Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
32
No. 1
January-March 2009
Contents
R& D Technology
Introduction
Diabetes
Features
Diabetes: Cure by Nature
4
Development of the Thiazolidinediones as
PPAR Agonists for the Treatment
of Type 2 Diabetes
22
Exploring Role of 5-Hydroxytryptamine in
Diabetes Mellitus and Cardiovascular
Complications
31
System Biology Enables Novel Strategies for
the Management of Type 2 Diabetes
40
Overview of Diabetes Mellitus Management 51
64
R&D Highlights
Cell-based Treatments for Diabetes
72
New Leads
89
100
Natural Products
Withania coagulans: Role in Diabetes
Marine Biota and Diabetics
106
113
Biotechnology
Latent Autoimmune Diabetes in Adults
(LADA)
Patents
CDRI Publications
119
123
129
Introduction
Diabetes
Diabetes is not a disease but a disorder, affecting 10% of the human population where the body does
not produce insulin or does not properly use insulin due to which the glucose concentration remains high in
the blood stream.
Types of Diabetes
Diabetes due to absence of insulin
This is frequently seen in childhood and hence called, Juvenile Onset or Childhood Diabetes. In this
diabetes which is called Type 1, the patient has failed to produce insulin and the only remedy to overcome
this is to go in for Insulin injections. The problem can happen in any age of the individual, though majority
are from childhood. The injected insulin, the frequency and dose is decided by the medical expert. The
synthesized insulin is injected and it mimics the natural insulin and the individual can lead a normal life.
Diabetes due to ineffective insulin
This is commonly seen in adults and called as Type 2. Though the body produces insulin it has trouble
using it, that is body is resistant to its own insulin. High blood sugar is found in the blood without being
transported to the cells. Routine checkups with dietary restrictions and healthy life style along with regular
affordable physical and mental activities are the only solution. There are medicines available which make
insulin more effective in such individuals and a combination of medicines and calorie control can help the
patients a lot in keeping the disorder under control.
Diabetes Management
Both types of diabetes have different treatment options and in general population the Type 2 diabetes
Introduction
is more prevalent than Type 1. More than 80% of the patients have Type 2 which means it is a problem of
ineffective insulin.
In case of Type 1, the objective of treatment is to give adequate insulin, in right intervals so that the
patient will not have Hypo or Hyper sugar levels. This requires frequent monitoring for sugar levels
and require higher frequency of medical supervision and intervention.
In case of Type 2, the objective of treatment is to make insulin more effective and reduce the
consumption of unwanted food materials. This is achieved by reduction in quantity of food or
modifications in type of food, increase in physical exercises or avoid sedentary life styles and also take
such medicines which improve the action of insulin. This requires less often blood sugar monitoring,
compared to Type 1, but requires constant and periodic medical monitoring and supervision.
Diabetes is a manageable disease if one knows how to control the sugar levels. But uncontrolled
diabetes can give rise to so many health complications such as Heart Disease, Kidney Disease, Blindness,
Brain Failure and Amputations of legs or Limbs.
How to Control?
Some manage it well but a lot of people with diabetes struggle continuously. It requires a lot of will
power to change the lifestyle and also to follow disciplined day to day activities. Specialists advise diabetic
patients to adopt following guidelines to live healthy with the disease:
Views expressed in the journal are those of the authors and the
Editorial Board/Publisher takes no responsibility for the same. We are
a secondary abstracting service and the veracity of information is of
the source quoted and not our primary responsibility.
Editor
Feature
Introduction
During evolutionary process of life on the
earth, microorganisms, plants and animals get
originated. All the living organisms are
interdependent in so many ways, as for food,
shelter etc. Some are parasitic saprophytic or
mutualists too. Plants possess innumerable
number of compounds, having innumerable
pharmacological profiles. By its wide range of
pharmacologically active compounds, plants
protect themselves from various diseases. At
the same time, animals are dependent on plants
for their food either directly or indirectly.
Animals taking food directly from plant get
cured from various diseases. Humans take
medication to cure or prevent diseases. From
very ancient time, wide range of plants is
reported to treat various diseases and
complications in various ancient medicinal
systems. In Ayurveda a number of plants are
reported to be used in curing diabetes.
Diabetes mellitus, arising as a global problem,
can be defined as a metabolic disorder, which
is most prevalent. Number of diabetic patients
is rising steadily day by day. Diabetes mellitus
is caused by the abnormality of carbohydrate
metabolism either by low blood insulin level
or insensitivity of target organs to insulin 42.
Diabetes can be defined as a group of
syndromes characterized by hyperglycemia,
altered metabolism of lipids, carbohydrates
and proteins. In type 1 diabetes, the pancreas
stops producing insulin due to autoimmune
destruction of pancreatic beta cells. In case of
type 2 diabetes, body cells do not respond to
4
Feature
pharyngitis. The powdered seeds of A. arabica
were administered in doses of 2, 3 and 4 gm/kg
body-weight to normal and alloxan-diabetic
rabbits. 2, 4, 6 and 8 hours after the
administration the blood glucose levels were
estimated. It exerted a significant (p<0.05)
hypoglycemic effect in normal rabbits. It acts
through release of insulin from pancreatic beta
cells8.
Aegle marmelos (L.) Correa ex Roxb.
(Family: Rutaceae)
Commonly known as Bael in Hindi.
Administration of an oral dose of 250 mg/ kg
of alcoholic leaf extract of A. marmelos
showed significant improvements in ability to
utilize the external glucose load in glucose
induced hyperglycemic rats. Efficacy of A.
marmelos was 71% of glybenclamide. This
increase in glucose utilization can be attributed
either by direct stimulation of glucose uptake
or by enhanced insulin secretion64. Aqueous
extract of fruits of A. marmelos is known to
exhibit hypoglycaemic effect in streptozotocininduced diabetes in rats. At the dose of 125
and 250 mg/ kg twice a day for 4 weeks
resulted in significant reductions in blood
glucose, plasma thiobarbituric acid reactive
substances, hydroperoxides, ceruloplasmin and
-tocopherol and a significant elevation in
plasma reduced glutathione and Vitamin C.
The effect of the extract at a dose of 250 mg
kg1 was more effective than glibenclamide35.
The effect of methanolic extract of A.e
marmelos has been studied on a battery of
targets
glucose
transporter
(Glut-4),
peroxisome proliferator activator receptor
gamma (PPAR) and phosphatidylinositol 3
kinase (PI3 kinase) involved in glucose
transport. It was found active at 100 ng/ml
dose
comparable
with
insulin
and
rosiglitazone5.
Aerva lanata (L.) Juss. ex Schult. (Family:
Amaranthaceae)
It is commonly known as Sunny khur. Its
alcoholic extract reduced the increase in blood
Current R&D Highlights, Jan.-Mar. 2009
S O
OH
O
S-methyl cysteine sulfoxide (SMCS)
The effects of two dietary doses of freezedried onion powder, i.e., onion low (ONL;
0.5%) and onion high (ONH; 2.0%) on
streptozotocin (STZ)-induced diabetes rat
model was studied. After 4 weeks on the
experimental diets, fasting blood glucose
levels for both onion-fed groups were found
elevated. Serum insulin concentrations and
insulin resistance were dose-dependently
increased in the onion-fed groups. The ONH
group had significantly higher lipid
concentrations, ONL group showed a similar
hyperlipidemic trend to a lesser extent31.
5
Feature
Allium sativum L. (Family: Alliaceae)
Commonly known as Lahasun in Hindi
and Garlic in English. Ethanolic extract of
garlic at the doses of 0.1, 0.25 and 0.5 g/kg
body weight was orally given to normal and
streptozotocin-induced diabetic rats for 14
days. The level of serum glucose, total
cholesterol, triglycerides, urea, uric acid,
creatinine, aspartate amino transferase (AST)
and alanine amino transferase (ALT) were
found decreased. The antidiabetic effect of the
extract was found more active than that of
glibenclamide18. The antidiabetic effect of
garlic is thought to be due to the formation of a
colloidal type suspension in the stomach and
intestines when the mucilaginous fiber of
S
S O
H 2N
OH
O
H 2C CHCH 2S SCH2 CH CH 2
O
Allicin
Nees
(Family:
and
King
of
bitters
in
English.
Andrographolide, a principle present in
O
HO
HO
H 3C CH2OH
Andrographolide
Feature
nicotinamide induced diabetic rats. At the dose
of 350 mg/kg ethanolic leaf extract has been
found to possess hypoglycemic as well as
antihyperglycemic potential in normal,
streptozotocin- diabetic rats and alloxanized
rabbits48
Areca catechu L. (Family: Arecaceae)
Commonly known as Supari in Hindi and
Betelnut in English. Subcutaneous
O
OCH 3
N
CH 3
Arecoline
indica
A.
Juss.
(Family:
Lindl.
(Family:
Feature
these effects except the increase in lipid
peroxidation. These findings indicated that the
use of B. vulgaris may decrease the
development of some diabetic complications23.
Boerhavia
diffusa
Nyctaginaceae)
L.
(Family:
HO
HO
HO
O
Camellia
Theaceae)
OH O
Shamimin
Brassica juncea
Brassicaceae)
(L.)
Czern.
(Family:
(Family:
OH
OH
OH
Millsp.
OH
(L.)
OH
Cajanus cajan
Fabaceae)
sinensis
Kuntze
(Family:
Feature
English. Oral feeding of diet containing (30%)
C. decidua fruit powder for 3 weeks to
alloxanized diabetic rats showed significant
hypoglycemia23.
Casearia
esculenta
Flacourtiaceae)
Roxb.
(Family:
L.
(Family:
O
N
N
H
O
Catharanthine
H
O
Vindoline
N
H
O
Vindolinine
Feature
Curcuma longa (Family: Zingiberaceae)
Gentiaceae)
HO
OH
O
O
Ferulic acid
littorale
Blume
(Family:
Eucalyptus
Myrtaceae)
globulus
Labill.
(Family:
Feature
readministered for three days at the same dose
level. There was no significant change in
fasting blood glucose (FBG), or glucose
tolerance test (GTT) in normal rabbits. There
was no fall in FBG but improvement in
glucose tolerance in alloxanrecovered rabbits.
In mildly diabetic rabbits there was 55.8% fall
in FBG values and an improvement in glucose
tolerance. The extract produced 68% fall in
FBG values in severely diabetic rabbits69. The
bark and aerial roots ethanolic extracts at a
dose of 100 mg/kg
HO
O
O
-amyrin acetate
H
18-glycyrrhetinic acid
Hook.f.
(Family:
R.
Br.
(Family:
Feature
glucose level in normal fasting, glucose-fed
hyperglycemic and diabetic rats compared
with placebo-treated animals. The maximum
glucose suppression occurred after 2 hour of
treatment by the effective dose of 200 mg/kg,
PO, of the extract 12,13.
Helicteres isora L. (Family: Sterculiaceae)
Administration of the bark extract of H.
isora at the doses of 100 and 200 mg/kg body
weight for 21 days resulted in significant
reduction in serum and tissue cholesterol,
phospholipids,
free
fatty
acids
and
triglycerides in STZ diabetic rats. Significant
(p< 0.05) decrease in high-density lipoprotein
(HDL) whereas significant increase (p<0.05)
low-density lipoprotein (LDL) and very lowdensity lipoprotein (VLDL) were observed in
STZ diabetic rats. The bark extract possesses
definite
hypotriglyceridemic
and
antiatherogenic properties in STZ diabetic rats
after 3 weeks of treatment39.
Hibiscus rosa-sinensis (Family: Malvaceae)
Commonly known as Gudhal in Hindi and
shoe flower in English. In streptozotocin
induced diabetic rats, oral administration of an
ethanol flower extract of Hibiscus rosa
sinensis lowered the total cholesterol and
serum triglycerides by 22 and 30%,
respectively. Maximal diminution in blood
glucose (4146%) and insulin level (14%) was
noticed after 21 days. The hypoglycemic
activity of this extract is comparable to that of
glibenclamide63 .
Hygrophila
Acanthaceae)
auriculata
(Family:
O
OHH
O
O
O
HO
H
O
OH
OH
H HO
H
O
O
HH
O
OH
O
HO
OHO
OH
OH
O
Lactucain C
Lactucaside
Mangifera
indica
Anacardiaceae)
L.
(Family:
Feature
English. Aqueous leaf extract at the dose of 1
g/kg p.o. showed hypoglycemic effect when
given 60 mins prior to glucose administration
in streptozotocin-induced diabetic rats2. The
chronic intraperitoneal administration of
mangiferin, a xanthone glucoside isolated from
the leaves of Mangifera indica at the doses of
10 and
OH
HO
HO
O
O
OH
Charantin
L.
(Family:
(L.)
DC.
(Family:
Feature
treatment with the aqueous leaves extract. A
fall of 19.2 and 30.8% in total cholesterol (TC)
and 22.97 and 37.1% in triglyceride (TG)
levels were also observed in the case of treated
normal as well as diabetic rats, respectively.
Feeding the extract increased the HDLcholesterol level by 16 and 29.4% in normal
and diabetic rats, respectively, as compared
with their initial values. In the normal rats after
1 month of oral administration of the extract
serum glutamate oxaloacetate and pyruvate
transaminases (SGOT and SGPT) levels were
decreased by 21.7 and 25.0%. Serum alkaline
phosphatase values of the treated normal
animals were also reduced by 33% while
negligible change was observed in the normal
control animals. In the case of diabetic rats,
SGOT and SGPT levels were reduced by 36.7
and 32.2%, respectively, whereas phosphatase
(ALKP) levels decreased by 39.7%. The serum
creatinine levels decrease in normal as well as
in the diabetic animals by 17.75 and 18.2%,
respectively, as compared to initial values. In
the diabetic control animals the urinary sugar
remains at +4 level but there was a decrease of
75% in urine sugar in the case of treated
diabetic rats 37.
Musa sapientum L. (Family: Musaceae)
Commonly known as Kela in Hindi and
Banana in English. Oral administration of
0.15, 0.20 and 0.25 g/kg of chloroform extract
of the M. sapientum flowers for 30 days
resulted in a significant reduction in blood
glucose, glycosylated haemoglobin and an
increase in total haemoglobin, but in the case
of 0.25 g/kg the effect was highly significant.
It also prevents decrease in body weight. There
was a significant improvement in glucose
tolerance in treated animals and the effect was
compared with glibenclamide57.
Nelumbo
nucifera
Nymphaeaceae)
Gaertn.
(Family:
Feature
Scrophulariaceae)
Pterocarpus
Fabaceae)
OCH3
OH
pongamol
O
Karanjin
Roxb.
(Family:
HO
OH
CH2
OH
OCH 3 O
OH
OH
OH
M arsupsin
(-) Epicatechin
OH
HO
OH
H 3 CO
Glc
OH
OH
Pterosupin
OCH 3
Pterostilbene
O
OCH3
marsupium
Feature
the diabetic rats for 20 days showed favorable
effects not only on fasting blood glucose, but
also on total lipid profile and liver and kidney
functions on 10th and 20th day68.
Rosmarinus officinalis (Family: Labiatae)
Commonly
known
as
Rosemary.
Hypoglycaemic effects of oral administration
of various doses (50, 100 and 200 mg/kg) of
the extract were examined in normoglycaemic
and glucose-hyperglycaemic rabbits. Optimal
effect was observed in both of the animal
groups with a dose of 200 mg/kg of the extract
and this activity was independent from the
effects of insulin. Acute effect of various doses
of the R. officinalis extract on blood glucose
and serum insulin levels was studied in
alloxan-induced diabetic rabbits. Of the three
doses of extract, the highest dose (200 mg/kg)
significantly lowered blood glucose level and
increased serum insulin concentration in
alloxan-diabetic rabbits. At the doses of 100
and 200 mg/kg, antihyperglycaemic effect of
extract was accompanied by a significant
increase in serum insulin levels in diabetic
rabbits. Furthermore, during 1 week of
treatment of diabetic rabbits with a dose of 200
mg/kg of the extract showed that the extract
possessed a capability to inhibit the lipid
peroxidation and activate the antioxidant
enzymes7.
Salacia oblonga Wall. (Family: Celastaceae)
S. oblonga root is an Ayurvedic medicine
with anti-diabetic and anti-obese properties.
Chronic oral administration of the water
extract from the root of S. oblonga to Zucker
diabetic fatty rats, a genetic model of type 2
diabetes and obesity, lowered plasma
triglyceride and total cholesterol levels,
increased plasma high-density lipoprotein
levels and reduced the liver contents of
triglyceride, non-esterified fatty acids and the
ratio of fatty droplets to total tissue. By
contrast, the extract had no effect on plasma
triglyceride and total cholesterol levels in
fasted Zucker diabetic fatty rats29.
16
Salacia
reticulata
Celastaceae)
Wight.
(Family:
L.
(Family:
Feature
from the hexane fraction of the plant,
identified as 1,8-dihydroxy-3,5-dimethoxyxanthone (swerchirin). It has a very significant
blood sugar lowering effect in fasted, fed,
glucose loaded, and tolbutamide pretreated
albino rat models. The ED50 for 40% blood
sugar lowering in CF male albino rats (body
weight 140-165 g) is 23.1 mg/kg/oral8.
O
O
OH
OH O
Swerchirin
Terminalia
catappa
Combretaceae)
L.
(Family:
Brandis
(Family:
Feature
of 1.29 (1/s). The inhibitory effect of
galactomannan on glucose uptake was found to
be in parallel with the degree of viscosity of
the fiber solutions. Because of its viscous
property, galactomannan has the potential to
reduce intestinal absorption of low or high
concentrations of glucose and hence for the
benefit of blood glucose management72 .
Tinospora
cordifolia
Menispermaceae)
(Family:
OH
HO
O
H O
O
O O
H
H
OH
H O
OH
OH
OH
O
H O
OH
H
OH
OH
HO
HO
18
officinale
Roscoe
OH
O
OH
Coagulin L
Coagulanolide
Zingiber
OH
H O
OH
HO
OH
Withanolide F
17-Hydroxywithanolide K
Coagulin C
H O
OH
(Family:
Zingiberaceae)
Current R&D Highlights, Jan.-Mar. 2009
Feature
Commonly known as Adrak in Hindi and
Ginger in English. Treatment with Z. officinale
produced a significant increase in insulin
levels and a decrease in fasting glucose levels
in diabetic rats. In an oral glucose tolerance
test, treatment with Z. officinale was found to
decrease significantly the area under the curve
of glucose and to increase the area under the
curve of insulin in STZ-diabetic rats.
Treatment with Z. officinale also caused a
decrease in serum cholesterol, serum
triglyceride and blood pressure in diabetic
rats3. 6-shogaol (6S) and 6-gingerol (6G),
present in Z. officinale significantly inhibited
the tumor necrosis factor- (TNF-) mediated
downregulation of the adiponectin expression
in 3T3-L1 adipocytes. 6S functions as a
PPAR agonist with its inhibitory mechanism
due to the PPAR transactivation, and 6G is an
effective inhibitor of TNF- induced c-JunNH2-terminal kinase signaling activation and
thus, its inhibitory mechanism is due to this
inhibitory effect99.
Conclusion
Treatment of diabetes with synthetic drugs
is associated with several complications. The
most severe complication associated is
condition of hypoglycemia. Plants and natural
products are in use to prevent and cure
diabetes since past. They show comparatively
less or no side effects. As far as cost is
concerned, herbal treatment is cheaper than
synthetic drugs. A wide and diverse range of
plants is reported to prevent and treat diabetes.
A lot of work has been done on the
antidiabetic potential of various plants by
numerous workers. We have worked on
Pongamia pinnata, Pterocarpus marsupium,
Withania coagulans, Zingiber officinale and
Ficus racemosa and have isolated antidiabetic
principals from them. There is endless scope in
natural product chemistry for the identification
of active leads. Immense work is needed to
make new drugs for diabetes of natural origin.
Active leads can be derivatized to ameliorate
their antidiabetic potential
8.
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21
Feature
Introduction
Diabetes mellitus (DM) is a major and
growing public health problem throughout the
world. Diabetes has reached epidemic
proportions and affects more than 170 million
individuals worldwide. It is a disease
characterized by high levels of blood glucose
resulting from defects in: insulin production,
insulin action or both. The basic types of
diabetes mellitus are type 1 and type 2. Type 1
(insulin dependant) DM can occur at any age
and is characterized by the marked and
progressive inability of the pancreas to secrete
insulin because of autoimmune destruction of
the beta cells. Therefore, these patients are
dependent on exogenous insulin.
