The proximal tubule reabsorbs glucose via apical, electrogenic Na/glucose cotransport and basolateral facilitated diffusion
The fasting plasma glucose concentration is normally 4 to 5 mM (70 to 100 mg/dL; see p. 1038) and is regulated by insulin and other hormones. The kidneys freely filter glucose at the glomerulus and then reabsorb it, so that only trace amounts normally appear in the urine (Fig. 36-3A). The proximal tubule reabsorbs nearly all the filtered load of glucose, mostly along the first third of this segment. More distal segments reabsorb almost all of the remainder. In the proximal tubule, luminal [glucose] is initially equal to plasma [glucose]. As the early proximal tubule reabsorbs glucose, luminal [glucose] drops sharply, falling to levels far lower than those in the interstitium. Accordingly, glucose reabsorption occurs against a concentration gradient and must, therefore, be active.
FIGURE 36-3 Glucose handling by the kidney. The yellow box indicates the fraction of the filtered load that the proximal tubule reabsorbs. The green boxes indicate the fraction of the filtered load that remains in the lumen at various sites. The values in the boxes are approximations. PCT, proximal convoluted tubule; PST, proximal straight tubule.
Glucose reabsorption is transcellular; glucose moves from the lumen to the proximal tubule cell via Na/glucose cotransport, and from cytoplasm to blood via facilitated diffusion (see Fig. 36-3B, C). At the apical membrane, Na/glucose cotransporters (SGLT1, SGLT2; see pp. 121–122) couple the movements of the electrically neutral D-glucose (but not L-glucose) and Na+. Phloridzin, extracted from the root bark of certain fruit trees (e.g., cherry, apple), inhibits the SGLTs. The basolateral Na-K pump maintains intracellular Na+ concentration ([Na+]i) lower than that of the tubule fluid. Moreover, the electrically negative cell interior establishes a steep electrical gradient that favors the flux of Na+ from lumen to cell. Thus, the electrochemical gradient of Na+ drives the uphill transport of glucose into the cell (i.e., secondary active transport), thereby concentrating glucose in the cytoplasm. N36-2
Using Membrane Vesicles to Study Glucose Transport
Contributed by Gerhard Giebisch, Erich Windhager, Emile Boulpaep, Walter Boron
We describe the membrane-vesicle technique in N33-5. Figure 5-12 illustrates the use of this technique to explore how the Na+ gradient affects glucose uptake. The vesicles are made from brush-border membrane vesicles (i.e., made from the apical membrane of the proximal tubule). In the absence of Na+ in the experimental medium, glucose enters renal brush-border membrane vesicles slowly until reaching an equilibrium value (green curve in the central graph of Fig. 5-12). At this point, internal and external glucose concentrations are identical. The slow increase in intravesicular [glucose] occurs by diffusion in the absence of Na+. In contrast, adding Na+ to the external medium establishes a steep inwardly directed Na gradient, which dramatically accelerates glucose uptake (red curve in the central graph of Fig. 5-12). The result is a transient “overshoot” during which glucose accumulates above the equilibrium level. Thus, in the presence of Na+, the vesicle clearly transports glucose uphill. Similar gradients of other cations, such as K+, have no effect on glucose movement, beyond that expected from diffusion alone.
A negative cell voltage can also drive Na/glucose cotransport, even when there is no Na+ gradient. In experiments in which the internal and external Na+ concentrations are the same, making the inside of the vesicles electrically negative accelerates glucose uptake (not shown in Fig. 5-12).
In vesicle experiments performed on vesicles made from the basolateral membrane, the overshoot in intravesicular [glucose] does not occur, even in the presence of an inward Na+ gradient. Thus, the Na/glucose cotransporter is restricted to the apical membrane.
