Research
Highlights 2002-2003
JDRFI
Annual Board Meeting
Complications
The
devastating complications suffered by type 1 patients — kidney
failure, adult blindness, non-traumatic amputations — occur
in patients with type 2 diabetes as well. In the United States
alone, these conditions affect an estimated 17 million people,
with an additional one million cases diagnosed each year.
With the well-documented increase in obesity, a cause of type
2 diabetes, this number is expected to rise dramatically in
the next two decades. The widespread prevalence of diabetes
and its complications makes for heavy financial burdens: The
disease accounts for 25 percent of all Medicare expenditures.
Best estimates put the annual cost of diabetes at slightly
more than $100 billion dollars in the U.S, and these costs
are expected to rise in the future.
Preventing
Organ Damage
Vascular
Disease
With
JDRF funding, a team headed by Michael Brownlee, M.D., at
Albert Einstein College of Medicine in New York, and collaborators
at three universities in Germany have found a drug that may
prove effective against many diabetes-related complications.
In preliminary research, the drug, benfotiamine, a synthetic
derivative of the dietary supplement thiamine (vitamin B1)
was found to block
three major biological mechanisms or “pathways” that lead
to the vascular damage associated with eye, kidney, and nerve
complications in diabetes. As the first drug with the potential
to block multiple pathways leading to complications, benfotiamine
could have a significant impact on a wide range of complications
in both type 1 and type 2 diabetes. The drug next will be
tested in human clinical trials.
Hammes
HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J,
Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino
I, Brownlee M.
Benfotiamine blocks three major pathways of hyperglycemic
damage and prevents experimental diabetic retinopathy.
Nat Med. 2003 Mar;9(3):294-9.
Retinopathy
Drugs
in Clinical Trials
Novartis
is testing somatostatin analog sandostatin LAR (octreotide
acetate) in Phase III clinical trials for diabetic retinopathy
in the United Kingdom. The purpose of the drug is to delay
progression of retinopathy including proliferative retinopathy.
Bausch
and Lomb is
in Phase III trials with fluocinolone acetonide implant,
which is placed directly into the eye and infuses to the
affected area for up to three years. The company partnered
with Control Delivery Systems to develop the implant.
Eli
Lilly currently,
has in Phase II/III trials a type of drug known as a "PKC
inhibitor”—so-called because it inhibits an enzyme, protein
kinase C beta (PKC-beta), which starts a chain of events
that leads to the type of blood vessel damage associated
with retinopathy.
Other
Retinopathy Advances
The cells that help maintain and protect the walls of small
blood vessels are called pericytes. In people with diabetes,
pericytes in the retina are commonly destroyed, with many
of these patients later diagnosed with diabetic retinopathy.
An international team of researchers wanted to find out whether
pericyte loss actually contributes to diabetic retinopathy
or is merely an unrelated phenomenon. They conducted experiments
with a strain of mice lacking half the gene for a growth factor,
PDGF-B, which promotes pericyte recruitment to the small vessel
wall during their development; as a result these animals have
fewer pericytes. The researchers induced retinopathy in these
pericyte-deficient mice and in normal mice to see if a shortage
of pericytes led to more severe forms of the condition. They
found that mice with a pericyte deficiency developed twice
as many blocked blood vessels as did normal mice, suggesting
that pericyte deficiency does contribute to diabetic retinopathy.
This raises the possibility that treatments aimed at helping
pericytes survive might delay or prevent diabetic retinopathy.
The scientific team, from six institutions in five
countries, includes JDRF-funded researcher, Michael Brownlee,
M.D.
Pericytes and the pathogenesis
of diabetic retinopathy.
Diabetes. 2002 Oct;51(10):3107-12.
