JULY - SEPTEMBER 2012 T1D RESEARCH ADVANCES
This summary contains important research advances that were reported during the period of
July - September 2012. They are arranged around the JDRF research goals and priority research
areas. Many, but not all of these advances were directly supported by JDRF. JDRF’s support is
noted within each entry. The relevance of each advance to those with T1D is described in a
brief summary. These are also posted in the Research section of the JDRF website.
CURE
Beta Cell Regeneration Research
BETA CELL STRESS MARKERS DETECTED IN INDIVIDUALS WITH T1D
Stress within the major cellular machinery that produces proteins can be caused by a buildup of mis-shaped
proteins. Due to their high degree of protein secretion, beta cells are uniquely sensitive to this type of cellular
stress and it has long been suggested that T1D is associated with increased beta cell stress leading to decreased
beta cell function and ultimately beta cell death. Much of the prior work on beta cell stress has been obtained
from animals. In this study, Dr. Decio Eizirik examined donated samples from patients with long-term or recentonset T1D for evidence of beta cell stress. Dr. Eizirik identified a significant increase in key markers of beta cell
stress in these human beta cell/islet samples regardless of stage of their T1D disease. These results demonstrate
that beta cell stress is an important component of human T1D and suggest that therapeutic strategies to alleviate
beta cell stress could have utility in preventing or delaying progression of all stages of T1D.
Reference:
Marhfour, I., Lopez, XM., Lefkaditis, D. et al. (2012). Expression of endoplasmic reticulum stress markers in the
islets of patients with type 1 diabetes. Diabetologia 55, 2417-2420.
Investigators and Institutions:
This work was led by Dr. Decio Eizirik at the University of Brussels.
Ramifications for Individuals with T1D:
This research confirms the occurrence of stress within the beta cell machinery of humans with T1D. This stress
appears to be playing a role in beta cell dysfunction and death in human T1D. These findings suggest that drugs
could be developed to alleviate this beta cell stress to help delay or stop progression of the T1D disease process – a
key goal of JDRF’s Regeneration Program.
JDRF Involvement:
This work was funded, in part, by a JDRF grant to Dr. Eizirik and through JDRF’s support of the Network of
Pancreatic Organ Donors with Diabetes (nPOD).
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BETA CELL STRESS AND INFLAMMATION LINKED TO BETA CELL DEATH
When mis-shaped proteins accumulate in the cell’s protein production machinery it creates stress within the cell’s
normal protein production processes. If the stress is unresolved, the cell will be rendered dysfunctional and will
die. Beta cells are specialized cells that produce and secrete large amounts of proteins including insulin and are
therefore uniquely sensitive to this type of stress. It has long been thought that this type of stress was responsible
for the beta cell dysfunction and death that occurs in T1D and T2D, but links between beta cell stress,
inflammation and cell death in diabetes remained elusive. In simultaneously published reports, Dr. Feroz Papa and
Dr. Fumihiko Urano independently linked stress in beta cells to activation of an inflammatory pathway and cell
death through a protein called TXNIP, known to be associated with cell death. Furthermore, the groups
demonstrated that inhibiting the pathway reduced inflammation and cell death and protected against beta cell
loss in a mouse model of diabetes. Together, these findings suggest that targeting this stress pathway or the TXNIP
protein could be a beneficial therapeutic approach for promoting beta cell health and survival in T1D.
References:
Lerner, AG., Upton, J., Praveen, PVK. et al. (2012). IRE1α Induces Thioredoxin-Interacting Protein to Activate the
NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress. Cell Metab 16, 250-264.
Oslowski, CM., Hara, T., O'Sullivan-Murphy, B. et al. (2012). Thioredoxin-Interacting Protein Mediates ER StressInduced β Cell Death through Initiation of the Inflammasome. Cell Metab 16, 265-273.
Investigators and Institutions:
This work was led by Dr. Feroz Papa at UCSF and Dr. Fumihiko Urano at Washington University School of Medicine.
Ramifications for Individuals with T1D:
This research identifies a potential drug development target to reduce stress and increase survival of beta cells to
delay or prevent T1D. Further work is required to identify drug-like compounds that can target the pathway and
demonstrate that they are safe and effective in animal models before moving to human studies.
JDRF Involvement:
Work in Dr. Urano’s laboratory was funded, in part, by JDRF. A previous JDRF grant to Dr. Papa supported the
development of tools and reagents necessary for the present study.
