system (GLUT4), glucose phosphorylation (hexokinase), and glycogen synthase [42,74,76,77]. Elevated intracellular levels of LC-FACoA are associated with increased concentrations of diacylglycerol (DAG) and ceramides which also cause serine phosphorylation of the insulin receptor and IRS-1, resulting in impaired insulin signaling and insulin resistance [78–80]. Collectively, these negative effects of LC-FACoA, DAG, and ceramides on insulin-stimulated glucose metabolism have been referred to as lipotoxicity . Amino acids also can enter a competition cycle with glucose, although somewhat less effectively than FFA. Increased amino acid provision enhances glucose production under conditions of insulin deficiency or resistance, and limits glucose utilization in the insulinized state . Furthermore, raising FFA has a hypoaminoacidemic effect in humans .
In summary, each of the three major substrates, if present in excessive amounts (whether by endogenous production or exogenous administration), can lower the level of the other two by stimulating insulin release. In this capacity, glucose is obviously favored, being a much more potent secretagogue than fat or amino acids. In addition, multiple substrate effects (not mediated by changes in insulin release) participate in the regulation of the substrates themselves: high FFA and amino acids raise glucose, while high FFA lower amino acids  (Figure 14.13).