Renal glucose reabsorption inhibitors
to treat diabetes
Clifford J. Bailey
Life and Health Sciences, Aston University, Birmingham B4 7ET, UK
Current therapies to reduce hyperglycaemia in type 2
diabetes mellitus (T2DM) mostly involve insulin-depen-
dent mechanisms and lose their effectiveness as pancre-
atic b-cell function declines. In the kidney, filtered
glucose is reabsorbed mainly via the high-capacity,
low-affinity sodium glucose cotransporter-2 (SGLT2) at
the luminal surface of cells lining the first segment of the
proximal tubules. Selective inhibitors of SGLT2 reduce
glucose reabsorption, causing excess glucose to be elim-
inated in the urine; this decreases plasma glucose. In
T2DM, the glucosuria produced by SGLT2 inhibitors is
associated with weight loss, and mild osmotic diuresis
might assist a reduction in blood pressure. The mecha-
nism is independent of insulin and carries a low risk of
hypoglycaemia. This review examines the potential of
SGLT2 inhibitors as a novel approach to the treatment of
hyperglycaemia in T2DM.
Treating hyperglycaemia
Treatment of hyperglycaemia in type 2 diabetes mellitus
(T2DM) is necessary to relieve acute symptoms and to
reduce the risk of chronic vascular complications. Lifestyle
interventions, notably diet and exercise, are important but
are generally insufficient to achieve or maintain glycaemic
control. Most current glucose-lowering therapies act to
address the underlying endocrine pathogenesis of insulin
resistance and b-cell dysfunction. However, these thera-
pies usually lose their effectiveness over time as b-cell
failure supervenes.
As a consequence, many patients receive multiple glu-
cose-lowering therapies and eventually require exogenous
insulin. Indeed, half or more of patients with T2DM do not
achieve guideline targets for glycaemic control [glycated
haemoglobin (HbA1c) of 6.5–7.0% (48–53 mmol/mol)] [1–4].
A majority of patients with T2DM are overweight or
obese [5], which increases insulin resistance and compli-
cates treatment [6]. However, several blood glucose-lower-
ing therapies (including insulin) are associated with
weight gain (Table 1), often of 2–5 kg [7]. This is predomi-
nantly due to reduced urinary glucose excretion, and ini-
tially approximates to the correction of glycaemia [8].
Except for a-glucosidase inhibitors, which slow the rate
of intestinal carbohydrate digestion, key antidiabetic
agents act, at least in part, through insulin-dependent
mechanisms (Table 1 and Figure 1). Thus, a new thera-
peutic approach without reliance on insulin or weight gain,
and suitable for use in combination with existing agents,
would be a valuable addition to the treatment choices for
hyperglycaemia in T2DM. Renewed interest in the role of
the kidney in glucose homeostasis has prompted the de-
velopment of sodium glucose cotransporter-2 (SGLT2)
inhibitors that fulfil these criteria by reducing renal glu-
cose reabsorption. This review examines the insulin-inde-
pendent mechanism of action of these agents and recent
clinical studies that indicate their potential as a novel
approach in the treatment of T2DM.
Role of the kidney in glucose balance
Therenal cortexproducesglucosebygluconeogenesis,main-
ly for utilization in the renalmedulla [9]. In T2DM, both the
liver and kidney contribute to excess glucose production,
and renal glucose production can contribute up to !20% of
the total glucose released into the circulation in the post-
absorptive state [9,10]. However, the kidneys substantially
affect the circulating glucose pool through reabsorption of
glucosefilteredby theglomeruli.Renal glucose reabsorption
isa constitutiveprocess thatdependsonthe concentrationof
glucose; it does not seem to be regulated by insulin and
might actually be increased in T2DM.
Almost all of the glucose entering the glomeruli in the
afferent glomerular arterioles is filtered into the nephron
fluid and enters the proximal convoluted tubule. Normal
kidneys (with a glomerular filtration rate of!125 mL/min)
filter approximately 180 L of plasma each day [11]. Thus, a
healthy individual with an average plasma glucose con-
centration of 5–5.5 mmol/L (90–100 mg/dL) will filter ap-
proximately 160–180 g of glucose daily, all of which will be
reabsorbed [12]. In theory, the amount of filtered glucose
that is reabsorbed will increase in proportion to the plasma
glucose concentration until the maximal reabsorptive
transport capacity of the tubules (Tm) is reached. Tm
usually occurs at an average filtered glucose load of ap-
proximately 375 mg/min, and all excess filtered glucose is
excreted in urine. In practice, however, some glucose usu-
ally escapes in the urine at plasma glucose concentrations
above!11mmol/L (200 mg/dL), the renal threshold. There
is a gradual increase in glucosuria above the renal thresh-
old up to the Tm value for glucose, which is called the splay
effect. These features of renal glucose handling largely
reflect the properties of the sodium glucose cotransporters
(SGLTs) in the proximal tubules.
Sodium glucose co-transporters
SGLT proteins are encoded by the solute carrier 5 (SLC5)
subfamily of sodium/substrate symporter genes [12]. The
Review
Corresponding author: Bailey, C.J. (c.j.bailey@aston.ac.uk).
