Sodium-Glucose Co-Transporter 1 (SGLT1) is a protein from the solute carrier family 5 (SLC5A) that moves glucose, a primary energy source, across cell membranes. This process is essential for maintaining the body’s energy balance.
Where SGLT1 is Found and What it Does
SGLT1 is primarily located in the small intestine, specifically in the jejunum, where it absorbs glucose and galactose from digested food. It moves these sugars from the intestinal lumen into the bloodstream, a necessary step for the body to acquire energy from carbohydrates.
SGLT1 also has a role in the kidneys, though less prominent than its intestinal function. In the kidneys, SGLT1 helps reabsorb glucose that has been filtered out of the blood, preventing its loss in urine. While SGLT2 handles the majority of glucose reabsorption, SGLT1 reabsorbs a smaller amount, approximately 3-10% of filtered glucose, particularly when blood glucose levels are low.
Beyond these primary locations, SGLT1 is found in other tissues, including the heart and lungs. In the heart, SGLT1 transports glucose into cardiomyocytes, the heart muscle cells. In the lungs, it may contribute to fluid absorption and energy supply.
The Mechanism of SGLT1 Transport
SGLT1 functions as a “cotransporter,” moving two different molecules across a cell membrane simultaneously and in the same direction. This process is secondary active transport, as it does not directly use cellular energy (ATP). Instead, SGLT1 harnesses energy from the movement of sodium ions.
The transporter uses the tendency of sodium ions to move into the cell, following their concentration gradient. This “downhill” movement of sodium provides the energy for SGLT1 to transport glucose “uphill,” against its own concentration gradient, into the cell. SGLT1 transports two sodium ions for every one glucose molecule (a 2:1 ratio), ensuring effective glucose uptake even when glucose concentrations are low on one side of the membrane.
Distinguishing SGLT1 from SGLT2
Both SGLT1 and SGLT2 are sodium-glucose cotransporters, but they differ in location, affinity, capacity, and physiological roles. SGLT1 is predominantly found in the small intestine, absorbing dietary glucose and galactose. SGLT2 is mainly expressed in the kidneys, in the early proximal tubule, where it reabsorbs most filtered glucose from the bloodstream.
Regarding affinity and capacity, SGLT1 has a high affinity for glucose, binding effectively even at low concentrations, but its transport capacity is lower. SGLT2 has a lower affinity but a much higher capacity, reabsorbing a large volume of glucose in the kidneys, accounting for 90-95% of filtered glucose.
These differences translate into distinct physiological roles. SGLT1 is the primary transporter for absorbing glucose from meals in the gut, ensuring nutrient uptake. SGLT2 plays a significant role in maintaining glucose balance by preventing excessive glucose loss in urine. Due to its high capacity in the kidney, SGLT2 is the main target for many diabetes medications, known as SGLT2 inhibitors, which work by increasing glucose excretion in the urine. SGLT1, while less targeted for glucose excretion, is being explored for its role in reducing post-meal glucose spikes by inhibiting intestinal absorption.
SGLT1 in Health and Disease
The proper functioning of SGLT1 is important for health, and its malfunction can lead to specific diseases. A notable genetic disorder associated with SGLT1 dysfunction is Glucose-Galactose Malabsorption (GGM). This rare inherited condition occurs when mutations in the SLC5A1 gene, which codes for SGLT1, impair the protein’s ability to absorb glucose and galactose in the small intestine. Infants with GGM experience severe diarrhea and dehydration shortly after birth due to the unabsorbed sugars drawing water into the intestines. Management of GGM involves a strict diet free of glucose and galactose, often relying on fructose as an alternative sugar source.
In the context of diabetes management, SGLT1 plays a secondary role. While SGLT2 is responsible for the majority of glucose reabsorption in the kidneys, SGLT1 reabsorbs a smaller percentage, around 3-10%. When SGLT2 is inhibited by medications, SGLT1 can act as a compensatory mechanism, increasing its activity to reabsorb some of the glucose that would otherwise be excreted.
This compensatory role has led to therapeutic strategies targeting SGLT1. SGLT1 inhibitors, or dual SGLT1/SGLT2 inhibitors, are being investigated for diabetes treatment. By blocking SGLT1 in the intestines, these drugs reduce the absorption of glucose from food, thereby lowering post-meal blood sugar spikes. In addition, dual inhibitors offer a more robust reduction in blood glucose by also inhibiting renal glucose reabsorption through SGLT1, especially when kidney function is reduced. Sotagliflozin, for example, is an oral dual SGLT1 and SGLT2 inhibitor has shown promise in improving glycemic control in both type 1 and type 2 diabetes, often with insulin therapy.