Global Journal of Pharmacology 6 (2): 86-93, 2012
ISSN 1992-0075
© IDOSI Publications, 2012
Overview on Sodium Glucose Transport Inhibitors as a
Therapeutic Tool Against Diabetes Mellitus
Manmohan Singhal, Shailee Rasania, Amit Gaur, V.R. Manchireddy Vishnu,
S. Vijaya Rama Raju and Yozana Upadhyay
School of Pharmaceutical Sciences, Jaipur National University, Jaipur, Rajasthan, India - 302025
Abstract: In the search for potential new drug targets for the treatment of diabetes, sodium-glucose cotransporters (SGLTs), in particular SGLT2, have been the subject of particular attention. SGLT2 plays an
important role in glucose reabsorption in the kidney and SGLT2 inhibitors enhance renal glucose excretion and
consequently lower plasma glucose levels. The main target is thereby the early proximal tubule where
secondary active transport of the sugar is mediated by the sodium glucose co-transporter SGLT2. The principle
behind SGLT2 inhibition involves the improvement of diabetic conditions without increasing body weight or
the risk of hypoglycemia. SGLT2 expressed in the proximal renal tubules accounts for about 90% of the
reabsorption of glucose from tubular fluid. Genetic defects of SGLT2 result in a benign familial renal glucosuria.
Pharmacological agents that block SGLT2 are being tested as potential treatment for type 2 diabetes mellitus.
Key words: Sodium Glucose Transport (SGLT)
Diabetes
INTRODUCTION
Glucosuria
Phlorizin
Dapagliflozin
metformin, insulin secretagogues (predominantly
-glucosidase
sulfonylureas),
thiazolidinediones,
inhibitors, insulin and more recently glucagon like
peptide-1 agonists and dipeptidyl-peptidase-IV inhibitors,
many patients do not achieve glycemic targets, partly due
to limiting side effects of current therapies, including
weight gain, hypoglycemia, fluid retention and
gastrointestinal side effects. Hence, the search for new
treatment strategies is ongoing [8].
Among the new therapies on the horizon, sodiumglucose co-transporter 2 (SGLT2) inhibitors seem
promising and there are a number of ongoing phase II
and III clinical trials with a variety of these compounds.
SGLT2 is almost exclusively expressed in the renal
proximal tubules and accounts for 90% of the renal
glucose reabsorption [8]. SGLT2 inhibitors work
independently of insulin and lead to negative energy
balance by enhanced urinary glucose excretion. This
makes it mechanistically possible for this class of drugs to
reduce glucose levels without causing hypoglycemia
and weight gain. However, the side effect profile
remains to be further elucidated in ongoing phase III
trials and these compounds will need to be proven safe
from a renal and cardiovascular perspective to meet
current regulatory requirements for new diabetes
treatment.
Sodium-dependent glucose co-transporters (SGLT)
are a family of glucose transporter found in the intestinal
mucosa (enterocytes) of the small intestine (SGLT1) and
the proximal tube of the nephron (SGLT2 in PCT and
SGLT1 in PST). They contribute to renal glucose
reabsorption. In the kidneys, 100% of the filtered glucose
in the glomerulus has to be reabsorbed along the nephron
(98% in PCT, via SGLT2). In case of too high plasma
glucose concentration (hyperglycemia), glucose is
excreted in urine (glucosuria); because SGLT are
saturated with the filtered monosaccharide. One must
know that glucose is never secreted by the nephron.
Diabetes mellitus is the most common metabolic disorder
characterized by hyperglycaemia. It is associated with
long term microvascular and neurological complications
affecting kidney, heart, eyes and nerves [1-6]. Insulin
regulates carbohydrate metabolism by aiding the
transport of glucose and amino acid from the blood stream
into the storage organs such as liver and muscles. In
diabetes mellitus, there is hindrance of glucose transport
of such a degree that threatens or impairs health [7].
Management of type 2 diabetes mellitus (T2DM)
remains complex and challenging. Although a wide range
of pharmacotherapy for T2DM is available, including
Corresponding Author: Manmohan Singhal, School of Pharmaceutical Sciences, Jaipur National University,
Jaipur, Rajasthan, India. Mob: +91-9829153193.
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Global J. Pharmacol., 6 (2): 86-93, 2012
Table 1: SGLT 1 and SGLT 2 and their properties
Gene
SLC5A1
SLC5A2
Protein
Sodium/GLucose coTransporter 1
Sodium/GLucose coTransporter 2
Acronym
SGLT1
SGLT2
Tissue distribution in
proximal tubule
S3 segment
predominately in the S1 and S2 segments
Na+: Glucose
Co-transport ratio
2:1
1:1
Contribution to
glucose reabsorption (%)
10
90
Table 2: Types of Sodium glucose transporters
Gene
Protein
Substrate
Tissue Distribution
SLC5A1
SLC5A2
SLC5A4
SLC5A9
SLC5A10
SLC5A11
SGLT1
SGLT2
SGLT3
SGLT4
SGLT5
SGLT6
Glucose and galactose
Glucose
Glucose sensor
Mannose, glucose, fructose and 1,5-AG
Glucose and galactose
Myo-inositol, xylose and chiro-inositol
Small intestine, trachea and kidney
Kidney
Small intestine, lung, uterus, thyroid and testes
Small intestine, kidney, lung andliver
Kidney
pinal cord, kidney, brain andsmall intestine
Types of SGLT: The two most well known members of
SGLT family are SGLT1 and SGLT2 (Tables 1, 2), which are
members of the SLC5A gene family [9, 10].