NOVEL FACTOR PROMOTES BETA CELL SURVIVAL AND FUNCTION
A novel factor that prevents the loss of beta cells and improves their insulin secretory capabilities has been
discovered by Dr. Newgard and his team at Duke University. Their previous research demonstrated that a gene
expression factor in human beta cells leads to an increase in beta cell replication, while enhancing beta cell
function. However, generally gene expression factors cannot be controlled with traditional drug-type compounds,
so an indirect control pathway needed to be found. In this new research they identified the protein called VGF as
the factor responsible for controlling the beneficial effects of this beta cell replication gene expression factor. VGF
is a protein made and secreted by beta cells and then cut into smaller active fragments. The scientists at Duke
found that one particular VGF fragment, called TLQP-21, was responsible for the beneficial effects, preventing
death and improving the functioning of human beta cells grown in culture. Also, when given to rats, the group
found that TLQP-21 preserves beta cell numbers and delays the onset of diabetes.
Reference:
Stephens, SB., Schisler, JC., Hohmeier, HE. et al. (2012). A VGF-Derived Peptide Attenuates Development of Type 2
Diabetes via Enhancement of Islet β-Cell Survival and Function. Cell Metab 16, 33-43.
Investigators and Institutions:
This work was led by Dr. Christopher Newgard at Duke University.
Ramifications for Individuals with T1D:
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This research identified a protein that has the potential to improve the functioning and survival of beta cells in
people with T1D. Work can now begin on evaluating the therapeutic potential of this protein in additional studies
and on designing related compounds that produce a similar therapeutic benefit by targeting this same pathway.
JDRF Involvement:
This work was funded, in part, by a collaborative JDRF grant to Dr. Newgard and a JDRF Postdoctoral Fellowship to
Dr. Stephens, the lead author on this paper.
MOLECULE THAT PROMOTES BETA CELL REGENERATION DISCOVERED
Restoring a sufficient number of beta cells is critical to reversing and curing T1D. So a key JDRF priority is
identifying molecules and factors that promote beta cell regeneration. However, this process is often slow and
time-consuming. Dr. Didier Stainier and his colleagues at the University of California, San Francisco developed a
fast screening strategy using specially engineered fish embryos to accelerate the normal process of finding an
“active” drug candidate. Using this engineered fish embryo system allowed rapid screening of available
compounds to find those that increased beta cell regeneration. The group used this novel system to evaluate 7,000
known, biologically active compounds and identified five that were able to improve beta cell regeneration in this
model. The most potent of the five positive compounds was one called NECA. In order to determine the
therapeutic potential of NECA, the group then tested its effects on adult mouse islets and in diabetic mice. As
predicted by the screening experiments, NECA treatment increased the proliferation of mouse beta cells and
increased beta cell numbers which translated into improved glycemic control in diabetic mice.
Reference:
Andersson, O., Adams, BA., Yoo, D. et al. (2012). Adenosine signaling promotes regeneration of pancreatic β cells in
vivo. Cell Metab 15, 885-894.
Investigators and Institutions:
This work was led by Dr. Didier Stainier at UCSF, in collaboration with Dr. Michael German at UCSF.
Ramifications for Individuals with T1D:
This early stage work identified a new pathway that could be the focus of a drug development effort to promote
beta cell regeneration in T1D. However, more work is required to determine if the pathway is effective on human
islets, if the pathway could be activated safely in a therapeutic setting, and if suitable drugs can be developed that
target the pathway.
JDRF Involvement:
This work was supported, in part, by a JDRF grant to Dr. Stainier, a JDRF Advanced Postdoctoral Fellowship to Dr.
Anderson and a JDRF Scholar Award to Dr. German.
Beta Cell Encapsulation Research
INDUCING TRANSPLANT TOLERANCE VIA MULTIPLE PATHWAYS
These researchers previously showed that giving special, chemically-treated white blood cells from the spleen
before an islet transplant allows indefinite survival of the transplanted islets in an animal model without the need
for any immunosuppression. How this regimen protects the transplanted islets is unclear. In this study, they
showed that the infused chemically-treated white blood cells from the spleen differentially target certain T cells
causing their rapid depletion. Other T cells are sequestered in the spleen preventing their attack on the
transplanted islets and another type of regulatory T cell is induced at the site of the graft. It was concluded that
these special infusions target host immune responses via a multitude of mechanisms, including T cell depletion,
induction of tolerance to islets, and immune regulation, which act in a synergistic fashion to induce robust
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transplant tolerance. This simple form of immune tolerance induction has significant potential for clinical
translation in human transplantation and in the context of JDRF’s beta cell regeneration program.
