Category Archives: Diabetes News

Diabetic
neuropathy, or nerve damage, is one of the most painful complications faced
by people with diabetes.  Over time, high
blood sugar associated with diabetes may lead to nerve damage.  In the legs and feet, this nerve damage
frequently results in numbness or lack of sensation, but it can also lead to
intense pain.  Until now, researchers
have not understood exactly why nerve disease leads to this pain, which is difficult
to treat and can negatively affect a person’s quality of life.

Now, a new study has discovered one cause of pain for people
with nerve damage from diabetes.  The results
of the study, funded in part by JDRF through a center
grant and conducted by an international collaboration of researchers
including Dr.
Michael Brownlee and the late Dr. Angelika Bierhaus,
were published in the journal Nature Medicine.  In the study, conducted in mice, the researchers
found that a molecule called methylglyoxal (MG), which is produced
excessively from glucose in people with diabetes, contributes to the pain.  In the mice in the study, the excess MG bound
to a protein called Nav 1.8, which is found in a specific type of nerve cell
responsible for the sensation of pain. 
When this bond occurs, the nerve becomes locked in the “on” position,
resulting in the feeling of pain that accompanies nerve damage in people with
diabetes.

Since researchers now better understand what causes the
severe pain associated with diabetic neuropathy, they can use that knowledge to
develop new treatments.  According to Dr.
Brownlee, the study “opens the way for new diabetic neuropathy treatments
targeting methylglyoxal accumulation.” 
One possible approach is to regulate an enzyme called glyoxalase 1,
which may be able to prevent or remove the modifications caused by MG and
therefore eliminate the pain.  According
to Dr. Helen Nickerson, JDRF’s senior scientific program manager for treatment
therapies, “better understanding the role of methyglyoxal could lead to
potential therapy for more than one complication of diabetes.”

This study highlights one of the approaches JDRF is taking
in its research strategy
to prevent complications.  This
approach is to identify pathways triggered by high glucose levels over time
that eventually lead to complications, and attempt to intervene in the process
as early as possible to prevent them.

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Recently, the Wall Street Journal published an article about matching patients with their ideal clinical trials, which focused on the growing trend of patient advocacy groups and their efforts to encourage clinical trial participation.  In addition to featuring programs being implemented by the Michael J. Fox Foundation for Parkinson’s Research and the Alzheimer’s Association, it also briefly mentioned JDRF’s program that many people with type 1 diabetes may already know about.

The Clinical Trials Connection (CTC) was started in 2009 as a way to connect people affected by type 1 diabetes (T1D) with up-to-date research progress and clinical trial opportunities.  Similar to an online dating service, CTC enables people to search the clinicaltrials.gov database of trials (including JDRF-funded trials) that involve diabetes cures and treatments to get information, make comparisons, and – if they are interested – directly contact trial centers. 

To get started on CTC, a person with T1D or a friend or loved one can register at trials.jdrf.org and provide basic information such as current age, age at diagnosis, and the area in which they would like to find a trial.  Through this web site, people can provide criteria like the type of trial they are interested in, how long they have had diabetes, and how far they'd be willing to travel, and the site will let them know about studies that match those characteristics.  The site also offers flexibility by allowing the searcher to look for clinical trials on behalf of a loved one with T1D, or look for a clinical trial for him or herself, even if they don’t have T1D. 

The idea of using the internet to find clinical trials is not new.  Clinicaltrials.gov, hosted by the United States National Library of Medicine, an arm of the National Institutes of Health, has been in existence online since 2000 and provides information on all clinical trials from its registry of over 90,000 studies.  However, CTC takes the vast, and often times daunting world of clinical research, and pares it down to the information that is most important for people with T1D.

Human clinical trials are a critical phase toward the development for a drug or therapy before becoming available to the market. Participants in clinical trials not only stand to reap any potential benefit offered by the therapy, they are also helping to pave the way for new drugs, therapies and ultimately a cure for T1D.

Since its beginning, CTC has found an audience that is ready and eager to take part in clinical trials.  Support for the website has been strong since its inception, and the number of registered users continues to grow as more people become aware of the importance of participating in a clinical trial, and are eager to make a difference in their lives and the lives of others with T1D.

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An oral treatment of harmless, specially engineered gut
bacteria was able to reverse type 1 diabetes (T1D) in experimental mice,
according to a partially JDRF-funded study in Belgium. The findings, which were recently published in the April edition of
the Journal of Clinical Investigation,
may hold implications for future translation of the treatment to people with
the disease, which has no known cause or cure.

