SGLT2 (sodium-glucose linked transporter 2) is an integral membrane protein responsible for the reabsorption of a substantial fraction of the excreted glucose passing through the S1 and S2 segments of the renal proximal tubule. Pharmacological inhibition of SGLT2 is expected to provide a safe and effective way to reduce blood glucose concentration in individuals with type 2 diabetes. This expectation is based on the phenotype of individuals affected by familial renal glucosuria (FRG), a condition resulting from mutations in the gene encoding SGLT2, SLC5A2. Individuals with FRG present with a prominent glucosuria, mild to moderate polyuria, and, in some cases, evidence of slight volume depletion attributable to natriuresis. Affected individuals are euglycemic and exhibit no signs of renal tubular dysfunction apart from their glucosuria.
In the vast majority of cases, type 2 diabetes is a disease of insulin resistance that is provoked by an increase in fat mass above a critical threshold. 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 promote the renewed uptake of glucose into fat. However the resulting expansion of an already hypertrophic adipose reservoir worsens the underlying metabolic imbalance. Because SGLT2 inhibitors dissipate excess glucose in urine, they do not contribute to the exacerbation of the root cause of diabetes. Instead, treatment with SGLT2 inhibitors has been shown to promote a moderate but enduring weight loss. An additional salutary effect of the inhibitors is a reduction in blood pressure attributable to natriuresis.
SGLT2 and the Kidney
The 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 6 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.