**2. Glucose homeostasis**

Glucose is an essential and principal fuel source for cellular metabolism in the human body and is the main energy resource for the central nervous system, muscles, and fat—and insulin plays a key role in its effective utilization. The glucose homeostasis is rapidly adjusted in response to physiological changes such as food intake, exercise, and acute stress, and its blood level is adjusted by control of absorption of glucose, its metabolism in the liver, its excretion by kidneys, and uptake into muscles and adipose tissue. Functions of various proteins associated with regulation of glucose metabolism and homoeostasis get affected by diseases such as DM and hepatic disorders [16].

### **2.1 Handling of glucose in the intestine**

After ingestion of carbohydrate-rich diet, blood glucose is regulated in response to the increase in glucose concentration in the intestinal lumen and in response to the increase in blood glucose level. The increase in glucose levels in the lumen of the small intestine provides a signal for the upregulation of intestinal glucose absorption [17] and leads to secretion of gut hormones such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), which increase the glucose-dependent stimulation of insulin secretion from the pancreatic β-cells and also influence appetite [18]. Insulin reduces glucagon secretion by acting on pancreatic alpha cells and also reduces blood glucose level by increasing glucose uptake in fat and muscle cells and changing glucose metabolism in the liver [1].

### **2.2 Glucose transport across plasma membrane**

Being a highly polar molecule, glucose is unable to cross the lipid bilayer of the plasma membrane of all living cells; therefore, transport proteins within the cell membrane are required to facilitate glucose transport from the extracellular to the intracellular space.

Two distinct groups of glucose transporters belonging to solute carrier gene series (SLC) containing more than 50 transporter families have been described [19]. The first one is facilitated glucose transporters (GLUT) which is encoded by the SLC2 family of transporters GLUT1–4 and GLUT6–12, which help in passive transportation of glucose from the extracellular to the intracellular space along its chemical gradient without consuming any energy and equilibrate glucose concentration on both sides of membrane. The other one is sodium-glucose cotransporters (SGLTs) which are encoded by SLC5 family of transporters SGLT1–6 which actively transport glucose across plasma membranes against its concentration gradient. This process requires energy which is provided by simultaneous coupled transportation of sodium along its concentration gradient [19]. In this way, SGLTs help in concentrating glucose inside the cells.

The two principal sites of action of SGLTs are the intestine and kidney where they mediate glucose transportation across the intestinal lumen and the epithelial cells in the proximal renal tubules, respectively [20].

#### **2.3 Handling of glucose by the kidney**

The kidney plays an important role in glucose homeostasis by the process of filtration and reabsorption. Renal glomeruli filter approximately 180 liters of plasma daily which translates into filtration of approximately 180 g of glucose. In normal healthy subjects, all of this glucose is reabsorbed completely so that virtually no glucose is excreted in urine. Around 90% of the filtered renal glucose is reabsorbed in early part (S1) of proximal convoluted tubules by low-affinity high-capacity SGLT2. High-affinity low-capacity SGLT1 in distal straight segment (S3) of the proximal tubules reabsorbs the remaining 10% of the filtered renal glucose [21].

This process of glucose reabsorption is achieved by active Na<sup>+</sup> removal at basolateral surface by the Na+ /K+ -ATPase which generates the electrochemical driving force for apical glucose entry via Na+ -driven SGLTs. Reabsorbed glucose exits from the basolateral surface of the cells along its concentration gradient primarily via GLUT2 and reenters the bloodstream [21].

When blood glucose level exceeds 200 mg/dL, the excess glucose starts appearing in urine as renal transport maximum (Tm) of glucose is reached. The blood glucose level at which Tm is reached is called threshold and is around 300 mg/dL in healthy nondiabetic individuals, but glucose starts appearing in urine at around 200 mg/dL due to heterogeneity of individual nephrons in their Tm property and mismatch between glomerular filtration and tubular reabsorption of glucose. This safety valve-like action prevents extreme hyperglycemia [22].

The Tm of the proximal tubules on average is around 375 mg/minute although it shows inter-individual variations. The filtered glucose load is directly proportional to blood glucose concentration. In normal nondiabetic individuals, the filtered glucose load is less than 375 mg/minute; therefore, the entire amount is reabsorbed, and their urine is free of any glucose. This process has survival benefits as it allows the kidneys to conserve glucose and can be viewed as an adaptive mechanism. In patients with T2DM, the filtered load may exceed 375 mg/minute; therefore, the Tm is exceeded, and all glucose in excess of the Tm spills over in urine [21]. In T2DM subjects, this adaptive mechanism becomes maladaptive. The increased expression of SGLT1/SGLT2 occurring in DM subjects results in increased renal

**79**

**Table 1.**

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

further exacerbates hyperglycemia [22].

glucose reabsorption which ultimately leads to maintenance of a state of persistent hyperglycemia [23, 24]. The tubular growth leads to increased Tm for glucose which

tenance of state of hyperglycemia in T2DM is quite evident. Therefore, SGLT2-I provide a pathophysiologically rational and novel approach to its treatment.

**3. Clinical effects of mutations in SGLT1 and SGLT2**

diet free of glucose, galactose, and lactose [25].

per 1.73 m2

be developed as safe OAH.

