The development of new medications targeting the body’s glucose handling systems represents a major advance in metabolic medicine. A class of drugs known as sodium-glucose linked transporter (SGLT) inhibitors modulates the function of specific transport proteins that move glucose across cell membranes. While one subtype is widely recognized, SGLT1 inhibitors are gaining focus due to their unique mechanism for influencing glucose levels by targeting the protein responsible for dietary sugar absorption.
Understanding the SGLT1 Transporter
SGLT1, or Sodium-Glucose Linked Transporter 1, is a protein embedded in the cell membranes of various tissues throughout the body. Its primary location, where it performs its most significant function, is on the apical membrane of the enterocytes lining the small intestine. Here, SGLT1 is responsible for the active transport of glucose and galactose, derived from digested food, from the gut lumen into the bloodstream.
This transporter uses a process called co-transport, harnessing the energy from the sodium gradient to move glucose against its own concentration gradient. Specifically, the SGLT1 protein moves two sodium ions along with one molecule of glucose or galactose across the cell membrane. This movement of sodium and glucose also plays a role in the intestinal absorption of water, which is driven by osmosis.
SGLT1 is also found in the kidneys, although it plays a smaller role in overall glucose balance. In the kidney’s proximal tubules, SGLT1 handles approximately 5% to 10% of the glucose that is reabsorbed back into the circulation. This portion of renal reabsorption typically occurs further down the tubule, acting as a final mechanism to reclaim any glucose.
How SGLT1 Inhibitors Function
SGLT1 inhibitors are molecules designed to physically block the binding site of the SGLT1 transporter protein. By occupying this site, the inhibitor prevents the simultaneous binding and transport of sodium and glucose across the cell membrane. This blockade directly interferes with the body’s ability to absorb dietary glucose and galactose from the small intestine following a meal.
The immediate physiological result of this blockage is a delay and reduction in the rate at which ingested glucose enters the bloodstream. This action effectively blunts the sharp increase in blood sugar that typically occurs immediately after eating, known as the postprandial glucose spike. By slowing the influx of glucose, SGLT1 inhibitors help flatten the overall glucose curve, leading to a smoother blood sugar profile.
The secondary effect occurs in the kidney, where the blockage reduces the reabsorption of the small fraction of glucose handled by SGLT1 in the distal tubules. The mechanism of action is independent of the body’s insulin production or sensitivity, making it a complementary strategy to existing glucose-lowering therapies.
Therapeutic Uses of SGLT1 Inhibition
The primary therapeutic application for SGLT1 inhibition centers on improving glycemic control, particularly in individuals with Type 1 and Type 2 Diabetes. The unique ability to reduce the rapid absorption of glucose from the gut makes these inhibitors especially useful for controlling blood sugar levels immediately following meals. Managing these postprandial glucose excursions is a challenge in diabetes care and is associated with long-term complications.
Use in Type 1 Diabetes
In Type 1 Diabetes, SGLT1 inhibitors are being investigated as an add-on therapy to insulin. They potentially help stabilize glucose levels that often fluctuate widely after carbohydrate intake.
Use in Type 2 Diabetes
For Type 2 Diabetes, this class of drug can be combined with other glucose-lowering agents to provide a comprehensive approach to managing hyperglycemia. Clinical studies demonstrate that this inhibition can moderate overall glycemic excursions and contribute to a reduction in the long-term marker of blood sugar control, HbA1c.
Distinguishing SGLT1 from SGLT2 Inhibitors
Despite the similar names, SGLT1 and SGLT2 inhibitors target distinct proteins with different primary locations and physiological effects.
SGLT2: High Capacity, Renal Focus
The SGLT2 protein is predominantly found in the early segments of the kidney’s proximal tubule. This location is where it performs the majority of glucose reabsorption, accounting for approximately 90% to 95% of the total filtered glucose being reclaimed. Therefore, SGLT2 inhibitors work mainly by increasing the amount of glucose excreted in the urine. SGLT2 is characterized as a low-affinity, high-capacity transporter, meaning it can move a large quantity of glucose when levels are high.
SGLT1: High Affinity, Intestinal Focus
In contrast, SGLT1 is primarily located in the small intestine, where it handles nearly all dietary glucose and galactose absorption. Its presence in the kidney is limited to the more distal segments, reabsorbing only the remaining 5% to 10% of glucose. SGLT1 inhibitors work mainly by reducing the amount of glucose absorbed from food. SGLT1 is a high-affinity, low-capacity transporter, allowing it to efficiently capture the last remaining molecules of glucose.
Dual Inhibition Strategy
This distinction explains why researchers are interested in dual SGLT1/SGLT2 inhibition, as combining the two mechanisms offers a full-spectrum approach. The dual inhibitors leverage the intestinal action of SGLT1 blockade to control post-meal spikes while utilizing the renal action of SGLT2 blockade to lower overall circulating glucose levels. Furthermore, some SGLT inhibitors are now approved as dual SGLT1/SGLT2 inhibitors, which extend their use to reducing the risk of urgent heart failure visits and cardiovascular death in certain high-risk patients.