The diabetic proximal tubule: part of the problem, and part of the solution?

Abstract

PHYSIOLOGICAL INTEREST IN RENAL glucose handling dates to the era of whole organ experiments, with the description of a renal glucose threshold (Tm) and osmotic diuresis (22). Micropuncture identified the proximal tubule as the locus of glucose reabsorption (3), and brush border vesicle preparations (1, 8) and cellular electrophysiology (4, 18) established the Na ϩ dependence of that luminal glucose flux. Careful analysis of vesicle kinetics suggested two glucose transporters, one highcapacity, low-affinity site and a second with high affinity and smaller fluxes (17). The low-affinity carrier localized to the outer cortical region, and the high-affinity carrier localized to outer medullary vesicles. Corresponding to the affinity difference was the determination of a 1:1 (glucose:Na ϩ ) stoichiometry of the cortical cotransporter (6) and a 1:2 stoichiometry of the high-affinity carrier (16). Perfusion of isolated tubule segments confirmed the high-capacity carrier in the proximal convoluted tubule and the high-affinity transporter in the proximal straight tubule, whose maximum flux was ϳ10 -15% of that of the convoluted segment (2). An important advance in renal glucose transport came with the cloning of the gene for the intestinal cotransporter SGLT1 (SLC5A1) (5). In situ hybridization localized SGLT1 to the S3 segment of the proximal tubule, precisely the site suggested by the kinetic data (9). Oocyte expression of SGLT1 enabled extensive electrophysiological investigation and formulation of a mathematical model of the transporter. This work revealed that solute binding affinity is asymmetric, comparing inside and outside of the carrier, and translocation of the empty carrier is the important rate-limiting step and sensitive to the transmembrane potential difference (14). In pursuit of the high-capacity Na ϩ -glucose cotransporter, homology screening revealed the gene for SGLT2 (SLC5A2), expressed in the kidney, for which the stoichiometry is 1:1 and which in situ hybridization localized to the S1 segment of the proximal tubule (7). Kinetic studies confirmed that SGLT2 is the low-affinity, high-capacity system identified in brush border vesicles (23).Subsequent study of Na ϩ -glucose cotransport became more biophysically oriented, until the recent development of safe and specific inhibitors of SGLT2 thrust the topic back into view of the larger biomedical community. These substances are related to phlorizin, the classic nonspecific Na ϩ -glucose cotransport inhibitor, and comprise a growing list, which includes dapagliflozin, canagliflozin, empaglibflozin, ipragliflozin, and tofogliflozin. When given to humans, especially at times of hyperglycemia, these drugs produce glycosuria; when given to diabetic patients, the glycosuria enhances glycemic control and in a manner that promotes caloric loss, rather than weight gain. With the advent of these medications, a new contingent of scientists and physicians has taken an interest in renal glucose metabolism. One point of concern in the adoption of these drugs was th...