Including SGLT1 and SGLT2, there are total seven
isoforms in the human protein family SLC5A, several of
which may also be sodium-glucose transporters [11, 12].
membranes. They belong to the SLC5 gene family, which
has nine members with known functions. Of these, six are
plasma membrane sodium/substrate co-transporters
for solutes such as glucose, myoinositol and iodide
(SGLT 1-6). SGLT1 is primarily expressed in the small
intestine but is also found in the trachea, kidney and heart
and its predominant substrates are glucose and galactose.
SGLT2 is expressed in the S1 and S2 segments of the
proximal convoluted tubules and is responsible for renal
reabsorption of glucose [15]. SGLT2 RNA is minimally
expressed in the ileum, the level of which was insignificant
by Northern blot analysis [16]. Although one study using
real-time PCR suggests widespread SGLT2 RNA
expression in a variety of tissues [17], there is no
published data to show that SGLT2 protein is found
outside the kidney. There have been attempts to examine
expression of SGLT proteins, but availability of antibodies
that are specific enough seems to be the limiting factor.
Therefore, the functional significance of mRNA
expression in nonrenal tissues has not been established.
However, there is some evidence for SGLT2 mRNA
expression by real-time PCR as well as for SGLT2 protein
expression in the placenta by Western blot analysis [18].
SGLT1 gene mutations lead to glucose-galactose
malabsorption, which causes potentially fatal diarrhea.
The oral rehydration therapy that saves millions of lives
from infectious diarrhea works via SGLT1 transporters in
the enterocytes [19, 20].
Much of the evidences for SGLT2 being a major
pathway for renal glucose reabsorption comes from
genetic studies of individuals with familial renal
glucosuria [21, 22]. Mutations in the SLC5A2 gene
encoding SGLT2 lead to familial renal glucosuria, which is
inherited as an autosomal recessive trait and is
characterized by normal blood glucose levels, normal oral
glucose tolerance test results and isolated persistent
glucosuria [23, 24]. A study analyzing 23 families with
Mechanism of SGLT: First, the Na+/K+ ATPase pump on
the basolateral membrane of the proximal tubule, cell
actively (requires ATP) transports sodium from this cell
into the peritubular capillary. This creates a downhill
sodium gradient inside the proximal tubule cell. The SGLT
proteins use the energy from this downhill sodium
gradient created by the ATPase pump to transport
glucose across the apical membrane against an uphill
glucose gradient. Therefore, these co-transporters are an
example of secondary active transport (The GLUT
uniporters then transport the glucose across the
basolateral membrane, into the peritubular capillaries).
Both SGLT1 and SGLT2 are known as symporters, since
both sodium and glucose are transported in the same
direction across the membrane.
Glucose Transport Across Biological Membranes:
Glucose absorption at the enterocytes, reabsorption at the
renal tubules, transport across the blood-brain barrier and
uptake and release by all cells in the body are affected by
two groups of transporters: glucose transporters (GLUTs)
and sodium-glucose co-transporters (SGLTs). GLUTs are
facilitative or passive transporters that work along the
glucose gradient. They belong to the SLC2 (solute carrier
family 2) gene family, which has 13 members: GLUT 1-12
and the H+-myoinositol co-transporters. They are
expressed in every cell of the body [13, 14].
SGLTs co-transport sodium and glucose into cells
using the sodium gradient produced by sodium/
potassium ATPase pumps at the basolateral cell
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Global J. Pharmacol., 6 (2): 86-93, 2012
index cases of renal glucosuria found that each family had
a unique mutation in the SGLT2 gene. Individuals who
were found to be carriers of two mutated alleles showed
severe glucosuria, defined by a urinary glucose of more
than 10 g/1.73 m2 per 24 hrs (55 mmol/1.73 m2 per 24 hrs).
The index patients who presented with mild glucosuria
and the family members of cases of severe glucosuria
were shown to be heterozygous carriers of SGLT2
mutations [22, 25]. Another study found 20 different
SLC5A2 mutations within 17 pedigrees. Glucosuria was
mild in heterozygotes ranging from 2.7 to 10 g/1.73 m2 per
24 hrs, whereas it was severe in homozygotes ranging
from 15.2 to 86.5 g/1.73 m2/24 hrs. Two patients in the
homozygous group had plasma renin and serum
aldosterone concentration raised to an average of 4.6- and
3.1-fold, respectively, suggesting activation of
compensatory mechanisms [26].
outwardly directed gradient from the tubular cells into the
interstitium. Hence, up-regulation of SGLT2 is an
important adaptation in diabetes to maintain renal tubular
glucose reabsorption. SGLT2 mRNA expression is upregulated in diabetic rat kidneys and this up-regulation is
reversed by lowering blood glucose levels [31]. Human
exfoliated proximal tubular epithelial cells from fresh urine
of diabetic patients express significantly more SGLT2 and
GLUT2 than cells from healthy individuals [32]. There is
also evidence for up-regulation of GLUT2 gene expression
in renal proximal tubules in diabetic rat models [33- 35].