The international, collaborative team, led by Chantal
Mathieu, M.D. at Belgium’s KU Leuven and ActoGenix, a biopharmaceutical company,
treated the mice with ActoBiotic therapy—genetically modified Lactococcus lactis—which secreted an
autoantigen called proinsulin, and an immune-modulatory protein molecule called
interleukin-10 (IL-10), an anti-inflammatory protein molecule with suppressive
effects in preventing autoimmune disease. When combined with a low dose of an
anti-CD3 antibody for five days, the therapy halted T1D progression in the newly-diagnosed,
non-obese diabetic (NOD) mice. CD3 is a protein required for T-cell activation.
T-cells are immune cells that are involved in the destruction of beta cells in
the pancreas during the autoimmune process of T1D.

Three months of follow-up after the mice were given the
ActoBiotic treatment showed that glucose levels in the mice remained stable. The
investigators also reported
that while there was no evidence the therapy triggered beta cell proliferation,
it did seem to reactivate beta cells that were deactivated by the
diabetes-related immune inflammation. The investigators suggested that this
combination resulted in a resetting of the immune system toward a long-term
tolerance of the body’s beta cells.

The KU Leuven study adds to our understanding of T1D, which
is why JDRF is actively supporting research that allows us to better understand
the process leading to the misguided immune attack on the beta cells and
potential therapeutic interventions at each stage of this complex disease. In
particular, JDRF is looking at ways to develop more specific therapies to
promote tolerance of the beta cell antigens that trigger the autoimmune
response, without generally weakening the immune system; such therapies are a
critical component of a comprehensive therapeutic approach to T1D.

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JDRF industry partner NGM Biopharmaceuticals, Inc., recently announced a new partnership with Daiichi Sankyo Company, Ltd., a Japanese pharmaceutical company.  The partnership will focus on discovering and developing drugs to regenerate pancreatic beta cells and improve their function. Such therapies would represent a significant advance for people with type 1 diabetes (T1D) or type 2 diabetes (T2D).  Beta cell regeneration is one of JDRF’s priority areas of research in T1D.

JDRF formed a partnership with NGM Biopharmaceuticals in September 2011. Prior to partnering with JDRF, NGM built a unique discovery platform and expertise that could enable the discovery of novel drugs to promote beta cell regeneration.   JDRF’s collaboration with NGM aims to translate the company’s successes to the discovery of regenerative medicines to help people with T1D. 

JDRF’s Industry Discovery and Development Partnership (IDDP) program exists to facilitate the creation of partnerships such as this one. Through the IDDP program, JDRF partners with biotechnology and pharmaceutical companies.  These partnerships are crucial because they provide access to scientific and financial resources that enable JDRF-funded research to advance more quickly and efficiently.  Industry involvement is a vital component of drug development and making new treatments available to people with T1D. 

The announcement of the new partnership between NGM and Daiichi Sankyo represents a success story for JDRF’s IDDP program.  The partnership will provide significant opportunities for scientific discoveries and clinical development of promising beta cell regenerative therapies for diabetes.  Daiichi Sankyo will be primarily responsible for conducting trials and bringing any new treatments to market.   JDRF is pleased that the NGM technology will be expanded by the partnership with Daiichi to advance beta cell regeneration research.

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In
a recent study published in
the current issue of Nature
Immunology, a JDRF-funded team led by Dr. Diane
Mathis from the Harvard Medical School and Massachusetts General Hospital
developed a technique that uses MRI and nanoparticles for predicting type 1
diabetes (T1D).

 In the study, which was conducted in mice, researchers
injected two sets of mice – one with a genetic predisposition to T1D and one
without – with magnetic nanoparticles designed to accumulate in inflamed
tissues.  The inflamed tissues are an
indicator of the autoimmune attack that causes T1D.  After scanning the mice  using MRI, the researchers discovered
increased inflammation in animals disposed to T1D starting from six to 10 weeks
of age.  According to the study’s author Dr.
Wenxian Fu, this result shows that the progression of the disease, at least in
this animal model, is determined very early in life.  In the case of these mice, it seems T1D does
not require an additional trigger such as a secondary infection or
environmental stress.

In addition to discovering and predicting T1D onset
in mice subjects, the researchers found other applications for the MRI imaging
technique. They identified a number of previously unknown molecular and
cellular elements that correlated with disease protection.  One of these protective elements is CRIg, the
complement receptor of the immunoglobulin superfamily. The presence of CRIg marked
a subset of macrophages associated with diabetes resistance.  The scientists injected CRIg engineered
molecules into mice predisposed to diabetes and found that it resulted in a
lower incidence of the disease.

