**5. Development of SGLT inhibitors**

Given the findings discussed in the above sections and considering the physiological functions of SGLT1 and SGLT2, it was an obvious idea to use SGLT1 and SGLT2 inhibitors as OAHs. Targeting hyperglycemia by inhibiting intestinal and renal glucose reabsorption appeared to be a novel therapeutic strategy.

Phlorizin was discovered around 150 years ago, which is a chemical found in the root bark, leaves, shoots, and fruit of the apple tree, and soon thereafter it was found to increase renal glucose excretion in healthy human beings. Phlorizin is a naturally occurring competitive nonselective inhibitor of SGLT1 and SGLT2.

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**Table 2.**

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

ipragliflozin, BI 44847, and LX 4211 [58, 59].

to inhibit SGLT1 in other organs (**Table 2**).

**6.1 Effects on diabetes and metabolism**

together for the sake of clarity.

insulin sensitivity [56].

SGLT2 compared to SGLT1.

In 1987, it was reported that subcutaneous phlorizin administration normalized plasma glucose profiles in insulin-resistant diabetic rats along with improving

However, due to poor water solubility and poor oral bioavailability as it is metabolized to phloretin by glucosidase in gut and unselective SGLT1 and SGLT2 inhibition, phlorizin was not an ideal therapeutic agent. It has low selectivity for

ment as it was again nonselective in nature and had safety concerns [57].

including AVE-2268, remogliflozin, sergliflozin, and WAY-123783.

**6. Clinical effects of SGLT2 inhibitors in diabetes mellitus**

T-1095 was the next agent developed but did not continue into clinical develop-

By modification in basic structure of phlorizin, other SGLT2-I were developed,

Currently, there are seven SGLT2 inhibitors approved for clinical use. They are given orally and absorbed by the intestine. Due to higher selectivity for SGLT2 versus SGLT1, inhibition of intestinal SGLT1 can be avoided, though it is still possible at high oral doses. At pharmacological doses, their serum levels achieved are too low

Clinical effects observed for different SGLT2-I will be described and discussed

In T2DM, upregulation of SGLT2 expression increases its Tm by around 20%. SGLT2-I is filtered in glomeruli and inhibits glucose reabsorption in S1 segment of

**Compound Preparation strength available SGLT2/SGLT1 selectivity Reference** Dapagliflozin 5, 10 mg 1200 [60] Canagliflozin 100, 300 mg 200 [61] Empagliflozin 10, 25 mg 2500 [62] Ertugliflozin 5, 15 mg 2000 [63] Ipragliflozin 25, 50 mg 254 [64] Luseogliflozin 2.5, 5 mg 1765 [65] Tofogliflozin 20 mg 2900 [66]

In the presence of functional SGLT2, less than 10% of glucose is absorbed through SGLT1; therefore, it is expected that SGLT2 inhibitor therapy would lead to around 90% reduction in Tm but the observed decrease of only 30–50% in Tm can be

proximal tubule leading to a reduction of 30–50% in Tm of SGLT2 [67].

explained by higher amount of SGLT1-mediated glucose reabsorption [70].

*Preparation strength and SGLT2 versus SGLT1 selectivity of various approved SGLT2 inhibitors.*

All of them have the glucoside moiety linked to a distal phenolic ring via an O-linkage. Due to susceptibility of O-linkage to degradation by β-glucosidases which reduced their utility, development of more metabolically stable C-linkage SGLT2 inhibitors was prompted with focus on increasing selectivity for SGLT2 versus SGLT1. This led to discovery of dapagliflozin, canagliflozin, empagliflozin, *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*

*4.2.3.2 Functions of SGLT2 in pancreatic alpha cells*

involved in direct regulation of glucagon secretion [31].

*4.2.4 Regulation of SGLT2*

SGLT2 promoter region [28].