Reference:
Ethylenecarbodiimide-fixed donor splenocyte infusions differentially target direct and indirect pathways of
allorecognition for induction of transplant tolerance. J Immunol. 2012 Jul 15;189(2):804-12.
Investigators and Institutions:
The study was led by Dr. Luo and her colleagues at Northwestern University.
Ramifications for Individuals with T1D:
Islet transplantation has been shown to have great efficacy in T1D individuals; making many people with T1D
insulin independent for at least a period of time and impacting hypoglycemia unawareness. One of the limiting
factors is the use of chronic immunosuppression (the other is the limited supply of human islets). This research is a
promising approach to remove or reduce the need for chronic immunosuppression following human islet
transplantation. It may also prove valuable in various encapsulation products and regeneration strategies.
JDRF Involvement:
This study was funded in part by JDRF grants to Dr. Luo’s laboratory.
ENHANCING BLOOD VESSEL GROWTH IMPROVES TRANSPLANTED ISLET SURVIVAL
The mechanisms underlying early failure of islet transplants are not entirely clear, but are thought to be related to
delayed blood vessel growth in the new islets. In addition to their nutritional and gas exchange role, it was thought
that blood vessels play an active role in cell-cell communications, a key requirement supporting islet survival and
engraftment. To test this concept the authors developed three dimensional blood vessel networks in engineered
pancreatic tissues. The experimental setup closely mimics the natural anatomical context of pancreatic
vasculature. Enhanced islet survival correlating with formation of functional tube-like blood vessels was
demonstrated. Addition of cells that make up connective tissue promoted blood vessel-like structure formation,
which further supported islet survival as well as insulin secretion. Implantation of prevascularized islets into
diabetic mice promoted the survival, integration and functioning of the transplanted engineered tissue, supporting
the suggested role of blood vessels in islet survival. These findings present potential strategies for preparation of
transplantable islets with increased survival prospects and insights for improving the success of islet encapsulation
products.
Reference:
Engineered vascular beds provide key signals to pancreatic hormone-producing cells. PLoS One. 2012;7(7):e40741.
Investigators and Institutions:
The study was led by Dr. Levenberg and her colleagues at Technion - Israel Institute of Technology.
Ramifications for Individuals with T1D:
Islet transplantation has been shown to have great efficacy in T1D individuals, but have limited availability. This
research shows a critical factor in transplantation that can improve transplantation outcome and may improve the
success of future islet encapsulation products.
JDRF Involvement:
This work was supported in part by JDRF.
PRO-SURVIVAL AGENT IMPROVES ISLET TRANSPLANTATION IN ANIMAL MODEL
Large numbers of islets are lost in the time immediately after a clinical islet transplant, through cell death or innate
inflammatory injury. The authors previously demonstrated the positive impact of a series of inhibitors in mouse
models on islet transplantation survival through reduction in early post-transplant cell death. Here they studied
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one specific inhibitor called IDN6556 in a large animal (pig) transplant model. Pigs receiving IDN6556 had lower
fasting blood glucose level after transplantation and a higher percentage (100% vs. 33.3%) showed fasting blood
glucose levels closer to normal. This translated into an enhanced metabolic reserve and acute insulin release for
pigs in the treatment group. In conclusion, IDN6556 led to enhanced islet survival and function in this large animal
islet transplant model.
Reference:
Caspase Inhibitor IDN6556 Facilitates Marginal Mass Islet Engraftment in a Porcine Islet Autotransplant Model
Transplantation 2012 Jul 15;94(1):30-5.
Investigators and Institutions:
The study was led by Dr. Shapiro and his colleagues at University of Alberta, Edmonton.
Ramifications for Individuals with T1D:
Islet transplantation has been shown to have great efficacy in T1D individuals. One of the limiting factors is the
shortage of islet cells such that many pancreases are needed to transplant one patient. This research is a promising
approach to attain successful single-donor islet transplantation by improving islet survival and function.
JDRF Involvement:
This study was not supported by JDRF, but JDRF supported the prior rodent studies. JDRF is supporting a clinical
trial in Edmonton testing this inhibitor in islet transplantation.
NOVEL AGENT TARGETING BETA CELLS WAS EFFECTIVE IN INDUCING LONG-TERM ISLET SURVIVAL
Immunologic rejection is a major barrier to successful long-term outcomes in clinical transplantation. Recently, a
novel class of clinical immunotherapeutic agents specific to the B-cells (the cells of the immune system that make
antibodies and can also function as antigen presenting cells) has emerged for the treatment of B-cell-mediated
diseases. In this study, the authors demonstrate the potential utility of B-cell directed immunotherapy in
preventing transplant rejection using an islet transplantation model. After treatment with these
immunotherapeutic agents, indefinite islet transplant survival was achieved. This treatment effectively induces
immune tolerance and promotes long-term islet transplant survival in mice. Therefore, B-cell-directed
immunotherapy may be effective in promoting transplantation survival and improved function via the induction of
immune tolerance.
