Sodium-glucose cotransporters (SGLTs) are a family of proteins that manage glucose movement across cell membranes, primarily in the intestinal lining and the kidneys. These proteins are involved in absorbing glucose from food and reabsorbing it in the kidneys. By transporting glucose, which is a primary energy source for cells, SGLTs help regulate blood sugar levels and conserve the body’s energy supply.
Mechanism of SGLT Action
The process by which SGLTs move glucose into cells is a form of secondary active transport. This mechanism does not use energy directly but relies on an existing electrochemical gradient for sodium ions (Na+). The SGLT protein acts as a symporter, binding to both sodium ions and a glucose molecule. The drive for sodium to move down its concentration gradient pulls the glucose molecule along with it, allowing transport into the cell against its own gradient.
The system is sustained by the Na+/K+-ATPase pump, which actively expels sodium from the cell in exchange for potassium, using cellular energy (ATP). By keeping the intracellular sodium concentration low, the pump ensures the gradient that powers SGLT-mediated transport remains effective.
Major SGLT Types and Locations
The two most well-understood types of these transport proteins are SGLT1 and SGLT2. SGLT1 is characterized by its high affinity but low capacity for moving glucose. It is located in the lining of the small intestine, where it is responsible for absorbing glucose and galactose from digested food. SGLT1 is also found in the kidneys, where it reabsorbs the small amount of glucose that escapes the earlier segments.
In contrast, SGLT2 is a high-capacity, low-affinity transporter. Its primary location is in the initial S1 segment of the proximal tubules within the kidneys. Here, SGLT2 reabsorbs around 90% of the glucose that is filtered from the blood into the urine.
SGLT Function in Bodily Processes
The actions of SGLT proteins are integral to maintaining glucose homeostasis, the body’s process of keeping blood sugar levels in a healthy range. In the kidneys, the reabsorption of glucose from the glomerular filtrate is almost entirely dependent on SGLTs. Under normal conditions, nearly all filtered glucose is returned to the bloodstream, ensuring this energy source is not wasted.
When the function of these transporters is compromised due to genetic mutations, specific health conditions can arise. For example, mutations in the SLC5A2 gene, which provides instructions for the SGLT2 protein, lead to familial renal glucosuria. Individuals with this condition excrete glucose in their urine despite having normal blood glucose levels because their kidneys cannot reabsorb it effectively. Similarly, mutations in the gene for SGLT1 cause glucose-galactose malabsorption, a disorder where the small intestine cannot absorb these sugars.
SGLT Inhibitors as Medical Treatments
The understanding of SGLT function has led to the development of SGLT inhibitors. The most prominent are SGLT2 inhibitors, identifiable by drug names ending in “-gliflozin,” such as empagliflozin, canagliflozin, and dapagliflozin. These drugs work by blocking the action of SGLT2 proteins in the kidneys, preventing glucose reabsorption and causing it to be expelled through urination.
This mechanism is effective for managing several medical conditions. Primarily, SGLT2 inhibitors are used to treat Type 2 diabetes by lowering high blood glucose levels independently of insulin. These medications have also shown benefits in treating heart failure and chronic kidney disease, even in individuals without diabetes. The effects are linked to reduced pressure within the kidney’s filters and the removal of excess fluid.
While effective, SGLT2 inhibitors are associated with certain side effects. Because these drugs increase sugar in the urine, they can raise the risk of developing genital yeast infections and urinary tract infections. Other potential side effects include an increased need to urinate and, in rare cases, diabetic ketoacidosis. Careful patient selection and monitoring are important aspects of their clinical use.