Year: 2014

Diabetes occurs when insulin producing pancreatic β-cells are impacted: type 1 diabetes due to destruction of β-cells, and type 2 diabetes due to a decrease in their number and/or potency. Consequently, therapy that aims to replace β-cells is a promising long term alternative to the currently prevalent insulin injections. However, the difficulty in finding viable […]

The development of MCS-based therapies for autoimmune diseases, including T1D, is a new field with a lot of promise, but also a lot of uncertainty. While successful treatment of disease allogeneic MSCs has been achieved, some MSC treatment failure has also been reported. The significance of this proposal is that it will fill a significant […]

In this preliminary screening of tissues, we propose to characterize B cells in the pancreas of cadavers that are autoantibody positive. Pancreas of non-autoantibody positive cadavers will be studied as controls. We propose to use immunohistochemistry to analyse cell surface marker expression, together with an analysis of the microantomical distribution of B cells and their relationship to other cells. […]

Type 1 diabetes (T1D) is one of the most common chronic diseases of childhood with onset peaking between 5-7 years of age and around puberty. Early childhood-onset T1D often exhibits severe beta-cell depletion compared to late adult onset T1D. We propose to test the hypothesis that immature beta-cells in early childhood are more susceptible to […]

The percentage of reduction of beta cell mass in patients with Type 1 diabetes (T1D) of recent onset cannot fully explain the reduction of endogenous insulin production that leads to hyperglycemia. In addition, functional defects of the beta cells may prevail from reduction of beta cell mass during Type 2 diabetes. In boty situation chronic […]

The trimolecular complex composed of autoreactive T-cell receptor, MHC class II, and an autoantigenic peptide plays a central role in the activation of pathogenic islet-specific CD4+ T cells in type 1 diabetes (T1D). We isolated and characterized novel antibodies against autoreactive T-cell epitopes associated with T1D. Our antibodies mimic the specificity of the T cell […]

We will select T2D patients, among them subjects with DNA variants, and profile gene expression, expressed mutants, and proteins from sub-areas down to the level of single islets and single cells within archived pancreas FFPE tissues using a novel in situ TO-Seq assay coupled with immunohistochemistry staining of protein biomarkers, retaining the morphologic context of […]

Human disease states that result in excess iron accumulation, e.g., hereditary hemochromatosis and beta thalassemia major, are associated with an increased incidence of diabetes. In these disorders surplus iron overwhelms normal transport and storage mechanisms leading to the appearance of excess free iron in circulation and the subsequent deposition of iron in tissues such as […]

It was earlier reported the finding that the incidence of type 1 diabetes correlates with small rodent abundance in Sweden. This and other findings initiated an effort to isolate novel infectious agents from small rodents in an attempt to find an etiological agent for type 1 diabetes in humans. As a result of these efforts, […]

The goal of this research project is to identify self-reactive T cell clones and monitor the frequency and activation state during the progression of autoimmune diabetes.  Identification of T-cell reactivity to beta-cell antigen epitopes is important to study pathogenesis and monitor antigen specific interventions in T1D.  We have successfully generated and validated human tetramer reagents […]

The overall goal of this proposal is to test the hypothesis that β-cell de-differentiation is an early stress-related response that may account for the early loss of β-cells in T1D. Furthermore, we believe that a small but significant population of long-term T1D patients might still have de-differentiated β-cells in their pancreatic islets, which creates hope […]

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing islet cells are targeted and destroyed by the immune system, especially by T cells. The events that lead to immune recognition of islet proteins in people genetically predisposed to autoimmunity are poorly understood. Many of the environmental triggers associated with T1D including viral infection, […]

Our project “Linking IHC profiles of duodenum and pancreas in T1D” aims to intensify our understanding of how the “gut immune system” contributes to the development of type 1 diabetes. Previous studies have shown that factors like the gut microbiome, gut permeability and the mucosal structure play a role in T1D pathogenesis. Studies are now […]

The process of β-cell decline in the lead-up to the overt diabetes could provide critical clues for timely therapeutic intervention. However the complexity, cell-type specificity, rapidly changing dynamics and the cumulative effects of inflammation all inform the outcome of the autoimmune attack on beta cell. This proposal is designed to use multiple in vitro models […]

Type 1 diabetes (T1D) is a progressive immune-mediated disease that is preceded by an asymptomatic preclinical period of highly variable duration. A better understanding of beta cell and islet function or dysfunction during this asymptomatic period and the nature of the “dialog” between islet endocrine cells and the immune system could lead to new therapeutic […]

This project will be the first to examine stress granule responses and the expression of long non coding RNAs in donor islet cells, a model beta cell line and the role of enterovirus infection in modulating these stress responses. This information will be used as a benchmark to examine nPOD tissues for these same stress […]

This CBDS program will establish an in situ RASL-Seq Islet Study Facility that will validate a novel in situ RASL-Seq platform for diabetes research using FFPE tissue from normal and Type 1 diabetes (T1D) diseased pancreas, and then apply this platform to address the gap in available methodology to take full advantage of T1D organ […]

Direct identification and validation of human β cell-specific biomakers is critical for monitoring the change of human β cell mass at prediabetes and the new-onset diabetes stage and during the therapeutic intervention. Due to technical and ethical constraints, our ability to prospective studies of human β cell biomarkers in response to β cell stress/apoptosis and […]

There are currently no clinically precise biomarkers that predict the development of type 1 diabetes (T1D). This limits the ability to identify patients who will become diabetic at a time when they have a greater beta cell mass and thus may respond more favorably to interventional therapeutics aimed at stopping T1D progression. To this end, […]