TIPS-842; No. of Pages 9
0165-6147/$ – see front matter ! 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2010.11.011 Trends in Pharmacological Sciences xx (2011) 1–9 1

SCL5 genes code for several proteins (!75 kDa) with>59%
amino acid identity, among which SGLT1 and SGLT2 are
the most well characterized [12]. SGLT1 is predominantly
expressed in enterocytes, where it mediates glucose and
galactose uptake from the gut lumen [12,13]. SGLT1 is also
expressed in the more distal segments (S2–3) of the proxi-
mal convoluted tubule, where it mediates the reabsorption
of glucose that has not been reabsorbed earlier in the
tubule by SGLT2. SGLT2 is almost entirely confined to
the first segment (S1) of the proximal tubules in the kidney
cortex [13,14], where it mediates reabsorption of most of
the filtered glucose [15].
SGLT1 and SGLT2 transport glucose across the luminal
membrane of epithelial cells lining the proximal tubules
against a concentration gradient by coupling with the
inward diffusion of sodium ions (Figure 2) [12]. This is a
secondary active process and is maintained by extrusion of
sodium across the basolateral membrane via the sodium-
potassium ATPase pump.
SGLT2 and SGLT1 exhibit different transport charac-
teristics [12]. SGLT2 transports glucose and sodiumwith a
1:1 stoichiometry, whereas SGLT1 transports one mole-
cule of glucose with two sodium ions. SGLT2 is a low-
affinity, high-capacity glucose transporter with K0.5 values
of !2 mM for glucose and 100 mM for sodium. By contrast,
SGLT1 is a high-affinity, low-capacity glucose transporter
withK0.5 values of 0.4 mM for glucose and 3 mM for sodium
[14]. Thus, SGLT2 in the S1 segment is suited to reabsorp-
tion of a high glucose concentration entering the proximal
tubule [16], whereas SGLT1 is suited to reabsorption of the
remaining lower glucose concentration in subsequent seg-
ments (Figure 3). After reabsorption from the lumen,
glucose within the proximal tubular cells passes into the
interstitium (and then to the plasma) by facilitative glu-
cose transporters in the basolateralmembranes (GLUT2 in
S1 and GLUT1 in subsequent segments).
Although glucosuria is a feature of poorly controlled
diabetes, there is evidence that the renal threshold for
Table 1. Current antidiabetic agentsa [4,54–61]
Agent Insulin-dependent mechanisms Comments
Insulin
action
Insulin
release
Body weight
change
a-Glucosidase inhibitors – – Neutral " Reduce rate of carbohydrate digestion in small
intestine, lowering postprandial glucose levels
" Only oral antidiabetic class currently available
that does not have an insulin-dependent
mechanism of action
Amylin agonistsb (pramlinitide) H – Reduce " Injected subcutaneously before each meal in
insulin-treated patients
" Slow gastric emptying, inhibit postprandial
glucagon production in a glucose-dependent
manner, thereby reducing the increase in
postprandial glucose levels
" Although not directly dependent on insulin,
suppression of glucagon by amylin agonists
might indirectly enhance insulin action
Biguanides (metformin) H – Neutral " Decrease hepatic glucose output and improve
peripheral glucose disposal
" Metformin is the only biguanide available in most
of the world
" Efficacy requires the presence of insulin
DPP-4 inhibitors – H Neutral " Prevent degradation of endogenous incretins,
c especially GLP-1, thereby raising incretin levels
" Increased GLP-1 levels potentiate glucose-dependent
insulin secretion and suppress glucagon release
Glinides – H Gain " Stimulate insulin secretion by binding to the
benzamido site of the sulfonylurea receptor SUR1
on pancreatic b-cells
GLP-1 receptor agonists – H Reduce " Bind to GLP-1 receptors on pancreatic b-cells and
potentiate glucose-dependent insulin secretion
and suppress glucagon release, resulting in
reduced postprandial hepatic glucose production
and enhanced peripheral glucose uptake
Sulfonylureas – H Gain " Stimulate insulin secretion by binding to the
sulfonylurea receptor SUR1 on pancreatic b-cells
TZDs H – Gain " Modulate PPAR-g activity to increase sensitivity
of muscle, fat and liver to insulin; reduce hepatic
glucose production
Bromocriptined H – Neutral " Dopamine D2 receptor agonist
Colesevelamd – H? Neutral " Bile acid sequestrant
" Mechanism uncertain, induces GLP-1 secretion in
rat models
aAbbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; PPAR-g, peroxisome proliferator-activated receptor gamma; SUR1, sulfonylurea receptor;
TZDs, thiazolidinediones; –, no effect; H, increase or enhancement;?, not established.
bAmylin is a neurohormone that is co-secreted with insulin in response to meals.
cIncretins are hormones released from the gastrointestinal tract during meal digestion which enhance nutrient-induced insulin secretion.
dThe dopamine D2 receptor agonist bromocriptine and the bile sequestrant colesevelam have recently been licensed for treatment of T2DM in some territories.
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