Uncontrolled diabetes leading to increased expression of
SGLT2 has practical significance in that the inhibitors are
likely to produce greater degrees of glucosuria in the
presence of higher prevailing plasma glucose levels. This
has been shown in preclinical studies with the nonspecific
SGLT inhibitor, T-1095 [36].
Interestingly, this up-regulation of SGLT2 receptors
is also seen in renovascular hypertensive rat models. The
authors speculated that angiotensin II-induced SGLT2
over expression probably contributes to increased
absorption of Na+ and thereby development or
maintenance of hypertension. Rats treated with either
Ramipril or Losartan showed significant reduction in the
intensity of immunostaining and levels of SGLT2 protein
and mRNA. This may have relevance in diabetes, given
the high prevalence of hypertension in diabetes [37].
Renal Glucose Transporter in Normal: Kidneys play a
very important role in glucose homeostasis. Blood
glucose is freely filtered by the glomeruli and is
essentially completely reabsorbed from the proximal
tubules via sodium-coupled transporters in the brush
border membrane. The glomeruli filter about 144 g of
glucose per 24 hrs, nearly 100% of which is reabsorbed in
the renal tubules. When blood glucose levels reach the
renal threshold for reabsorption, which is about 8 to 10
mmol/liter (180 mg/dl), glucosuria starts to develop [27].
The proximal tubule has traditionally been divided into S1,
S2 and S3 segments based on the cell morphologies,
although more recent ultra structural analyses of
computer- assisted three-dimensional reconstruction of
mouse proximal tubules revealed no obvious
morphological segmentation of the proximal tubule [28].
There is evidence, however, for heterogeneity of sodiumdependent glucose transport along the proximal tubule.
The S1 and S2 segments of the proximal convoluted
tubules show low affinity and high capacity for sodiumdependent glucose absorption, whereas the more distal
parts show higher affinity and low capacity for the same
[29]. SGLT2 is located in the S1 and S2 segments where
the majority of filtered glucose is absorbed and SGLT1
is located in S3 segments responsible for reabsorbing the
remaining glucose [15, 30].
Discovery of Therapeutic Potential of SLGTs to Produce
Glucosuria: Phlorizin is a glucoside consisting of a
glucose moiety and two aromatic rings (aglycone moiety)
joined by an alkyl spacer. In the 19th century, French
chemists isolated it from the bark of apple tree to be used
in treatment of fever and infectious diseases, particularly
malaria. Von Mering observed in 1886 that Phlorizin
produces glucosuria. It has been used as a tool for
physiological research for more than 150 yr [38]. In 1975,
DeFronzo et al. showed that infusion of Phlorizin in dogs
increased fractional excretion of glucose by 60%, whereas
glomerular filtration rate and renal plasma flow remained
unchanged [39].
Phlorizin is a high-affinity competitive inhibitor of
Na-dependent glucose transport in renal and intestinal
epithelia [40]. Hence, it causes malabsorption of glucose
and galactose from the small intestines and of glucose
from the renal tubules. Phlorizin caused heavy glucosuria
and marked inhibition of glucose uptake in the small
intestine during enteric perfusion in normal rats. It also
significantly reduces blood glucose on oral glucose
tolerance test in mice and lowers blood glucose in
Renal Glucose Transporter in Diabetics: Renal tubular
reabsorption is known to undergo adaptations in
uncontrolled diabetes; particularly relevant in this context
is the up-regulation of renal GLUTs. The increase in
extracellular glucose concentration in diabetes lowers its
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Global J. Pharmacol., 6 (2): 86-93, 2012
streptozotocin-induced diabetic rats [41]. It improves
counter-regulatory responses reducing the risk of
hypoglycemia in animal models [42]. In 1986, Unger’s
group reported that i.v. glucose failed to suppress the
marked hyperglucagonemia found in insulin-deprived
alloxan-induced diabetic dogs; however, when
hyperglycemia was corrected by phlorizin, the
hyperglucagonemia became readily suppressible. Phlorizin
treatment of partially pancreatectomized rats completely
normalized insulin sensitivity but had no effect on insulin
action in controls [43, 44], suggesting that the effect on
insulin sensitivity was by reversal of glucotoxicity, rather
than by a direct effect on insulin sensitivity. Animal
studies with Phlorizin have shown that its effect of
changing the ambient glucose independent of insulin
levels can up-regulate the glucose transport response to
insulin in adipose cells, which may be as a result of
changes in GLUT functional activity [45].