Type 2 (non-insulin-dependent) DM,
which affects 90% of diabetic individuals, is
more of a lifestyle related disorder, with
obesity being a major risk factor for its
development. It is characterized by insulin
resistance: the inability of insulin-sensitive
tissues to respond to normal circulating
concentrations of insulin. To offset resistance
to insulin, the beta cells of the pancreas
increase insulin secretion. However over time,
beta-cell function deteriorates, less insulin is
secreted and hyperglycemia
develops.
Treatment of type 2 diabetes is aimed at
22
Peroxisome
Proliferator-activated
Receptor Gamma (PPAR ) Role in
Type 2 Diabetes
The peroxisome proliferator-activated
receptors belong to the superfamily of nuclear
receptors and are ligand-activated transcription
factors. There are three PPAR isoforms, which
are the products of distinct genes and are
Current R&D Highlights, Jan.-Mar. 2009
Feature
commonly designated as PPAR , PPAR and
PPAR /
. The three subtypes of PPAR bind
to fatty acids and fatty acid metabolites and
regulate the expression of genes involved in
the transport, metabolism and buffering of
these ligands within the cells. PPARs are
known to be activated by a wide array of
structurally diverse ligands, ranging from
prostaglandins and thiazolidinediones(TZDs)
to fibrates, eicosanoids, nonsteroidal NSAIDs,
glucocorticoids, PUFAs, and aromatic fatty
acids[2].
While PPAR regulates fatty acid
oxidation and PPAR is involved in
cholesterol homeostasis, PPAR agonists
regulate adipogenesis and are effective insulin
sensitizers. Thus, the PPARs possess the
ability to address many features of the diabetic
phenotype. PPAR agonists and PPAR /
dual agonists are interesting compounds for the
development of anti-diabetic agents. PPAR
agonists reduce plasma glucose, lipids and
insulin levels in type 2 diabetic patients while
PPAR / dual agonists improve both lipid
metabolism and glucose tolerance- two key
factors in the treatment of type 2 diabetes.
Feature
compounds with tail group modifications
NH
O
NH
O
Ciglitazone
S
O
NH
O
HO
Troglitazone
NH
S
O
Rosiglitazone
S
O
Pioglitazone
24
Feature
of novel PPAR modulating drugs that retain
efficacious insulin sensitizing properties while
O
O
NH
BRL-48482
N
H
NH
S
F3 C
Englitazone
NH
PAT5A
DRF-2189
NH
NH
S
KRP-297
OCH 3
O
R
NH
O
COOCH3
H3 CO
NH
O
S
O
CLX-0921
Feature
recently terminated, owing to findings of a rare
malignant tumor in mice.
3.
Compounds
Modifications
Since the structure of the thiazolidine-2, 4dione ring was considered to be optimum and
the acidic functionality of the ring was
considered to be essential for its insulinsensitizing activity, replacement of this ring
has been tried using closely related acidic
heterocyclic rings as well as acyclic acidic
moieties.
with
Head
Group
NH
O
Figure 4: JTT-501
Feature
a) A Carboxylated Hydroxyurea: The
first acyclic non-carboxylic acid compound,
was able to normalize blood glucose level in
an in vivo study [19].
CO 2H
N
O
O
N
N
O
CF3
SB-219994
CO 2H
NH2
OCH
O
O
b)
-Carbon
Substituted
Phenylpropanoic Acid Based PPAR
Agonists: The thiazolidine-2,4-dione ring can
be replaced by -acyl-, -alkyl- and (aralkyl)-carboxylic acids. Inclusion of an
additional
lipophilic
moiety
affords
compounds which are equipotent to BRL
48482. These results were surprising since it
had previously been shown that in the
heterocyclic series, the thiazolidine-2, 4-dione
ring was preferred over the oxazolidine-2, 4dione. It was assumed that the role of the
acidic thiazolidine-2,4-dione was played by
carboxylic acid in these compounds and that
an appropriate substituent at the -position
could alter the chemical environment around
the carboxylic acid in such a way that the
whole group came to mimic the thiazolidine2,4-dione ring. Higher binding affinities and
functional activity for PPAR were observed
for the (S)-enantiomers of this series.
Several -oxy-acids showed activities an
order of magnitude more potent than BRL48482. In particular the -ethoxyacid SB
213068 is one of the most potent antihyperglycemic agents yet reported[20](figure
6).
SB-213068
27
Feature
O
S
O
O
H 3C
CO 2H
O
N
CO2 H
Ragaglitazar
Tesaglitazar
CO2 H
N
O
O
O
OCH 3
CO2 H
Muraglitazar
Aleglitazar
CO2 H
CO2 H
O
O
HN
HN
CO2H
HN
H3CO 2C
Farglitazar
GW-1929
GW-7845
Feature
GW1929 possesses potent and efficacious anti-hyperglycemic activity in ZDF rats.
undesirable action of these agents, research is
Farglitazar has shown potent reduction of
glucose activity, reduction of triglycerides and now being done to develop partial PPAR /
agonists, which combine the beneficial
elevation of HDL cholesterol in diabetic
patients in Phase II studies. The positive lipid metabolic effects of PPAR and PPAR
effects of farglitazar may be due to residual activation with fewer side effects. Along with
PPAR activity in the compound [26]. the dual agonists, PPAR pan agonists are also
However, owing to side effects, its further being explored which would combine the
development has been discontinued
agonist activities of PPAR , PPAR and
PPAR in a single ligand and may prove to be
Conclusion
the ultimate combination of PPAR activities
The demonstration that PPAR was the
for the treatment of type 2 diabetes and its
receptor through which the glitazone drugs
further complications. Also, recent findings
mediate their biological activity has led to from genetic and pharmacologic studies
resurgence in nuclear receptor research to suggest that activating PPAR in moderation
develop drugs for diabetes and cardiovascular can lead to better therapeutic outcomes
disease. Knowledge of the molecular targets compared with modifying the receptor with a
for the glitazones has enabled medicinal high affinity, full agonist. These results have
chemists to synthesize a new generation of
been translated into the identification and
drugs that have been optimized for activity exploration of PPAR partial agonists and
against the human PPARs. Several of these
selective PPAR modulators (SPPARMs) which
drugs are currently in clinical development. would retain efficacious insulin sensitizing
Compounds with dual PPAR and PPAR
properties while minimizing the adverse side
activity, which may combine the benefits of
effects. With recent advances in our
insulin sensitization and lipid lowering into a
understanding of the molecular mechanism of
single drug, are also being investigated. The
PPAR action, the future holds great promise
safety liabilities of the dual agonists may be
towards
developing
anti-diabetic
the result of the imbalanced activities on PPARcompounds with greater efficacy as well
PPAR and PPAR . To overcome the
as reduced side effect profile.
References
1. Vats,R.K,Kumar,V,et al.,Current Science,
2005, 88, 241.
2. Kliewer SA, Lenhard JM, Lehmann JM.
Proc Natl Acad Sci USA, 1997, 94, 431823.
3. Nolte, R.T. et al., Nature, 1998, 395, 137143.
4. Y. Lu et al., Bioorg. Med. Chem. Lett.,
2006, 16 915919
5. Lehmann, J.M. et al., J. Biol. Chem., 1995,
270, 1295312956.
6. Yoshioka, T. et al., J. Med. Chem., 1989,
32, 421428
7. Press
Release:
21March,
2000,
lambert.com/press/release.asp?release=109
Current R&D Highlights, Jan.-Mar. 2009
Feature
49, 14171424.
18. Shinkai, H. et al., J. Med. Chem., 1998, 41,
1927-1933.
19. Goldstein, S.W. et al. J. Med. Chem., 1993,
36, 22382240.
20. Buckle, D. R., Cantello, B. C. C., Smith,
S.A. et al., Bioorg. Med. Chem. Lett.,
1996, 6, 2127-2130.
21. Buse J, Rubin C, Frederich R, et al. Clin
Ther., 2005, 27,11811195.
22. Wilding J.P, Gause-Nilsson I, Persson A.,
30
Volume
No.
Biotherapeutics
Marine Based Bioactives
Peptidomometics
Drug Targets
23
23
23
23
1
2
3
4
Month
Jan.,-March 2000
Apr.,-June 2000
July- Sept., 2000
Oct.,-Dec., 2000
Immunotherapeutics
Gene Therapy
Neurologicals
Bioinformatics
24
24
24
24
1
2
3
4
Jan.,-March 2001
Apr.,-June 2001
July- Sept.,2001
Oct.,-Dec., 2001
25
25
25
25
1
2
3
4
Jan.,-March 2002
Apr.,-June 2002
July- Sept., 2002
Oct.,-Dec., 2002
26
26
26
26
1
2
3
4
Jan.,-March 2003
Apr.,-June 2003
July- Sept., 2003
Oct.,-Dec., 2003
Musculosketel Disorders
Proteomics
Pharmacogenomics
Cerebrovascular Disorders
27
27
27
27
1
2
3
4
Jan.,-March 2004
Apr.,-June 2004
July- Sept., 2004
Oct.,-Dec., 2004
Heart Failure
Osteoporosis
Asthma
Obesity
28
28
28
28
1
2
3
4
Jan.,-March 2005
Apr.,-June 2005
July- Sept., 2005
Oct.,-Dec., 2005
Ageing
Cancer
Tuberculosis
Malaria
29
29
29
29
1
2
3
4
Jan.,-March 2006
Apr.,-June 2006
July- Sept., 2006
Oct.,-Dec., 2006
Herbal Medicines
Antioxidants
Diagnostics
Systems Biology
30
30
30
30
1
2
3
4
Jan.,-March 2007
Apr.,-June 2007
July- Sept., 2007
Oct.,-Dec., 2007
Psoriasis
Metabolic Syndrome
Viral Infections
Leishmaniasis
31
31
31
31
1
2
3
4
Jan.,-March 2008
Apr.,-June 2008
July- Sept., 2008
Oct.,-Dec., 2008
Feature
Feature
5-HT or a peripheral 5-HT receptor agonist
can elevate plasma glucose levels in rats37,7.
Peripherally acting 5-HT1A/1D receptor agonist
N, N-di-propyl-5-carboxamidotryptamine (DP5-CT) also elicits hyperglycemia in rats38,8.
Peripheral 5-HT3 receptor agonist 2-methyl-5HT does not produce any effect on blood
glucose, insulin or glucagons levels which rule
out the involvement of 5-HT3 receptor in blood
glucose, insulin or glucagons levels. These
conclude involvement of 5-HT1 and 5-HT2 in
glucose Homeostasis. However, involvement
of subtype 5-HT1 and 5-HT2 receptor namely,
5-HT1A, 5-HT2A and 5-HT2C receptors in 5-HT
induced hyperglycemia were studied38,7 and
reported that 5-HT2A antagonist sarpogrelate
and 5-HT2A/2C antagonist mianserin inhibited
5-HT induced hyperglycemia. However, a
fairly detailed characterization of 5-HT
receptor subtypes from our laboratory revealed
that 5-HT2A and 5HT3 receptors are involved
in 5-HT induced hyperglycemia9.
in
the
32
Feature
Table-1 summary of beneficial effect of sarpogrelate and its mechanism
Mechanism
Anti platelets
Antithrombotic
Antiatherosclerotic
Antianginal
It
inhibits
vasoconstriction
of
non
atherosclerotic human coronary. It has
protective effect with the patients with stable
angina.
Pulmonary Hypertension
33
Feature
Table-2 Effect of 6 week treatment with sarpogrelate on various parameters in STZ diabetic rats
Parameter
Non-diabetic
control
Non-diabetic
Diabetic
treated
with control
sarpogrelate
Diabetic treated
with sarpogrelate
290.26 18.12
291.25 8.26
160.0 6.5*
181.66 9.29*
Food intake
41.29 5.63
44.5 2.20
115 2.88*
82.5 4.33**
53.75 5.05
40.0 1.15
118.75 0.72*
87.5 7.21**
105.62 10.12
98.23 8.23
146.23 3.75*
82.5 3.22**
405.23 22.68
385.56 23.73
321.25
12.31*
4.34 0.7
4.58 0.41
14.89 0.6*
6.69 0.9**
514.02 25.08
474.72 81.36
342 29.58*
595.98 62.88**
(g/day/rat)
Water intake
(ml/day/rat)
Blood pressure
(mmHg)
Heart rate
(beats/min)
Serum glucose
378.75 10.48**
(mmol/L)
Serum insulin
(pmol/L)
Data is shown as mean S.E.M. (n = 6). *Significantly different than non-diabetic control (p < 0.05), **significantly different than
diabetic control (p <0.05)
Feature
release activity and to show the evidence of
involvement of 5-HT receptors in insulin
release activity of extracts and fractions of
drug, insulin release studies using cultured
pancreatic islet cells were carried out. In our
laboratory these experiments involved
incubation of 5-HT alone with diabetic
pancreatic islets and co-incubation of 5-HT
with sarpogrelate (Sanjay, 2004). Thus
involvement of 5-HT in insulin releasing effect
of these agents, was evident from our data.
Pancreas
5-HT2A Receptors
Insulin
Sarpogrelate
(-)
(-)
5-HT in blood
(Higher in Diabetes)
(-)
Glucose
Insulin Receptor
(-)
(-)
GLUT
Sarpogrelate
Target Cell
(Cardiomyocyte, Skeletal muscle, Adipocyte)
Role of 5-HT
complications
in
Cardiovascular
35
Feature
Table-3 List of the main peripheral cardiovascular responses caused by 5-HT receptors and their
selective ligands
Receptor
5-HT1B/1D
Agonist
Sumatriptan
Antagonist
GR127935
5-HT1B
CP-93129 In Rats
GR 55562
Cardiovascular effect
Reduce sympathetic drive (i.e. reduction in
noradrenaline release to the heart and
vasculature)
Vasoconstriction
5-HT1D
BRL15572
-----
5-HT2A
PNU-109291
PNU-142633
DOI
Also has affinity for
5-HT2C
MDL 100907
5-HT2B
BW723C86
RS 127445
36
Feature
5-HT3
PBG
Granisetron
Ondansetron
5-HT4
BMIU4
GR113808
SB-204070
5-ht5A/5B
None
None. SB-269970
does have good
affinity, but is also a
5-HT7 antagonist
5-HT7
Vasodilation
Tachycardia in cats
Feature
function.
Table: 4 Effects of ginger methanolic and ethyl acetate extracts on body weight, serum glucose and
insulin levels on goldthioglucose-induced obesity in mice34.
Groups
Glucose (mg/dl)
Insulin (U/ml)
22.5 1.1
78.5 1.1
31.0 0.8
41.6 1.6a
156.7 1.7a
91.3 2.1a
OB+
methanolic
(250mg/kg)
extract
32.5 1.1
124.4 2.5
75.0 1.5b
OB+
ethyl
(250mg/kg)
extract
35.8 0.8b
128.7 2.1b
88.3 1.8b
acetate
N=6, values represent mean S.E.M. a Significantly different from normal control P<0.05. b Significantly different from obesity
control P<0.05.
38
Feature
Conclusions
From the forgoing discussion, it is evident
that sarpogrelate is a specific 5HT2A receptor
antagonist. Many experimental studies suggest
that
sarpogrelate
has
number
of
pharmacological effect namely, anti-platelet,
References
1.
62
2.
3.
72.
25. Doyle VM,
4.
5.
6.
110.
7.
46.
8.
Laude D,
620.
31. Schreiber, R. et al., J.. Progr. Neuro-Psychopharmacol.
Biol. Psychiatry 2002, 26, 441449.
32. Clifton, P.G. et al. Psychopharmacology 2000, 152, 256
267.
33. Akhani SP, et al., J Pharm pharmacol 2004; 56 101.
14. Umrani DN, et al., Mol Cell Biochem 2003, 249: 5357.
444446.
215230.
79:761-733.
19. Van Den Berg EK, et al., Circulation 1989, 79:116-124.
20. Pierce GN, et al., Am J Physiol 1985a, 248: E170-E175
21. Pierce GN, et al., Can J Cardiol 1985b, 1: 48-54.
22. Penpparkgul S, et al., Sonnenblick EH, Scheuer J. J Mol
39
Feature
systems.
Robustness consists of four basic
mechanisms, which ensure the robustness of
the system: system control, alternative means
of redundancy (or fail safe) and diversity,
modularity and decoupling in which physicallevel perturbation is isolated from functional
level activities of the system. Robustness is
enhanced in biological systems as there are
multiple means to achieve a specific function.
This encompasses redundancy, overlapping
function and diversity. Redundancy generally
refers to a situation, in which several identical,
or similar, components (or modules) can
replace with each other, when another
component fails. This implies that drugs
targeting such pathways are likely to have
limited efficacy. Diversity, or heterogeneity,
represents the other extreme, whereby a
specific function can be attained by different
means available in a population of
heterogeneous components. The biological
system has evolved decoupling mechanism for
its robustness like capacitors in electrical lines
decouple the voltage fluctuations. The
biological systems have also evolved
decoupling mechanisms for its robustness by
assigning different functions to different cell
constituents, which is known as physical
separation of various functions inside the cell
so that functional fluctuations in one part is not
transferred to another and also repairing
mechanism e.g. heat shock proteins fix misCurrent R&D Highlights, Jan.-Mar. 2009
Feature
folded proteins as a result of environmental
stress, which also decouples genetic variations
from the phenotype variations. System control
introduces positive and negative feed back,
feed forward and other regularity loops to
maintain homeostasis of the system as well as
bi-stable behaviors, which enables the system
to move between two stable states.
Positive
feedback
contributes
to
robustness by amplifying the stimuli, often
producing bi-stability, so that the activation
level of a downstream pathway can be clearly
distinguished from non-stimulated states, and
so that these states can be maintained. Positive
feedback is also used in signal transduction
and the cell cycle to form switchlike behavior
of the system by amplification of stimuli, so
that it initiates transition and a new state of the
system is made that is more robust against
noise and fluctuations of stimuli.
Negative feedback is the principal mode
of control that enables robust response to
perturbations. For example in relation to
obesity and diabetes, food intake and its
disposition is controlled by anabolic and stress
hormones. Leptin secreted by adipocytes and
ghrelin by the stomach, are centrally regulated
by hypothalamus, a brain loci, controlling
appetite. Hypothalmus also activate release of
stress hormone noradrenaline from adrenal
glands to initiate thermogenesis to protect
animals from cold. These negative feed back
mechanisms respond with perturbations for
adaptation to the dynamic environment and
hence can be utilized for drug interference in
diabetes and obesity.
Type-2 diabetes is a major manifestation
of metabolic syndrome, which is a highly
complex disease comprising obesity, insulin
resistance, hyperlipidemia and hypertension.
Metabolic syndrome is a systemic disease
affecting multiple organ systems through the
narrowing of macro- and micro-vascular
systems under the influence of the oxidative
stress provided in the system and thereby
Current R&D Highlights, Jan.-Mar. 2009
Feature
as resistin and glucocorticoids and that these
may serve newer targets for diabetes.
In the light of the robustness and fragility
of the biological systems, Kitano et al (1994)
has analyzed diabetes in detail and categorized
it into energy supply, its utilization and
maintenance of homeostatic status and their
failure leads to diabetes. This opens new vistas
to understand the therapeutic measures and to
future designing strategies for developing
novel drugs. We will attempt a brief
description of these categories and treatment
available and the targets currently being
pursued in-view of the recent advancements in
molecular biology of the disease.
OH
OH
OH
HO
OH
HO
NH
OH
HO
HO
OH
Miglitol
OH
OH
HO
HO
OH
HO
O
OH
HO
OH
O
O
HO
OH
OH
HO
N
H
OH
OH
Acarbose
Voglibose
Feature
induce insulin secretion in a glucosedependent manner. They also stabilize other
F
H
O
CN
N
H
NH2
OH
N
NH2
F
BMS-477118 (Saxagliptin)
NH
CN
H
N
H2N
N
N
HO
NC
SYR-322 (Alogliptin)
F
F
N
N
N
NH2
F
F
MK0431(Sitagliptin)
Feature
membrane, opening of voltage-gated Ca2+
channels, elevation of the cytoplasmic Ca2+
concentration and stimulation of Ca 2+ ion
dependent exocytosis of the insulin. The KATP
channel is a heteroctameric complex composed
of four inwardly rectifying K+ channel subunits
(Kir6.2) and four sulfonylurea receptors
(SUR1). Two isoforms of the receptor have
been indentified, SUR1 on pancreatic cells
and SUR2 on vascular smooth muscle and
cardiac termed as SUR2B and SUR2A
respectively. This KATP channel has been
utilized to enhance insulin secretion from
pancreatic cells in diabetic patients.
i) KATP closing by sulfonylurea stimulated
secretion:
The first-generation agents include
acetohexamide, chlorpropamide, tolazamide,
and tolbutamide.