Although these findings are promising, future studies
will be necessary to determine the technique’s potential for discovering markers
of T1D progression in humans and developing new drug therapies to prevent the
disease.  The findings open the
possibility that imaging of inflammation in the pancreas will help identify
individuals who will develop T1D and predict how rapidly the disease might
progress.  This result would be important
for prevention trials as well as for studies aimed at preserving
beta cell function.  Furthermore, the
ability of CRIg to prevent disease and reduce inflammation as determined by
this imaging technique opens up the possibility for novel therapeutic
approaches. The study is another step forward for JDRF’s research
focus on discovering pathways to prevent T1D from occurring or stopping
the autoimmune attack that causes the disease.  

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Replacing the body’s insulin-producing beta cells is one potential method for curing type 1 diabetes (T1D).  Researchers are attempting to solve a number of challenges to make beta cell replacement a reality.  These include:

• overcoming the misguided immune system attack on these cells that causes T1D in the first place (through strategies such as encapsulation) and the immune response to the foreign new beta cells,
• identifying a source for new beta cells,
• and ensuring that the new beta cells have the environment they need to survive, function, and ultimately produce insulin once they’re in the body.

In a new study published in the journal Proceedings of the National Academy of Science (PNAS), researchers from the Diabetes Research Institute (DRI) may have developed a solution to the final challenge.  Beta cells need oxygen and other nutrients in order to survive and function.  New beta cells introduced to the body lack a vascular network of blood vessels to deliver oxygen and other nutrients, which is a major impediment to their survival.  To overcome this challenge, the DRI scientists developed a new biomaterial that generates oxygen and delivers it to newly implanted beta cells, allowing them to function until a vascular network develops.  Since this initial study was conducted using a laboratory model, researchers will now seek to clinically apply the results.  The goal is to use this technology as part of the encapsulation system of  islets for transplantation in people with T1D.  

The DRI researchers who conducted this study were funded by JDRF and the Helmsley Charitable Trust (HCT) as part of a collaboration to accelerate the pace of research and development to deliver better treatments, devices, and diagnostics for improving the lives of people with T1D.  This study also illustrates the success of two JDRF research funding strategies in addition to the HCT collaboration.  Dr. Camillo Ricordi, DRI’s scientific director, has been the recipient of a number of substantial JDRF funding grants.  One of these grants specifically helped fund this and other DRI research related to beta cell replacement.  Also, the study’s lead researcher, Dr. Cherie Stabler, is the past recipient of a postdoctoral fellowship from JDRF that enabled her to investigate methods for beta cell survival using her biomedical engineering background.  JDRF provides postdoctoral fellowships to attract qualified, promising scientists in the early stages of their professional careers to the T1D research field with the long-term goal that, as independent investigators, they will contribute to research aimed at curing, treating, and preventing T1D.

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In
a study published this month in Diabetes Technology & Therapeutics, researchers
concluded that the automatic suspension of insulin delivery by a low glucose
suspend (LGS) system greatly reduces the severity and duration of hypoglycemia (extreme
low blood sugar) in people with type 1 diabetes (T1D). An LGS system is built into
an insulin pump and halts insulin delivery when it detects low blood glucose
levels from a continuous glucose monitor (CGM). When blood sugars are low,
insulin delivery could increase the risk of hypoglycemia, which, if untreated,
could lead to a multitude of complications, including lack of consciousness,
coma, and even death. LGS systems are precursors to a fully automated closed-loop
artificial pancreas, which could revolutionize the way of life and the health of
people with T1D.

The
study was conducted by Satish Garg, M.D., editor-in-chief of Diabetes Technology & Therapeutics
and professor of pediatrics at the University of Colorado in Denver, along with
colleagues from the Barbara Davis Center for Childhood Diabetes in Colorado;
Rainier Clinical Research Center in Washington; and the AMCR Institute, Inc.,
Stanford University Medical Center, Mills-Peninsula Health Services, and
Medtronic Inc. in California.

In
the randomized cross-over trial, subjects with T1D fasted overnight and
exercised to induce hypoglycemia. In random order, the LGS feature was turned
on in some exercise sessions, and turned off in others. After comparing data
from the successful sessions, researchers found that use of the LGS feature
reduced the length and intensity of hypoglycemic episodes, without resulting in
a rebound effect of hyperglycemia.