These findings provided important proof of concept
data, although Phlorizin itself is unsuitable for
development as a drug for the treatment of diabetes
because of its non-selectivity and low oral bioavailability
[36, 46]. T-1095 is a synthetic Phlorizin derivative, which
unlike Phlorizin is absorbed into the circulation on oral
administration and is metabolized to its active form T1095A. It suppresses the activity of SGLT1 and -2 in the
kidney and increases urinary glucose excretion in diabetic
animals, thereby decreasing blood glucose levels. With
long-term T-1095 treatment, both blood glucose and
glycosylated hemoglobin (HbA1c) levels were reduced in
streptozotocin-induced diabetic rats and the obese insulin
resistant yellow KK rat models [36]. Chronic
administration of T-1095 lowered blood glucose and
HbA1c levels, partially improved glucose intolerance and
insulin resistance and prevented the development of
diabetic neuropathy in the diabetic insulin-resistant GK
rat models. There were no adverse side effects reported at
the end of the study. This drug, however, did not proceed
to clinical development, presumably because it also
inhibits SGLT1 [47].
Dapagliflozin was rapidly absorbed after oral
administration and maximum plasma concentrations (Cmax)
were observed within 2 hrs of administration. The mean
half-life after the last dose in the MAD study ranged from
11.2 to 16.6 hrs and the data were similar for the SAD
study with high dose. In the MAD study, a dose of 100
mg produced urine glucose of 58.3 g per 24 hrs and 55.4 g
per 24 hrs on d 14. Dapagliflozin had no effect on urine
and serum electrolytes, serum albumin, osmolality, or renal
tubular markers such as N-acetyl-b-d-glucosaminidase
and 2-microglobulin. Two events of mild asymptomatic
hypoglycemia were reported in the SAD study. No
treatment-related serious adverse events were reported in
either study [49]. In a phase IIa study, 47 patients with
T2DM were randomized to receive 5, 25, or 100 mg of
dapagliflozin or placebo for 14 d. Those receiving 25 and
100 mg dapagliflozin had approximately 40% inhibition of
renal glucose reabsorption as compared with baseline
resulting in glucose excretion of up to 70 g per 24 hrs.
Two of the 24 women who received dapagliflozin were
diagnosed with mild vulvovaginal mycotic infections that
resolved in 4 d with treatment. The most frequently
reported treatment emergent adverse events were
gastrointestinal, including constipation, nausea and
diarrhea. There were no drug discontinuations due to
adverse events [50]. A phase IIb multiple-dose study to
evaluate safety and efficacy of dapagliflozin-randomized
T2DM patients to five dapagliflozin doses (2.5, 5, 10, 20,
or 50 mg), metformin extended release, or placebo for 12
wk has recently been reported. Dapagliflozin improved
hyperglycemia and caused weight loss by inducing
controlled glucosuria with urinary loss of approximately
200-300 kcal/d. There was a weight loss of 2.5 to 3.4 kg in
the dapagliflozin-treated patients, compared with 1.2 kg
with placebo and 1.7 kg with metformin. Dapagliflozin
treatment was not associated with clinically significant
osmolarity, volume, or renal status changes. There was
also no compensatory increase in hunger as assessed by
visual analog scales. The rates of bacterial urinary tract
infections (UTIs) were similar in the treatment and placebo
arms, but there was higher incidence of genital infections
in the dapagliflozin vs. placebo, especially at higher doses
[51].
SLGT Inhibitors in Clinical Development
Dapagliflozin: Dapagliflozin is a potent and highly
selective SGLT2 inhibitor. The elimination half-life after
intraarterial administration was 4.6, 7.4 and 3.0 hrs in rats,
dogs and monkeys, respectively [48]. Single and multiple
ascending dose (SAD and MAD) studies with
dapagliflozin confirmed that it has a pharmacokinetic
profile consistent with once-daily dosing and produces a
dose-dependent increase in glucosuria in humans.
Sergliflozin: Sergliflozin (KGT-1251), a prodrug of SGLT2
inhibitor Sergliflozin A was developed by Kissie
Pharmaceuticals, Japan and currently, it is being
developed by GlaxoSmithKline. It has been shown 7-fold
selectivity for human SGLT2 Vs human SGLT1 in cell
culture system. It has been induced glucosuria in healthy
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Global J. Pharmacol., 6 (2): 86-93, 2012
mice, rats and dogs and also lower postprandial blood
glucose in diabetic rats independently of insulin secretion
[52]. According to study conducted by Hussey et al.,
sergliflozin has shown dose dependent glucosuric effect
[53]. The study was conducted in 18 healthy over weight
and obese subjects (18-55 years) to evaluate safety,
pharmacokinetic and pharmacodynamic of sergliflozin
over 14 days of dosing. These eighteen subjects were
divided in two cohorts of equal subjects and six subjects
of each cohort were kept on 500 and 1000 mg of
sergliflozin and rest of three subjects in each cohort were
on placebo. The treatment was given three times per day
for 14 days. Sergliflozin was well tolerated in both cohorts
and had stable pharmacokinetic parameters. After 14 days
treatment, subjects treated with sergliflozin reduced
bodyweight of average 1.5kg compare to placebo treated
subjects. Hypoglycemia was not reported. The urinary
electrolyte level was raised on day1 in sergliflozin treated
subjects but it was resolved by day 14. Two randomized,
double blinded, placebo controlled and single dose
escalation crossover studies were done to evaluate
safety, pharmacokinetic and pharmacodynamic of
sergliflozin. In one study sergliflozin was given in a dose
range of 5-500 mg in 14 healthy subjects while in other
study dapagliflozin was given in dose range of 50-500 mg
in 8 type 2 diabetes patients. No variation was observed
in pharmacokinetic parameters between two groups and
segliflozin has shown dose dependent glucose excretion
in urine. The duration of glucose excretion was related to
plasma concentration of sergliflozin A. In subjects with
type 2 diabetes, 500 mg segliflozin reduced mean plasma
glucose from 18.2 mmol to 11.2 mmol/L, with minor,
transient alterations in urine electrolytes. Some minor
adverse events like headache, sore throat in healthy
subjects and headache, dyspepsia in diabetic patients
were seen. Thus, sergliflozin have shown promising
profile for treatment of diabetes along with obesity and
also excellent safety.