Reference:
Murine islet allograft tolerance upon blockade of the B-lymphocyte stimulator, BLyS/BAFF Transplantation. 2012
Apr 15;93(7):676-85
Investigators and Institutions:
The study was led by Dr. Naji and his colleagues at University of Pennsylvania.
Ramifications for Individuals with T1D:
Islet transplantation has been shown to have great efficacy in T1D individuals, but is not an option for most people.
One of the limiting factors is the use of chronic immunosuppression. This research is a promising approach to help
remove this barrier.
JDRF Involvement:
This work was supported in part by JDRF.
A NOVEL MONOCLONAL ANTIBODY PROLONGS ISLET TRANSPLANT SURVIVAL
The importance of the CD40 pathway in T1D immunosuppression strategies is well-documented. Here the authors
present the development of a novel monoclonal antibody, called 2C10, to block the CD40 pathway as a T1D
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immune therapy. Monkeys were treated with 2C10 or a placebo before being injected with a protein antigen to
cause an immune reaction. Treatment with 2C10 successfully inhibited T cell-dependent antibody responses.
Subsequently, the monkeys underwent islet transplantation and received standard immunosuppression therapies
with or without 2C10. Islet graft survival was significantly prolonged in animals receiving 2C10 compared to those
who did not. The survival advantage conferred by treatment with 2C10 provides further evidence for the
importance of blockade of the CD40 pathway in preventing immune responses following islet transplantation.
2C10 is a particularly attractive candidate for translation to clinical studies given its favorable clinical profile.
Reference:
A Novel Monoclonal Antibody to CD40 Prolongs Islet Allograft Survival. Am J Transplant. 2012 Aug; 12(8):2079-87.
Investigators and Institutions:
This work was led by Drs. Kirk and Larsen at Emory University.
Ramifications for Individuals with T1D:
Islet transplantation has been shown to have great efficacy in T1D individuals, but its availability is limited. This
research helps develop a novel immunosuppressive reagent for use in islet transplantation.
JDRF Involvement:
This work was supported in part by JDRF.
Cure R&D Tools Research
MRI IMAGING CAN DETECT CHANGES IN PANCREAS SIZE IN PEOPLE WITH T1D
Shrinking of the pancreas is common in people with T1D over a long time, but there are limited data concerning
pancreas size at the time of diagnosis. The objective of the study was to determine whether pancreatic size was
reduced in patients with recently diagnosed T1D and assess whether pancreatic size was related to residual betacell function or the presence of autoantibodies. The study included 20 people with recent-onset T1D and 24 nonT1D people as controls. The size of each person’s pancreas was measured using noninvasive magnetic resonance
imaging (MRI) in addition to collection of fasting blood samples and glucagon stimulation testing. After adjustment
for body weight, the mean pancreatic volume was 26% less in people with recent onset T1D than in controls,
suggesting that the pancreas begins shrinking years before the onset of clinical disease. Decreased pancreatic size
within individuals is therefore a potential clinical marker of disease progression reflecting the immunological
destruction of pancreatic beta cells. The ability to accurately quantify beta cell numbers and function is an unmet
need for diabetes drug development and clinical assessment that could be aided with MRI imaging
Reference:
J Clin Endocrinol Metab. 2012 Nov;97(11):E2109-13. doi: 10.1210/jc.2012-1815. Epub 2012 Aug 9.
Pancreatic Volume Is Reduced in Adult Patients with Recently Diagnosed Type 1 Diabetes.
Williams AJ, Thrower SL, Sequeiros IM, Ward A, Bickerton AS, Triay JM, Callaway MP, Dayan CM.
Investigators and Institutions:
University of Bristol (A.J.K.W.), School of Clinical Sciences, Learning and Research, Southmead Hospital, Bristol,
United Kingdom; Departments of Diabetes and Endocrinology (S.L.T.) and Radiology (I.M.S., M.P.C.), Bristol Royal
Infirmary, Bristol BS10 5NB, United Kingdom; Department of Diabetes and Endocrinology (A.W.), Royal United
Hospital, Bath BA1 3NG, United Kingdom; Department of Diabetes and Endocrinology (A.S.B.), Yeovil District
Hospital, Yeovil, Somerset BA21 4AT, United Kingdom; Department of Diabetes and Endocrinology (J.M.T.), Weston
General Hospital, Weston-super-Mare BS23 4TQ, United Kingdom; and Centre for Endocrine and Diabetes Science
(C.M.D.), Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom.