LGS
systems would be key to the safety and effectiveness of an artificial pancreas—
which would combine an insulin pump with a CGM, allowing the devices to
"talk" to one another via sophisticated computer software—making this
latest study a step forward for people with T1D.

JDRF
is driven toward improving the lives of every person living with T1D, and
toward preventing, treating, and curing the disease and its complications
through the support of research. That is why the artificial pancreas is one of JDRF’s research priorities, and why we have been a
leader in propelling its development and testing. Not only would an artificial
pancreas allow people with T1D to take a break from their full-time jobs of managing
their diabetes; studies have shown that blood glucose regulation improves with
its use—particularly during sleeping hours, when the
risk of hypoglycemia increases. A myriad of benefits continue to surface as research progresses, showing the
potential of an artificial pancreas to vastly improve lives, and keep people
with T1D safe.

The
Food and Drug Administration (FDA) issued guidance for the testing of LGS
systems
in June 2011, and in December 2011, following strong advocacy efforts by JDRF and
other supporters, the FDA issued its draft guidance for
artificial pancreas systems. This guidance is needed to move research to the
next stage of testing outside the hospital setting, in more real-life conditions. JDRF plans to submit its comments to the FDA on
the draft AP guidance in March.

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Nonprofit organizations focused on disease research are transforming their traditional roles, and emerging as key players in accelerating the development of better treatments and cures, according to a recent report by the Harvard Stem Cell Institute (HSCI) and the Multiple Myeloma Research Foundation (MMRF).  The Harvard Business School convened a roundtable panel in 2011 that addressed the obstacles facing drug development today.  JDRF was one of a handful of nonprofits—which also included the Michael J. Fox Foundation for Parkinson’s Research, the Cure Alzheimer’s Fund, and the Bill & Melinda Gates Foundation—who participated in the panel, and discussed how they are stepping in to bridge gaps between laboratory research and the commercialization of new products and treatments. 

Despite many scientific advances, targeted treatments and cures for many complex diseases remain elusive.  Therefore, drug development in areas like type 1 diabetes (T1D), Parkinson’s disease, or Alzheimer’s disease remains a challenge.  In addition, regulatory hurdles can make the approval process for new drugs difficult, and more companies and venture capitalists are reluctant to invest in early stage research given the current economic environment.  These are a few of the factors that are contributing to the changing landscape of drug development, which formed the basis of the roundtable conversations at Harvard.

The discussions from the panel were documented in HSCI and MMRF’s recently released white paper, “The Advancing Role of Non-Profit Organizations in Drug Development.”  The paper outlines case studies, best practices, and the most effective new models that nonprofit organizations are using to accelerate research and development efforts leading to better treatments and cures for diseases.  Like many other diseases, T1D is complex and remains a huge, unmet medical need.  As the leading charitable organization focused on T1D research, JDRF continually looks at what has to happen to bring therapies to people faster, identify critical gaps and try to find innovative opportunities so that promising early stage research can progress to potential therapies.   

To bridge these gaps, nonprofits like JDRF are assuming the role of a “trusted third party” and facilitating collaborations with industry and others to influence research strategy.  In this unique role, nonprofits are not only providing financial support, but additional expertise on research plans and even regulatory guidance.  Furthermore, strategic partnerships between nonprofits and industry help reduce the risk of early-stage research that is often considered “high risk” since the science is not yet proven or the return on investment uncertain.  As a result, more companies are seeing a benefit to entering previously empty arenas, further helping to advance research toward better treatments and cures for diseases like T1D.  JDRF’s industry partnerships program, developed in 2006, is an integral part of the organization’s overall strategy to accelerate better treatments and cures, supporting critical research that otherwise would not have advanced without JDRF’s involvement. 

Of note, JDRF’s chief scientific officer, Dr. Richard Insel, highlighted JDRF’s collaboration with the Genomics Institute of the Novartis Research Foundations (GNF) as an example of innovative deal structures that nonprofits are creating to allow them to partner more meaningfully with innovators throughout the drug development pipeline.  The GNF collaboration is part of JDRF’s industry partnerships program. 

Dr. Insel pointed out that through funding basic academic research, JDRF had proven that it was possible to generate new pancreatic beta cells.  But like the other nonprofits at the roundtable, JDRF discovered a gap between the research being performed at academic institutions and the products being developed for commercial use.  By partnering with GNF, Novartis and GNF would undertake the responsibility for commercializing and developing beta cell regeneration products while JDRF would provide access to its significant academic networks and experience in the T1D space.  Should GNF succeed in commercializing a product based on this research, JDRF would be entitled to a modest return on its investments.