normal rats [54]. A study with 13 T2DM patients
supported its co-administration with metformin in patients
with T2DM with minimal risk of hypoglycemia. There was
no drug interaction affecting the pharmacokinetics of
either drug [55]. In another study, Remogliflozin etabonate
administered to 10 healthy subjects (doses ranging
from 20 to 1000 mg) and six subjects with T2DM
(doses ranging from 50 to 500 mg) was rapidly absorbed
and converted to remogliflozin, which had a plasma
half-life of 120 min across doses and groups. It caused a
dose-dependent increase in urinary glucose excretion in
all subjects. There were no effects on plasma electrolytes
and no serious adverse events [56]. Remogliflozin
etabonate also showed antihyperglycemic effects in both
streptozotocin-induced diabetic rats in oral glucose
tolerance and in diabetic (db/db) mice in the fed condition.
Chronic treatment with Remogliflozin etabonate reduced
the levels of fasting plasma glucose and glycated
hemoglobin. In high-fat diet-fed Goto-Kakizaki rats,
remogliflozin etabonate improved hyperglycemia,
hyperinsulinemia, hypertriglyceridemia and insulin
resistance. Thus study performed on rodent models
by Fujimori et al., suggests that remogliflozin etabonate
may be a new and useful drug for the treatment of
diabetes.
Remogliflozin Etabonate: Remogliflozin etabonate is
metabolized to its active form remogliflozin, which is a
benzylpyrazole glucoside. Its skeleton differs from that of
phlorizin, T-1095, or sergliflozin and hence is from a new
category of SGLT2 inhibitors. Its inhibitory effect for
human SGLT2 is approximately three times greater than
that of Phlorizin, but for SGLT1 it was only 1/20 that of
Phlorizin in in vitro studies. Animal studies have shown
good linearity between urinary glucose excretion and
the dose of Remogliflozin etabonate. It did not
significantly alter the plasma glucose level in 16-h fasted
Demerits of SGLT Inhibitors: There may be a risk of
negative effect of glucosuria on the kidneys, polyuria and
increased thirst, but there is no strong evidence about it.
Another theoretical problem in relation to the
genitourinary tract is increased risk for either bacterial or
fungal infection, but only long term clinical trial can
answer about this risk [57].
Merits of SGLT Inhibitors: Weight loss or weight
maintenance, is a key target for any type 2 diabetes
treatment.
No hypoglycemia because SGLT2 inhibitors do not
induce insulin secretion or inhibit hepatic glucose
production.
Improve insulin sensitivity and indirectly preserve
-cells by depletion of toxic glucose concentration in
blood.
SGLT2 inhibitors also produce osmotic diuretic effect
which may be advantageous in patients with
hypertension and CHF.
Other SGLT Inhibitors in Clinical Development [58]:
A number of other SGLT2 inhibitors are under
development like:
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Global J. Pharmacol., 6 (2): 86-93, 2012
AVE-2268- Sanofi-Aventis(USA)
KGT-1681- Kissei Pharmaceutical Co. Ltd/
GlaxoSmithKline
TS-033- Taisho Pharmaceuticals Co. Ltd, Tokyo,
Japan*
YM-543- Astellas Pharmaceutical Inc., Tokyo, Japan
JNJ-28431754/ TA-7284 (Canagliflozin)- Johnson and
Johnson Pharmaceutical, USA/ Mitsubishi Tanabe
Pharma, Japan.
7.
8.
9.
CONCLUSION
SGLT2 inhibitors have a unique mechanism of action
and have the potential to become a new treatment for
T2DM. Several phase III trials with these compounds are
ongoing and if their efficacy and safety profile are proven
to be adequate, these agents may gain a place in the
management of T2DM, particularly where weight gain is
a concern. The potential for use as an insulin-sparing
agent in patients on insulin has been highlighted in a
recent trial and a future role in the management of type 1
diabetes mellitus cannot be ruled out, although SGLT2
inhibitors have not yet been tested for this indication.
10.
11.
12.
REFERENCES
1.
2.
3.
4.
5.
6.
13.
Tian, H.L., L. S. Wei, Z.X. Xu, R. T. Zhao, D.L. Jin,
J.S. Gao, 2010. Correlations between blood glucose
level and diabetes signs in streptozotocin induced
diabetic mice. Global J Pharmacol., 4: 111-116.
Arora, S., S.K. Ojha, D. Vohora, 2009. Characterization
of streptozotocin induced Diabetes mellitus in swiss
albino mice. Global J. Pharmacol., 3: 81-84.
