SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 11 NUMBER 2 • JUNE 2014
71
45 mg pioglitazone. This study also showed that balaglitazone was
effective in reducing total insulin requirements and increased insulin
sensitivity. While there were no statistically significant differences in
adverse effects between the two agents, the 10-mg dose of bala-
glitazone showed a trend towards less weight gain, fluid retention,
cardiovascular complications, and effects on bone density. Multiple
phase III trials are underway in Europe and the USA to further
examine balaglitazone.
Aleglitazar is a member of a new class of dual PPAR-
γ
and -
β
agonists, named glitazars, which is being investigated in phase
III trials. Aleglitazar has been reported to improve levels of HbA
1c
,
triglycerides and HDL-C in a dose-dependent manner.
26
Given these promising results, these agents have great potential
for management of T2DM.
Therapies targeting metabolic enzymes
11
β
Hydoroxysteroid dehydrogenase type 1 (11
β
-HSD1)
inhibitors
The role of glucocorticoids in adipose tissue metabolism and
distribution, lipid and glucose metabolism has long been known,
with high levels of glucocorticoids promoting hyperglycaemia
and insulin resistance, hyperlipidaemia, and visceral obesity.
27, 28
11
β
- HSD is an enzyme that is involved in the interconversion of
cortisol and cortisone and is present in two isoforms, 11
β
-HSD1
and 11
β
-HSD2. 11
β
-HSD1 is predominantly expressed in the liver
and adipose tissue and its main function appears to be conversion
of cortisone to cortisol.
27
11
β
-HSD2 is primarily expressed in the
kidneys and colon and acts to inactivate cortisol by converting it to
cortisone.
27-31
The incentive to develop 11
β
-HSD1 inhibitors for the treatment
of diabetes has come from our increased understanding of the role
between glucocorticoid excess and insulin resistance. The potential
benefits of developing compounds that inhibit 11
β
-HSD1 include
weight loss, and decreased serum insulin, glucose LDL-C and TG
levels.
27,30,31
However, many compounds that have an inhibitory effect
on 11
β
-HSD1 also inhibit 11
β
-HSD2. For example, carbenoxolone
is a non-selective inhibitor of both 11
β
-HSD1 and 11
β
-HSD2
derived from licorice root. In type 2 diabetics, it was found to
improve hepatic insulin sensitivity, but also led to sodium retention,
hypertension and hypokalaemia due to its 11
β
-HSD2 inhibition.
29, 31
11
β
-HSD1 inhibitory effects have been demonstrated in previously
known compounds including rosiglitazone, oestrogens, which
may help to explain the protective effect they demonstrate in pre-
menopausal women, and fibrates.
31
Many new 11
β
-HSD1 selective
compounds are in development, which include INCB13739, an
antisense oligonucleotide. In one study, INCB13739 was added
to metform-in, resulting in an average reduction in HbA
1c
level of
0.6% and up to 1.1 kg weight loss. Concerning limitations include
interference with the hypothalamic–pituitary–adrenal (HPA) axis
leading to mineralocorticoid excess resulting in sodium retention,
hypertension, virilisation, and menstrual irregularities.
30,31
While the
potential utility of these compounds is clear, phase III studies are
needed to determine the safety and efficacy of these 11
β
-HSD1
inhibitors.
Glucokinase activators
Glucokinase (GK) or hexokinase IV is an enzyme that catalyzes
the addition of phosphate to glucose for further intracellular
metabolism. It serves as a glucose sensor in beta-cells and initiates
the release of insulin from the beta-cell. In the liver, this enzyme
directs glucose toward glycogen synthesis and lipogenesis. In
diabetics, activity of GK is preserved, although decreased due to a
lesser number of functional beta-cells.
32
Currently, several GK activators are undergoing studies to
evaluate their efficacy and safety. This class of molecules targets
beta-cell core defect in T2DM and liver production of glucose.
In a phase I trial, piragilatin resulted in a decrease in fasting and
post-prandial glucose in mild diabetes.
32
Concerns include a time-
dependent effect on the central nervous system and reproductive
system due to the expression of GK in these tissues.
Protein tyrosine phosphatase 1B (PTP1B) inhibitors
This enzyme acts as a negative regulator of insulin signalling by
deactivating the insulin receptor. Current data show its inhibition
improves both insulin and leptin action in animals.
33
It may be an
option for the treatment of diabetes, but due to its expression in
multiple other tissues, other studies are needed to ensure selectivity
of these inhibitors to the desired tissues.
Fructose 1,6-bisphosphatase (FBP) inhibitors
FBP is a rate-limiting enzyme for gluconeogenesis and its inhibition
can result in improved blood sugars. A small phase I trial showed
improvement in fasting blood sugars in individuals with diabetes.
34
Conclusion
In the coming years, multiple new therapeutic options will be
available to address hyperglycaemia and its undesirable side effects.
These new therapeutics show great promise for controlling and
managing T2DM, but are by no means a cure. The corner stone
of prevention of T2DM lies in healthy lifestyle. Dietary modification
and adequate physical activity is the ideal intervention for keeping
the threat of diabetes development and its complications at bay.
We should continue to emphasise and allocate resources to the
education and prevention of T2DM rather than solely depending
on treating diabetes after it has occurred.
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