Sodium-dependent glucose cotransporters (or sodium-glucose linked transporter, SGLT) are a family of

glucose transporter Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose across the plasma membrane, a process known as facilitated diffusion. Because glucose is a vital source of energy for all life, these transporter ...

found in the intestinal

mucosa A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...

(

enterocytes Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its s ...

) of the

small intestine The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...

(SGLT1) and the

proximal tubule The proximal tubule is the segment of the nephron in kidneys which begins from the renal pole of the Bowman's capsule to the beginning of loop of Henle. It can be further classified into the proximal convoluted tubule (PCT) and the proximal straig ...

of the

nephron The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...

(

SGLT2 The sodium/glucose cotransporter 2 (SGLT2) is a protein that in humans is encoded by the (solute carrier family 5 (sodium/glucose cotransporter)) gene. Function SGLT2 is a member of the sodium glucose cotransporter family, which are sodium-d ...

in PCT and SGLT1 in PST). They contribute to

renal glucose reabsorption Renal glucose reabsorption is the part of kidney (renal) physiology that deals with the retrieval of filtered glucose, preventing it from disappearing from the body through the urine. If glucose is not reabsorbed by the kidney, it appears in the u ...

. In the kidneys, 100% of the filtered glucose in the

glomerulus ''Glomerulus'' () is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn". ''Glomerulus'' may refer to: * the filter ...

has to be reabsorbed along the nephron (98% in PCT, via SGLT2). If the plasma glucose concentration is too high (

hyperglycemia Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...

), glucose passes into the urine (

glucosuria Glycosuria is the excretion of glucose into the urine. Ordinarily, urine contains no glucose because the kidneys are able to reabsorb all of the filtered glucose from the tubular fluid back into the bloodstream. Glycosuria is nearly always caused ...

) because SGLT are saturated with the filtered glucose.

Types

The two most well known members of SGLT family are SGLT1 and SGLT2, which are members of the SLC5A gene family. In addition to SGLT1 and SGLT2, there are 10 other members in the human protein family SLC5A. Of these, SLC5A4/SGLT3 (SAAT1) is a low-affinity transporter for glucose, but seems to have more of an electric function. The other SLC5 proteins transport mannose, myo-inositol, choline, iodide, vitamins, and short-chain fatty acids.

SGLT2 inhibitors for diabetes

SGLT2 inhibitors, also called ''gliflozins'', are used in the treatment of

type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

. SGLT2 is only found in kidney tubules and in conjunction with SGLT1 resorbs glucose into the blood from the forming urine. By inhibiting SGLT2, and not targeting SGLT1, glucose is excreted which in turn lowers blood glucose levels. Examples include

dapagliflozin Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes. It is also used to treat adults with heart failure and chronic kidney disease. Common side effects include hy ...

(Farxiga in US, Forxiga in EU),

canagliflozin Canagliflozin, sold under the brand name Invokana among others, is a medication used to treat type 2 diabetes. It is a third-line medication to be tried after metformin, a first-line medication for type 2 diabetes. It is used together with ex ...

(Invokana) and

empagliflozin Empagliflozin, sold under the brand name Jardiance among others, is an antidiabetic medication used to improve glucose control in people with type2 diabetes, to reduce the risk of cardiovascular death in adults with type2 diabetes and establis ...

(Jardiance). Certain SGLT2 inhibitors have shown to reduce mortality in type 2 diabetes. The safety and efficacy of SGLT2 inhibitors have not been established in patients with

type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

, and FDA has not approved them for use in these patients.

Function

Firstly, an Na⁺/K⁺ ATPase on the

basolateral The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (th ...

membrane of the proximal tubule cell uses ATP molecules to move 3 sodium ions outward into the blood, while bringing in 2 potassium ions. This action creates a downhill sodium ion gradient from the outside to the inside of the

cell (that is, in comparison to both the blood and the tubule itself). The SGLT proteins use the energy from this downhill sodium ion gradient created by the ATPase pump to transport

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...

across the apical membrane, against an uphill glucose gradient. These co-transporters are an example of

secondary active transport In cellular biology, ''active transport'' is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellul ...

. Members of the GLUT family of glucose

uniporters Facilitated diffusion (also known as facilitated transport or passive-mediated transport) is the process of spontaneous passive transport (as opposed to active transport) of molecules or ions across a biological membrane via specific transmem ...

then transport the glucose across the basolateral membrane, and into the

peritubular capillaries In the renal system, peritubular capillaries are tiny blood vessels, supplied by the efferent arteriole, that travel alongside nephrons allowing reabsorption and secretion between blood and the inner lumen of the nephron. Peritubular capillaries s ...

. Because sodium and glucose are moved in the same direction across the membrane, SGLT1 and SGLT2 are known as symporters.

History

In August 1960, in Prague,

Robert K. Crane Robert Kellogg Crane (December 20, 1919 – October 31, 2010) was an American biochemist best known for his discovery of sodium–glucose cotransport. Biography Crane was born on December 20, 1919 in Palmyra, New Jersey, to Wilbur Fiske Crane, J ...

presented for the first time his discovery of the sodium-glucose

cotransport In Cellular Biology, cellular biology, ''active transport'' is the movement of molecules or ions across a cell membrane Second law of thermodynamics, from a region of lower concentration to a region of higher concentration—against the concentra ...

as the mechanism for intestinal glucose absorption. Crane's discovery of cotransport was the first-ever proposal of flux coupling in biology.

References

External links