Marjani, A. and A. Shirafkan, 2011. The metabolic
syndrome in type 2 diabetic patients in Gorgan:
According to NCEP ATP III and IDF definitions.
Advan. Biol. Res., 5: 200-205.
Ibrahim, M.Y., A.M. Abdelatif, 2011. Effects of
alloxan-induced diabetes mellitus on blood
metabolites and serum minerals and hormones in
rabbits (lepus cuniculus) in relation to starch
supplementation and season. Advan. Biol. Res.,
5: 45-58.
Hossien, B.M. and A.A. Mohammad, 2008. Effect of
Education on Improvement of Quality of Life by
SF-20 in Type 2 Diabetic Patients. Middle-East J. Sci.
Res., 3: 67-72.
Khushk, I., M.U. Dahot, S.A. Baloach and
M.A. Bhutt, 2010. The evaluation of soybean extracts
in alloxan induced diabetic rabbits. World Appl. Sci.
J., 8: 22-25.
14.
15.
16.
17.
18.
19.
91
Udoh, B.E., B.C. Ezeokpo, K.K. Agwu and O.C. Okpal,
2010. Effects of Type Two Diabetes Mellitus on the
Plantar Aponeurosis of Nigerians. World J. Med. Sci.,
5: 81-84.
Kanai, Y., W.S. Lee, G. You, D. Brown and
M.A. Hediger, 1994. The human kidney low affinity
Na+/glucose cotransporter SGLT2, Delineation of the
major renal re-absorptive mechanism for D-glucose.
J. Clin Invest., 93: 397-404.
Wright, E.M., B.A. Hirayama and D.F. Loo, 2007.
Active sugar transport in health and disease. J. Intern
Med., 261: 32-43.
Wright, E.M., 2001. Renal Na(+)-glucose
cotransporters. Am. J. Physiol. Renal. Physiol.,
280: 10-18.
Chen, J., J. Feder, I. Neuhaus and J.M. Whaley, 2008.
Tissue expression profiling of the sodium-glucose
co-transporter (SGLT) family: implication for targeting
SGLT2 in type 2 diabetes patients. Diabetes, 57: 2493.
Jabbour, S.A. and B.J. Goldstein, 2008. Sodium
glucose co-transporter 2 inhibitors: blocking renal
tubular reabsorption of glucose to improve glycaemic
control in patients with diabetes. Int. J. Clin Pract.,
62: 1279-84.
Uldry, M. and B. Thorens, 2004. The SLC2 family of
facilitated hexose and polyol transporters. Pflugers
Arch., 447: 480-489.
Wood, I.S. and P. Trayhurn, 2003. Glucose
transporters (GLUT and SGLT): expanded families of
sugar transport proteins. Br. J. Nutr., 89: 3-9.
Wright, E.M. and E. Turk, 2004. The sodium/ glucose
co-transport family SLC5. Pflugers Arch, 447: 510-518.
Wells, R.G., A.M. Pajor, Y. Kanai, E. Turk,
E.M. Wright and M.A. Hediger, 1992. Cloning of a
human kidney cDNA with similarity to the
sodium-glucose cotransporter. Am. J. Physiol.,
263: F459-F465.
Zhou, L., E.V. Cryan, M.R. D'Andrea, S. Belkowski,
B.R. Conway and K.T. Demarest, 2003. Human.
cardiomyocytes express high level of Na+/glucose
cotransporter 1 (SGLT1). J. Cell Biochem., 90: 339-346.
Li, H., Y. Gu, Y. Zhang, M.J. Lucas and Y. Wang,
2004. High glucose levels down-regulate glucose
transporter expression that correlates with increased
oxidative stress in placental trophoblast cells in vitro.
J. Soc. Gynecol Invest., 11: 75-81.
Turk, E., M.G. Martin and E.M. Wright, 1994.
Structure of the human Na+/glucose cotransporter
gene SGLT1. J Biol Chem., 269: 15204-15209.
Global J. Pharmacol., 6 (2): 86-93, 2012
20. Martin, M.G., E. Turk, M.P. Lostao, C. Kerner and
E.M. Wright, 1996. Defects in Na+/glucose
cotransporter (SGLT1) trafficking and function
cause glucose-galactose malabsorption. Nat Genet.,
12: 216-220.
21. Vanden, L.P.H., K. Assink, M. Willemsen and
L. Monnens, 2002. Autosomal recessive renal
glucosuria attributable to a mutation in the
sodium glucose cotransporter (SGLT2). Hum Genet.,
111: 544-547.
22. Santer, R., M. Kinner, C.L. Lassen, R.
Schneppenheim, et al., 2003. Molecular Analysis of
the SGLT2 Gene in Patients with Renal Glucosuria.
J. Am. Soc. Nephrol., 14: 2873-2882.
23. Elsas, L.J. and L.E. Rosenberg, 1969. Familial renal
glycosuria: a genetic reappraisal of hexose transport
by kidney and intestine. J Clin Invest., 48: 1845-1854.
24. Elsas, L.J., D. Busse and L.E. Rosenberg, 1971.
Autosomal recessive inheritance of renal glycosuria.