H 3C
O
O
H
H
S N C N
O
O
H
H
S N C N
O
CH 3
Cl
Tolbutamide
O
H3C
Chloropropamide
H
H
S N C N N
O
Tolazamide
CH3
O
H 3C
O
H
H
S N C N
O
Acetohexamide
The
second-generation
agents
include
glimepiride, glipizide, and glyburide. The
second-generation agents are more potent and
in general have better pharmacokinetic and
safety profiles. This mechanism only works if
insulin is present in the -cells. Sulfonylureas
display more pronounced action in the
presence of glucose. The increased insulin
flows into the portal veins to suppress the
elevated basal rate of hepatic glucose
production. One concern with these agents is
the loss of efficacy over time, which may be
related to the potential to exhaust -cell
function. Because these agents increase plasma
levels of insulin, they may cause
44
C
H2
O
N C HN
O
O
S NH C NH
H 2 C H2 C
CH 3
O
O
Glimepiride
Cl
O
C
O
CH3
H
N
H2
H 2C C
S NH C NH
O
Glibenclamide
Feature
H3 C
H2 H H O H 2
CH C C N C C
H3 C
N
COOH
O
CH 3
H3 C
CH
H3 C
channel
opener
stimulated
O
N
H
N
MCC 134
CH 3
O
S
N
N
H
O H
2 H H2
N C C C C
COOH
KAD-1229 (Meglitinide)
Nateglinide
Repaglinide
iii) KATP
secretion:
O
H H H2
C N C C
COOH
NH 2
N
N
H
CH 3
NN 414
N CH
3
CH 3
NH2
BTS 67582
MeO
MeO
NH
N
NH
O
Prazosin
Centpiperalone
H 3C
O
N
HN
RX 801080
O
N
N
H
H3 C
O
N
HN
Efaroxan
HN
RX 871024
KU 14R
Feature
the kidney. 90% of renal glucose re-absorption
is facilitated by SGLT2 residing on the surface
of the epithelial cells lining the S1 segment of
the proximal tubule, while the remaining 10%
is likely to be mediated by SGLT1 localized on
the more distal S3 segment of the proximal
tubule. Humans with SGLT1 gene mutations
experience glucose-galactose mal-absorption,
resulting in frequent, watery diarrhoea and
dehydration, when on a glucose diet,
confirming that SGLT1 is the major glucose
transporter in the small intestine. These
individuals present with little or no glucosuria,
suggesting that SGLT1 is not the major
glucose transporter in the kidney. However,
since persistent renal glucosuria is the sole
reported phenotype of humans with SGLT2
gene mutations, selective inhibition of SGLT2
has been proposed to aid in the normalization
of plasma glucose levels in patients with
diabetes by preventing the renal glucose reabsorption process and promoting glucose
excretion in urine. Selective SGLT2 inhibitors
would be desirable, since gastrointestinal side
effects associated with SGLT1 inhibition
would be minimized. This mechanism is
expected to be associated with a low risk of
hypoglycemia, because there is no interference
with the
normal counter regulatory
mechanisms for glucose.
Cl
HO
OEt
HO
OH
OH
Dapagliflozin
Feature
internal membrane vesicles to the plasma
membrane.
Insulin resistance is a central feature of the
metabolic syndrome, leading to hyperinsulinaemia and involves multiple defects of
insulin receptor and post-receptor signaling.
Pathways that control non-genomic effects of
insulin appear to be more vulnerable to the
disruption. In the insulin resistance state,
insulin fails to induce normal GLUT-4 protein
translocation in skeletal muscles, resulting in
the hyperglycemic stage in the plasma.
Adipocytes play a regulatory role in the
development of insulin resistance as they can
produce adipokines (hormones and cytokines)
and also as they become saturated with their
excess lipid storage capacity leading to the
abnormal distribution of lipids to other organs
and tissues. Adipocytokines such as TNF-
and IL-6 are pro-inflammatory factors
contributing to the development of insulin
resistance. TNF- induces the serine
phosphorylation of IRS-1 causing serine
phosphorylation of the insulin receptor
resulting in blockade of normal tyrosine
phosphorylation of the insulin receptor causing
interference with insulin signal transduction.
Further IL-6 and TNF- induce suppression of
cytokines signaling-3 (SOC-3) resulting in
inhibition of tyrosine phosphorylation of IRS-1
and thus reduce the activation of Akt (PKB),
which finally results in reduction in the release
of GLUT-4 from secretory vesicles. Leptin is
an adipocyte hormone which decreases TG
synthesis, stimulates -oxidation and enhance
insulin secretion through modulation of
various insulin targets including IRS-1,
MAPK, ERK, p38 MAP kinase, PKB, P kinase
and PI-3 kinase. Adiponectin increases insulin
sensitivity by activation of AMPK and by
increase in tyrosine phosphorylation of insulin
receptor. In liver it inhibits both the hepatic
gluconeogenesis enzyme and the rate of
endogenous glucose synthesis while in
muscles it increases glucose transport and
increases fatty acid oxidation. It suppresses
Current R&D Highlights, Jan.-Mar. 2009
Feature
properties. It acutely and selectively stimulates
p44/ p42 MAP kinase. Adverse effects of
metformin therapy include gastrointestinal
distress, such as abdominal pain, nausea, and
diarrhoea in up to half of patients.
CH3
H
N
NH2
H3C
NH
NH
Metformin
NH
N
Pioglitazone
BRL-49653
O
NH
NH
CO2 H
O
Englitazone
Murglitazar
CH 3
NH
O
NH
O
HO
Ciglitazone
Troglitazone
Feature
The thiazolidinediones more specifically
enhance insulin sensitivity, but they also
potently promote adipocyte differentiation and
often increase total fat mass. For example
rosiglitazone and pioglitazone are effective
glucose-lowering drugs but have moderate
effects on lipids resulting in increase of
adipocytes in patients with type 2 diabetes.
However, the L-tyrosine analogue farglitazar
has robust effects on glucose, high-density
lipoprotein as well as on triglycerides in
diabetic patients.
COOH
O
N
HN H
Farglitazar
thermogenesis:
Adipose tissue serves not only as a depot
for triglyceride storage but also as a dynamic
endocrine organ involved in the control of
energy balance. Adipocytes are responsible for
the storage of fat and its breakdown (lipolysis)
is primarily controlled by the sympathetic
nervous system. Activation of -adrenergic
receptors decreases lipolysis and activation of
-adrenergic receptors increases lipolysis.
They are members of the large family of Gprotein-coupled receptors that regulate an
assortment of intracellular second messenger
systems, including cAMP, phospholipid
hydrolysis, ion fluxes, and mitogen-activated
protein (MAP) kinase cascades. 3-adrenergic
receptor is expressed in white, brown as well
in skeletal tissue and its stimulation elevates
the levels of cAMP and thereby stimulation of
lipolysis and adipose specific genes. The
increased expression of uncoupling protein-1
in skeletal muscle and UCP-2, and - 3 in
adipose tissues uncouples the fatty acid
oxidation from oxidative phosphorylation. The
process increases heat production with a boost
in energy consumption rendering 3-adrenergic
receptor agonist as potential anti-obesity
agents and through stimulation of lipolysis
sensitization of insulin action. Some of the 3OH
NH
OH
HN
O
NH
O S O
H
N
NH2
O
O
HN
HN
LY 377604
L-757, 793
OH
HO
NH
OH
O
CH 3
Cl
N
H
NH
OH
N
NH2
AJ-9677
CP-331, 684
OH
O
NH
CH3
Cl
COONa
COONa
CL-316,243
Feature
receptor agonist. It has been observed that it
increases lipolysis, fat oxidation and insulin
action in human. However due to its poor
bioavailability it has been abandoned. At
present the compound LY 377604 up in phase
III trial. With regard to thyroid hormone
stimulation, tyrosine analogs have also been
prepared and one of these compounds
farglitazar, dual activators of PPAR- and
PPAR- lowers lipids and improves insulin
action and is in phase III clinical settings.
Thus the several mechanistic aspect of
energy homeostasis including energy intake,
storage and its supply has been considered for
drug design. However, the area of adipocyte
cytokines e.g. tumor necrosis factor-,
interlukin-6, IKK-, JNK-1 etc. which are
Further Readings:
1.
6.
(2008). J. R. White.
7.
Muramatsu.
2.
4.
5.
8.
(1999). J.C.
9.
2003.
S. M. Bruce.
sodium-dependent
glucose
co-transporter
2(SGLT2)
50
Feature
Feature
often used to allow for a more tailored regimen
the most common types of insulin currently in
of blood sugar control. The table below lists use in the U.S. and their specific properties.
Table 1: Insulin Formulations Available[4,5]
Insulin
Onset of action
Peak
Duration
10-20
minutes15-30 1-3 hours.5-2.5 hours1-1.5 3-5 hours3-6.5 hours3minutes10-15 minutes hours
5 hours
Short-acting (human)
Regular
30-60 minutes
1-5 hours
6-10 hours
1-2 hours
6-14 hours
16-24+ hours
No significant
significant peak
Intermediate (human)
NPH
Long-acting (analog)
detemirglargine
peakNo Up to 24 hoursUp to 24
hours
Premixed (analog)
70%
APS/30%
aspart 10-20
minutes10-30 1-4 (2.4) hours1-6.5(2.6) Up to 24 hoursUp to 24
75%
NPL/25%
lispro minutes10-30 minutes hours0.8-4.8 (2.3) hours hoursUp to 24 hour
50% NPL/50% lispro
Premixed (human)
70% NPH/30% regular50% 30-60
NPH/50% regular
minutes
Range (mean)NPH = neutral protamine Hagedorn; APS = aspart protamine suspension; NPL = neutral protamine
lispro
Advantages
Disadvantages
Reusable pen, eg, NovoPen Discreet Sturdier than prefilled pens As above Need to change cartridges
52
Feature
(Novo Nordisk), HumaPen Injection may be more comfortable (time consuming and less convenient
MEMOIR (Eli Lilly and Co), than vial and syringeAccurate dosing than prefilled pens)
OptiClik (Aventis Pharma
Holding GmbH)
Dosers, eg, InnoLet (Novo Easy to use Accurate dosing Suitable As above Not currently available with
for patients with visual/ dexterity insulin analogs
Nordisk)
problems Disposable
Insulin pump
Jet injectors
Insulin
Manufacturer
FlexPen
Lilly
Pen
Novo Nordisk
Prefilled Humalog, Humalog Mix 70/30, Humalog Mix 75/25, Humalog Mix Eli Lilly
50/50, Humulin N
SoloSTAR
Lantus, Apidra
Sanofi-Aventis
Novo Nordisk
NovoPen Junior
Novo Nordisk
HumaPen
LUXURA
Humalog, Humulin
Eli Lilly
53
Feature
HumaPen
MEMOIR
Humalog
Eli Lilly
OptiClik
Lantus, Apidra
Sanofi-Aventis
Novo Nordisk
Dosers
InnoLet
Feature
an insulin pump. This number is growing
dramatically as these devices become smaller
and more user-friendly. Insulin pumps allow
for tight blood sugar control and lifestyle
flexibility while minimizing the effects of low
blood sugar (hypoglycemia). At present, the
pump is the closest device on the market to an
artificial pancreas. More recently, newer
models of the pump have been developed that
do not require a tubing, in fact - the insulin
delivery device is placed directly on the skin
and any adjustments needed for insulin
delivery are made through a PDA like device
that must be kept within a 6 foot range of the
insulin delivery device, and can be worn in a
pocket, kept in a purse, or on a tabletop when
working.
Probably the most exciting innovation in
pump technology is the ability to use the pump
in tandem with newer glucose sensing
technology. Glucose sensors have improved
dramatically in the last few years, and are an
option for patients to gain further insight into
their patterns of glucose response to tailor a
more individual treatment regimen. The
newest generation of sensors allows for a real
time glucose value to be given to the patient.
The implantable sensor communicates
wirelessly with a pager-sized device that has a
screen. The device is kept in proximity to the
sensor to allow for transfer of data, however, it
can be a few feet away and still receive
transmitted information. Depending on the
model, the screen displays the blood glucose
reading, a thread of readings over time, and a
potential rate of change in the glucose values.
The sensors can be programmed to produce a
"beep" if blood sugars are in a range that is
selected as too high or too low. Some can
provide a warning beep if the drop in blood
sugar is occurring too quickly.
To take things one step further, there is
one particular sensor that is new to the market
that is designed to communicate directly with
the insulin pump. While the pump does not yet
respond directly to information from the
Current R&D Highlights, Jan.-Mar. 2009
Feature
very small doses of insulin. Nevertheless, in
the right population, this is a great option.
Intranasal, Transdermal: Other routes for
the delivery of insulin have also been tried.
Intranasal insulin delivery was thought to be
promising. However, this method was
associated with poor absorption and nasal
irritation. Transdermal insulin (skin patch
delivery) has also yielded disappointing results
to date. Insulin in pill form is also not yet
effective since the digestive enzymes in the gut
break it down.
Pancreas transplantation: Ultimately, the
goal in the management of type 1 diabetes is to
provide insulin therapy in a manner that
mimics the natural pancreas. Perhaps the
closest therapy available at this time is a
transplant of the pancreas. Several approaches
to pancreatic transplantation are currently
being studied, including the whole pancreas
and isolated islet cells (these groups of cells
contain beta cells that are responsible for
insulin production). Data available from 1995
indicates that almost 8,000 patients underwent
pancreatic transplantation. Most patients
undergo pancreatic transplantation at the time
of kidney transplantation for diabetic kidney
disease.
Transplantation is not without risk. Both
the surgery itself and the immnosuppression
that must occur afterward pose significant risks
to the patient. For these reasons, the kidney
and pancreas are usually transplanted at the
same time. At present, there is disagreement
about whole pancreas transplantation in
patients not currently requiring kidney
transplantation. The issue of whether the
benefits outweigh the risks in these patients is
under debate. There is also a chance that
diabetes will occur in the transplanted
pancreas. Selectively transplanting islet cells is
an interesting alternative to whole pancreas
transplantation. However, the concern over
rejection remains. Attempts to disguise the
islet cells in tissues that the body won't reject
56
o
o
o
o
o
o
Feature
should work closely with their physicians to
achieve an approach that provides the greatest
benefits while minimizing risks.
Patients with diabetes should never forget
the importance of diet and exercise. The
control of diabetes starts with a healthy
lifestyle regardless of what medications are
being used.
Medications that increase the insulin
output by the pancreas - sulfonylureas and
meglitinides :
Sulfonylureas - Historically, increasing
insulin output by the pancreas has been the
major area targeted by medications used to
treat type 2 diabetes. Medications that increase
the output of insulin belong to a class of drugs
called sulfonylureas. Sulfonylureas primarily
lower blood glucose levels by increasing the
release of insulin from the pancreas. Older
generations
of
these
drugs
include
chlorpropamide and tolbutamide, while newer
drugs include glyburide (DiaBeta), glipizide
(Glucotrol), and glimepiride (Amaryl). These
drugs are effective in rapidly lowering blood
sugar but run the risk of causing hypoglycemia
(abnormally low and dangerous levels of blood
sugar). In addition, they are sulfa-containing
drugs and should be avoided by patients who
are allergic to sulfa.
Meglitinides - Repaglinide and Nateglinide:
The class of drugs known as meglitinides is
relatively new. Meglitinides also work on the
pancreas to promote insulin secretion. Unlike
sulfonylureas that bind to receptors on the
insulin producing cells, meglitinides work
through a separate potassium based channel on
the cell surface. Unlike the sulfonylureas
which last longer in the body, repaglinide and
nateglinide are very short acting, with peak
effects within one hour. For this reason, they
are given up to three times a day just before
meals. Since these drugs also increase
circulating insulin levels, they may cause
hypoglycemia, but the literature suggests this
is less frequent than the hypoglycemia seen
Current R&D Highlights, Jan.-Mar. 2009
with sulfonylureas.
In a three month study, repaglinide
dropped fasting blood glucose values by 61
mg/dL and post meal blood glucose values by
100 mg/dL. Because repaglinide is short acting
and given before meals, it is particularly
beneficial in lowering blood glucose after
meals and does not tend to lower fasting
glucose levels to the same degree. Repaglinide
has been used in combination with other
medications, such as metformin (Glyciphage),
with impressive results. In 83 patients with
type 2 diabetes, blood sugar control improved
significantly with the addition of repaglinide to
Glyciphage.
Repaglinide
interacts
with
other
medications. Therefore, the doctor must be
aware of all other medications a patient is
taking before prescribing repaglinide. The
usual starting dose is 0.5mg before each meal
and can be increased to 4mg. The maximum
daily dose is 16mg. Repaglinide is used with
caution in people with kidney or liver
abnormalities. Since repaglinide increases
insulin levels, it has the risk of causing
abnormally low blood sugars. Blood sugars
that remain severely low can result in
sweating, tremors, confusion, and may lead to
coma and seizure. In addition, the use of
repaglinide has been associated with
headaches, muscle and joint aches, along with
sinus infections in some individuals. This drug
should not be used in pregnancy or by nursing
mothers. The dose may need to be adjusted in
older people, since the elderly may metabolize
(eliminate) medications at a slower rate. For
more, please read the drug information on
repaglinide.
Nateglinide has essentially the same
profile of side effects and interactions as
repaglinide. The major benefit of Nateglinide
is that the starting dose of 120mg does not
need to be adjusted upward, but rather remains
constant. These medications are also relatively
safe to use in people with impaired kidney
57
Feature
function..
Biguanides: Medications that decrease the
amount of glucose produced by the liver : A
class of drugs called biguanides has been used
for many years in Europe and Canada. In 1994,
the FDA approved the use of the biguanide
metformin (Glyciphage) for the treatment of
type 2 diabetes in the U.S. Glyciphage is
unique in its ability to decrease glucose
production by the liver. Briefly, because
metformin does not increase insulin levels,
when used alone, it does not usually cause
hypoglycemia. In addition, metformin has an
effect whereby it tends to suppress appetite,
which may be beneficial in diabetics who tend
to be overweight. Metformin may be used by
itself or together with other oral drugs or
insulin. It should not be used in patients with
kidney impairment and should be used with
caution in those with liver impairment. The
older biguanides that preceded metformin were
associated with a serious condition called
lactic acidosis, a dangerous acid build up in the
blood resulting from accumulation of the drug
and its breakdown products. While metformin
is safer in this regard, it is recommended that
the drug be discontinued for 24 hours before
any procedure involving the intravenous
injection of dyes (such as for some x-ray
studies of the kidney) or surgery is performed.
The dyes may impair kidney function and
cause a build up of the drug in the blood.
Metformin can be restarted after these
procedures once the patient is urinating
normally.
Medications that increase the sensitivity of
cells to insulin: The class of drugs known as
thiazolidinediones lowers blood glucose by
improving target cell response to insulin (that
is, increasing the sensitivity of the cells to
insulin). Troglitazone (Rezulin) was the first of
this class in the U.S. Because of severe toxic
liver effects, troglitazone has been taken off
the market. Sister compounds are now
available with a better safety profile. These
drugs include pioglitazone and rosiglitazone.
58
and
rosiglitazone
are
thiazolidinediones approved for use in the
India. While they are sister compounds to
Rezulin, extensive studies have failed to show
that they are associated with any liver
problems. Both Pioglitazone and rosiglitazone
act
by
increasing
the
sensitivity
(responsiveness) of cells to insulin. They
improve the sensitivity of muscle and fat cells
to insulin. These drugs have been effective in
lowering blood sugars in patients with type 2
diabetes, Pioglitazone and rosiglitazone act
within one hour of administration and are
taken once daily. It is important to note that it
takes up to six weeks to see a drop in blood
glucose levels with these drugs and up to 12
weeks to see a maximum benefit. Pioglitazone
and rosiglitazone have been approved as first
line therapy in diabetes and for use in
combination with other drugs. Both drugs may
be used in patients taking other oral drugs as
well as those using insulin.
Pioglitazone
Feature
drug. Weight gain is more pronounced in
patients who are also taking insulin. In general,
the ankle swelling and puffiness due to the
accumulation of fluid can be controlled with
the addition of a diuretic such as
spironolactone (Aldactone) furosemide
(Lasix) does not work as well) or by
reducing the dose. On occasion, patients may
be symptomatic enough from fluid retention to
warrant withdrawal of the drug. Some recent
studies have suggested an association between
pioglitazone and rosiglitazone and untoward
cardiac events, for example, heart attacks,
though this association is controversial.
Regardless of the controversy, it is well
established that pioglitazone and rosiglitazone
should be avoided in patients with
symptomatic heart failure or heart failure.