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Ramifications for Individuals with T1D:
A reduction in overall size of the pancreas as measured by MRI was found in patients with T1D within months of
diagnosis, suggesting that this measure has potential to be a clinical marker of disease progression.
JDRF Involvement:
JDRF did not support this study.
BETA CELL PROTEIN SPECIFIC ANTIBODY AS POTENTIAL BIOMARKER OF BETA CELLS
This publication presents a novel monoclonal antibody directed against a human beta cell membrane protein
called TMEM27. TMEM27 has previously been described as a beta cell marker and is proposed to be a regulator of
beta cell proliferation. Previous proof of concept work has been performed with existing antibodies that react
with the beta cell, but this is the first successful generation of a new antibody raised against this protein with
promising features for use in beta cell imaging in humans.
Reference:
Multimodal imaging of pancreatic beta cells in vivo by targeting transmembrane protein 27 (TMEM27).
Diabetologia (2012) 55:2407–2416
Investigators and Institutions:
D. Vats & H. Wang & D. Esterhazy & K. Dikaiou & C. Danzer & M. Honer & F. Stuker & H. Matile & C. Migliorini & E.
Fischer & J. Ripoll & R. Keist &W. Krek & R. Schibli & M. Stoffel & M. Rudin ETH, Hoffman-LaRoche
Ramifications for Individuals with T1D:
Non-invasive measurement of TMEM27 levels has the potential to be a clinical marker of disease progression.
JDRF Involvement:
Previous JDRF support to one of the authors (Markus Stoffel) provided the basis for the discovery of TMEM27 as a
potential biomarker of pancreatic beta cell numbers. The new study in partnership with Roche and other scientists
provides the basis for a translational advance defining a biomarker of beta cell numbers.
Immune Therapies Research
POTENTIAL BIOMARKERS IN SUBJECTS AT RISK FOR THE DEVELOPMENT OF T1D
The innate immune system, the part of the immune system that is tasked with defending the host from infections
in a non-specific manner, has been implicated in the T1D disease process. In this paper, the investigators analyzed
innate immune responses in T1D autoantibody positive individuals and compared them to individuals without
autoantibodies. The investigators found that two immune system pathways, one involving Interleukin-1b and one
involving Interleukin-6 were altered in autoantibody positive individuals when stimulated by TLRs compared to
autoantibody negative individuals. TLRs are responsible for recognizing pathogens and activating the innate
immune system, including interleukins, which are signaling molecules within the innate immune system.
Furthermore, they showed that autoantibody-positive subjects have lower levels of CXCL-10 in their blood. CXCL10 is a protein which is involved in the immune response as well as in the suppression of beta-cell proliferation.
These results suggest that altered innate immunity exists in individuals before disease onset. This suggests that
innate immune pathways may be involved in T1D pathogenesis and that molecules and pathways involved in the
innate immune system may be useful as biomarkers of T1D for at-risk individuals.
Reference:
Alkanani AK, Rewers M, Dong F, Waugh K, Gottlieb PA, Zipris D. Diabetes. 2012 Oct;61(10):2525-33. Epub 2012 Jun
29. Dysregulated Toll-Like Receptor-Induced Interleukin-1β and Interleukin-6 Responses in Subjects at Risk for the
Development of Type 1 Diabetes.
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Investigators and Institutions:
This study was led by Dr. Danny Zipris at the Barbara Davis Center for Childhood Diabetes, University of Colorado
Denver.
Ramifications for Individuals with T1D:
This study suggests that individuals at-risk for developing T1D, namely those individuals who are autoantibodypositive for T1D antigens, have altered innate immune pathways before disease onset. While an interesting
finding, longitudinal studies in individuals from the at-risk stage who progress to overt T1D will needed to be
evaluated to confirm and evaluate the potential involvement of the innate immune system in T1D pathogenesis. If
the role of the innate immune system is confirmed, the innate immune system could be a potential target for
therapeutics as well as for biomarkers for monitoring disease progression.
JDRF Involvement:
This study was funded by JDRF through grants to Dr. Danny Zipris.