Metabolism, 20: 968-975.
25. Oemar, B.S., D.J. Byrd and J. Brodehl, 1987.
Complete absence of tubular glucose reabsorption.
A new type of renal glucosuria (type-0). Clin
Nephrol., 27: 156-160.
26. Calado, J., Y. Sznajer, D. Metzger, A. Rita, et al., 2008.
Twenty-one additional cases of familial renal
glucosuria: absence of genetic heterogeneity, high
prevalence of private mutations and further
evidence of volume depletion. Nephrol Dial
Transplant, 23: 3874-3879.
27. Ganong, W.F., 2005. Formation and excretion of urine.
Rev. Med. Physiol., 22: 699-734.
28. Zhai, X.Y., H. Birn, K.B. Jensen, J.S. Thomsen,
A. Andreasen and E.I. Christense, 2003. Digital threedimensional reconstruction and ultrastructure of the
mouse proximal tubule. J. Am. Soc. Nephrol., 14: 611619.
29. Turner, R.J. and A. Moran, 1982. Heterogeneity of
sodium-dependent D-glucose transport sites along
the proximal tubule: evidence from vesicle studies.
Am. J. Physiol., 242: F406-F414.
30. Pajor, A.M., B.A. Hirayama and E.M. Wright, 1992.
Molecular evidence for two renal Na+/glucose
cotransporters. Biochim Biophys Acta, 1106: 216-220.
31. Freitas, H.S., G.F. Anhe, K.F. Melo, M.M. Okamoto,
M. Oliveira-Souza, S. Bordin and U.F. Machado, 2008.
Na+-glucose transporter-2 messenger ribonucleic
acid expression in kidney of diabetic rats correlates
with glycemic levels: involvement of hepatocyte
expression and activity.
nuclear factor-1
Endocrinol., 149: 717-724.
32. Rahmoune, H., P.W. Thompson, J.M. Ward,
C.D. Smith, G. Hong and J. Brown, 2005. Glucose
transporters in human renal proximal tubular cells
isolated from the urine of patients with non-insulindependent diabetes. Diabetes, 54: 3427-3434.
33. Kamran, M., R.G. Peterson and J.H. Dominguez, 1997.
Overexpression of GLUT2 gene in renal proximal
tubules of diabetic Zucker rats. J. Am. Soc. Nephrol.,
8: 943-948.
34. Dominguez, J.H., K. Camp, L. Maianu, H. Feister and
W.T. Garvey, 1994. Molecular adaptations of GLUT1
and GLUT2 in renal proximal tubules of diabetic rats.
Am. J. Physiol., 266: F283-F290.
35. Chin, E., A.M. Zamah, D. Landau, H. Gronbcek,
A. Flyvbjerg, D. LeRoith and C.A. Bondy, 1997.
Changes in facilitative glucose transporter messenger
ribonucleic acid levels in the diabetic rat kidney.
Endocrinol., 138: 1267-1275.
36. Oku, A., K. Ueta, K. Arakawa, T. Ishihara, et al., 1999.
T-1095, an inhibitor of renal Na+-glucose
cotransporters, may provide a novel approach to
treating diabetes. Diabetes, 48: 1794-1800.
37. Bautista, R., R. Manning, F. Martinez, C. AvilaCasado Mdel, V. Soto, A. Medina and B. Escalante,
2004. Angiotensin II-dependent increased expression
of Na+-glucose cotransporter in hypertension. Am.
J. Physiol. Renal. Physiol., 286: F127-F133.
38. Ehrenkranz, J.R., N.G. Lewis, C.R. Kahn and J. Roth,
2005. Phlorizin: a review. Diabetes Metab Res. Rev.,
21: 31-38.
39. Defronzo, R.A., M. Goldberg and Z. Agus, 1975.
Effects of phlorizin and insulin on tubular phosphate
reabsorption. Evidence for 2 transport pathways.
Kidney Int., 8: 470-472.
40. Panayotova-Heiermann, M.,
D.D.
Loo and
E.M. Wright, 1995. Kinetics of steady-state currents
and charge movements associated with the rat
Na+/glucose cotransporter. J. Biol. Chem.,
270: 27099-27105.
41. Tsujihara, K., M. Hongu, K. Saito, M. Inamasu,
K. Arakawa, A. Oku and M. Matsumoto, 1996.
Synthesis and pharmacological properties of 4'dehydroxyphlorizin derivatives based on a new
concept. Chem. Pharm. Bull, 44: 1174-1180.
42. Shi, Z.Q., K.S. Rastogi, M. Lekas, S. Efendic,
D.J. Drucker and M. Vranic, 1996. Glucagon response
to hypoglycemia is improved by insulin-independent
restoration of normoglycemia in diabetic rats.
Endocrinol., 137: 3193-3199.
92
Global J. Pharmacol., 6 (2): 86-93, 2012
43. Rossetti, L., D. Smith, G.I. Shulman, D. Papachristou
and R.A. DeFronzo, 1987. Correction of
hyperglycemia with phlorizin normalizes tissue
sensitivity to insulin in diabetic rats. J. Clin Invest.,
79: 1510-1515.