JDRF’s partnership with GNF is just one example of how nonprofits are forming strategic alliances with industry to develop better treatments and cures, and accelerate the delivery of these advances to the marketplace.  

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JDRF-funded scientists at Yale
University recently found a mechanism of action by which teplizumab, an
anti-CD3 antibody may be working as an immune therapy for T1D.   

Currently, once T1D starts to develop,
there’s no intervention developed to stop it. The immune system slowly and
inevitably kills the pancreatic beta cells that produce insulin, a hormone that
enables people to get energy from food. As a result, people with T1D have to
test their blood sugar and give themselves insulin (with injections or an
insulin pump) multiple times every day in order to stay alive. What’s more, reversing
T1D remains an elusive and complicated challenge, requiring restoration of the
insulin-producing cells that were destroyed, as well as solutions to turn off
the misguided immune system attack on insulin-producing cells.

Teplizumab, the drug used in the study, is thought to work by
shutting off a part of the immune system most responsible for attacking these
insulin-producing cells and generating long-term immunoregulation to control
this misguided autoimmune response. While previous trials tested whether
teplizumab might preserve insulin production in people recently diagnosed with
T1D, researchers are now also studying whether the drug might preemptively prevent
or delay the development of T1D in at-risk individuals.  One such study is being
conducted by the National Institutes of Health’s Type 1 Diabetes TrialNet.  

The latest findings about teplizumab are reported in the current
issue of the journal Science Translational Medicine.  In
the study, which was funded by JDRF, NIH, Yale University, and the Health
Service Executive of Ireland, researchers led by Dr. Kevan Herold, M.D.,
professor of immunobiology at Yale School of Medicine used a mouse model with a
functional human immune system, and focused on the effect of the drug on T
cells, a critical immune system component involved in the development of
T1D.  The team found that the drug
induced certain T cells to migrate from the circulatory and lymph systems to
the small intestine, where they produced the immunoregulatory protein
interleukin-10 (IL-10).  IL-10 is an important
regulator of the immune
system that has a role in preventing or controlling autoimmune diseases.  These T cells were also converted into
regulatory T-cells, known to be helpful in restoring and maintaining normal
immune system balance.

While researchers have yet to fully understand teplizumab’s potential
role in treatment or prevention of T1D, this study underscores the importance
of understanding the mechanism of action of therapies in translational research
– the ability to effectively convert lab findings into useful therapies in
clinical studies. The work provided important clues about how the
investigational drug works in human cells and demonstrated that humanized mice
can be successfully used to identify how drugs such as this one work in people.
 

By better understanding a therapy’s exact mechanism of
action, it allows researchers to improve the design of future trials, including
developing biomarkers to determine dosing and assess efficacy. In this case,
the Yale study unlocks doors for more studies to explore the extent to which therapies
that target the immune system may prevent the onset of T1D.

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Nearly 20 years ago, the Diabetes Control and Complications Trial (DCCT) proved that keeping tight control over blood sugar levels can help prevent or delay the onset of complications for people with diabetes.  Since then, researchers have continued to study complications with the goal of discovering how to predict, prevent, and reverse them on an individual level.

The results of two studies reported in the Journal of the American Society of Nephrology may for the first time allow doctors to accurately determine an individual’s risk for developing diabetic kidney disease, and ultimately kidney failure.  In the studies, researchers identified two proteins, TNFR1 and TNFR2, whose presence was strongly associated with the development of severe kidney complications in people with type 1 and type 2 diabetes.  The studies both followed people with diabetes over a number of years and found that those with higher concentrations of these two proteins were at the greatest risk for kidney disease, regardless of any other factors.  They also found that the presence of the proteins could predict the progression of kidney disease, as people with higher concentrations experienced a more rapid decline in kidney function.  JDRF provided part of the funding for the studies.

The findings from this research could benefit people with diabetes both in the near future and in the long term.  The most immediate impact may be the development of new diagnostic tests that measure TNFR1 and TNFR2 and can predict who is at the highest risk of developing diabetic kidney disease.  No such tests are currently available.  In the long term, the findings contribute to our knowledge of how diabetic kidney disease develops and can inform efforts to prevent or reverse it.

JDRF continues to fund this and other research with the goal of preventing and reversing the complications of diabetes.

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