Research by a JDRF-funded scientist supports the concept that
much of the eye damage caused by diabetic retinopathy occurs
early in the course of the disease, soon after exposure to
high blood glucose levels begins. Renu Kowluru, Ph.D., of
the Kresge Eye Institute at Wayne State University, found
that levels of two agents, nitric oxide synthase and nitrotyrosine,
are elevated by high glucose after a period of poor glycemic
control, and remain high for at least six months after good
glucose control is restored. The finding implicates oxidative
stress and nitrative stress (as measured by levels of nitric
oxide synthase and nitrotyrosine) in the development of diabetic
retinopathy.
Further,
Dr. Kowluru suggests that the duration of poor control before
the initiation of good control influences the outcome of the
reversal. The research, reported in the March issue of the
journal Diabetes, was conducted with diabetic rats
but the same principles are thought to apply to humans with
diabetes.
Effect
of reinstitution of good glycemic control on retinal oxidative
stress and nitrative stress in diabetic rats.
Diabetes. 2003 Mar;52(3):818-23.
Neuropathy
Clinical Trials
Autonomic
Neuropathy:
The
JDRF
Center for Complications in Diabetes at the University of
Michigan, led by Eva
Feldman, M.D., Ph.D., has
recently begun a pilot clinical trial to test combinations
of anti-oxidant therapies to prevent diabetic autonomic neuropathy.
The rationale behind this strategy is that most tested single
therapies have not been successful when given alone. The investigators will use a combination of powerful anti-oxidants,
each of which is known to intervene at different points in
the oxidative stress pathway that contributes to the pathogenesis
of diabetes complications.
Neurobiological
Technologies, Inc.
of Richmond, California, is investigating the use of Memantine
for painful peripheral neuropathy—chronic pain related to
damaged peripheral nerves—in people with diabetes. Memantine
appears to restore the function of damaged nerve cells and
block abnormal signals to the brain by modulating a receptor
on nerve cell membranes.
Memantine has been used for other treatments in the past,
but not approved for neuropathy. Ongoing Phase II-b trials
conducted by the company indicate that it could be effective
against this condition; new data reflecting this will be available
in April. Neurobiological Technologies, Inc. anticipates completion
of a second clinical trial testing Memantine soon. Because
Memantine has been prescribed for a number of other uses in
the past, a large amount of safety data already exist, which
could speed the transition to market.
At a recent scientific meeting, the drug company Eli Lilly
presented encouraging
results from a Phase II human clinical trial in
which a compound called LY333531 positively impacted nerve
function and sensory symptoms present in diabetic neuropathy,
including tingling or numbness. The
company is now recruiting patients for Phase III studies and
also preparing Phase III trials for this PKC inhibitor for
diabetic retinopathy and diabetic macular edema.
Other
Advances
Neurovascular
Research:
Researchers
in California, Germany, and Japan found evidence in embryonic
mice that sensory nerves help guide arteries as they grow
and diverge. The scientists, at the California Institute of
Technology, the Max Delbruck Center for Molecular Medicine
in Germany, and the University of Tokyo, state that nerve
cells and/or Schwann cells (which wrap around nerve cells
to provide insulation) apparently provide a template that
determines the pattern of branching the developing vessels
will follow as they form. The nerve and/or Schwann cells do
this by secreting vascular endothelial growth factor (a protein
that helps vessels grow) at specific sites as the embryo develops,
spurring vessel growth at those locations. The researchers
also showed that disrupting the formation of nerve or Schwann
cells (by knocking out certain genes) also can prevent or
disrupt artery formation. These findings add weight to the
growing evidence demonstrating links between improper function
of blood vessels and malfunctioning nerves. This finding may
have important implications for the study of diabetic neuropathy.
Sensory nerves determine the
pattern of arterial differentiation and blood vessel branching
in the skin.
Cell. 2002 Jun 14;109(6):693-705.
