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Diabetes Management SGLT2 Inhibitors
Figure 1: Normal Glucose Reabsorption in the Kidneys
Instead, mutations in the SGLT2 gene lead to the rare disorder familial
renal glucosuria (FRG), where glucose reabsorption in the kidneys is
Apical Basolateral severely impaired and large amounts of glucose are excreted in the
membrane membrane
urine.
20,21
Despite this severe glucosuria, FRG appears to be a benign
(lumen) (blood)
+ condition, causing no serious adverse events or problems in kidney
Na
function. No negative complications have been reported with this
disease and glucosuria does not appear to cause any particular harm.Glucose
Glucose Research involving these inherited disorders therefore suggests that
(~90%)
drugs inhibiting SGLT2 should be safe and are a superior choice
SGLT2 GLUT2
to SGLT1 inhibition.
Segment of proximal tubule
S1
Early Animal Studies
Early studies in animals using the compound phlorizin found in apple
+
Na trees showed the potential of SGLT inhibition in improving plasma
glucose levels. This molecule is a natural competitive inhibitor of both
Glucose
SGLT1 and SGLT2
15
and provided proof-of-concept for SGLT inhibition.
Glucose
Phlorizin was shown in animal studies to reduce both fasting and post-
(~10%)
prandial blood glucose levels without a risk for hypoglycemia.
22
It also
SGLT1 GLUT1
provided positive outcomes in terms of decreasing insulin resistance at
Segment of proximal tubule
the peripheral tissue level.
16,22
Although phlorizin showed encouraging
S3
results, certain factors prevented it from proceeding beyond pre-clinical
studies. Plorizin is poorly absorbed from the intestine and is easily
GLUT = glucose transporter; SGLT = sodium-coupled glucose co-transporter.
38
Source: Lee and Han, 2007.
hydrolyzed by lactase–phlorizin hydrolase.
23
Furthermore, phlorizin is
non-specific, inhibiting both SGLT1 and SGLT2, thereby limiting its
through the high-affinity, low-capacity glucose/galactose transporter potential as a diabetes treatment since disruption of SGLT1 will
SGLT1 in the S3 segment of the proximal tubule (see Figure 1).
12,13
As a necessarily result in gastrointestinal side effects. Instead, research has
result, no glucose is found in the urine of healthy individuals. focused on finding a drug that safely and specifically blocks SGLT2.
However, these early studies provided important insights into the
However, individuals with diabetes are frequently hyperglycemic, with concept of SGLT inhibition, and phlorizin is still the model on which many
plasma glucose levels capable of saturating the SGLTs in the kidney novel SGLT inhibitors are based.
and exceeding its maximal reabsorptive capacity. Once glucose
concentrations surpass 180–200mg/dl, the kidneys are no longer able to Studies of Sodium-coupled Glucose
reabsorb all of the glucose in the filtrate despite overexpression of the Co-transporter 2 Inhibitors
co-transporters in the proximal tubules of these individuals,
15,16
and any T-1095
excess sugar is excreted in the urine, leading to glucosuria.
12,13,17
SGLTs T-1095 is a prodrug analog of phlorizin taken orally that is readily
have therefore become a potential target in diabetes research; by absorbed from the intestine into the bloodstream, where it is converted
inhibiting these transporters, physicians can potentially further increase into its active form.
24
Because T-1095 is inactive in the small intestine, it
the amount of glucose excreted in the urine and lower plasma glucose does not affect the SGLT1s in the gastrointestinal tract and will not cause
levels in people with diabetes, thereby reducing hyperglycemia. the negative events associated with such inhibition. Active T-1095 is
filtered by the kidneys, where it competitively inhibits both SGLT2 and
Intestinal Glucose–Galactose Malabsorption and SGLT1, increasing glucosuria and decreasing blood glucose levels.
25
Familial Renal Glucosuria Studies using diabetic rats showed that T-1095 treatment increased the
Before developing any drugs to inhibit SGLT function, it is useful to amount of glucose excreted in the urine while decreasing plasma
consider the possible clinical effects of such inhibition by looking at rare glucose levels and glycated hemoglobin (HbA
1c
).
25,26
Despite these
inherited disorders of SGLT dysfunction. SGLT1 is expressed in both the encouraging results, T-1095 was not developed past phase II trials, most
small intestine and the kidneys, where it filters glucose and galactose likely due to its inability to specifically target SGLT2. Several other SGLT2
into the bloodstream. Individuals with mutations in the SGLT1 gene inhibitors have since been developed with slightly different structures
develop the rare autosomal recessive disorder intestinal glucose– from their predecessors, and are currently undergoing testing.
galactose malabsorption (GGM).
18,19
GGM causes severe and potentially
fatal diarrhea after carbohydrate consumption, and can develop as early Sergliflozin
as the neonatal period.
18
Only mild glucosuria is observed with this Unlike plorizin or T-1095, sergliflozin specifically inhibits SGLT2,
condition, and symptoms can be treated by removing glucose, exhibiting a 296-fold greater selectivity for SGLT2 over SGLT1.
27
galactose, and lactose from the diet. Preliminary animal studies of this oral drug showed that when given to
human subjects, the maximal resorptive capacity of the kidney for
SGLT2s are found exclusively in the kidneys and, as a result, no glucose was reduced by more than 60%, resulting in dose-dependent
gastrointestinal issues are observed when their function is disrupted. glucosuria after oral glucose loading.
27
Sergliflozin also decreased blood
76 US ENDOCRINOLOGY
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