Another newer concern is an association
of treatment with a small increase in the
frequency of fractures of the distal long bones
of the arms and legs. At present, this does not
translate into fractures of the hip and spine,
which would be clinically more worrisome.
More data is needed to make a definitive
statement about cause and effect at this time.
As
an
aside,
Pioglitazone
and
rosiglitazone have an added benefit of
changing cholesterol patterns in diabetes. HDL
(or good cholesterol) increases with these
medications, and triglycerides often decrease.
While there is some controversy regarding
what happens to bad cholesterol (LDL) levels,
there is a suggestion that Pioglitazone may be
superior in changing lipid profiles than
rosiglitazone. In this population of diabetics
that is already at an increased risk for heart
disease, an improvement in cholesterol profile
is beneficial. As more and more data becomes
available, there is mounting evidence that this
class of drugs may provide direct benefits to
the heart and large blood vessels and may
actually be valuable in preventing the
progression of diabetes in high-risk individuals
by reducing inflammation and by decreasing
clotting factors. As time goes on, there is no
Current R&D Highlights, Jan.-Mar. 2009
Feature
a nursing infant when the mother is taking
pioglitazone is unknown.
Side Effects and Precautions-The most
common side effects seen in clinical trials with
pioglitazone alone or in combination with
sulfonylureas, metformin, or insulin were
upper respiratory tract infection, headache,
sinusitis, muscle aches, tooth disorders,
hypoglycemia, and sore throat. In addition,
fluid accumulation (edema) occurred in less
than 5% of patients taking pioglitazone alone
but 15% of patients taking pioglitazone and
insulin (as compared with 2% and 7% of
patients receiving placebo, respectively). Fluid
accumulation can lead to heart failure.
To date, no formal studies to evaluate
drug interactions of pioglitazone with other
drugs have been conducted. Nevertheless,
because it interacts with the liver enzymes that
eliminate some other drugs, there is the
potential for pioglitazone to increase the
elimination of such drugs as erythromycin,
calcium channel blockers (e.g., Cardizem),
cisapride
(Propulsid),
corticosteroids,
cyclosporine, tracrolimus, trizolam (e.g.,
Halcion), trimetrexate, and HMG-CoA
reductase inhibitors (e.g., Lipitor). This would
reduce their effectiveness.
Since
another
thiazolidinedione
antidiabetic drug has been associated with liver
injury, it is recommended that periodic
monitoring of liver-related side effects and
liver function be done in patients taking
pioglitazone. Side effects while taking
pioglitazone which may be due to liver injury
include nausea, vomiting, abdominal pain,
fatigue, anorexia (loss of appetite), or dark
urine. Blood liver tests also are recommended
during pioglitazone therapy.
Rosiglitazone, combined with diet,
exercise, weight control and cessation of
smoking is used for treating type II diabetes.
Rosiglitazone may be used alone or in
combination with other types of anti-diabetic
drugs such as metformin or sulfonylureas as
60
Feature
angina, but left the association as inconclusive.
Additionally, there isn't enough evidence that
the risk of heart attack and angina is any
greater with rosiglitazone than with other oral
medicines used in the treatment of diabetes.
Uses: Rosiglitazone is an anti-diabetic
drug (thiazolidinedione-type, also called
"glitazones") used with a proper diet and
exercise program to control high blood sugar
in patients with type 2 diabetes (non-insulindependent diabetes). Rosiglitazone works by
helping to restore your body's proper response
to insulin, thereby lowering your blood sugar.
Effectively controlling high blood sugar helps
prevent heart disease, strokes, kidney disease,
blindness, and circulation problems, as well as
sexual function problems (impotence).
Rosiglitazone is used either alone or in
combination
with
other
anti-diabetic
medications (e.g., metformin, sulfonylureas,
insulin).
Medications
that
Decrease
the
Absorption of Carbohydrates from the
Intestine
Before being absorbed into the
bloodstream, carbohydrates must be broken
down into smaller sugar particles, such as
glucose, by enzymes in the small intestine.
One of the enzymes involved in breaking
down carbohydrates is called alpha
glucosidase. By inhibiting this enzyme,
carbohydrates are not broken down as
efficiently and glucose absorption is delayed.
Acarbose: The alpha glucosidase inhibitor
available in the India. is arcabose (Multibay).
In clinical trials with over 700 patients, the use
of arcabose was associated with a reduction in
hemoglobin Alc values (a well known
measurement of average blood sugars over the
preceding three months) that was significantly
greater than the use of placebo (no treatment).
However, as a single agent, arcabose is not as
effective as the other medications for diabetes.
Since arcabose works in the intestine, its
effects are additive to diabetic medications that
Current R&D Highlights, Jan.-Mar. 2009
Feature
mealtime insulin requirements. Studies have
shown it improves A1C beyond the effect of
insulin alone.
Symlin is taken just prior to meals, three
times a day. It is given in injection form and is
used for: Type 2 diabetes, as an additional
treatment in patients who use mealtime insulin
therapy and have failed to achieve desired
glucose control despite optimal insulin
therapy, with or without a concurrent
sulfonylurea agent and/or metformin. Type 1
diabetes, as an additional treatment in patients
who use mealtime insulin therapy and who
have failed to achieve desired glucose control
despite optimal insulin therapy.
Symlin is considered a therapy option in
patients with insulin-using type 2 or type 1
diabetes, that are unable to achieve adequate
glycemic control despite individualized insulin
management. Insulin-using patients with type
2 diabetes may also be taking a concurrent
sulfonylurea agent and/or metformin.
The major side effect of Symlin is nausea,
and this can be reduced with a slow, steady,
increase in dose. The other major side effect is
hypoglycemia (dangerously low levels of
blood sugar). To avoid this, the dose of
mealtime insulin should be cut in half when
starting Symlin. Of note is the degree of
weight loss seen with Symlin therapy. Studies
for up to six months show weight loss of
greater than six pounds more than placebo
(inactive pills). For more, please read the drug
information on pramlintide (Symlin).
Byetta (exenatide)- Byetta (exenatide) is a
new medication on the market that has it's
origins in an interesting place--the Gila
monster's saliva. Scientists studying this small
lizard noted it could go a long time without
eating. They found a substance in it's saliva
that slowed stomach emptying, thus making
the lizard feel fuller longer. This substance was
similar in nature to a gut hormone found in
humans known as GLP-1. GLP-1 is broken
down in the body by an enzyme called DPP62
Feature
hypoglycemia is still a possibility with Byetta,
especially when used in combination with
sulfonylureas. Your physician may choose to
decrease the dose of some of your other
medications when initially evaluating how you
respond to Byetta.
Similar to Symlin, weight reduction is
seen with Byetta in the majority of patients.
This makes it particularly suitable for the
typical patient with type 2 diabetes who is also
overweight. For more, please read the drug
information pamphlet on exenatide (Byetta).
A longer acting from of Byetta is currently
being considered for approval by the FDA.
This would allow for the same benefits (and
side effects) without need for such frequent
injections. DPP-IV inhibitors. GLP-1 in the
body is broken down by an enzyme called DPP
IV. Logically, you can either make a synthetic
GLP-1 that is not broken down by this enzyme
(for example, Byetta) or you could try to stop
the enzyme that breaks down the GLP-1 your
body already makes. Hence, the new class of
drugs called DPP IV inhibitors. They do just
that, that is, they inhibit this enzyme from
breaking down GLP-1. This allows GLP-1
already in the blood to circulate longer. There
are a number of companies working on this
class of drug and the FDA just approved the
first drug in this class made by Merck and
called Januvia. Januvia can be used in
combination with certain other medications
and must be dose adjusted in patients with
poor kidney function. For more, please read
the Januvia pamplet.
These drugs have essentially the same side
effect profile as Byetta; however, they are in
Combination Medications
Glyburide/ metformin, rosiglitazone/
metformin,
glipizide/
metformin,
and
pioglitazone/metformin are four relatively new
combination pills in varying strengths are in
the market to treat diabetes.
The benefit to these combination drugs is
that there are fewer pills to take, hopefully
leading to better compliance. While they work
well, it is preferable to give patients individual
medications until we know what doses are
working, and then switch to a combination pill
once the patient has been stable on the doses of
individual medications for a period of time.
A Final Word
These last few years have been an exciting
time in diabetes care. Many agents for the
treatment of type 2 diabetes are under
development and the options for insulin
therapy continue to grow and methods for
insulin delivery continue to become more
refined. While research continues to expand in
these areas, one thing remains constant.
Achieving the best blood sugar control
possible remains the ultimate goal in both type
1 and type 2 diabetes. We now know, beyond a
doubt, that good blood sugar control
minimizes the long-term complications of
diabetes, including blindness, nerve damage,
and kidney damage. Finally, a healthy lifestyle
can do nothing bad...it should remain the
cornerstone of management for diabetes.
.
63
Inhaled
Insulin
Avesthhgen Launches
Control Blood Sugar
Bioactive
to
Aventis Pharma has launched a new prefilled disposable insulin pen for diabetic
patients as it expects to increase its market
share to 9 per cent with the launch.
Lifestyle
Diabetes
Modification
Can
Delay
Dear Readers
We are happy to receive your encouraging response to our
journal. We shall, however, appreciate receiving your critical
comments and suggestions for further improvements. We are
always looking forward to your specific contributions on
various aspects of the journal. The contributions shall be
duly acknowledged.
Editor
71
R & D Highlights
R & D Highlights
insulin, and to release it in sufficient amounts
to maintain plasma glucose in a narrow range
(5-8 mM) in the face of sporadic food intake.
Too much insulin is as potentially lethal as too
little insulin, so the cells must be able to
respond rapidly to changes in plasma glucose
in either direction. Pancreatic -cells have
evolved complex stimulus-response coupling
mechanisms to monitor and respond to
changes in nutrients, hormones and
neurotransmitters and substitute -cells will
require similar mechanisms to enable a tightly
regulated release of insulin in response to
environmental cues. Second, the proliferative
capacity of the replacement cells must be
tightly regulated to avoid post-transplantation
expansion of -cell mass leading to the
development
of
hyperinsulinaemic
hypoglycaemia. This is not a problem when
using authenic -cells/islets derived from
human donors because they have an
exceedingly low proliferative capacity, but it is
a potential drawback when using cells
generated in vitro from proliferative precursor
populations.
This combination of highly specialised
secretory function and controlled proliferative
capacity is a challenging target, and some
ofthe suggested starting materials (Box 1) fail
to meet one or other of these criteria and so
will not be considered in detail in this review.
For example, transformed cells derived from
human -cells offer the potential of generating
in vitro the (thousands of) billions of cells
required for transplantation therapy, and
insulin-secreting cell lines can be engineered
to produce regulated secretory responses. Such
cells show unregulated proliferation and form
insulinomas in vivo, and so are unlikely to
offer any therapeutic benefit in the foreseeable
future. Another suggested source of
replacement -cells is to engineer non--cells
to make insulin, and this has been done in a
variety of cell types including fibroblasts,
skeletal muscle, neuroendocrine, kidney and
ovarian cells. This approach has the potential
Current R&D Highlights, Jan.-Mar. 2009
Islets/(
-Cells from other Species:
Xenografts to Treat Type 1 Diabetes
Using islets of Langerhans from other
species is an obvious way of providing the
large amounts of functional tissue required for
transplantation therapy of diabetes. Most effort
in this area has been directed towards using pig
islets because: (i) Western countries have preexisting
facilities
for
high-throughput
breeding, rearing and slaughtering of pigs
(porcine pancreas as a by-product of pork
production was a source of insulin for treating
TIDM for many years before recombinant
human insulin became widely available); (ii)
high islet yields can be obtained from porcine
pancreas using techniques similar to those for
human islet isolation; and (iii) pigs are
amenable to genetic modification to make
human insulin or to protect against immune
assault. Two important impediments have
however restricted the widespread use of pig
islets in humans. First, the hyperimmune
response to xenografts has proved difficult to
avoid. Numerous attempts to hide the
transplanted xenografts from the host immune
73
R & D Highlights
system by islet encapsulation have largely
failed to maintain islet viability and insulin
secretory responses over the prolonged periods
required of. transplanted islets. Second, the
demonstration that porcine endogenous
retroviral (PERV) sequences in the porcine
DNA
may
become
activated
on
xenotransplantation raised the possibility of
novel viral infections in humans receiving
porcine islet implants. Until recently, these
drawbacks
made
it
unlikely
that
xenotransplantation would find any major
clinical application in the treatment of TIDM.
but several recent developments have placed it
back in the spotlight.
R & D Highlights
transcription factors (e.g. PDX-l, nkx2.2,
nkx6.1, neurogenin-3, NeuroDl/Beta2, Pax4,
Pax6 and Isl1) regulating both processes.
Other tissue stem cells
There have been sporadic reports that
progenitor/stem cells from other tissues can be
induced to differentiate intoinsulin-expressing
cells, including cells localised to intestinal
epithelium, dermis, spleen, salivary gland and
blood monocytes. These studies have not
always proved to be reproducible, and have
been reviewed elsewhere
Embryonic stem cells
Embryonic stem (ES) cells have great
potential in cell/organ replacement therapies
because of two intrinsic properties. First, ES
ce\ls can produce cells of all three embryonic
germ layers (pluripotent). Second, ES cells can
proliferate indefinitely in viir.o if they are
maintained in their initial undifferentiated
state, so they are capable of produdng the large
numbers of cells required for transplantation
therapies. Initial attempts to differentiate ES
cells to insulin-expressing cells used mouse ES
(mES) cells, as did many subsequent studies,
because mES cells are much easier to obtain
and use than human ES(hES) cells, and
because they are not subject to the ethical and
legal constraints that accompany hES cells.
Concluding Remarks
Transplantation therapy offers a novel
treatment for diabetes and the potential gains,
both clinical and commercial, are enormous.
The availability of unlimited amounts of
functionally competent graft material would
allow islet transplantation to evolve from a
restricted, experimental treatment to a more
widespread applicability, much as has
happened for other organ transplantation
procedures in the past. The problems
associated with graft immunogenicity and
autoimmune destruction of engrafted material
are common to all sources of replacement cells, and beyond the scope of this review, but
Current R&D Highlights, Jan.-Mar. 2009
75
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Adipose tissue transplantation may be a
potential treatment for diabetes, atherosclerosis and nonalcoholic steatohepatitis.
Sanal, Madhusudana Girija et al.
Medical Hypotheses
Adipose tissue is critical in energy
homeostasis. Adipose tissue buffers the lipids
and energy rich compounds which are pumped
into the blood stream soon after meals. It
senses, signals other organs like liver and brain
about the energy reserves via adipokines.
Adiponectin, the most abundant adipokine has
insulin
sensitizing,
anti-inflammatory
antiatherogenic and antisteatotic effects.
Adipose tissue dysfunction is accompanied by
abnormal lipid distribution and storage which
contributes to diseases like diabetes,
nonalcoholic fatty liver disease and
atherosclerosis. Obesity and lipodystrophy are
associated with dysfunctional adipocytes. Preadipocytes are easy to isolate and culture. A
personalized depot specific liposuction to
remove the inactive adipocytes followed by
adipocyte repopulation could be useful in the
treatment of these diseases. (Scienedirect)
Attenuation of diabetic nephropathy by
tocotrienol: Involvement of NFkB signaling
pathway.
Kuhad, Anurag et al.
Life Sciences
Diabetic nephropathy is a serious
complication for patients with diabetes
mellitus. Approximately 30-40% of patients
with type I and 15% with type II diabetes
mellitus develop end stage renal disease. The
study was designed to evaluate the impact of
tocotrienol on renal function and renoinflammatory cascade in streptozotocininduced diabetes. Streptozotocin (STZ)induced diabetic rats were treated with
tocotrienol (25, 50 and 100 mg/kg), [alpha]tocopherol (100 mg/kg) or with vehicle form
5th to 8th weeks. After 8 weeks, urine albumin
excretion, urine output, serum creatinine,
blood urea nitrogen, creatinine and urea
clearance were measured. Cytoplasmic and
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novel preventive and regenerative therapies
have emerged in the past decade with the aim
to preserve beta-cell mass and delay the onset
of diabetes. The goal of this review is to
provide a comprehensive overview of current
efforts in the fight against diabetes, and
attempt to document all strategies that have
emerged in clinical studies within the past 25
years. First, strategies to identify individuals at
risk, ranging from whole-genome scans to
autoantibody screening, will be discussed.
Second, novel approaches to prevent or delay
the onset of disease will be covered. Particular
focus is given on emerging strategies for
individuals at risk for type 1 diabetes that
target T-cell regulation and induction of
tolerance, while new pharmaceutical concepts
in combination with lifestyle interventions are
discussed within the scope of type 2 diabetes
prevention. Lastly, important efforts to halt
disease progression with emphasis on beta cell
regeneration are presented. (Scienedirect)
Suppression of NF-[
][
] signaling
pathway by tocotrienol can prevent diabetes
associated cognitive deficits.
Kuhad, Anurag et al.
Pharmacology Biochemistry and Behavior
The etiology of diabetes associated
cognitive decline is multifactorial and involves
insulin receptor down regulation, neuronal
apoptosis and glutamatergic neurotransmission. The study was designed to evaluate
the impact of tocotrienol on cognitive function
and neuroinflammatory cascade in streptozotocin-induced diabetes. Streptozotocininduced diabetic rats were treated with
tocotrienol for 10 weeks. Morris water maze
was used for behavioral assessment of
memory. Cytoplasmic and nuclear fractions of
cerebral cortex and hippocampus were
prepared
for
the
quantification
of
acetylcholinesterase
activity,
oxidativenitrosative stress, tumor necrosis factor-alpha
(TNF-[alpha]), interleukin-1beta (IL-1[beta]),
NF[kappa][beta]
and
caspase-3.
After
10 weeks of streptozotocin injection, the rats
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of SMBG in non-insulin treated type 2
diabetes. Whether non-insulin treated type 2
diabetic patients benefit from SMBG, a largescale randomized controlled trial with the
follow-up period to investigate long-term
effects should be carried out. A general
recommendation is that insulin treated patients
perform SMBG at least three times per day.
SMBG frequency for non-insulin users should
be individualized to treatment regimen and
level of control.
Mutations in C2orf37, encoding a
nucleolar protein, cause hypogonadism,
alopecia,
diabetes
mellitus,
mental
retardation, and extrapyramidal syndrome.
Alazami, Anas M. et al.
The American Journal of Human
Genetics, 83(6), 684 (Dec., 12, 2008)
Hypogonadism,
alopecia,
diabetes
mellitus,
mental
retardation,
and
extrapyramidal syndrome (also referenced as
Woodhouse-Sakati syndrome) is a rare
autosomal recessive multisystemic disorder.
We have identified a founder mutation
consisting of a single base-pair deletion in
C2orf37 in eight families of Saudi origin.
Three other loss-of-function mutations were
subsequently discovered in patients of
different ethnicities. The gene encodes a
nucleolar protein of unknown function, and the
cellular phenotype observed in patient
lymphoblasts implicates a role for the
nucleolus in the pathogenesis of this disease.
Our findings expand the list of human
disorders linked to the nucleolus and further
highlight
the
developmental
and/or
maintenance functions of this organelle.
Polyelectrolyte biomaterial interactions
provide nanoparticulate carrier for oral
insulin delivery.
Catarina Pinto Reis et al.
Drug Delivery. 15: 127-139, 2008
Nanospheres are being developed for the
oral delivery of peptide-based drugs such as
insulin.
Mucoadhesive,
biodegradable,
biocompatible,
and
acid-protective
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cross-sectional study. Fasting serum resistin,
leptin, adiponectin, insulin and CRP were
measured by enzyme immunoassay. The
relation between these variables was studied
by univariate and multiple regression analysis.
Serum resistin levels were significantly
reduced in non-obese treated T2DM patients.
In the correlation analysis after controlling for
age and BMI authors found that resistin is
significantly associated with leptin (0.687,
p < 0.002) and CRP (0.549, p < 0.018) in only
control females and with CRP (0.642,
p < 0.01) in T2DM female patients. In multiple
linear regression analysis resistin was
independently predicted by the leptin
(p < 0.01) and leukocyte (p < 0.004) in
controls, treated T2DM patients. Reduced
resistin and leptin levels in non-obese treated
T2DM and significant association between
these two in control and treated T2DM suggest
interplay between these two adipocytokines. In
addition, the weak association of resistin with
diabetes indicates that it may be playing an
indirect role in the pathogenesis of T2DM.
(Scienedirect)
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allelic association was observed for two
markers, VEGF (-460 T>C) and PON1
(Arg192Gly) among NI diabetic CRI subjects.