ALTERED PEPTIDES AS POTENTIAL ANTIGENS IN CAUSING T1D
Chromogranin A is a protein produced by beta cells that has recently been implicated as a potential autoantigen in
T1D. In a mouse model of autoimmune diabetes, a part of chromogranin A has been shown to be targeted by a
series of specific T cells. When treated with an enzyme that has been linked to celiac disease, chromogranin A
becomes more antigenic. Spontaneous protein changes are known to occur in other autoimmune diseases, and a
similar process might trigger T1D. In this study, Dr. Haskins and her colleagues show that such a process is at least
feasible in a mouse model of autoimmune diabetes. Preliminary work from Dr. Haskins’s group also shows that
this process may be relevant in humans as well.
Reference:
Delong T, Baker RL, He J, Barbour G, Bradley B, Haskins K. Diabetes. 2012 Aug 21. [Epub ahead of print]
Diabetogenic T-Cell Clones Recognize an Altered Peptide of Chromogranin A.
Investigators and Institutions:
This study was led by Dr. Katie Haskins at the University of Colorado at Denver School of Medicine and National
Jewish Health.
Ramifications for Individuals with T1D:
In T1D and other autoimmune diseases, the body mistakenly mounts an immune response to normal or native
body components and these targets are known as antigens. The mechanisms by which this occurs in T1D are
complex and not very well understood. One possibility is that modifications of the antigens might play a role. After
undergoing these modifications, the altered components look different to the immune system than the
unmodified or normal components. The immune system then recognizes the modified protein as foreign and
mistakenly mounts an immune response to similar native components. In this research, Dr. Haskins concludes that
modified antigens do occur in a mouse model of autoimmune diabetes. If this can translate to human disease,
understanding their role in disease progression could lead to better therapeutics and biomarkers for T1D.
JDRF Involvement:
This study was funded through a grant to Dr. Katie Haskins and a post-doctoral fellowship to Dr. Thomas Delong.
EFFECTOR MEMORY T CELL BLOCKADE REVERSES T1D IN MICE BY PROMOTING PROTECTIVE T CELLS AND
IMMUNE TOLERANCE
In T1D, a subset of T cells, known as effector memory T cells, are thought to be responsible for perpetuating the
immune response to pancreatic antigens. It may be possible to curtail the response of these cells and reign in the
autoimmune response to T1D. In this research by Dr. Hans Dooms and colleagues, they blocked a marker on the
surface of these T cells and were able to prevent and reverse autoimmune diabetes in a mouse model. This
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treatment approach also increased the balance towards protective T cells; cells involved in maintaining tolerance.
These data suggest that this type of blockade may be a reasonable approach for treating established T1D.
Reference:
Penaranda C, Kuswanto W, Hofmann J, Kenefeck R, Narendran P, Walker LS, Bluestone JA, Abbas AK, Dooms H.
Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12668-73. Epub 2012 Jun 25. IL-7 receptor blockade reverses
autoimmune diabetes by promoting inhibition of effector/memory T cells.
Investigators and Institutions:
This study was led by Dr. Hans Dooms, currently at Boston University School of Medicine.
Ramifications for Individuals with T1D:
The investigators show that blockade of certain T cells may be a viable approach for treating established T1D in
humans, as it effectively decreased destructive T cells and resulted in conditions favorable for tolerance in a mouse
model of diabetes. However, this approach is not without risks, as it is a non-specific approach that could increase
the susceptibility for infections. These non-specific therapeutic approaches are a current limitation for the use of
these agents in T1D. However, it may be possible to combine this approach with an antigen-specific approach,
which may increase its potency and reduce the risk of serious side-effects.
JDRF Involvement:
This study was funded through a JDRF grant to Dr. Hans Dooms.
TREAT
Artificial Pancreas Project Research
MODULAR DESIGN FACILITATES ARTIFICIAL PANCREAS SOFTWARE DEVELOPMENT AND TESTING
Drs. Marc Breton and Boris Kovatchev’s team at the University of Virginia are employing a novel approach to
design, test and implement progressive improvements of artificial pancreas software based on a modular
architecture concept. This approach would allow the various components, such as a software module focused on
avoiding hypoglycemia or one that keeps glucose within a target range, to be seamlessly integrated in systems that
can be implemented and tested in a stepwise fashion in clinical studies.
The advantages of this module-based approach were demonstrated in two inpatient clinical trials. Each trial used
software packages in which different modules were used: a standard control to range software module (sCTR) and
a more sophisticated enhanced control to range (eCTR) software module. Both inpatient trials compared sCTR and
eCTR vs. standard pump therapy and included meals, overnight rest and 30 minutes of exercise. The studies were
conducted in 11 adolescents and 27 adults with T1D at the Universities of Virginia, Padova and Montpellier. sCTR
was found to significantly increase the time spent in the normal blood glucose range while reducing hypoglycemia.
eCTR was found to further improve mean blood glucose from 139 to 120 mg/dl without increasing hypoglycemia
and reduced variability overnight.