44. Rossetti, L., G.I. Shulman, W. Zawalich and
R.A. DeFronzo, 1987. Effect of chronic hyperglycemia
on in vivo insulin secretion in partially
pancreatectomized rats. J. Clin Invest., 80: 1037-1044.
45. Kahn, B.B., G.I. Shulman, R.A. DeFronzo,
S.W. Cushman and L. Rossetti, 1991. Normalization of
blood glucose in diabetic rats with phlorizin treatment
reverses insulin-resistant glucose transport in
adipose cells without restoring glucose transporter
gene expression. J. Clin Invest., 87: 561-570.
46. Katsuno, K., Y. Fujimori, Y. Takemura, M. Hiratochi,
F. Itoh, Y. Komatsu, H. Fujikura and M. Isaji, 2007.
Sergliflozin, a novel selective inhibitor of low-affinity
sodium glucose cotransporter (SGLT2), validates the
critical role of SGLT2 in renal glucose reabsorption
and modulates plasma glucose level. J. Pharmacol.
Exp. Ther., 320: 323-330.
47. Ueta, K., T. Ishihara, Y. Matsumoto, A. Oku,
M. Nawano, T. Fujita, A. Saito and K. Arakawa, 2005.
Long-term treatment with the Na+-glucose
cotransporter inhibitor T-1095 causes sustained
improvement in hyperglycemia and prevents
diabetic neuropathy in Goto-Kakizaki Rats. Life Sci.,
76: 2655-2668.
48. Meng, W., B.A. Ellsworth, A.A. Nirschl, et al., 2008.
Discovery of dapagliflozin: a potent, selective renal
sodium-dependent glucose cotransporter 2 (SGLT2)
inhibitor for the treatment of type 2 diabetes. J. Med.
Chem., 51: 1145-1149.
49. Fujimori, Y., K. Katsuno, I. Nakashima, Y. IshikawaTakemura, H. Fujikura and M. Isaji, 2008.
Remogliflozin etabonate, in a novel category of
selective low-affinity sodium glucose cotransporter
(SGLT2) inhibitors, exhibits antidiabetic efficacy in
rodent models. J. Pharmacol. Exp. Ther., 327: 268-276.
50. Komoroski, B., N. Vachharajani, D. Boulton,
D. Kornhauser, M. Geraldes, L. Li and M. Pfister,
2009. Dapagliflozin, a novel SGLT2 inhibitor, induces
dose-dependent glucosuria in healthy subjects.
Clin Pharmacol. Ther., 85: 520-526.
51. Komoroski, B., E. Brenner and L. Li, 2007.
Dapagliflozin (BMS-512148), a selective SGLT2
inhibitor, inhibits glucose resorption and reduces
fasting glucose in patients with type 2 diabetes
mellitus. Diabetologia, 50: S315.
52. Katsuno, K., Y. Fujimori and Y. Takemura, 2007.
Sergliflozin, a novel selective inhibitor of low-affinity
sodium glucose cotransporter (SGLT2), validates the
critical role of SGLT2 in renal glucose reabsorption
and modulates plasma glucose level. J. Pharmacol.
Exp. Ther., 320: 323-330.
53. Hussey, E.K., R.L. Dobbins and R.R. Stolz, 2007.
A double-blind randomized repeat dose study to
assess the safety, tolerability, pharmacokinetics and
pharmacodynamics of three times daily dosing of
sergliflozin, a novel inhibitor of renal glucose
reabsorption, in healthy overweight and obese
subjects. Diabetes, 56: 491.
54. Fujimori Y., K. Katsuno, I. Nakashima, Y. IshikawaTakemura, H. Fujikura and M. Isaji, 2008.
Remogliflozin etabonate, in a novel category of
selective low-affinity sodium glucose cotransporter
(SGLT2) inhibitors, exhibits antidiabetic efficacy in
rodent models. J. Pharmacol. Exp. Ther., 327: 268-276.
55. Hussey, E.K., R.L. O'Connor-Semmes, W. Tao,
J.L. Poo and R.L. Dobbins, 2009. Safety,
pharmacokinetics and pharmacodynamics of
remogliflozin etabonate (SGLT2 inhibitor) and
metformin when co-administered in type 2 diabetes
mellitus patients. Proc of the 69th Scientific Session of
the American Diabetes Association; 5-9: New
Orleans, LA (Abstract 582-P).
56. Kapur, A.R., E. Hussey, R.L. Dobbins, W. Tao,
M. Hompesch and D.J. Nunez, 2009. First human
dose escalation study with remogliflozin etabonate
(RE) in healthy subjects and in subjects with type 2
diabetes mellitus. Proc of the 69th Scientific Session
of the American Diabetes Association; 5-9: New
Orleans, LA (Abstract 509-P).
57. Calado, J., J. Loeffler and O. Sakallioglu et al., 2006.
Familial renal glucosuria: S LC5A2 mutation
analysis and evidence of salt-wasting. Kidney Int.,
69: 852-855.
58. Isaji, M., 2007. Sodium-glucose cotransporter
inhibitors for diabetes. Curr. Opin Investig Drugs,
8: 285-292.
93