**5. Development of SGLT inhibitors**

and macroalbuminuria which culminate into renal failure [49].

combined with glomerular hypertrophy, enlarged proximal tubules, inflammation, and interstitial fibrosis. These hyperglycemia-induced alterations lead to micro-

During fasting when blood glucose level is low, several counter-regulatory responses are generated to increase and maintain blood glucose within normal range. Pancreatic alpha cells secrete glucagon which stimulates glycogenolysis and gluconeogenesis in the liver. Conversely, glucagon secretion is inhibited when blood glucose level increases after taking food [51]. Inhibition of glucagon secretion is mediated by paracrine effect of insulin and direct glucose-mediated regulation of glucagon secretion. In alpha cells, SGLT2-mediated glucose uptake is a critical step

The expression of SGLT2 at mRNA level increases in alpha cells in obesity and prediabetes. Once T2DM develops, the glucotoxicity leads to decrease in its expression. The glucagon secretion blockage which normally occurs at high plasma glucose levels gets blunted due to downregulation of SGLT2 causing enhanced endogenous glucose production in the liver which further aggravates hyperglycemia [31].

SGLT2 gene is located at chromosome 16 p11.2 and is expressed primarily in renal cortex. Various transcription factors are involved in regulation of SGLT2 such as SP-1, HNF1-alpha, and HNF4A, and their binding sites have been identified on

High-sodium intake promotes urinary sodium and glucose excretion by increas-

Activation of transcription factor NFκB (nuclear factor kappa-light-chainenhancer of activated B cells) downregulates transcription of SGLT2 in the presence of hyperglycemia due to increase in ROS [53]. Sympathetic innervation has been found to be involved in transcriptional upregulation of SGLT2 in the

Posttranscriptional regulation of SGLT2 is yet to be understood well. Recently, it was found that the 17 kDa protein membrane-associated protein 17 (MAP17)

Given the findings discussed in the above sections and considering the physiological functions of SGLT1 and SGLT2, it was an obvious idea to use SGLT1 and SGLT2 inhibitors as OAHs. Targeting hyperglycemia by inhibiting intestinal and

Phlorizin was discovered around 150 years ago, which is a chemical found in the root bark, leaves, shoots, and fruit of the apple tree, and soon thereafter it was found to increase renal glucose excretion in healthy human beings. Phlorizin is a naturally occurring competitive nonselective inhibitor of SGLT1 and SGLT2.

upregulates functional activity of SGLT2 in the plasma membrane [55].

renal glucose reabsorption appeared to be a novel therapeutic strategy.

ing plasma adiponectin level through stimulation of peroxisome proliferatoractivated receptor delta in adipose tissue. The enhanced adiponectin downregulates SGLT2 leading to reduced reabsorption of sodium and glucose. Due to hyperglycemia, this mechanism gets dampened in DM. Binding of SP-1 and HNF1-alpha at the promoter site is involved in this regulation [52], while HNF4A participates in glucose-dependent regulation of SGLT2 in alpha cells of the pancreas [31].

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kidney [54].

In 1987, it was reported that subcutaneous phlorizin administration normalized plasma glucose profiles in insulin-resistant diabetic rats along with improving insulin sensitivity [56].

However, due to poor water solubility and poor oral bioavailability as it is metabolized to phloretin by glucosidase in gut and unselective SGLT1 and SGLT2 inhibition, phlorizin was not an ideal therapeutic agent. It has low selectivity for SGLT2 compared to SGLT1.

T-1095 was the next agent developed but did not continue into clinical development as it was again nonselective in nature and had safety concerns [57].

By modification in basic structure of phlorizin, other SGLT2-I were developed, including AVE-2268, remogliflozin, sergliflozin, and WAY-123783.

All of them have the glucoside moiety linked to a distal phenolic ring via an O-linkage. Due to susceptibility of O-linkage to degradation by β-glucosidases which reduced their utility, development of more metabolically stable C-linkage SGLT2 inhibitors was prompted with focus on increasing selectivity for SGLT2 versus SGLT1. This led to discovery of dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, BI 44847, and LX 4211 [58, 59].