**4. Sodium-glucose cotransporters**

SGLT1 (SLC5A1) 22q12.3 Glucose,

SGLT4 (SLC5A9) 1p32 Glucose,

SGLT5 (SLC5A10) 17p11.2 Glucose,

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

Based upon these facts, the contribution of the kidney in development and main-

Autosomal recessive mutations in SGLT1 lead to a disorder called glucose galactose malabsorption (GGM). SGLT1 becomes nonfunctional, and infants with GGM develop severe watery diarrhea, dehydration, and metabolic acidosis that cease on

In 1927, the first case of familial renal glycosuria was reported, in which a mutation in gene for SGLT2 resulted in loss of glucose in urine ranging from 1 to 150 g

These observations further strengthen the belief that SGLT2-I could potentially

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].

**Transporter Gene Substrate Distribution and localization**

SGLT2 (SLC5A2) 16p12.p11 Glucose Kidney, brain, liver, thyroid, heart, muscle SGLT3 (SLC5A4) 21q22.12 Glucose Intestine, testis, uterus, lung, brain, thyroid

Intestine, trachea, kidney, heart, brain, testis, prostate

Intestine, kidney, liver, brain, lung, trachea, uterus, pancreas

Renal cortex

galactose

mannose

galactose

SGLT6 (SLC5A11) 16p12.1 D-chiro-inositol Spinal cord, kidney, brain

so far leading to this condition which is characterized by urinary glucose excretion in the presence of normal plasma glucose levels and an absence of signs of general renal tubular dysfunction. Patients have normal oral glucose tolerance test and usually present with osmotic symptoms without any serious complications [26, 27]. The condition is not associated with any change in intravascular volume, serum glucose levels, or renal or bladder dysfunctions. These patients do not show higher incidence of kidney disease, DM, or urinary tract infections although those affected with severe forms of the disease may demonstrate activation of renin-angiotensin-

aldosterone axis as indirect evidence of volume contraction [20, 26, 27].

body surface areas per day. Almost 50 mutations have been identified

*Type 2 Diabetes - From Pathophysiology to Modern Management*

Being a highly polar molecule, glucose is unable to cross the lipid bilayer of the plasma membrane of all living cells; therefore, transport proteins within the cell membrane are required to facilitate glucose transport from the extracellular to the

Two distinct groups of glucose transporters belonging to solute carrier gene series (SLC) containing more than 50 transporter families have been described [19]. The first one is facilitated glucose transporters (GLUT) which is encoded by the SLC2 family of transporters GLUT1–4 and GLUT6–12, which help in passive transportation of glucose from the extracellular to the intracellular space along its chemical gradient without consuming any energy and equilibrate glucose concentration on both sides of membrane. The other one is sodium-glucose cotransporters (SGLTs) which are encoded by SLC5 family of transporters SGLT1–6 which actively transport glucose across plasma membranes against its concentration gradient. This process requires energy which is provided by simultaneous coupled transportation of sodium along its concentration gradient [19]. In this way, SGLTs help in concentrating glucose inside the cells.

The two principal sites of action of SGLTs are the intestine and kidney where they mediate glucose transportation across the intestinal lumen and the epithelial

The kidney plays an important role in glucose homeostasis by the process of filtration and reabsorption. Renal glomeruli filter approximately 180 liters of plasma daily which translates into filtration of approximately 180 g of glucose. In normal healthy subjects, all of this glucose is reabsorbed completely so that virtually no glucose is excreted in urine. Around 90% of the filtered renal glucose is reabsorbed in early part (S1) of proximal convoluted tubules by low-affinity high-capacity SGLT2. High-affinity low-capacity SGLT1 in distal straight segment (S3) of the proximal tubules reabsorbs the remaining 10% of the filtered renal glucose [21].



removal at baso-

This process of glucose reabsorption is achieved by active Na<sup>+</sup>

safety valve-like action prevents extreme hyperglycemia [22].

the basolateral surface of the cells along its concentration gradient primarily via

When blood glucose level exceeds 200 mg/dL, the excess glucose starts appearing in urine as renal transport maximum (Tm) of glucose is reached. The blood glucose level at which Tm is reached is called threshold and is around 300 mg/dL in healthy nondiabetic individuals, but glucose starts appearing in urine at around 200 mg/dL due to heterogeneity of individual nephrons in their Tm property and mismatch between glomerular filtration and tubular reabsorption of glucose. This

The Tm of the proximal tubules on average is around 375 mg/minute although it shows inter-individual variations. The filtered glucose load is directly proportional to blood glucose concentration. In normal nondiabetic individuals, the filtered glucose load is less than 375 mg/minute; therefore, the entire amount is reabsorbed, and their urine is free of any glucose. This process has survival benefits as it allows the kidneys to conserve glucose and can be viewed as an adaptive mechanism. In patients with T2DM, the filtered load may exceed 375 mg/minute; therefore, the Tm is exceeded, and all glucose in excess of the Tm spills over in urine [21]. In T2DM subjects, this adaptive mechanism becomes maladaptive. The increased expression of SGLT1/SGLT2 occurring in DM subjects results in increased renal

**2.2 Glucose transport across plasma membrane**

cells in the proximal renal tubules, respectively [20].

/K+

**2.3 Handling of glucose by the kidney**

lateral surface by the Na+

force for apical glucose entry via Na+

GLUT2 and reenters the bloodstream [21].

intracellular space.

**78**

glucose reabsorption which ultimately leads to maintenance of a state of persistent hyperglycemia [23, 24]. The tubular growth leads to increased Tm for glucose which further exacerbates hyperglycemia [22].

Based upon these facts, the contribution of the kidney in development and maintenance of state of hyperglycemia in T2DM is quite evident. Therefore, SGLT2-I provide a pathophysiologically rational and novel approach to its treatment.