The nonreplication of association suggests
differential genetic susceptibility of the two
populations to diabetic chronic renal
insufficiency. In the SI diabetic subjects,
oxidative stress pathway genes might be an
important predictor for the development of
diabetic complications. Further, the association
of wild-type alleles may suggest that they
confer greater survival ability to comorbid
complications and may be nephroprotective.
Poor vitamin D status may contribute
to high risk for insulin resistance, obesity,
and cardiovascular disease in Asian Indians.
McCarty, Mark F
Medical Hypotheses, 72(6), 647 (2009)
Asian Indians are highly prone to insulin
resistance syndrome, obesity, diabetes, and
coronary disease. At any given BMI, they tend
to have more body fat and more central fat
than other groups - yet their insulin resistance
is disproportionately high relative to their body
composition. They are also tend to have very
poor vitamin D status, even in UV-drenched
India, primarily owing to highly pigmented
skin and a cultural tendency to avoid direct sun
exposure. The resulting up-regulation of
parathyroid hormone (PTH) arguably may play
a role in their high risk for insulin resistance
and associated pathologies. There is suggestive
evidence that moderate elevations of PTH may
promote insulin resistance, weight gain,
hypertension, left ventricular hypertrophy, and
the acute phase response, while increasing risk
for ischemic arrhythmias and cardiovascular
mortality. Controlled studies should assess the
impact of optimal vitamin D supplementation,
with or without added calcium, on risk factors
associated with insulin resistance in Asian
Indians, as well as in other highly pigmented
urbanized ethnic groups that are at high risk
for insulin resistance and obesity.
Efficacy and safety of sitagliptin in the
treatment of patients with type 2 diabetes in
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logically to LADA nor former fruste of Type
1DM, having absence of markers for
autoimmune destruction of [beta]-cells and
good insulin and C-peptide reserve for a
prolonged period of life. They constitute an
independent variant of Type 2 DM with
inherent peculiarities of insulin kinetics in the
liver along with altered profile and behaviour
of key enzymes related to carbohydrate
metabolism which are marked by excess
extraction of insulin in hepatic bed,
hyperactive cytochrome system and nonsupressible glucokinase activity. These
peculiarities are reflected in the peripheral
circulation as states of low circulating levels of
insulin, hyperglycemia, dyslipidemia without
low high density lipoprotein cholesterol
(HDLc), raised triglycerides (Tg), low levels
of plasma homocysteine and BMI below 19
make these diabetics less prone to develop
macrovascular disease. Peripheral neuropathy
and the consequences of poor glycemic control
such as increased succeptibility to infections
and endothelial dysfunction manifesting as
proteinuria dominate the clinical picture. In
view of more of infective complications and
coexistent severe hyperglycemia (glucose
toxicity) many of these diabetics may not
respond to OHA adequately at the initiation of
therapy. However, due presence of insulin
resistance and good []-cell reserve for insulin,
despite of lean habitus, most of them respond
well to OHA for long periods of life, as may
be comparable with any other phenotype of
Type 2 diabetes. The insulin resistance
observed in Type 2 DM-lean is not consequent
to anthropometric parameters like central
obesity and WHR as these diabetics are lean
with poor fat depot and thus it could be an
integral part of the pathogenic mechanism of
Type 2 DM per se.
Inhibition of aldose reductase from
cataracted eye lenses by finger millet
(Eleusine coracana) polyphenols.
Chethan, S. et al.
Bioorganic & Medicinal Chemistry,
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diagnosed T2DM, undiagnosed T2DM and
other abnormalities of glucose tolerance
studied in 3032 subjects from Kashmir Valley
of India. The study included a questionnaire,
anthropological
measurements,
blood
sampling, and a standard OGTT. Eight (0.3%)
of surveyed subjects were previously
diagnosed to have diabetes. Of 3024 subjects
screened, prevalence of diabetes, impaired
glucose tolerance (IGT), and impaired fasting
glycemia was 2.5%, 2.0%, 11.9% and 26.7%,
respectively. Overall, age-adjusted prevalence
of T2DM (known plus unknown), IGT, IFG
(WHO) and IFG (ADA) was 2.4% (95% CI:
1.9-3.0), 1.6% (95% CI: 1.3-2.2), 11.1% (95%
CI: 10.0-12.3), and 25.2% (95% CI: 23.726.8), respectively. The difference in diabetes
prevalence was significant by age, habitat,
family history of diabetes and BMI. The ratio
of known-to-unknown diabetes was 1:10. This
is the first large scale study from North India
on prevalence of type 2 diabetes in the younger
age group of 20-40 years. Abnormal glucose
tolerance including undiagnosed T2DM is
common in young adults.
Synthesis and elucidation of absolute
stereochemistry of salaprinol, another
thiosugar sulfonium sulfate from the
ayurvedic traditional medicine Salacia
prinoides.
Tanabe, Genzoh et al.
Tetrahedron, 64(43), 10080 (Oct., 20,
2008)
Synthesis and elucidation of absolute
stereochemistry of salaprinol (3) isolated from
the root and stems of Salacia prinoides, which
has been used for the treatment of diabetes in
India, Sri Lanka, and Southeast Asia countries,
is described. Compound 3 and its 2'-epimer,
epi-salaprinol (epi-3) were synthesized via the
coupling reaction of a cyclic sulfate, 2-Obenzylglycerol 1,3-cyclic sulfate (5), with a
thiosugar, 1,4-dideoxy-1,4-epithio-d-arabinitol
(6), as the key reaction, and S configuration of
the asymmetric center in the side chain of 3
was elucidated by the X-ray crystallographic
82
analysis.
High prevalence of type 2 diabetes
mellitus in affluent urban Indians.
Boddula, R et al.
Diabetes Research and Clinical Practice,
81(2), e4 (Aug., 2008)
The highest prevalence of type 2 diabetes
mellitus in developing countries occurs in the
upper socio-economic group, but this has not
been well documented in Indians. The age and
sex standardized prevalence of diabetes in
1112 affluent adult Indian subjects was 21.1%.
This is the highest prevalence of diabetes
reported from India.
Global diabetes landscape--type 2
diabetes
mellitus
in
South
Asia:
Epidemiology, risk factors, and control.
Gupta, Rajeev et al.
Insulin, 3(2), 78 (Apr., 2008)
Type 2 diabetes mellitus (DM) is a new
epidemic in South Asia and is the result of
societal influences and changing lifestyles.
Epidemiologic studies suggest that the
prevalence of DM has increased exponentially
in urban and rural populations. This study was
conducted to determine trends in the
prevalence of DM in various countries in
South Asia. We performed an extensive,
systematic MEDLINE search for primary
articles that reported on the epidemiology of
DM in South Asia. Additional articles were
obtained from personal collections and
references cited in the primary articles. No
formal meta-analysis was performed because
of differing methodologies and diagnostic
criteria. Epidemiologic studies conducted in
India during the 1960s and 1970s, using
random and postload blood glucose
estimations, reported DM in 1% to 4% of
urban populations and 1% to 2% of rural
populations. More standardized epidemiologic
studies in adults since the late 1980s reported
DM in 5% to 15% of urban populations, 4% to
6% of semiurban populations, and 2% to 5%
of rural populations. A significantly increasing
trend has been observed in urban populations
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(exponential trend R2 = 0.74), whereas the
increase is slower (R2 = 0.29) in rural
populations. The diabetes scenario is similar in
other South Asian countries. Current
prevalence rates are 5% to 16% in urban areas
and 2% to 8% in rural areas. Risk factors for
DM in this region are increasing sedentariness,
dietary excess, obesity (especially high waistto-hip ratio), low birth weight, and genetic
influences. DM is a major public health
problem in South Asia. The prevalence is
higher in urban areas than in rural areas and is
increasing. Population-based measures to
control the epidemic of DM include avoidance
of adiposity through enhanced physical
activity and regulated calorie intake. A
comprehensive national chronic care program
is needed.
Prevalence of autoantibodies and risk
estimation of development of youth onset
type 1 diabetes in northern India.
Ahmad, Jamal et al.
Diabetes and Metabolic Syndrome:
Clinical Research and Reviews,2(1), 59 (Feb.,
2008)
Autoantibodies to islet cell antigens such
as insulin (IAA), the 65-kDa isoform of
glutamate decarboxylase (GAD65) and the
protein tyrosine phosphatase (PTP) like
antigen IA-2 are markers of the autoimmune
process preceding type 1 diabetes (T1DM) and
may help to predict the rapid decrease in
residual [beta]-cell function. The present
investigation was undertaken to evaluate the
relation between GAD65 and IA-2 in children
with newly diagnosed T1DM and to compare
the frequency and levels of autoantibodies with
clinical characteristics. A total of 102 T1DM
subjects (age at onset <30 years; mean
duration of disease 6.7 2.8 years) from north
India were characterized by serological
determination of the islet cell antibodies,
GAD65 and IA-2. One hundred and two age
and sex matched non-diabetic subjects of the
non-diabetic parents served as control.
Prevalence of autoantibodies in diabetic
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are heterogeneous diseases with alterations in
many genes and their products. Not all
transcriptional alterations lead to protein
changes, which makes it very important to, in
conjunction with mRNA expression studies,
also address changes in cellular protein levels.
Various proteomic techniques are available for
measuring
many
protein
changes
simultaneously. Many proteomic studies have
been performed in the context of diabetes
research, with the aims of both describing the
healthy tissue and to unravel the complex
pathophysiology behind the disease. In
addition, effects on proteins induced by
different treatments have
also been
investigated using proteomic approaches. In
this paper the field of diabetes proteomics
today will be reviewed. Findings from
proteomic studies investigating pancreatic
islets and -cells as well as serum, fat, skeletal
muscle and liver are described.
The GK rat beta-cell: A prototype for
the diseased human beta-cell in type 2
diabetes?
B. Portha et al.
Molecular and Cellular Endocrinology,
297, 73-85 (2009)
Increasing evidence indicates that
decreased functional beta-cell mass is the
hallmark of type 2 diabetes (T2D) mellitus.
Nowadays, the debate focuses on the possible
mechanisms responsible for abnormal islet
microenvironment,
decreased
beta-cell
number, impaired beta-cell function, and their
multifactorial aetiologies. This review
illustrates to what extend the GotoKakizaki
rat, one of the best characterized animal
models of spontaneous T2D, has proved be a
valuable tool offering sufficient commonalities
to study these aspects. Authors have proposed
that the defective beta-cell mass and function
in the GK model reflect the complex
interactions of multiple pathogenic players: (i)
several independent loci containing genes
responsible for some diabetic traits (but not
decreased beta-cell mass); (ii) gestational
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secretory function and inadequate -cell mass.
Growth hormone (GH) is a multifunctional
hormone, involved in cellular metabolism,
mitogenesis and differentiation. In pancreatic
islets, GH is involved in maintaining -cell
mass, stimulating islet hormone production
and insulin secretion, and, therefore, plays a
role in maintaining normal insulin sensitivity
and glucose homeostasis. The intracellular
events that convey the GH signal into various
cellular responses remain incompletely
understood. In this review, we discuss GH
signaling in the -cells, with emphasis on Ca2+
handling and insulin secretion regulated by
human GH (hGH). hGH-stimulated rise in
[Ca2+]i is dependent on extracellular Ca2+ and
is mediated by Ca2+-induced Ca2+ release
(CICR) in the -cell. This process is triggered
by hGH-stimulated activation of the nonreceptor tyrosine kinases JAK2 and c-Src,
which causes tyrosine phosphorylation of
RyRs, resulting in sensitization of CICR. The
rise in [Ca2+]i elicited by hGH is associated
with an enhanced insulin secretion, effects that
are mediated mainly through the prolactin
receptor. These mechanisms indicate that a rise
in [Ca2+]i elicited by activation of PRLR is
JAK2-dependent and is associated with
enhanced insulin secretion. In contrast, GH
receptor-mediated increase in [Ca2+]i is JAK2independent and is dissociated from insulin
secretion.
The AMP-regulated kinase family:
Enigmatic targets for diabetes therapy.
Guy A. Rutter et al.
Molecular and Cellular Endocrinology,
297, 41-49 (2009)
AMP-activated protein kinase (AMPK) is
a widely conserved Ser/Thr-specific protein
kinase, homologous to Saccharomyces
cerevisiae Snf1, and involved in nutrient
sensing in lower organisms. In 2003, authors
reviewed the role of this enzyme in glucose
homeostasis in mammals. In the subsequent 5
years, dramatic strides have taken place in our
understanding of the role of AMPK in the
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The importance of RNA binding
proteins in preproinsulin mRNA stability
Rikard G. Fred et al.
Molecular and Cellular Endocrinology,
297, 28-33 (2009)
A dynamic production of insulin is
necessary for proper glucose homeostasis. In
order to generate enough insulin available for
exocytosis in response to the demands of the
organism, the level of preproinsulin mRNA in
the pancreatic -cell needs to fluctuate. In
animal models for type 2 diabetes the contents
of preproinsulin mRNA are lowered, which
might suggest that an impaired metabolism of
preproinsulin mRNA contributes to the
development of glucose intolerance and
diabetes. Thus, it is of importance to
understand the mechanisms by which
preproinsulin mRNA levels are regulated.
Although extensively studied, there are aspects
of the regulation of insulin gene expression
that still remain enigmatic. Our understanding
of insulin gene transcription has improved
considerably the last 20 years, but less effort
has been invested into the control of
preproinsulin
mRNA
stability.
The
preproinsulin mRNA has a long half-life and
changes in preproinsulin mRNA stability,
induced by glucose, are likely to be regulated
through specific mechanisms. Recent findings
indicate that the polypyrimidine tract-binding
protein (PTB), also named hnRNP I, by
binding to the 3-UTR (untranslated region) of
the preproinsulin mRNA molecule, stabilizes
the messenger, thereby participating in the
glucose-induced increase in preproinsulin
mRNA. Both recent findings pertinent to PTB
function in general, and on the specific role of
PTB on the production of insulin in -cells
have been discussed in the review. The
putative co-operativity between PTB and other
proteins in the control of preproinsulin mRNA
stability, and review -cell signaling events
that may control the mRNA stabilizing effect
of PTB.
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merely represent the tip of the iceberg in the
explanation behind T2D. Refined tools will
have to provide a more complete picture of the
genetic complexity of T2D over the next few
years. In addition to common variants
increasing susceptibility for the disease, rare
variants with stronger effects, copy number
variations, and epigenetic effects like DNA
methylation and histone acetylation will
become important. Nevertheless, today we are
able for the first time to anticipate that the
genetics of a complex disease like T2D really
can be dissected.
Fetal programming of glucoseinsulin
metabolism
R. Huw Jones et al.
Molecular and Cellular Endocrinology,
297, 4-9 (2009)
Epidemiological studies have shown a link
between poor fetal growth and increased risk
of developing type 2 diabetes. These
observations are highly reproducible in many
populations
worldwide
although
the
mechanisms behind them remain elusive. The
Thrifty Phenotype Hypothesis was proposed
to explain the underlying causes of these
relationships. Animal models of poor
intrauterine nutrition have been utilised to help
to define the causal factors and identify the
molecular mechanisms. Programmed changes
in beta cell function and insulin action have
been a common feature of animal models of
poor intrauterine nutrition. Fundamental
underlying mechanisms are starting to emerge,
including changes in the epigenotype and
mitochondrial function
Insulin exhibits short-term antiinflammatory
but
long-term
proinflammatory effects in vitro.
Yasumasa Iwasaki et al.
Molecular and Cellular Endocrinology,
298, 25-32 (2009)
Although insulin is indispensable for
maintaining glucose homeostasis, it is still
controversial whether or not a high
concentration of insulin is deleterious. Authors
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glucose homeostasis. The glucoregulatory
effects of incretins are the basis for new
therapies currently being developed for the
treatment of type 2 diabetes mellitus (T2DM).
Drugs that inhibit dipeptidyl peptidase-4
(DPP-4), a ubiquitous enzyme that rapidly
inactivates both GLP-1 and GIP, increase
active levels of these hormones and, in doing
so, improve islet function and glycemic control
in T2DM. Scope: In this review, we briefly
describe (1) the role of pancreatic islet
dysfunction in the onset and progression of
T2DM, (2) the rationale for developing drugs
that enhance incretin activity, (3) the evidence
that inhibition of DPP-4 is effective in
ameliorating islet dysfunction and improving
glycemic control in T2DM, (4) the efficacy,
safety, and tolerability of DPP-4 inhibitors as
monotherapy and in combination with other
antidiabetic agents, and (5) the potential utility
of DPP-4 inhibitors relative to existing oral
antidiabetic agents and newer antidiabetic
drugs in the pipeline. The review is based upon
MEDLINE literature searches (1966-August
2006) and abstrs and presentations from the
American Diabetes Assocn. Scientific Sessions
(2002-2006) and the European Assocn. for the
Study of Diabetes Annual Meetings (19982006).
Basic science, preclin., and clin.
studies and review articles published in the
Views expressed in the journal are those of the authors and the
Editorial Board/Publisher takes no responsibility for the same. We are
a secondary abstracting service and the veracity of information is of
the source quoted and not our primary responsibility.
Editor
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Diabetic Nephropathy
Diabetes and hypertension are major risk
factors for the development of end-stage renal
disease. Increased albumin excretion is seen in
the early stage of diabetic nephropathy before
the glomerular filtration rate decreases.
Microalbuminuria, macroalbuminuria and endstage renal disease are all associated with an
increased risk of death. People with chronic
kidney disease have a greater risk of
developing cardiovascular disease and
diabetes, as seen in a multiethnic population.
Patients with type 2 diabetes are at risk of
developing chronic kidney disease. The
isotopic glomerular filtration (iGFR) rate was
measured in type 2 diabetic patients at
Current R&D Highlights, Jan.-Mar. 2009
Cardiovascular Disease
Cardiovascular disease is the main cause
of mortality in patients with diabetes, and risk
reduction is an important goal in the treatment
of diabetes. In individuals, little is known
about the importance of progressive change or
variability over time in risk factors for
atherosclerotic vascular disease. Data have
shown a significant increase for major
cardiovascular events and procedures in
subjects with type 2 diabetes..
Endothelial dysfunction, carotid intimamedia thickness (CIMT) and lipoprotein
abnormalities are factors contributing to
cardiovascular disease. One study found that
abnormalities in flow-mediated dilatation and
CIMT are present in young type 1 diabetic
patients and correlate well with lipoprotein
abnormalities. The PREDICT study measured
the coronary artery calcification score (CACS)
and found it to be a powerful predictor of
cardiovascular events in asymptomatic patients
with type 2 diabetes.
Both metabolic syndrome and type 2
diabetes are associated with a high
cardiovascular risk due to clustering of
atherothrombotic risk factors such as insulin
resistance,
dyslipidemia,
hypertension,
hypercoagulability and dysglycemia. Insulin
resistance in type 2 diabetic patients may be
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responsible for hypertension and dyslipidemia.
It was found that prehypertension is associated
with obesity but not specifically with insulin
resistance or metabolic syndrome. Although
the majority of type 2 diabetic patients are
obese, the body mass index was found to be a
poor discriminator of cardiovascular risk in
these patients.
Ischemic heart disease (IHD) is the most
frequent macroangiopathic complication and
the main cause of death in subjects with type 2
diabetes. Myocardial infarction often occurs in
type 2 diabetic patients with no previous
cardiac symptoms. Diabetes is an important
determinant of death after acute myocardial
infarction (AMI) and adversely affects the
outcome after AMI. Another study found
hypertension to be a risk factor for IHD in a
Scottish type 1 diabetic population and highdensity lipoprotein (HDL) was found to have a
protective effect against cardiovascular
disease.
Endothelial
dysfunction
leads
to
atherosclerosis, which is the leading cause of
macrovascular complications and death in
patients with type 2 diabetes. Investigations
within the endothelium have been limited by
access until the recent development of a new
technique to sample cells from a forearm vein
in humans.
Type 2 diabetes is associated with
increased vascular superoxide levels and
impaired endothelial function. Researchers
from Glasgow examined the effect of diabetes
on vascular superoxide production in patients
undergoing coronary artery bypass graft. They
concluded that reduced superoxide production
in patients with type 2 diabetes may be
attributable to increased use of modifiers of the
angiotensin system and oral hypoglycemic
agents. Thus, other factors such as impaired
smooth muscle function and reduced
endothelial nitric oxide generation may be
responsible
for
impaired
endothelium
dependent vasorelaxation in diabetes.
