**4. Sodium-glucose cotransporters**

So far, six different SGLTs have been described; however, apart from SGLT1 and SGLT2 which are well characterized, little is known about the function and clinical significance of the others [20]. Both SGLT1 and SGLT2 are large-membrane proteins consisting of 670 amino acids, and each has 14 transmembrane helical domains. The homology between SGLT1 and SGLT2 is around 58% (**Table 1**) [20].


#### **Table 1.**

*Genes, substrates, and distributions of SGLT [28].*

## **4.1 Sodium-glucose cotransporter 1 (SGLT1)**

## *4.1.1 Locations of SGLT1*

Studies have classically localized SGLT1 to the small intestine and the kidney where their pathophysiological roles are known in details [28].

Various other body organs such as the heart, lung, trachea, liver, skeletal muscle, gall bladder, rectum, colon, brain, blood vessels, breast, uterus, testis, and pancreatic alpha cells have shown mRNA level expression of SGLT1 [28–33].

#### *4.1.2 Functional properties of SGLT1*

SGLT1 transports one molecule of glucose or galactose together with two sodium ions. This stoichiometric ratio of 1:2 enables to raise the intracellular glucose level orders of magnitude above the corresponding extracellular concentration. The apparent Michaelis-Menten Km values for glucose and galactose at physiological extracellular sodium concentration and membrane potential are 0.5 and 1.0 mM, respectively. It has high affinity for both glucose and galactose but has a lower transport capacity (Tmax = 2 nmol/mg protein per minute) [28, 34].

### *4.1.3 Physiological functions of SGLT1*

SGLT1 is highly expressed in the small intestine and is located in the brush border membrane (BBM) of the enterocytes and in endocrine cells of gut and the K- and L-cells which secrete GIP and GLP-1/GLP-2, respectively. SGLT1-mediated translocation of glucose is the rate-limiting step for small intestinal glucose absorption [17, 28, 29]. Absorbed glucose in the enterocytes is released across the basolateral membrane and enters blood circulation via GLUT2. During bacterial infection, SGLT1 protects the small intestine from lipopolysaccharide-induced inflammation because of high luminal glucose concentrations [35].

In the kidney, SGLT1 is located at BBM of S3 segment of renal tubules and is responsible for the first and rate-limiting step in reabsorption of glucose which escaped SGLT2-mediated reabsorption in S1 and S2 segments. In normal healthy adults, it only absorbs around 10% of the filtered glucose load, but in DM patients with uncontrolled hyperglycemia, the fraction of SGLT1-mediated renal glucose absorption increases significantly. Similarly, in patients on SGLT2-I therapy, the fraction increases to around 50–70% [17, 28, 29]. SGLT1 may play a protective role during treatment with nephrotoxic drugs such as cisplatin [36].

SGLT1 mRNA has been detected in the frontal cortex, hypothalamus, and Purkinje cells of cerebellum and hippocampus in brains of human, rabbit, and rat [33, 37, 38]. It is mainly localized in the luminal membrane of the endothelial cells, and its location and functional activity suggests a pivotal role in securing energy supply to neurons during conditions of increased energy and glucose demand such as hypoxia and/or hypoglycemia. SGLT1-mediated neuronal glucose uptake is involved in glucose-induced neurotoxicity during ischemic stroke [39].

SGLT1 is located at the myocyte sarcolemma and in small blood vessels of the heart [29, 32]. SGLT1-mediated glucose uptake is of clinical significance as it leads to ATP generation by glycolysis during myocardial ischemia and/or hypoglycemia [40]. At the same time, it may increase toxic effects that are mediated by generation of reactive oxygen species (ROS) during hyperglycemia [41].

SGLTI1 mRNA has been detected in the lung, trachea, and bronchi, and its protein has been localized to alveolar type 2 cells and to the luminal membrane of bronchiolar Clara cells by immunohistochemistry [30, 31]. SGLT1-mediated

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*SGLT2 Inhibitors Therapy in Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.84152*

have a possible role in immune reactions [43].

occurs during chronic intestinal inflammation [47].

**4.2 Sodium-glucose cotransporter 2 (SGLT2)**

*4.1.4 Regulation of SGLT1 expression*

*4.2.1 Locations of SGLT2*

*4.2.2 Functional properties*

are 5 and 25 mM, respectively [28].

*4.2.3 Physiological functions of SGLT2*

*4.2.3.1 Functions of SGLT2 in the kidney*

the development of diabetic nephropathy [50].

mentioned earlier in Section 2.3.

Clara cells [42].

glucose absorption contributes to fluid absorption and may provide energy for surfactant production in alveolar type 2 cells as well as for mucin and surfactants in

Similarly, the human gall bladder and liver have shown the presence of SGLT1 mRNA [29, 30]. Its expression at mRNA and protein level has been demonstrated in human pancreatic alpha cells; however, little is known about its functional role [30, 31]. SGLT1 has also been expressed in activated T-lymphocytes of mice where it may

The complex process of regulation of activity and expression of SGLT1 occurs in a tissue-specific manner. In the small intestine, upregulation of SGLT1 expression occurs in response to high-salt and/or high-glucose diet through transcriptional regulation which is also responsible for the circadian periodicity of SGLT1 expression [44, 45]. Its expression gets upregulated in the small intestine in diabetics [46] and in response to bacterial infections [35], while downregulation of SGLT1 expression

In humans, SGLT2 is strongly expressed in the kidney where it has been localized to the brush border membrane of the S1 and S2 segment of the proximal tubules. On the other hand, SGLT1 has been localized to the brush border membrane of the S3 segment of proximal convoluted tubules of the kidney [28–30, 48]. Proteins and mRNA of SGLT2 have also been found in alpha cells of the pancreas [31]. In addition to the kidney and pancreas, small amount of SGLT2 mRNA have

been identified in the testis, liver, lung, and cerebellum [21, 28–30, 48].

