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SGLT2 and the Kidney

beakersThe kidney functions in a default elimination mode predicated on the expectation that environmental toxins (the most important of which are dietary) cannot be predicted. Hence the kidney voids all components in the blood that fall below the molecular weight of the glomerular cutoff, and then actively reabsorbs the plasma constituents of interest. Of the approximately 180 liters of plasma and 1.5 kg of sodium chloride that pass through the human kidney each day the kidney actively reabsorbs all but 2 liters of water and 64 g of salt. The kidney also reabsorbs essentially all of the glucose, amino acids, vitamins, and a few other metabolites of interest in the bloodstream. Although this process is energetically expensive, it protects the organism from a vast array of toxins that otherwise would be lethal.

Most of the filtered solutes destined to be reabsorbed by the kidney are extracted from the filtrate by co-transport with extracellular ions via transporters of the solute linked carrier (SLC) supergene family. Sodium linked transport is an especially widespread mechanism for concentrative (as opposed to equilibrative) transport in the kidney, and relies on the transmembrane potential for sodium to drive solute flux across the plasma membrane.

SGLT2 (General Public Version)

SGLT2 is an acronym for sodium-glucose linked transporter 2, a membrane protein that acts as a portal for glucose into the cell. SGLT2 is found on cells lining the proximal tubules of the kidney, and allows the kidney to recover from urine a fraction of the glucose that has been excreted. Blockade of SGLT2 results in excretion of glucose in urine, and thereby decreases the blood glucose concentration. SGLT2 inhibitors have been found to be useful for the treatment of type 2 diabetes, a disorder in which blood glucose levels are elevated to an unhealthy degree.

Type 2 diabetes is a disease of insulin resistance that in the vast majority of cases is provoked by an increase in body weight above a healthy threshold. The threshold can be low in susceptible populations and varies greatly from individual to individual. Under normal circumstances, the action of insulin promotes the conversion of excess bloodstream glucose into fat. As the amount of fat increases the challenge of pumping additional glucose into it becomes greater, and the fat cells resist further insulin-promoted expansion. Many existing anti-diabetic treatments, such as insulin, agents that promote insulin secretion, and insulin sensitizers, magnify the effect of insulin or increase the amount of insulin, and allow the continued uptake of glucose into fat. The resulting expansion of the fat reservoir, however, worsens the fundamental metabolic problem. Because SGLT2 inhibitors dissipate excess glucose in urine, they do not contribute to the exacerbation of the root cause of diabetes.

SGLT2 and the Kidney (General Public Version)

The kidney is the organ in the human body that eliminates toxins and waste from the bloodstream. The most important natural source of toxins is diet, and the toxins in a given diet cannot be predicted. Hence the kidney performs as though all the components in the blood are toxic, except for the specific substances that are known to be safe. Each day approximately 180 liters of plasma containing 1.5 kg of salt pass through the human kidney into urine, and each day the kidney actively reabsorbs all but 2 liters of water and 64 g of salt. The kidney also reabsorbs essentially all of the glucose, amino acids, vitamins, and a few other nutrients found in the bloodstream. Although this process is energetically costly, it protects the organism from a vast array of toxins that otherwise would be lethal.

To reabsorb glucose and other nutrients, the kidney relies on a strategy that is based on the fact that every cell in the body normally expends energy pumping sodium ions out of the cell. As a result the fluids outside the cell contain excess sodium compared to the fluids inside the cell, a situation not unlike water held behind a dam in a reservoir. If a channel is opened in the dam, the water will rush out, and in the case of the SGLT2 channel, as the sodium rushes into the cell it carries glucose with it. Because this process is driven by the difference in sodium concentration, it can function even when the concentration of glucose outside the cell is quite low, allowing glucose to be concentrated in the cell. The same strategy is used by intestinal cells to absorb glucose from dietary sources, and relies on the action of a related transporter called SGLT1.