Diabetic Neuropathy
Neuropathy in diabetic patients is a major
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source of morbidity. The pathogenesis of
diabetic
neuropathy
remains
poorly
understood. Diabetic peripheral neuropathy is
a common and debilitating consequence of
diabetes. There are established risk factors for
the development of peripheral neuropathy in
patients with diabetes, such as poor glycemic
control and hypertension. Increasing subject
height was found to be associated with an
increased long-term risk of developing
neuropathy in type 1 diabetic patients who
participated in the DCCT follow-up study. In
type 1 diabetic patients, the additional
diagnosis of celiac disease appears to lead to
poorer nerve conduction even when
controlling for glycemic control.
Depression may be a major confounder of
outcomes in clinical trials in diabetic
peripheral neuropathy. Subjects with even
moderate levels of depression are more likely
to have higher baseline pain scores and to
respond favorably to any intervention, whether
placebo or active.
Although there is an increased propensity
for the development of carpal tunnel syndrome
in people with diabetes, the basis for this has
not been established. Increased upregulation of
hypoxia-inducible factor 1 (HIF-1),
vascular endothelial growth factor (VEGF) and
vascular endothelial growth factor receptor 2
(VEGFR2), suggestive of increased hypoxia
and vascular permeability, was found in
diabetic patients with established carpal tunnel
syndrome.
In an animal study, glycation adducts were
found in the extracellular matrix of the sciatic
nerve of streptozotocin-induced diabetic rats,
which may contribute
to decreased
regeneration of sensory neurons, leading to
peripheral neuropathy.
The accurate quantification of diabetic
neuropathy is important to define at-risk
patients and anticipate deterioation. Corneal
confocal microscopy is a rapid, noninvasive
technique that has been shown to be a reliable
Current R&D Highlights, Jan.-Mar. 2009
Diabetic Retinopathy
Digital retinal screening was performed in
both type 1 and type 2 diabetic patients to
measure the prevalence of diabetic retinopathy.
The prevalence rate for diabetic retinopathy in
type 2 diabetic patients on oral hypoglycemic
drugs appeared to be lower than in other
population studies. Visual acuity was well
preserved and type 2 diabetic patients
receiving insulin were at high risk of diabetic
retinopathy, particularly maculopathy. A
retrospective analysis found that the
prevalence of sight-threatening maculopathy is
highest in eyes with sight-threatening diabetic
retinopathy and negligible in eyes with screennegative retinopathy.
A study from London indicated that sleepdisordered breathing, which is quite common
in type 2 diabetic patients, plays an etiological
91
R & D Technology
role in diabetic retinopathy. Another study
mentioned that sleep-disordered breathing may
play a role in metabolic syndrome via the
inflammatory pathway.
Hypoglycemia
Hypoglycemia is a common adverse event
of diabetes treatment and remains a major
barrier to achieving optimal glycemic control
in both type 1 and type 2 diabetic patients,
particularly those who are on insulin.
Hypoglycemic episodes may compromise the
patients' quality of life. Bedtime blood glucose
is a significant risk factor for nocturnal
hypoglycemia in type 1 diabetic subjects and
these subjects did not show any rebound
hyperglycemia
following
nocturnal
hypoglycemia. Gill et al. found that all the
nocturnal hypoglycemic episodes in patients
with type 1 diabetes were associated with
tachycardia and a subgroup appeared prone to
develop bradycardia, which may be
responsible for sudden death.
Researchers documented a wide range of
Q-T lengthening following inhaled salbutamol
in type 1 diabetic patients. These results can be
compared with the responses during
experimental hypoglycemia to establish it as a
screening test for those at risk of abnormal
cardiac repolarization leading to fatal cardiac
arrhythmias
during
severe
nocturnal
hypoglycemia.
Type 1 diabetic patients are likely to be
unaware of hypoglycemia because of
impairment of the protective neurohumoral
counterregulatory responses to impending
hypoglycemia due to repeated hypoglycemic
episodes. Impaired awareness of hypoglycemia
(IAH) is thought to affect approximately 25%
of subjects with type 1 diabetes. Despite
improvements in insulin therapies, intensification of insulin regimens and innovative
patient education, a survey of a large hospitalbased clinical population confirmed that 19.5%
of type 1 diabetic patients continue to have
IAH. Two different studies from the same
92
Metabolic Syndrome
The metabolic syndrome increases
cardiovascular risk in type 2 diabetes.
Abdominal adiposity is considered a major risk
factor for type 2 diabetes, metabolic syndrome
and cardiovascular diseases. This is supported
by Yang et al., who found that visceral
adiposity remains a strong and significant
determinant of insulin resistance in WHO
grade III obesity. Neck circumference rather
than subcutaneous fat is a more reproducible
and precise measurement in this severely obese
cohort. An association between increased
central obesity and lower serum adiponectin
and an intimate relationship between
triglycerides and insulin resistance were found
in schizophrenic patients treated with
clozapine. Changes in waisthip ratio over time
may result in abnormal glucose handling and
routine measurement of this parameter is
necessary in this group of patients. Another
study suggested that plasma triglycerides and
the albumin:creatinine ratio are associated with
type 2 diabetes in morbid obese subjects.
Musculoskeletal Disease
Early detection of microvascular and
macrovascular complications in subjects with
diabetes could prevent fatal outcomes.
Locomotor disease is found in 57% of patients
with type 1 diabetes. Capsulitis invariably
coexisted with other upper limb abnormalities
and predicted the presence of retinopathy
and/or neuropathy. The mean glycosylated
hemoglobin (HbA1c) was also higher
Current R&D Highlights, Jan.-Mar. 2009
R & D Technology
inpatients with shoulder problems and these
results are very similar to those found in type 2
diabetic patients. Another study found that the
presence of diabetic peripheral neuropathy,
retinopathy and nephropathy was significantly
higher in patients with limited joint mobility.
Therefore, all diabetic patients should be
clinically examined for upper limb locomotor
disease and limited joint mobility, and if
present, they should be evaluated further for
other diabetic complications.
Ethnic Variation
The incidence of diabetes and its
complications varies in different ethnic
populations. A cross-sectional survey revealed
higher plasma glucose, serum leptin, Yon
Willebrand factor, tissue
plasminogen
activator and fat mass-bioimpedence in South
Asian children compared with Europeans,
which make an important contribution to the
differences in insulin resistance observed in
these populations (50). Another similar study
found higher mean truncal skinfold thickness,
HbA 1 c, fasting insulin and triglycerides, and
lower HDL cholesterol in South Asian children
compared with age-adjusted white Europeans.
In a study it was found that the prevalence of
microvascular
complications
such
as
retinopathy, nephropathy and neuropathy and
mean HbA 1 c are significantly higher and the
use of metformin, sulfonylureas and insulin is
significantly lower in India compared to
Mauritius and the UK. Poor glycemic control
in South Asian subjects with type 2 diabetes
and chronic disease comorbidity may be
responsible for the increased risk of mortality
and morbidity. Although a higher proportion
of South Asians were found to have poor
glycemic control, the prevalence of obesity,
smoking and hypertension was lower in this
group than in non-South Asians. Therefore,
there may be important opportunities for the
early prevention of type 2 diabetes and other
microvascular and macrovascular complications in this high-risk ethnic group.
(Based on the Conference Report published in Drugs
of the Future 2008, 33(5): 463-468)
R & D Technology
diabetes, later in life. Moreover, the risk of the
metabolic syndrome is increased 3-fold in
these women. Their offspring have an 8-fold
risk of diabetes/prediabetes at 19-27 years of
age. Thus, GDM is part of a vicious circle
which increases the development of diabetes in
the coming generations.
(ScienceDirect)
Fasting homocysteine levels in a crosssection of Saudi adults with type 1 diabetes
mellitus.
Al-Attas, Omar S. et al.
Diabetes and Metabolic Syndrome:
Clinical Research and Reviews
Studies have shown homocysteine to be
an independent risk factor for atherosclerosis
and CVD in both diabetic and non-diabetic
subjects. However, the association between the
levels of homocysteine and type 1 diabetes
mellitus remains a controversial one. A study
was conducted with the aim to test this in a
cross-section of the Saudi type 1 diabetics
against non-diabetics to establish the
relationship of homocysteine with regards to
type 1 diabetics and non-diabetics. A total of
97 subjects (41 males, 56 females) participated
in this cross-sectional study done at the
diabetic clinic of King Abdul-Aziz University
Hospital Diabetic Centre, Riyadh, KSA. They
were divided according to the presence of type
1 DM. Glycemic and lipid parameters were
measured using routing procedures. Hcys was
measured using photometric assay. Among
males, Hcys levels were significantly lower
among the diabetic subjects (p-value 0.03).
Females with type 1 diabetes however have
higher total cholesterol levels than their control
counterparts (p-value 0.003). Among the
control group, gender and HDL-cholesterol
exhibited significant inverse relationships with
hcys (p-values 0.028 and 0.032, respectively)
and a strong positive association with body
mass index (p-value 0.034). Among the
diabetic group, only age was significantly
associated with Hcys (p-value 0.009). In the
Arab population, hcys is decreased in IDDM
subjects compared to non-diabetic subjects.
94
R & D Technology
Diabetes Research and Clinical Practice,
83(1), 83 (Jan., 2009)
Cardiac autonomic functions were
assessed in 145 consecutive recently detected
type 2 diabetics. Ninety-nine healthy persons
served as controls. Criteria for normalcy were,
heart rate variation during deep breathing
>=15 beats/min, deep breathing expiratory to
inspiratory R-R ratio >=1.21, Valsalva ratio
>=1.21, sustained handgrip test >=16 mm of
mercury, cold pressor test >=10, BP response
to standing <=10 mm of mercury and 30:15 RR ratio on standing >=1.04. An abnormal test
was defined as the above parameters being
<10 beats/min, <1.21, <1.21, <=10 mm of
mercury, <10, >=30 mm of mercury and
<=1.0, respectively. A borderline test was
defined as, heart rate variation during deep
breathing 11-14, sustained handgrip test 1115 mm of mercury, BP response to standing
11-29 mm of mercury and 30:15 R-R ratio on
standing
1.01-1.03.
Parasympathetic
dysfunction was found in 44.2% and
sympathetic dysfunction in 51.9% diabetics.
Among healthy controls, these figures were
11.9% and 22.1%, respectively. Cardiac
autonomic function was normal in 7.8%
patients and 32.5% healthy controls.
Efficacy and safety of sitagliptin in the
treatment of patients with type 2 diabetes in
China, India, and Korea.
Mohan, Viswanathan et al.
Diabetes Research and Clinical Practice,
83 (1), 106 (Jan., 2009)
The efficacy and safety of sitagliptin as
monotherapy were evaluated in Chinese,
Indian, and Korean patients with type 2
diabetes inadequately controlled by diet and
exercise. In a randomized, placebo-controlled,
double-blind, 18-week trial, 530 patients with
HbA1c >=7.5% and <=11.0% (mean baseline
8.7%) received sitagliptin 100 mg once daily
or placebo. Compared with placebo, sitagliptin
significantly (p < 0.001) reduced mean HbA1c
(-1.0%), fasting plasma glucose (-1.7 mmol/L),
and 2-h postprandial glucose (-3.1 mmol/L),
Current R&D Highlights, Jan.-Mar. 2009
R & D Technology
The training significantly improved knowledge
on treatment, complications, pathophysiology
and diagnosis of diabetes (p < 0.001). The
participants considered information on
preventive aspects of diabetes and foot care as
highly educative. Patient education and teamtraining were considered important in diabetes
management. Interest was evinced in raising
public awareness about the disease. Wellplanned short training programmes are useful
in improving knowledge and in creating
enthusiasm to improve diabetes care and
awareness.
Proton
magnetic
resonance
spectroscopy and biochemical investigation
of type 2 diabetes mellitus in Asian Indians:
observation of high muscle lipids and Creactive protein levels.
Sinha, Sanjeev et al.
Magnetic Resonance Imaging, 27(1), 94
(Jan., 2009)
Authors report the determination of
intramyocellular lipids (IMCLs) of the soleus
muscle of patients with type 2 diabetes
mellitus (T2DM) using proton magnetic
resonance spectroscopy. In addition, the
various anthropometric and biochemical
profiles of these patients were determined,
including estimation of C-reactive protein
(CRP), an inflammatory marker of coronary
heart disease, and insulin resistance
[Homeostasis Model Assessment (HOMAIR)]. The estimated CRP level and the IMCL
content in these patients were correlated with
body mass index, percentage of body fat, other
measures of abdominal obesity, serum
lipoproteins, fasting and post-oral glucose load
serum insulin levels and other surrogate
markers of insulin resistance. The IMCL
content (P=.04), CRP (P=.008) and insulin
resistance (P=.0007) were significantly higher
in T2DM patients compared to healthy
controls. However, IMCL content did not
correlate with values of fasting insulin,
HOMA-IR or CRP in either group. These
findings have strong implications of increased
96
R & D Technology
Clinical Research and Reviews
Diabetic dyslipidemia is characterized by
a preponderance of small dense LDL which is
highly atherogenic. The aim of this study was
to examine the interrelationship between LDL
Phenotype and atherosclerosis; to determine
the factors determining LDL phenotype; and
evaluate LDLc:apo-B ratio as a surrogate for
the assessment of LDL phenotype in a group
of North Indian Type 2 diabetic subjects. 285
diabetic subjects attending the outpatient
Endocrine Clinic were subjected to detailed
anthropometry and fasting serum lipid and
apo-B was measured. The carotid intimamedia thickness (IMT) was determined using a
high resolution B-mode Ultrasonography.
LDLc:apo-B ratio was taken as a surrogate
index for LDL size. 29.5% patients with
normal triglyceride levels and 52.1% patients
with normal LDLc levels showed the presence
of small dense LDL or Phenotype B as
estimated by the LDL cholesterol/apo-B ratio.
The mean IMT in Phenotype B group was
higher (0.88 mm vs. 0.68 mm). Triglycerides
was the most important predictor variable
predicting
carotid
IMT
(R2 = 0.15,
[beta] = 0.376) as well as LDL phenotype B
(R2 = 0.28, [beta] = 0.561). Triglycerides and
HDLc contribute independently to the
variability in LDL particle size, and LDL
particle size was associated with preclinical
atherosclerosis as determined by carotid IMT
in North Indian Type 2 diabetic subjects. LDL
cholesterol/apo-B ratio serves as an easy
clinical tool to determine the elevated small
dense LDL. .
(ScienceDirect)
Vibration perception threshold and the
law of mobility in diabetic mellitus patients.
Manivannan, M et al.
Primary Care Diabetes (In Press)
Diabetic neuropathy is a family of nerve
disorders with progressive loss of nerve
function in 15% of diabetes mellitus (DM)
subjects. Vibration Perception Threshold
(VPT) is one of the modalities of testing loss
of protective sensation. Law of mobility for
Current R&D Highlights, Jan.-Mar. 2009
R & D Technology
Significantly higher HbA1c was associated
with lower age (CI of [beta]: -0.024 to -0.001,
p = 0.039), female gender (CI of [beta]: 0.0390.552, p = 0.024) and medication use (CI of
[beta]:
0.577-1.250,
p < 0.001).
The
proportions with good glycemic control for the
all diabetic, hypertensive, normotensive
subjects were 0.235, 0.249 and 0.207,
respectively. No significant difference was
shown for the two groups'proportions
(p=0.283). Lower proportions of good control
were shown in females (CI of OR: 0.3980.905, p=0.015) and those on medication (CI
of OR: 0.211-0.543, p<0.001) by stepwise
logistic regression. The hypertensive diabetic
patients had better glycemic control than the
normotensives.
Vildagliptin dose-dependently improves
glycemic control in Japanese patients with
type 2 diabetes mellitus.
Kikuchi, Masatoshi et al.
Diabetes Research and Clinical Practice,
83(2), 233 (Feb., 2009)
To assess the efficacy and tolerability of
vildagliptin (10, 25 or 50 mg bid) in Japanese
patients with type 2 diabetes mellitus (T2DM),
this 12-week, multicenter, randomized,
double-blind, placebo-controlled, parallelgroup study was performed in 291 patients.
The primary assessment was change from
baseline to endpoint in HbA1c. Baseline
HbA1c averaged 7.4%, and the betweentreatment difference (vildagliptin-placebo) in
the HbA1c adjusted mean change was -0.8%, 1.0% and -1.2% with vildagliptin 10, 25 and
50 mg bid, respectively (p < 0.001). Relative
to baseline, body weight did not change
significantly in vildagliptin groups. There was
no increase in incidence of adverse events in
the vildagliptin groups (62.0%, 62.5% and
61.8%, 10, 25 and 50 mg bid, respectively)
compared to placebo (73.6%). No deaths or
drug-related serious adverse events were
reported. Seven hypoglycemic events were
observed (four events (n = 3), two events
(n = 2), and one event (n = 1) in the
98
R & D Technology
genetics study report 2.
Raman, Rajiv et al.
Ophthalmology, 116(2), 311 (Feb., 2009)
The aim of the study was to estimate the
prevalence of diabetic retinopathy in an urban
Indian population older than 40 years. A
population-based cross-sectional study. Five
thousand nine hundred ninety-nine subjects
residing in Chennai, India, were enumerated.
A multistage random sampling, based on
socioeconomic
criteria,
was
followed.
Identified subjects with diabetes mellitus
(based on the World Health Organization
criteria) underwent detailed examination at the
base hospital. The fundi of all patients were
photographed using 45, 4-field stereoscopic
digital photography. The diagnosis of diabetic
retinopathy was based on Klein's classification
of the Early Treatment Diabetic Retinopathy
Study scale. These included age- and genderadjusted prevalence of diabetes and diabetic
retinopathy, and correlation of prevalence with
history-based risk factors. The age- and
gender-adjusted prevalence rate of diabetes in
an urban Chennai population was 28.2% (95%
India
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New Leads
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main adverse events are nausea and diarrhea at
the beginning of treatment, which are mild to
moderate and transient. The formation of antiliraglutide antibodies has not been observed.
Dapagliflozin [1-[4-Chloro-3-(4ethoxybenzyl) phenyl]-1-deoxy-
-D-glucopyranose
(1S)-1
,5-anhydro-1-C-[4-chloro-3-(4ethoxybenzyl) phenyl]- D -glucitol (2S, 3R,
4R, 5S, 6R)-2 -[ 4-chloro-3-(4-ethoxybenzyl)
phenyl]-6-(hyd roxymethyl)tetrahydro-2Hpyran-3,4,5-triol-] SGL T2 inhibitor
antidiabetic agent.
Cole P et al.
Drugs of the Future, 33(9): 745-751
(2008)
One potential means of treating diabetes is
via modulation of glucose uptake. A novel
strategy for achieving this is through inhibition
of sodium-dependent glucose transporters
(SGL Ts), which mediate the process by which
plasma glucose filtered in the kidney
glomerulus is reabsorbed. The great majority
of this process of reabsorption is mediated by
SGL T2 and SGL T2 inhibitors have therefore
been sought and identified in order to prevent
renal glucose reabsorption and increase
glucose excretion in urine. The compound that
has advanced the furthest is dapagliflozin,
which demonstrated superior metabolic
stability
compared
to
early
agents.
Dapagliflozin also exhibited potent inhibition
of SGL T2 and selectivity over SGL T1 in
vitro, and was associated with reduced plasma
glucose levels in animal models of diabetes
after acute and chronic dosing. Dapagliflozin
has proven safe and well tolerated in humans,
with pharmacokinetic and pharmacodynamic
variables indicating that daily dosing is
appropriate. Double-blind trials in patients
with type 2 diabetes revealed reductions in
fasting and postprandial glucose, as well as
significant reductions in HbA 1 c.
Dapagliflozin has entered phase III evaluation.
Saxagliptin [(1 S,3S,5S)-2-[2( S)-amino2-(3-hydroxyadamantan-1-yl)acetyl]-2azabicyclo [3.1.0] hexane-3-carbonitrile]
Current R&D Highlights, Jan.-Mar. 2009
dipeptidyl
peptidase
IV
inhibitor
antidiabetic agent.
Cole P et al.
Drugs of the Future, 33(7), 577 (2008)
Targeting glucagon-like peptide 1 (GLP1) is an attractive strategy for the treatment of
type 2 diabetes, as this incretin hormone
enhances postprandial insulin secretion in a
manner dependent on glycemia. Evidence also
indicates that GLP-1 reduces glucagon
secretion, induces satiety, delays gastric
emptying and enhances -cell functio'n
through stimulation of neogenesis and
inhibition of apoptosis. One means of utilizing
this target is by inhibiting its degradation,
which is mediated by dipeptidyl peptidase IV
(DPP IV). Saxagliptin is a DPP IV inhibitor
that has displayed promising preclinical
characteristics, such as dosedependent
clearance of glucose in animal models of
diabetes. Data from clinical trials show
significantly
improved
glycosylated
hemoglobin (HbA1c) and fasting serum
glucose in diabetes patients with saxagliptin
alone and in combination with metformin, and
the agent was well tolerated. Results from
phase III studies are expected to soon provide
a comprehensive view of saxagliptin's role in
the expanding effort to improve the lives of
diabetic patients.