In addition to demonstrating improved glucose control and reduced hypoglycemia with both sCTR and eCTR these
studies highlighted the efficient use of modules in the design, testing and implementation of artificial pancreas
algorithms.
Reference:
Fully Integrated Artificial Pancreas in Type 1 Diabetes: Modular Closed-Loop Glucose Control Maintains Near
Normoglycemia, Diabetes. 2012 Sep;61(9):2230-7. Epub 2012 Jun 11.
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Investigators and Institutions:
Marc Breton1, Anne Farret2, Daniela Bruttomesso3, Stacey Anderson1, Lalo Magni4, Stephen Patek1, Chiara Dalla
Man, Jerome Place2, Susan Demartini1, Simone Del Favero4, Chiara Toffanin4, Colleen Hughes-Karvetski1, Eyal
Dassau6,7, Howard Zisser6,7, Francis J. Doyle III6 , Giuseppe De Nicolao4, Angelo Avogaro3, Claudio Cobelli5, Eric
Renard2 and Boris Kovatchev1, on behalf of the International Artificial Pancreas (iAP) Study Group.
1
University of Virginia, Charlottesville Virginia; University Hospital of Montpellier, University of Montpellier,
Montpellier France; 3University of Padova, Padua Italy, 4University of Pavia, Pavia, Italy, 6University of California
Santa Barbara, Santa Barbara, 7Sansum Diabetes Diabetes Research Institute, Santa Barbara California
Ramifications for Individuals with T1D:
The modular approach described by Drs. Marc Breton and Boris Kovatchev has accelerated the development and
testing of control-to-range artificial pancreas software by facilitating the stepwise development and testing of
discrete software modules. Control-to-range systems are now being tested in outpatient pilot studies and a larger
pivotal trial to assess efficacy is in the planning stages for 2013. Most importantly, these systems can be
developed with today’s available technologies, and set the stage for the development of future generation AP
systems and advanced devices.
JDRF Involvement:
JDRF funded this research through a grant to Dr. Boris Kovatchev at the University of Virginia. Dr. Kovatchev is a
member of the JDRF Artificial Pancreas Consortium.
Complications Prevention and Treatment Research
LIFE EXPECTANCY INCREASED 15 YEARS FOR THOSE MORE RECENTLY DIAGNOSED WITH T1D
This study reports results from the Pittsburgh Epidemiology of Diabetes Complications study that has tracked 933
individuals diagnosed with T1D at Children’s Hospital of Pittsburgh for around 30 years. In this study they compare
people diagnosed with T1D from 1950-1964 with those diagnosed between 1965 and 1980 and show that those
diagnosed more recently have 15 years greater life expectancy than those in the earlier group. The average life
expectancy from birth in those diagnosed in the 1960s and 1970s is only 4-6 years less than the general
population, compared to more than 17 years less for those diagnosed earlier. Several explanations are proposed
for this difference. Firstly, no early childhood deaths were reported in the latter group, likely reflecting better
diagnosis and early treatment of T1D. Another potential explanation is a decline in both short and long-term
complications with better insulin therapy and glucose monitoring. In particular, some reduction in diabetic
nephropathy, or kidney disease, may be important as previous studies have shown that in the absence of diabetic
nephropathy, the long-term mortality risk for T1D is the same as the general population.
Reference:
Improvements in the life expectancy of type 1 diabetes: The Pittsburgh Epidemiology of Diabetes Complications
Study cohort. Miller RG, Secrest AM, Sharma RK, Songer TJ, Orchard T. Diabetes. 2012 Nov;61(11):2987-92. doi:
10.2337/db11-1625. Epub 2012 Jul 30.
Investigators and Institutions:
Dr. Trevor Orchard and colleagues, University of Pittsburgh
Ramifications for Individuals with T1D:
The significant increase in life expectancy for those more recently diagnosed with T1D reflects the results of past
research and development expenditures translated into better medical treatment and self-management of T1D in
recent years. However, the importance of excellent glucose control and self-care are not changed by this finding
and several studies have noted that many with T1D are not achieving the recommended goals for glucose control.
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JDRF Involvement:
JDRF did not fund this study but remains committed to improving outcomes for those with T1D including finding
ways to improve glucose control and reduce complications of diabetes. Several ongoing studies are focused on
reducing complications, including diabetic kidney disease, by searching for and validating new therapeutic targets
as well as developing and testing new therapies.