SGLT2 is highly selective for glucose over galactose. It has low affinity for glucose with Km = 2 mM but with high transport capacity with Tmax = 10 nmol/mg protein per minute and operates with a 1:1 stoichiometry of sodium and glucose. The apparent Michaelis-Menten Km values for glucose and sodium in human SGLT2

Details of the physiological functions of SGLT2 in the kidney have already been

In T2DM, SGLT2-mediated reabsorption of glucose and sodium is increased and can be considered physiologically maladaptive as it prevents an increase in urinary glucose excretion at high blood glucose levels. The increase in proximal tubular sodium reabsorption leads to fall in the distal tubular sodium and chloride concentrations which result in glomerular hyperfiltration [49] and plays a central role in

The triad of hyperglycemia, elevated GFR, and the increased proximal tubular glucose reabsorption altogether leads to increase in kidney size and volume which is

#### *SGLT2 Inhibitors Therapy in Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.84152*

*Type 2 Diabetes - From Pathophysiology to Modern Management*

where their pathophysiological roles are known in details [28].

atic alpha cells have shown mRNA level expression of SGLT1 [28–33].

transport capacity (Tmax = 2 nmol/mg protein per minute) [28, 34].

Studies have classically localized SGLT1 to the small intestine and the kidney

Various other body organs such as the heart, lung, trachea, liver, skeletal muscle, gall bladder, rectum, colon, brain, blood vessels, breast, uterus, testis, and pancre-

SGLT1 transports one molecule of glucose or galactose together with two sodium ions. This stoichiometric ratio of 1:2 enables to raise the intracellular glucose level orders of magnitude above the corresponding extracellular concentration. The apparent Michaelis-Menten Km values for glucose and galactose at physiological extracellular sodium concentration and membrane potential are 0.5 and 1.0 mM, respectively. It has high affinity for both glucose and galactose but has a lower

SGLT1 is highly expressed in the small intestine and is located in the brush border membrane (BBM) of the enterocytes and in endocrine cells of gut and the K- and L-cells which secrete GIP and GLP-1/GLP-2, respectively. SGLT1-mediated translocation of glucose is the rate-limiting step for small intestinal glucose absorption [17, 28, 29]. Absorbed glucose in the enterocytes is released across the basolateral membrane and enters blood circulation via GLUT2. During bacterial infection, SGLT1 protects the small intestine from lipopolysaccharide-induced inflammation

In the kidney, SGLT1 is located at BBM of S3 segment of renal tubules and is responsible for the first and rate-limiting step in reabsorption of glucose which escaped SGLT2-mediated reabsorption in S1 and S2 segments. In normal healthy adults, it only absorbs around 10% of the filtered glucose load, but in DM patients with uncontrolled hyperglycemia, the fraction of SGLT1-mediated renal glucose absorption increases significantly. Similarly, in patients on SGLT2-I therapy, the fraction increases to around 50–70% [17, 28, 29]. SGLT1 may play a protective role

SGLT1 mRNA has been detected in the frontal cortex, hypothalamus, and Purkinje cells of cerebellum and hippocampus in brains of human, rabbit, and rat [33, 37, 38]. It is mainly localized in the luminal membrane of the endothelial cells, and its location and functional activity suggests a pivotal role in securing energy supply to neurons during conditions of increased energy and glucose demand such as hypoxia and/or hypoglycemia. SGLT1-mediated neuronal glucose uptake is

SGLT1 is located at the myocyte sarcolemma and in small blood vessels of the heart [29, 32]. SGLT1-mediated glucose uptake is of clinical significance as it leads to ATP generation by glycolysis during myocardial ischemia and/or hypoglycemia [40]. At the same time, it may increase toxic effects that are mediated by generation

SGLTI1 mRNA has been detected in the lung, trachea, and bronchi, and its protein has been localized to alveolar type 2 cells and to the luminal membrane of bronchiolar Clara cells by immunohistochemistry [30, 31]. SGLT1-mediated

**4.1 Sodium-glucose cotransporter 1 (SGLT1)**

*4.1.1 Locations of SGLT1*

*4.1.2 Functional properties of SGLT1*

*4.1.3 Physiological functions of SGLT1*

because of high luminal glucose concentrations [35].

during treatment with nephrotoxic drugs such as cisplatin [36].

involved in glucose-induced neurotoxicity during ischemic stroke [39].

of reactive oxygen species (ROS) during hyperglycemia [41].

**80**

glucose absorption contributes to fluid absorption and may provide energy for surfactant production in alveolar type 2 cells as well as for mucin and surfactants in Clara cells [42].

Similarly, the human gall bladder and liver have shown the presence of SGLT1 mRNA [29, 30]. Its expression at mRNA and protein level has been demonstrated in human pancreatic alpha cells; however, little is known about its functional role [30, 31]. SGLT1 has also been expressed in activated T-lymphocytes of mice where it may have a possible role in immune reactions [43].