B1-1356 [ 8-[3(R)-aminopiperidin-1-yl]7-(2-butynyl)-3-methyl-1-(4methylquinazolin-2-ylmethyl)xanthine,]
dipeptidyl-peptidase
IV
inhibitor
antidiabetic agent.
Wang Y et al.
Drugs of the Future, 33(6): 473-477
(2008)
BI-1356 is a dipeptidyl-peptidase IV (DPP
IV, or CD26) inhibitor developed at for the
treatment of type 2 diabetes. BI-1356
demonstrated long-lasting DPP IV inhibition
both in vitro and in vivo. In vitro, BI-1356 was
at least 10,000-fold more selective for DPP IV
than for DPP-8 and DPP-9. High potency and
long-lasting inhibitory effects were also
101
New Leads
observed in vivo in' mice and rats, the
inhibition induced by BI-1356 being longer
lasting than that induced by any other DPP IV
inhibitor tested. BI-1356 exhibited nonlinear
pharmacokinetics in healthy volunteers and
patients with type 2 diabetes. Oral BI-1356
administered once daily proved to be well
tolerated in healthy volunteers and patients
with type 2 diabetes. Treatment with BI-1356
increased concentrations of GLP-1 and
reduced concentrations of glucose in patients
with type 2 diabetes, and it also significantly
reduced Hb1Ac in diabetic patients. Phase III
clinical trials are under way.
Taspoglutide--[L-Histidyl-2methylalanyl-L-glutamyl-glycyl-L-threonylL-phenylalanyl-L-threonyl-L-seryl-Laspartyl-L-valyl-L-seryl-L-seryl-L-tyrosylL-Ieucyl-L-glutamyl-glycyl-L-glutaminyl-L
alanyl-Lalanyl-L-lysyl-L-glutamyl-Lphenyl-alanyl-LisoleucylL-alanyl-Ltryptophyl-L-leucyl-L-valyl-L-lysyl-2methylalanyl- L-argininamide ] GLP-1
analogue for the treatment of diabetes.
Arjona A et al.
Drugs of the Future, 33(11): 938-943
(2008)
Incretin agonists and analogues are
receiving increasing attention as potential
antidiabetic agents due to their ability to
stimulate insulin secretion only during
hyperglycemic states. Exploitation of the
incretin effect reduces the risk of rebound
hypoglycemia that accompanies many
antidiabetic treatments. Taspoglutide (R-1583,
BIM-51077, ITM-077) is a long-acting
glucagon-like peptide 1 (GLP-1) analogue that
shows promise for the treatment of type 2
diabetes. In addition to having enhanced
resistance to enzymatic degradation by the
protease dipeptidyl peptidase 4 (DPP4),
clinical studies have shown that taspoglutide
increases insulin levels and lowers glycemia.
Phase II trials have also demonstrated that
weekly administration of a slowrelease
formulation was associated with enhanced
102
New Leads
mg) benfotiamine (150 mg) and benzamine
(850 mg), a proprietary blend of paraaminobenzoic acid (PABA), vitamin E and a.lipoic acid (ALA). Zycose protects vascular,
retinal and kidney function by improving
cellular health and promoting peripheral nerve
health in people with diabetes. Zycose's
therapeutic benefit is believed to be due to the
additive effects of its compounds on lowering
homocysteine levels (folic acid), reducing the
production of advanced glycation end products
(benfotiamine), improving endothelial function
(folic acid, benfotiamine, ALA), reducing
oxidative stress (ALA, vitamin E) and
reducing carbonyl stress (benzamine). The
complex composition of Zycose allows the
therapeutic
intervention
of
several
hyperglycemiamediated
disorders.
The
compound consists mainly of vitamins,
therefore explaining, in part, the good safety
profile and reduced adverse effects.
People with type 2 diabetes have a 2- to 5fold increased risk for cardiovascular mortality
when compared to the nondiabetic population.
The
main
causes
are
accelerated
atherosclerosis, microvascular disease causing
complications
such
as
neuropathy,
nephropathy and retinopathy, as well as a
prothrombotic status. Pathomechanisms of
diabetes are related to hyperglycemia,
hyperlipidemia, hyperinsulinemia, increased
oxidative stress and accelerated aging. An
important role in triggering these changes is
attributed to the endothelium. Endothelial cells
are mainly responsible for the production of
nitric oxide (NO), a key mediator contributing
to vascular health. NO promotes vasodilatation
and has antiatherosclerotic, anti oxidative and
antithrombotic properties. Endothelial NO
results from the transformation of L-arginine
into citrullin and NO by the enzyme NO
synthase (NOS).
AVE-0010[H-His-GIy-Glu-GlyThrPhe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-G
lu-Glu-Glu-Ala-Val-Arg-Leu-Phe-lle-GluTrp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-SerCurrent R&D Highlights, Jan.-Mar. 2009
New Leads
glucagon-like peptide (GLP-1) and glucosedependent insulinotropic polypeptide (GIP),
thus it is a promising target for the treatment of
Type 2 Diabetes mellitus (T2DM). Inhibition
of plasma DPP IV enzyme leads to enhanced
endogenous GLP-1 and GIP activity, which
ultimately results in the potentiation of insulin
secretion by pancreatic beta-cells and
subsequent lowering of blood glucose levels,
HbA[1(c)], glucagon secretion and liver
glucose production.
Various classes of
structurally different DPP IV inhibitors are
currently being explored and few of them such
as Sitagliptin and Vildagliptin were
successfully launched. These drugs have been
approved as a once-daily oral monotherapy or
as a combination therapy with current antidiabetic
agents
like
pioglitazone,
glibenclamide, metformin etc. for the
treatment of T2DM. Several other novel DPP
IV inhibitors are in pipeline. The present
review summarizes the latest preclinical and
clinical trial data of different DPP IV
inhibitors with a special emphasis on their
DPP8/9 fold selectivity and therapeutic
advantages over GLP-1 based approach.
New frontiers in the management of
type 2 diabetes.
Mudaliar Sunder
The Indian Journal of Medical Research
(2007), 125(3), 275-96
.
Type 2 diabetes is a chronic, debilitating
disease characterized by insulin resistance,
impaired
insulin
secretion,
and
hyperglycaemia, and afflicting at least 171
million people worldwide (31.7 million in
India). This chronic disease is not benign and
patients with diabetes suffer from numerous
microvascular
and
macrovascular
complications which cause a lot of morbidity
and mortality. Results from the UKPDS
(United Kingdom Prospective Diabetes Study)
clearly demonstrate that tight glucose and
blood pressure control in patients with type 2
diabetes prevents the development of and
delays the progression of microvascular
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New Leads
must therefore address more than just blood
glucose levels. Novel approaches to the
treatment of type 2 diabetes are now at various
stages of development or regulatory approval.
Exenatide and pramlintide, analogues of gutderived hormones glucagon-like peptide-1
(GLP-1) and amylin, respectively, have
demonstrated improvements in glycaemic
control and bodyweight in clinical studies and
have been recently approved for treatment of
type 2 diabetes. Initial studies have indicated
that agents that activate both peroxisome
proliferator-activated receptor (PPAR)alpha
and gamma improve glycaemic control and
have beneficial effects on lipid profiles. Two
dual PPARalpha/gamma agonists, muraglitazar
and tesaglitazar, are under regulatory review
and in phase III trials, respectively.
Modulation
of
the
endogenous
endocannabinoid system by rimonabant, which
is under regulatory review, has been shown to
improve body weight, atherogenic lipid
profiles and glycaemic control. In addition,
enhanced
understanding
of
the
pathophysiology underlying the microvascular
complications of type 2 diabetes has led to the
development of targeted therapies for
conditions such as diabetic retinopathy,
including the protein kinase C (PKC)antagonist ruboxistaurin, now in phase III
trials. Such therapies should enable physicians
to achieve more for their patients with type 2
diabetes.
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105
Natural Products
Introduction
Since ancient time plants are being used
for their medicinal properties. Natural products
have been the basis of treatment of human
diseases. Many of todays drugs are of plant
origin, e.g., penicillin, morphine and paclitaxel
(taxol), artemisinin etc. Plant derived drugs
have safer side over synthetic drugs as they
show lesser or no side effects. Withania
coagulans Dunal (family Solanaceae), is
reported in Ayurveda for its biological
potentials. It is commonly known as Paneer
ke phool in Hindi and Indian cheese maker
or Vegetable rennet in English, distributed in
drier parts of India [1]. The effective treatment
of diabetes is dependent on active constituents
of medicinal plants capable of controlling
106
Chemical Costituents
Withania coagulans is rich in steroidal
lactones, which are known as withanolides (137). Withanolides are naturally occurring
polyhydroxy C28 steroidal lactones. In the
basic structure of all withanolides six- or fivemembered lactone ring is attached to an intact
or rearranged ergostane skeleton.
Natural Products
dihydroxy-14,20-epoxide-1-oxo-(22R)-witha3,5,24-trienolide (1) [4]. Two withanolides,
14,15-epoxywithanolide
I
[(20S,22R)
17,20-dihydroxy-14,15-epoxy-1-oxowitha-3,5,24-trienolide] (2)
and
17hydroxywithanolide K [(20S,22R) 14,7,20trihydroxy-1-oxo-witha-2,5,24-trienolide] (3) [5,6].
Four withanolides, coagulin B (4), coagulin C (5),
coagulin D (6), coagulin E (7) [7], two withanolides
(steroidal lactones) named coagulin F (27-hydroxy14,20-epoxy-1-oxo-(22R)-witha-3,5,24-trienolide)
(8) and coagulin G (17,27-dihydroxy-14,20epoxy-1-oxo-(22R)-witha-2,5, 24-trienolide) (9) [8],
five
withanolides,
namely
coagulin
H
(17S,20S,22R)-5,6,14,15,17,20hexahydroxy-1-oxowitha-2,24-dienolide
(10),
coagulin
I
(14R,17S,20S,22R)-5,6,17trihydroxy-14,20-epoxy-1-oxowitha-2,24-dienolide
(11), coagulin J (14R,17R,20R,22R)-3,27dihydroxy-14,20-epoxy-1-oxowitha-5,24-dienolide
(12), coagulin K (14R,17R,20R,22R)-14,20-epoxy3-(O--D-glucopyranosyl)-1-oxowitha-5,24dienolide (13), coagulin L (14R,17S,20S,22R)14,17,20-trihydroxy-3-(O--D-glucopyranosyl)[9]
1-oxowitha-5,24-dienolide
(14)
.
Three
withanolides, coagulin M (14R,17R,20,22R)5,6,27-trihydroxy-14,20-epoxy-1-oxo-with
a24-enolide) (15), coagulin N (14R,17S,20,22R)15,17-dihydroxy-14,20-epoxy-3-(O-b-Dglucopyranosyl)-1-oxo-witha-5,24-dienolide) (16),
coagulin O (14R,20,22R)-14,20-dihydroxy-3(O--D-glucopyranosyl)-1-oxo-witha-5,24dienolide) (17) [10]. Three withanolides, coagulin P
(20,27-dihydroxy-3-(O--D-glucopyranosyl)-1oxo-(20S,22R)-witha-5,14,24-trienolide)
(18),
coagulin Q (1,20-dihydroxy-3- (O--Dglucopyranosyl)-(20S,22R)-witha-5,24-dienolide)
(19), coagulin R (3,17-dihydroxy-14,20-epoxy
1-oxo-(22R)-witha-5,24-dienolide) (20) [11]. Three
withanolides,
20-hydroxy-1-oxo-(22R)-witha2,5,24-trienolide (21), withacoagulin (22), and
17-hydroxy-14, 20-epoxy-1-oxo-(22R)-witha3,5,24-trienolide (23) [12]. A withanolide, coagulin
S (24) and dimeric lignan, bispicropodophyllin
glucoside (25) have been isolated from the
ethanolic extract of whole plant of Withania
coagulans [13].
Current R&D Highlights, Jan.-Mar. 2009
107
Natural Products
CH3
H3C
H 3C HO
O
CH3
CH3
HO
CH 3 H
H3 C
H 3C
O
O
CH2 OH
HO
CH 3 H
OH
OH
11 : Coagulin I
HO
12: Coagulin J
CH 3
CH 3
H 3C
H3C H
O
CH3 H
HO
O
HO
HO
H O
O
O
HO
OH
H 3 C OH
H 3C
H O
O
OH
CH 3 H
CH 3
HO
HO
OH
13: Coagulin K
H3 C
O
OH
14: Coagulin L
CH 3 H
CH 3
H 3C
CH 2OH
HO
CH3
H 3C HO
O
O
HO
HO
HO
OH
OH
CH 3 H
HO
OH
O
OH
16 : Coagulin N
CH3
CH3
H3 C OH
H 3C
O
HO
O
HO
H 3C OH
CH 3
H3 C
O
CH 3 H
H
O
OH
17: Coagulin O
108
15: Coagulin M
HO
HO
CH3
H3 C
CH 3
HO
OH
HO
HO
CH 3 H
HO
H
CH 2OH
O
H
O
OH
18: Coagulin P
Natural Products
CH3
H3C OH
H3C
HO
HO
HO
H3C
CH3
HO
H
OH
CH3 H
CH3
CH3 H
H3C OH
CH3
H3C OH
CH3
HO
H
H3 C
O
HO
H
CH3 H
CH2OH
O
22: Withacoagulin
21
CH3
CH3
H3C
H3C HO
O
20: Coagulin R
CH3
CH3 H
HO
19: Coagulin Q
HO
OH
H3C
CH3
H3C HO
CH3 H
H3C OH
CH3
HO
CH3
O
CH3 H
H O
OH
CH2OH
O
O
H
OH OH
OH
OH
23
24:Coagulin S
OH
H3CO
HO
HO
OH
O
O
O
O
O
H3CO
OCH3
OCH3
OCH3
OCH3
O
HO
O
OH
OH
O
HO
109
Natural Products
28
CH 3
H 3C OH
H3C
O
CH 3
HO
OH
CH 3 H
H
OH
24
CH3
26
CH3 H
H
OH
OH
HO
HO
26:3Hydroxy-2,3-dihydro-withanolide F
27:Ergosta-5,25-diene-3,24-diol
CH 3
H 3C OH
H3C
O
CH3
OH
HO
CH3 H
H
HO
HO
OH
CH3 H
HO
O
OH
HO
H
O
28: 3-hydroxy-2,3-dihydrowithanolide H
29: Sitosterol--D-glucoside
CH3
H3 C OH
CH 3 H O
OH
H
CH 3
OH
CH3
H 3C OH
CH 3 H O
OH
H
CH 3
O
CH 3
30: coagulanolide
CH 3
O
OH
OH
31:Withanolide F
CH 3
H 3C OH
CH 3
O
CH 3
HO
CH3 H
H
H 3C H
CH3
O
CH3 H
H
H
O
OH
OH
CH2OH
HO
H
33: Withaferin A
CH3
H 3C H
CH3
O
CH 3 H
H
OH
32
CH 3
CH 2OH
HO
H
H 3C OH
CH 3
CH 3 H
CH3
HO
H
OH
34
35: Withacoagin
CH 3
H 3C OH
CH3
HO
CH 3
CH3 H
H
OH
H 3C H
CH 3
H
O
CH3
O
36
CH3
HO
CH3 H
H
OH
H
O
37
Pharmacology
It has a prominent place in Ayurvedic,
Unani, and ancient Indian systems of
medicine. The berries of the plant are used for
milk coagulation [3]. A number of reports
reveal that the withanolides isolated from
110
Natural Products
levels in streptozotocin induced diabetic rats
after 7 days of treatment (p<0.001). Such lipid
lowering activity in streptozotocin induced
diabetic rats may also help in preventing
associated atherogenesis and other secondary
complications of diabetes mellitus. Its serum
LPO and liver LPO reducing activity suggests
that it may prevent lipid peroxidation and may
protect tissues from free radicals. It also
significantly (p<0.01) decreased blood glucose
level in normal rats (at the dose 1 g/kg; po) [23].
We
have
demonstrated
significant
antihyperglycemic activity in the aqueous
extract of W. coagulans fruits in
normoglycemic as well as in STZ-induced
diabetic rat models at 250 mg/kg po dose level.
We have isolated five withanolides identified
as coagulin C (5), 17-hydroxywithanolide K
(3), withanolide F (31), coagulanolide
[(17S,20S,22R)-14,15,17,20tetrahydroxy-1-oxowitha2,5,24-trienolide]
(30), which is a new compound and coagulin L
(14) from the aqueous extract of its fruits. The
compounds were evaluated for their
antihyperglycemic activity in normoglycemic
rat model (SLM) and in streptozotocin induced
diabetic rat model (STZ) as well as in a well
characterized model of type 2 diabetes, that is,
C57BL/KsJ-db/db mice. Compound 14 was
most active, it was found to improve glucose
tolerance up to the tune of 29.8% in SLM and
23.3% in STZ-induced diabetic rats at a dose
of 100 mg/kg body weight. Compounds 5, 3,
31
and
30
exhibited
significant
antihyperglycemic activity, 22.8%, 20.4%,
24.9% and 28.1% in SLM and 16.9%, 15.8%,
18.2% and 19.3% in STZ, models,
respectively. Compound 14 was further
evaluated in db/db mice. The C57BL/KsJdb/db mice at 12 weeks of age exhibited most
of the human characteristics of type 2 diabetes
including hyperglycemia in the fasting and fed
states, hyperinsulinemia and insulin resistance.
111
Natural Products
References
[1] Kirtikar, K.R., Basu, B.D.; 1995; Indian Medicinal
Plants; International Book Distributors, Dehradune,
India.
112
P.N.,
of
Natural Products
Natural Products
sample collection, preservation, extract
preparation and newer test models. In future,
Bioinformatics is going to play a very
Hwang, C. G.
System and method for modifying a fluid for oral
administration.
ed. (Remote Clinical Solutions, I. U. 2005-US30146
[2006023985], 41-20060302. WO. 8-23-2005.
Marshall, W. S.
IgG Fc-domain peptide conjugates as glucagon
antagonists.
ed. (Amgen Inc., U. 2001-US14321[2001083527], 5420011108. WO. 5-3-2001.
Bosch, H. W.
Novel nanoparticulate nimesulide compositions.
ed. (Elan Pharma International Ltd., I. 2003US32731[2005051356], 87-20050609. WO. 10-312003.
Bosch, W. H.
114
Natural Products
activities; affecting the cardiovascular, immune and
nervous
systems
and
other
miscellaneous
mechanisms of action.
Comp.Biochem.Physiol., Part C: Toxicol.Pharmacol.
140C[3-4], 265-286. 2005.
Urakami, T. et al.
Process for producing oxazopyrroloquinolines, novel
oxazopyrroloquinolines, and use of oxazopyrroloquinolines.
ed. (Mitsubishi Gas Chemical Co., I. J. 90-403176
[429333], 59-19910529. EP. 11-8-1990.
Sato, N.
Health food compositions for prevention and
treatment of obesity.
eds. (Someya, H. J. & Tangolwood K.K.). 2004203833[2006020606], 12-20060126. JP. 7-9-2004.
Van Kaer, L.
Drugs from the sea: A marine sponge-derived
compound prevents type 1 diabetes.
The Scientific World 1, 630-632. 2001
(Compiled byDr. RK Sharma,Botany Division, Central Drug
Research Institute, Lucknow)
Natural Products
source. This was studied by measuring the
contents of total sugar, uronic acid, amino
sugar, and sulfate in the streptozotocin-induced
diabetic rats. Total sugar content decreased in
liver, spleen, and brain, while an increase was
observed in heart and lungs. Uronic acid
content in liver, spleen, and brain decreased,
and marginal increase was observed in testis.
Amino sugar content decreased in liver,
spleen, lungs and heart during diabetes, and
augmentation was observed to different
extents.
Decrease
in
sulfation
of
glycoconjugates was observed in liver, spleen,
lungs and heart during diabetes and was
significantly ameliorated by bitter gourd and
spent turmeric, except brain. Protein content
decreased in liver, while an increase was
observed in brain. The studies clearly showed
alteration in glycoconjugate metabolism during
diabetes and amelioration to different extents
by feeding bitter gourd and spent turmeric.
Improvement is due to slow release of glucose
by fiber in the gastrointestinal track and shortchain fatty acid production from fiber by colon
microbes.