In the early part of the proximal tubule (S1 segment), a high-capacity, low-affinity transporter called SGLT2 (SLC5A2) mediates apical glucose uptake (see Fig. 36-3B). This cotransporter has an Na+-to-glucose stoichiometry of 1 : 1 and is responsible for 90% of the glucose reabsorption. Indeed, SGLT2 inhibitors have recently become available to treat patients with hyperglycemia due to diabetes mellitus. N36-3 In the later part of the proximal tubule (S3 segment), a high-affinity, low-capacity cotransporter called SGLT1 (SLC5A1) is responsible for apical glucose uptake (see Fig. 36-3C). Because this cotransporter has an Na+-to-glucose stoichiometry of 2 : 1 (i.e., far more electrochemical energy per glucose molecule), it can generate a far larger glucose gradient across the apical membrane (see Equation 5-20). Paracellular glucose permeability progressively diminishes along the proximal tubule, which further contributes to the tubule's ability to maintain high transepithelial glucose gradients and to generate near-zero glucose concentrations in the fluid emerging from the proximal tubule.
Clinical Use of SGLT2 Inhibitors
Contributed by Emile Boulpaep
SGLT2 inhibitors are novel “glucuretics” that have been approved for the treatment of type 2 diabetes. The low-affinity, high-capacity cotransporter SGLT2 reabsorbs the bulk of the filtered glucose in the S1/S2 segments of the proximal convoluted tubule, whereas the low-affinity, high-capacity cotransporter SGLT1 in the S3 segment reabsorbs the remainder. Thus, specific SGLT2 inhibition causes the bulk of filtered glucose to be excreted in the urine, whereas about 10% of filtered glucose is still reabsorbed by SGLT1, so that [glucose]plasma is prevented from falling below normal. However, in clinical practice, SGLT2 inhibitors inhibit only 30% to 50% of renal glucose reabsorption.
Phlorizin, the 2′-glucoside of phloretin, is a natural compound in the bark of fruit trees and a competitive inhibitor of both SGLT1 and SGLT2. Before the discovery of insulin, phlorizin was used in the treatment of diabetes, although the compound is poorly absorbed by gastrointestinal tract and not stable. The U.S. Food and Drug Administration approved two specific SGLT2 inhibitors for oral use in the treatment of type 2 diabetes in adults: canagliflozin and dapagliflozin (Farxiga). Urinary tract infections and genital fungal infections are common adverse effects of this treatment due to chronically high glucose concentration in the urine.
Abdul-Ghani MA, DeFronzo RA. Lowering plasma glucose concentration by inhibiting renal sodium-glucose co-transport. J Intern Med. 2014;276(4):352–363.
Once inside the cell, glucose exits across the basolateral membrane via a member of the GLUT (SLC2) family of glucose transporters (see p. 114). These transporters—quite distinct from the SGLTs—are Na+-independent and move glucose by facilitated diffusion. Like the apical SGLTs, the basolateral GLUTs differ in early and late proximal-tubule segments, with GLUT2 in the early proximal tubule (see Fig. 36-3B) and GLUT1 in the late proximal tubule (see Fig. 36-3C). In contrast to the apical SGLTs, the basolateral GLUTs have a much lower sensitivity to phloridzin.
Glucose excretion in the urine occurs only when the plasma concentration exceeds a threshold
The relationship between plasma [glucose] and the rate of glucose reabsorption is the glucose titration curve. Figure 36-4A shows how rates of glucose filtration (orange curve), excretion (green curve), and reabsorption (red curve) vary when plasma [glucose] is increased by infusing intravenous glucose. As plasma [glucose] rises—at constant GFR—from control levels to ~200 mg/dL, glucose excretion remains zero. It is only above a threshold of ~200 mg/dL (~11 mM) that glucose appears in the urine. Glucose excretion rises linearly as plasma [glucose] increases further. Because the threshold is considerably higher than the normal plasma [glucose] of ~100 mg/dL (~5.5 mM), and because the body effectively regulates plasma [glucose] (see p. 1038), healthy people do not excrete any glucose in the urine, even after a meal. Likewise, patients with diabetes mellitus, who have chronically elevated plasma glucose concentrations, do not experience glucosuria until the blood sugar level exceeds this threshold value.