CORNEAL NERVE FIBER CHANGES AS A BIOMARKER FOR DIABETIC NERVE DAMAGE
The LANDMARK study has confirmed previous findings that changes to the nerves in the cornea of the eye may
reflect changes in peripheral nerves and indicate the presence of peripheral nerve damage. Corneal nerves can be
imaged non-invasively using confocal microscopy. The current paper finds that changes in corneal nerve fibers,
such as decreased length of fibers, correlate with the presence of peripheral nerve damage in trial subjects with
T1D.
Reference:
Utility of corneal confocal microscopy for assessing mild diabetic neuropathy: baseline findings of the LANDMARK
study. Clin Exp Optom. 2012 May;95(3):348-54. Edwards K, Pritchard N, Vagenas D, Russell A, Malik RA, Efron N.
Investigators and Institutions:
Dr. Nathan Efron, Queensland University of Technology, Rayaz Malik, University of Manchester and colleagues
Ramifications for Individuals with T1D:
Peripheral nerve damage can lead to numbness, pain and contribute to non-healing ulcers and the need for
amputation in those with diabetes. There are currently no disease-modifying therapies. Current tests to detect
and stage peripheral nerve damage such as measurement of nerve conduction speed can be complex, invasive or
not very sensitive to change. More sensitive techniques and biomarkers could help earlier detection of diabetic
nerve damage and might even be used in clinical trials to detect effects of therapy to treat diabetic peripheral
nerve damage. Previous clinical trials for therapies to treat diabetic peripheral nerve damage have been of
substantial length and with complex endpoints. Biomarkers that could detect a therapeutic effect earlier in a trial
could help to de-risk the development pathway for companies developing new therapies in this area.
JDRF Involvement:
JDRF funds the LANDMARK study through a milestone-managed clinical award (PI: Dr. Nathan Efron). JDRF also
coordinates a group of international, collaborating investigators working on different aspects of validation of this
biomarker and to develop software to assist in more rapidly analyzing images of corneal nerve fibers which would
be essential for more widespread use of this biomarker.
NEW THERAPY APPROVED BY FDA FOR DIABETIC MACULAR EDEMA
On August 10th, the FDA approved the use of ranibizumab (Lucentis), to treat diabetic macular edema (DME). This
drug blocks a protein called VEGF, or vascular endothelial growth factor. VEGF is a protein usually involved in
formation of blood vessels, but in people with diabetic eye disease, the levels of this protein can be too high
causing leaky blood vessels and contributing to DME. Lucentis is one of several drugs developed to block VEGF, and
is now the first drug therapy to be approved by the FDA for DME. Compared to standard laser photocoagulation
therapy, clinical trials have shown that Lucentis has the potential to improve rather than just stabilize vision in
many people with DME.
The success of anti-VEGF therapy in DME also represents a critical insight into the biological pathways that cause
diabetic eye disease. VEGF is now validated as a single protein that can be targeted to block the disease, which
gives us more confidence that we can find other such targets to develop drugs both for different stages of eye
disease, as well as in those who do not respond to anti-VEGF therapy. Lucentis was previously approved in the US
and Europe for treatment of another eye condition, wet age-related macular degeneration, and in Europe for
DME.
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Reference:
FDA press release: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm315130.htm
Investigators and Institutions:
Genentech, Inc., CA
Ramifications for Individuals with T1D:
People with T1D are at risk for diabetic eye disease, including DME, which can cause significant loss of vision and,
in extreme cases, even blindness. Laser therapy has been used as standard treatment for the past few decades and
has dramatically helped to reduce blindness. However, laser photocoagulation is not a perfect therapy, and though
it can in many cases prevent people with DME from losing even more vision, it very rarely improves vision. AntiVEGF therapies, such as Lucentis, have been shown in clinical trials to preserve and even improve vision in those
with DME.
JDRF Involvement:
JDRF funded multiple research grants in the 1990s which helped establish the basic role for VEGF in diabetic eye
disease. Since then JDRF has also been involved in supporting and funding numerous clinical studies including
through the Diabetic Retinopathy Clinical network, the READ, READ-2 and READ-3 studies led by Dr. Quan Nguyen
at Johns Hopkins Medical Institute, which helped demonstrate that anti-VEGF can treat diabetic macular edema, as
well as advocating for those with T1D and eye disease. JDRF did not directly support Genentech in the clinical
development and commercialization of Lucentis and does not endorse the use of this product.
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