Protective role of arjunolic acid in
response to streptozotocin-induced type-I
diabetes via the mitochondrial dependent
and independent pathways.
Manna, Prasenjit et al.
Toxicology (In Press)
Increasing evidences in both experimental
and clinical studies suggest that oxidative
stress is involved in the pathogenesis of
diabetic tissue damage. Pancreatic [beta]-cell
death is the cause of decreased insulin
production in diabetes. Streptozotocin (STZ) is
widely used to induce experimental diabetes
due to its ability to selectively target and
destroy insulin producing pancreatic [beta]cells via the formation of both reactive oxygen
species (ROS) and RNS (reactive nitrogen
species). This study investigated the
prophylactic role of arjunolic acid (AA)
against STZ-induced diabetes in the pancreas
tissue of the Swiss albino rats (as a working
116
Natural Products
N,N'-methylenebisacrylamide as crosslinker.
The present paper discusses the effect of pH on
swelling kinetics of the hydrogels and release
dynamics of insulin from drug-loaded
hydrogels, for the evaluation of the swelling
mechanism and drug release mechanism from
the
hydrogels.
Non-Fickian
diffusion
mechanism has been observed for the release
of insulin in pH 2.2 buffer and pH 7.4 buffer.
Inhibition of 11[beta]-hydroxysteroid
dehydrogenase type 1 by plant extracts used
as traditional antidiabetic medicines.
Gumy, Christel et al.
Fitoterapia
Elevated glucocorticoids are a key risk
factor for metabolic diseases, and the
glucocorticoid-activating enzyme 11[beta]hydroxysteroid dehydrogenase 1 (11[beta]HSD1) represents a promising therapeutic
target. Authors have measured the potential of
six traditional antidiabetic medicinal plants
extracts to inhibit 11[beta]-HSD1 activity and
glucocorticoid receptor (GR) activation in
transfected HEK-293 cells. Leave extracts of
Eriobotrya japonica preferentially inhibited
11[beta]-HSD1 over 11[beta]-HSD2. Extracts
of roasted but not native coffee beans
preferentially inhibited 11[beta]-HSD1 over
11[beta]-HSD2, emphasizing the importance
of sample preparation. Thus, natural
compounds inhibiting 11[beta]-HSD1 may
contribute to the antidiabetic effect of the
investigated plant extracts. (ScienceDirect)
Antihyperglycemic
and
insulin
secretory activity of Costus pictus leaf
extract in streptozotocin induced diabetic
rats and in in vitro pancreatic islet culture.
Gireesh, G. et al.
Journal of Ethnopharmacology
The leaves of Costus pictus D Don were
used extensively for its anti hyperglycemic
activity by the people in Kerala, India. In the
present study, the antihyperglycemic and
insulin secretory activity of an aqueous extract
of Costus pictus leaf extract was investigated
in streptozotocin induced diabetic rats. Oral
Current R&D Highlights, Jan.-Mar. 2009
Natural Products
hemoglobin (HbA1c), hepatic glycogen, and
activities of carbohydrate metabolizing
enzymes, such as glucokinase, glucose 6phosphatase, fructose 1,6-bisphosphatase and
glucose-6-phosphate
dehydrogenase
and
hepatic marker enzymes, such as aspartate
aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP)
and gammaglutamyl transferase (GGT) in
normal and streptozotocin-diabetic rats. 3-
Place of Publication
: Lucknow
2.
: Bi-Monthly
3.
Printer's Name
(Whether citizen of India?)
Address
4.
Publisher's Name
(Whether citizen of India?)
Address
5.
Editor's Name
(Whether citizen of India?)
Address
6.
I, Dr. Sheela Tandon, hereby declare, that the particulars given above are true to the best of my
knowledge and belief.
Dated: 31.03.2009
Signature of Publisher
NOT TO BE RETURNED TO THE PRESS REGISTRAR
118
Biotechnology
GAD/ICA positivity and/or high-titer antiGAD was found to correlate with an early age
of onset, reduced -cell function, the presence
of other autoimmune disorders, fewer markers
of metabolic syndrome (high body mass index,
hypertension, dyslipidemia) and increased
frequency of high-risk diabetes type 1associated HLA class II alleles (discussed
below).
Clinical Symptoms
As mentioned earlier, LADA shares
metabolic features with type 1 and type 2
diabetes. Thus, type 2 diabetes and LADA
patients have been shown to present with a
similar degree of insulin resistance and
elevated glucagon levels, but the latter exhibit
severe and progressive defects in -cell
function, hence resembling type 1 diabetes.
However, unique clinical features may be
associated with this form of diabetes.
Fourlanos et al. found that, compared to
patients with type 2 diabetes, most patients
with LADA exhibited at least two of the
following five clinical parameters: 1) age of
onset < 50 years; 2) acute symptoms; 3) body
mass index (BMI) < 25 kg/m2; 4) personal
history of autoimmune disease; or 5) family
history of autoimmune disease. Moreover, the
presence of at least two of these features at
diagnosis had a sensitivity and specificity for
LADA detection of 90% and 70%,
respectively. Alternatively, the presence of less
than two distinguishing clinical parameters
resulted in a negative predictive value of 99%,
hence representing a highly reliable method for
excluding the disease. When compared to type
1 diabetes patients, LADA subjects have been
119
Biotechnology
noted to show higher BMI, elevated
triglycerides and HDL cholesterol, greater
insulin resistance, as well as greater plasma Cpeptide concentrations, an indicator of insulin
production by -cells.
The criterion of insulin independence in
LADA can be rather subjective and may
depend on insulin-prescribing trends, among
other factors. A recent study showed that the
time to insulin treatment depended on whether
autoantibody testing was performed or not,
thus being shorter in those centers that
routinely performed laboratory tests for
diabetes-associated autoantibodies.
Pathophysiology of LADA
The loss of tolerance to self-antigens
present in insulin-secreting -cells in
pancreatic islets appears to be the underlying
pathogenic process in LADA, as well as in
type 1 diabetes. However, both LADA and
type 1 diabetes present with specific
serological markers. The four islet antibody
subtypes, namely ICAs, GAD antibodies,
insulinoma antigen 2 (IA-2) antibodies and
insulin autoantibodies, are also present in type
1 diabetes, whereas IA-2 and insulin
autoantibodies are rarely seen in LADA
patients. Detection of ICAs and GAD
antibodies is thus key in the diagnosis of
LADA. The enzyme GAD has two isoforms,
GAD65 and GAD67, which catalyze the
formation of -aminobutyric acid (GABA) in
neurons and pancreatic Langerhans islets. The
GAD65 isoform appears to be particularly
important in the detection of type 1 diabetes,
since it is found in up to 80% of patients and is
considered a predictive marker. GAD65 antibodies appear to bind specific epitopes
comprised in the N-terminal region of the
GAD enzyme (the membrane anchoring site),
according to a study in patients with "slowly
progressive type 1 diabetes". In contrast,
GAD65 antibodies from the sera of type 1
diabetes patients did not react with this
specific N-terminal site.
120
Genetics
Similarly to what occurs in type 1
diabetes, certain HLA class II genes appear to
be associated with higher LADA risk.
Particularly, HLA DR3 and/or DR4 and DQ2
and/or DQ8 are the highest-risk HLA alleles
for type 1 diabetes, which have also been
found in LADA patients, hence suggesting a
similar genetic basis. For instance, LADA and
type 1 diabetes patients exhibited an increased
prevalence of the high-risk HLA-DQB1*0302,
-DR4, -D3 and -DR3/DR4 genotypes and the
high-risk DR3/DR4-DQB1*0302 haplotype
compared
to
a
control
population.
Interestingly, another study evaluating the
genotypes of patients with LADA and
nondiabetic individuals found that DR4
antigen specificity subtypes may confer a
differential risk for LADA, with DRB1*0401
and DRB1*0403(06/07) being predisposing
and protective, respectively. Besides HLA
genes, LADA has also been associated with
other genetic factors. Thus, variations in the
variable number of tandem repeats (VNTR)
minisatellite upstream of the insulin gene
region 100M2, which accounts for about 10%
of familial risk for type 1 diabetes, have also
been
significantly
associated
with
susceptibility to LADA. However, these
genetic variations did not help to distinguish
between type 1 diabetes and LADA. Also,
outside the HLA region, the tyrosine-protein
phosphatase non-receptor type 22 gene
(PTPN22) encoding a lymphoid-specific
Current R&D Highlights, Jan.-Mar. 2009
Biotechnology
phosphatase known as LyP, which is a
powerful inhibitor of T-cell activation, has
been identified with type 1 diabetes in young
subjects. A recent study has demonstrated an
association between the PTPN22 C1858T gene
polymorphism and patients with adult-onset
diabetes and high GAD antibody titers,
compared to those with low antibody titers,
type 2 diabetes and a control population. Other
authors have encountered a higher frequency
of the C1858T gene polymorphism in LADA
patients compared to type 1 diabetes and
nondiabetic subjects. The PTPN22 C1858T
gene variant has also been linked to other
autoantibody-producing autoimmune diseases.
A recent study confirmed these findings
and showed that LADA shared genetic features
with type 1 diabetes, namely associations with
HLA-DQB1, insulin gene (INS) VNTR and
PTPN22, but LADA patients also presented
with a variant of the transcription factor 7 -like
2 (TCF7L2) gene, which is strongly associated
with type 2 diabetes. The authors concluded
that these results support the hypothesis that
LADA is a combination of type 1 and type 2
diabetes, rather than just a form of type 1
diabetes. Another study investigated the
potential relationship of LADA with cytokine
genes involved in the pathogenesis of other
autoimmune disorders and found an increased
frequency in the interleukin 1L10-1082A1G
gene variant in LADA compared to type 2
diabetics. Other studies have shown
associations of LADA with insulin resistance
genes (lRS1, IRS2) and vitamin D receptor
(VOR) gene polymorphisms.
Treatment
In general, the treatment of LADA, as
well as the major diabetes types, is aimed at
providing optimal glycemic control and
preserving -cell function. However, it is not
121
Biotechnology
Table 1: Summary of Therapeutic Strategies in LADA
Drug
Design
Treatments
Rosiglitazone
Randomized
Rosiglitazone,
Unblinded
Human
recombinant
GAD65
mg/d
Conclusions / Objectives
23
Insulin,
160
Randomized
Human recombinant
Double-blind
safety
1 and 4 Placebo
and
efficacy
of
DiamycfID
Randomized
Double-blind
Human recombinant
47
This
randomized,
double-blind,
dose-
at wks 1 and 4
Placebo
DiaPep277
Randomized
DiaPep277,
Double-blind
Placebo
s.c.
100
(Based on the article written by E. Ferrer, C. Dulsat and published in Drugs of the Future 2008, 33(11): 963-967)
122
Patents
herb
composition
for
the
123
Patents
Bicyclic pyrazolo protein kinase
modulators
Bounaud , et al.
SGX Pharmaceuticals, Inc. San Diego,
California, US
US Patent 7,473,783 January 6, 2009
Appl. No. 11/016,126 December 17, 2004
The invention provides novel bicyclic
pyrazolo kinase modulators and methods of
using the novel bicyclic pyrazolo kinase
modulators to treat diseases mediated by
kinase activity.
Pyrazole compounds useful as protein
kinase inhibitors.
Davies; Robert , et al.
Vertex Pharmaceuticals Incorporated
Cambridge, Massachussetts, US
US Patent 7,473,691 January 6, 2009
Appl. No.: 09/952,875 September 14, 2001
This invention describes novel protein
kinase inhibitors of formula are useful for
treating diseases such as cancer, diabetes and
Alzheimer's disease.
Metastable benzoxepne derivatives
which can be used in the treatment of
dyslipidaemia atherosclerosis and diabetes,
pharmaceutical compositions comprising
them and processes for the preparation
thereof..
Bosc; Nathali et al.
Merck
Patent
GmbH
,Darmstadt,
Germany
US Patent 7,470,719 December 30, 2008
Appl. No.: 10/530,571 September 1, 2003
The present invention relates to novel
metastable derivatives of benzoxepines of the
formula (I) in which n represents 0, 1 or 2; and
the radicals R, which may be identical or
different, are alkyl or alkoxy groups, or
halogen atoms, which can be used in the
treatment of dyslipidaemia, atherosclerosis and
diabetes.
Proteins in type 2 diabetes.
Hojlund; Kurt et al.
Pride Proteomics A/S ,Odense M,
124
Denmark
US Patent 7,470,542 December 30, 2008
The invention relates to the use of
naturally occurring compounds and derivatives
thereof as markers for predisposition of
diabetes related diseases. The invention also
relates to a pharmaceutical composition for
treatment of the diabetes related diseases.
Use of gp130 activators in diabetic
neuropathy.
Dreano; Michel, et al.
Laboratoires
Serono
SA
,Vaud,
Switzerland
US Patent 7,465,441 December 16, 2008
Appl. No.: 10/492,087 October 10, 2002
The invention relates to the use a
substance signaling through gp130 for the
manufacture of a medicament for the treatment
and/or prevention of diabetic neuropathy. The
use of IL-6 is preferred.
System and method for evaluating
impaired glucose tolerance and diabetes
mellitus within a patient using an
implantable medical device.
Bharmi; Rupinder et al.
Pacesetter, Inc., Sylmar, California, US
US Patent 7,462,150 December 9, 2008
Appl. No.: 11/450,937 June 9, 2006
Techniques are described for use by a
pacemaker or implantable cardioverter/
defibrillator (ICD) or other implantable
medical device. The techniques are provided
for evaluating the likelihood that the patient, in
which the device is implanted, has impaired
glucose tolerance (IGT) or diabetes mellitus.
Briefly, a value representative of sleep quality
of the patient is detected and then the
likelihood that the patient has IGT or diabetes
mellitus is determined based on the sleep
quality value. In this regard, it has been found
that a decrease in overall sleep quality is
associated with an increased likelihood of IGT
or diabetes mellitus, which is in turn
associated with an increased risk of mortality.
Hence, sleep quality may be used as a proxy
for evaluating the likelihood that the patient
Current R&D Highlights, Jan.-Mar. 2009
Patents
has IGT or diabetes mellitus and for assessing
associated mortality risk.
Treatment of diabetes with copper
binding compounds
Baker; John Richard et al.
US Patent 7,459,446 December 2, 2008
Appl. No 11/023,827 December 28, 2004
Novel methods of treating a patient for
diseases, disorders, and conditions including
diabetes mellitus, comprising administering,
for example, copper binding compounds.
Substituted carboxylic acid derivatives
for the treatment of diabetes and lipid
disorders, their preparation and use
Choi; Yong Moon et al
SK Holding Co., Ltd., Seoul, Korea
US Patent 7,456,293 November 25, 2008
Appl. No 11/391,031 March 28, 2006
The invention is concerned with racemic
or enantiomerically enriched substituted
carboxylic
acids
and
derivatives
or
pharmaceutically acceptable salts thereof. The
present invention also includes pharmaceutical
compositions comprising an effective amount
of a compound of Formula 1 in admixture with
a pharmaceutically acceptable carrier or
excipient. The compositions may include
additional therapeutic agents for combination
therapy. The present invention provides a new
class of pharmaceutically active compounds,
which are useful in the treatment and control
of diabetes and its related metabolic diseases.
Cyclohexylglycine
derivatives
as
dipeptidyl peptidase inhibitors for the
treatment or prevention of diabetes.
Edmondson; Scott D. et al
Merck & Co., Inc.,Rahway, New Jersy,
US
US Patent 7,456,204 November 25, 2008
Appl. No 10/560,771 June 10, 2004
The present invention is directed to novel
cyclohexylglycine derivatives which are
inhibitors of the dipeptidyl peptidase-IV
enzyme ("DP-IV inhibitors") and which are
useful in the treatment or prevention of
Current R&D Highlights, Jan.-Mar. 2009
Patents
species or an extract thereof, at least one
Artemisia species or an extract thereof, and an
extract of at least one Morus species, wherein
this extract is prepared of morus leaves and
comprises morus latex further are disclosed
methods for the preparation of these
compositions, uses thereof in treating and /or
preventing diabetes, related conditions and
hypertriglyceridemia, as well as methods of
treating subjects suffering from these
conditions.
Biomarkers
for
pre-diabetes,
cardiovascular
diseases,
and
other
metabolic-syndrome related disorders and
methods using the same.
Hu, Yun, Fu;
Metabolon, Inc.; Capitola, Durham, North
Carolina, US
WO/2009/014639 Application No.PCT/
US2008/008756 Publication Date:29.01.2009
Filing Date:17.07.2008
Biomarkers relating to insulin resistance,
pre-diabetes, type-2 diabetes, metabolic
syndrome,
atherosclerosis,
and
cardiomyopathy are provided, as well as
methods for using such biomarkers as
biomarkers for insulin resistance, pre-diabetes,
type-2
diabetes,
metabolic
syndrome,
atherosclerosis, and cardiomyopathy. in
addition, methods for modulating the
respective disorders or conditions of a subject
are also provided also provided are suites of
small molecule entities as biomarkers for
insulin resistance, pre-diabetes, type-2
diabetes, metabolic syndrome, atherosclerosis,
and cardiomyopathy.
Herbal formulations for controlling
blood glucose levels in patients with
diabetes.
ATP Marketing & Promotion AG Niederumen, Switzerland
WO/2009/024175 Application No.: PCT/
EP2007/007426 Publication Date:26.02.2009
Filing Date:21.08.2007
The present invention relates to herbal
formulations for controlling blood glucose
126
Patents
A method for treating diabetes.
Mclane, Michael et al.
Genaera Corporation, Campus Drive,
Plymouth Meeting, Pennsylvania, US
WO/2009/032321 Application No.:PCT/
US2008/010455 Publication Date:12.03.2009
Filing Date:08.09.2008
This application is directed to the use of
steroid compounds for the selective inhibition
of the enzyme ptp1b in a mammal for the
treatment of diabetes.
Therapeutic agent for type-2 diabetes.
Ishii, Shinichi et al.
Mitsubishi Tanabe Pharma Corporation
Osaka, Japan.
WO/2009/011420 Application No.: PCT/
JP2008/063008 Publication Date:22.01.2009
Filing Date:18.07.2008
Disclosed is a medicinal agent comprising
ursodeoxycholic acid or a pharmacologically
acceptable salt thereof as an active ingredient,
which can be act as a therapeutic agent for
type-2 diabetes accompanied by fatty liver or
liver dysfunction.
The use of compounds such as
pyridoxal derivatives for the treatment of
diabetes or diseases associated with the
metabolic syndrome.
Erlinge, David et al.
Strom and Gulliksson AB, Malmo,
Sweden
WO/2009/005469 Application No.: PCT/
SE2008/050831 Publication Date:08.01.2009
Filing date:03.07.2008
The invention relates to compounds
having the general formula (i), (ii) or (iii), and
which are useful for the treatment or
prevention of diabetes or diseases associated
with the metabolic syndrome.
Biomarkers for diabetes, obesity,
and/or hypertension.
Hancock, William, S et al.
Northeastern
University,
Boston,
Massachusetts, US
WO/2009/006568 Application No.:PCT/
Current R&D Highlights, Jan.-Mar. 2009
Patents
US2008/067725 Publication Date:24.12.2008
Filing Date:20.06.2008
A simulation environment for in silico
testing of monitoring methods, open-loop and
closed-loop treatment strategies in type 1
diabetes
some
exemplary
principal
components of the simulation environment
comprise, but not limited thereto, the
following: 1) a 'population' of in silico
'subjects' with type 1 diabetes in three age
groups; 2) a simulator of cgm sensor errors; 3)
a simulator of insulin pumps and discrete
insulin delivery; 4) an interface allowing the
input of user-specified treatment scenarios;
and 5) a set of standardized outcome measures
and graphs evaluating the quality of the tested
treatment strategies these components can be
used separately or in combination for the
preclinical evaluation of open-loop or closedloop control treatments of diabetes.
Method for monitoring diabetes insulin
therapy.
Chuvashov, Vladimir Dmitryevitch et al.
Petersburg, Russia
WO/2009/031943 Application No.:PCT/
RU2008/000577 Publication Date:12.03.2009
Filing Date:25.08.2008
The invention relates to medicine, in
particular to endocrinology, more specifically
to the monitoring of insulin therapy of patients
suffering from diabetes. the method for
monitoring diabetes insulin therapy is based on
the measurement of a glucose concentration in
128
CDRI Publications
Satyendra;
Mehrotra,
Nitin;
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(Based on the information available in Annual reports of C.D.R.I.
Occurance of any error or omission may kindly be ignored.
Compiled by: Wamiq F. Rahman)
132