Nephropathy
Biostratum,
Inc. of Durham, North Carolina, is developing a drug for diabetic
nephropathy (kidney disease) that is taken in the form of
a daily pill. The drug, Pyridorin,
inhibits the formation of harmful Advanced Glycation Endproducts
(AGEs), which interfere with cell function, damage small blood
vessels, and can eventually cause the kidney to fail. Pyridorin
is in Phase II-b clinical trials for this complication, and
was recently granted “Fast
Track” status by the FDA. (Phase
II-b trials are well-controlled trials to evaluate safety
and efficacy in patients who have the disease or condition
to be treated, diagnosed or prevented. These trials usually
represent the most rigorous demonstration of a medicine's
efficacy.) Pyridorin also has shown some effectiveness in
mouse models against both retinopathy and neuropathy.
Other Nephropathy Advances
A drug that had shown promise in blocking progression of diabetic
neuropathy (nerve damage) and retinopathy (eye disease) in
human clinical trials now shows promising results in blocking
nephropathy (kidney disease) as well. In rodents with diabetes,
the drug, LY3333531, slowed kidney damage even though the
animals had high blood glucose and high blood pressure --
two conditions brought on by the development of diabetes.
The drug is a "PKC inhibitor" because it inhibits
an enzyme, protein kinase C beta (PKC-beta), which starts
a chain of events that leads to the type of blood vessel damage
associated with nephropathy, neuropathy, and retinopathy.
The latest study was funded by JDRF and led by Richard E.
Gilbert, M.D. Ph.D., at the University of Melbourne, in Victoria,
Australia. JDRF funded early research on PKC's role in damaging
small blood vessels, conducted by George King, M.D. professor
of medicine at Harvard Medical School.
Scientists at the University of Valencia in Spain and Northwestern
University discovered an early warning sign for diabetic nephropathy.
Normally, a person’s systolic blood pressure dips slightly
overnight before rising again in the morning hours. However,
many patients with type 1 diabetes do not show this overnight
drop. The researchers found that type 1 patients whose blood
pressure did not dip during nighttime were more likely to
develop a condition called microalbuminuria-accumulation of
the blood protein albumin in the urine, which is an early
indicator of nephropathy. They suggest that the higher level
of nighttime blood pressure may play an important role in
the development of diabetic nephropathy and may serve as the
earliest indicator that someone with type 1 diabetes is at
high risk for the condition.
Increase
in nocturnal blood pressure and progression to microalbuminuria
in type 1 diabetes.
N
Engl J Med. 2002 Sep 12;347(11):797-805.
High levels of glucose in the blood lead to the formation
of harmful products called Advanced Glycation Endproducts
(AGEs), which cause damage to the vulnerable small blood vessels
that feed the kidneys. High blood pressure speeds up the damage
to these vessels and the kidney in general, so drugs used
for this condition are encouraged to prevent or delay kidney
disease.
One type of blood pressure drug known as an Angiotensin-Converting
Enzyme (ACE) inhibitor has been shown in studies to
slow the progression of kidney disease significantly in patients
with type 1 diabetes. The ACE inhibitors interrupt a key
biological pathway called the renin-angiotensin system (RAS),
which helps regulate blood flow by constricting and relaxing
the vessels. While researchers knew
ACE inhibitors helped against diabetic nephropathy, they were
uncertain of the exact mechanism.
A team of researchers in Melbourne, Australia, tested the
effect of one ACE inhibitor, ramipril, on the formation of
AGEs in rats with diabetes. The scientists found that ramipril
stops the buildup of AGEs in the animals. The rats also had
far less damage to their kidneys. The results suggest that
diabetic nephropathy is caused partly by some kind of link
between RAS and AGEs, so that interfering with RAS will affect
production of AGEs.
Although the present finding relates to animal models,
the team is now measuring AGEs in the blood of people with
diabetes who take ACE inhibitors to see if their AGE levels
are lower in those who do not.
Forbes JM, Cooper ME, Thallas V, Burns WC, Thomas MC, Brammar
GC, Lee F, Grant SL, Burrell LA, Jerums G, Osicka TM.
Reduction
of the accumulation of advanced glycation end products by
ACE inhibition in experimental diabetic nephropathy.
Diabetes. 2002 Nov;51(11):3274-82.
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