FIGURE 36-4 Effect of increasing plasma glucose concentrations on glucose excretion and clearance. In A, Tm is the transport maximum for reabsorption. In A and B, the darker vertical bands represent the physiological range of plasma [glucose], which spans from a fasting [glucose] to the peak value after a meal.
The glucose titration curve shows a second property, saturation. The rate of glucose reabsorption reaches a plateau—the transport maximum (Tm)—at ~400 mg/min. The reason for the Tm value is that the SGLTs now become fully saturated. Therefore, these transporters cannot respond to further increases in filtered glucose.
Figure 36-4A also shows that the rate of glucose reabsorption reaches the Tm gradually, not abruptly. This splay in the titration curve probably reflects both anatomical and kinetic differences among nephrons. Therefore, a particular nephron's filtered load of glucose may be mismatched to its capacity to reabsorb glucose. For example, a nephron with a larger glomerulus has a larger load of glucose to reabsorb. Different nephrons may have different distributions and densities of SGLT2 and SGLT1 along the proximal tubule. Accordingly, saturation in different nephrons may occur at different plasma levels. N36-4
Clinical Correlates of Splay in the Glucose Titration Curve
Contributed by Erich Windhager, Gerhard Giebisch
Splay can be clinically important. Patients with proximal-tubule disease—mainly of hereditary nature and often observed in children—have a lower threshold, but a normal Tm. Thus, splay is exaggerated, presumably because some individual cotransporters have a low glucose affinity but normal maximal transport rate (see Equation 5-16). This abnormality results in glucose excretion at a lower-than-normal plasma [glucose]. Other patients have a normal threshold but a significantly reduced Tm (primary renal glucosuria). These patients, including those with Fanconi syndrome, have a reduced number of Na/glucose cotransporters. Thus, once plasma [glucose] exceeds the threshold, these patients excrete more glucose than normal. In addition, destruction of renal parenchyma by disease processes may diminish the activity of the basolateral Na-K pump and thus reduce the driving force for Na+ across the brush-border membrane, resulting in glucosuria.
At low filtered glucose loads, when no glucose appears in the urine (see Fig. 36-4A), the clearance (see p. 731) of glucose is zero. As the filtered load increases beyond the threshold, and glucose excretion increases linearly with plasma [glucose], the clearance of glucose progressively increases. At extremely high glucose loads, when the amount of glucose reabsorbed becomes small compared with the filtered load, glucose behaves more like inulin (i.e., it remains in the tubule lumen). Thus, if we replot the glucose-excretion data in Figure 36-4A as clearance (i.e., excretion divided by plasma [glucose]), we see that, as the filtered glucose load rises, glucose clearance N36-5 (see Fig. 36-4B, red curve) approaches inulin clearance (orange curve).
Contributed by Erich Windhager, Gerhard Giebisch
As stated in the text, the glucose clearance is zero at plasma glucose values below the threshold and gradually rises as plasma glucose level rises. We can express the excretion of glucose quantitatively at plasma concentrations beyond the threshold, where the glucose reabsorption rate (Tm) has reached its maximum:
All three terms in the above equation are plotted in Figure 36-4A. The first term in the equation () is represented by the green curve. The second term (GFR × PG) is the yellow curve. The term (TG) is the red curve. Dividing both sides of the equation by PG yields the glucose clearance (CG):
Thus, as plasma [glucose] approaches infinity, the right-hand term reduces to GFR, and therefore glucose clearance approaches inulin clearance (see Fig. 36-4B). In patients with an extremely low threshold, N36-4 glucose clearance even more closely approximates GFR.
The four key characteristics of glucose transport—(1) threshold, (2) saturation (Tm), (3) splay, and (4) clearance approaching GFR at infinite plasma concentrations—apply to several other solutes as well, including amino acids, organic-anion metabolites (e.g., lactate, citrate, and α-ketoglutarate [α-KG]), PAH, and phosphate.