Glucagon-like Peptide 1 (GLP-1) and glucagon shares the same precursor molecule proglucagon, but each arises from a distinct posttranslational process in a tissue-specific manner. Recently GLP-1 has been shown to be co-expressed with glucagon in pancreatic islet cells. Our preliminary data showed GLP-1 was progressively up-regulated in pancreatic islets during type 2 diabetes development. These […]

Increased levels of reactive oxygen species (ROS) lead to dysfunction and subsequent loss of insulin-producing beta cells in pancreatic islets. Several lines of evidence support the importance of increased NADPH oxidase (NOX) activity as one of the contributing factors to elevated levels of ROS in beta cells. NOX-1 activity has been established as one of […]

The progression of type 2 diabetes is mediated to a large extent by the deaths of β-cells, the cells in the pancreas that synthesize and secrete insulin.  We discovered that ARC (Apoptosis Repressor with CARD), an endogenous inhibitor of cell death, is expressed at high levels in β-cells of the mouse pancreas.  Using cell culture […]

Diabetogenic B-lymphocyte activity may be enhanced by SHM induced increases in Ig antigen affinity. -SHM requires AID induced double strand DNA breaks repaired by RAD51 complex proteins. -AID is expressed at higher levels in B-lymphocytes from NOD mice than control strains -A small RAD51 blocking molecule specifically induces apoptosis of AID expressing B-lymphocytes from both […]

Compared to the general population, studies show 2-3 times increased risk of developing metabolic syndrome in drug naïve patients with severe mental illnesses like schizophrenia or bipolar disorder. Impaired glucose metabolism in non-obese never-treated patients and in first degree relatives of schizophrenic patients, suggests a possible genetic association between diabetes and schizophrenia. We are proposing […]

We have found that people with type 1 diabetes fall into one of six subtypes that can be defined on the basis of the genetic variants they have. These subtypes differ with respect to various clinical features, including immunological traits and risk of diabetic complications. In this proposal, we plan to use genetic information from […]

A clinically viable means to measure pancreatic beta-cell mass (BCM) is essential for evaluating the physiological basis of therapeutic approaches to restore deficient insulin secretory capacity. Major advances in imaging BCM have been made by taking advantage of receptor-specific imaging probes that have been successfully used for neuroimaging. Hence, Positron Emission Tomography (PET) imaging ligands […]

Diabetes is a disorder of complex interaction between genetic susceptibility and environmental perturbation. Various epigenetic models, such as intra-uterine growth retardation, have been shown to contribute to pancreatic beta-cell dysfunction. More recently, beta-cell dedifferentiation has been discovered as a mechanism for beta-cell dysfunction in diabetic mouse model. The project aim to understand the role of […]

We are searching for abnormal products of insulin metabolism that appear in beta cell as a result of the increased demands for insulin. These abnormal catabolites in NOD mice select for very unique CD4 T cells that initiate this chronic autoimmune reaction. The plans are to search for these abnormal products in islets from early […]

Fibroblast activation protein is an extracellular membrane bound and soluble protease that is commonly used as a marker of activated fibroblasts. Expression of FAP in healthy adult tissues is limited, but up-regulation is observed in a number of inflammatory and tissue remodeling processes, including wound healing, liver fibrosis and epithelial cancer, where it is thought […]

The rapid worldwide incidence increase suggests a major role for environmental factors in the aetiology of type 1 diabetes (T1D). According to cross-sectional and prospective studies on T1D patients and/or prediabetic individuals, virus infections may be one of these. Influenza viruses are known to cause severe pancreatic damage in birds and in some mammals, and […]

T1D is recognized to result from both genetic and environmental factors.  Chief among environmental factors that are strongly linked to T1D are Type B enteroviruses (HEV-B), yet the association of these viral triggers is not proven and many questions exist. Which of the 60 HEV-B serotypes trigger T1D, what type of infections do they cause […]

Several lines of evidence, in particular genetic association data of antiviral response genes with T1D risk, point to a role of viral infections in T1D etiology. However, multiple questions remain about the causal mechanisms and the type of viruses implicated. To contribute to these research questions, we are using high throughput sequencing technologies to find […]

There is now strong evidence that persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) are major risk factors for type 2 diabetes.  While the mechanisms involved are not known with any certainty, the associations between development of type 2 diabetes and blood concentrations of POPs are stronger than those for almost any other factor, […]

Despite convincing evidence linking human enteroviruses (HEV) with type 1 diabetes (T1D) onset, it is not known whether  certain HEV are the ones which are most commonly associated with T1D onset or if T1D onset is associated with any HEV serotype.

The etiology of the type 1 diabetes (T1D) is unclear but it has been shown that genetic factors influence the pathogenesis. In addition, several studies have shown that environmental factors likely contribute to the disease development. One such factor is virus infections, particularly the Coxsackie B viruses (CBVs), are among the main candidates and there […]

If type 1 diabetes (T1D) is caused/triggered by a viral infection in select genetic backgrounds – and Enteroviruses (EVs) are felt as major culprits –  investigators are expecting to find EVs into pancreatic Langerhans islets and also in association with spleen, lymph nodes, peripheral blood leukocytes. Infection of lymphoid cells, in fact, is common in […]

The overall goal of this project is to extend studies examining human beta cells and immune cells in type 1 diabetes (T1D) to a new 3D fluorescent microscopy format for 500um or greater sized samples. These studies will adapt new tissue imaging methods (CLARITY) developed by  Dr. K. Deisseroth (Nat Methods 2013). The specific aims […]

Cystic fibrosis related diabetes is a major morbidity for patients with cystic fibrosis and negatively impacts mortality.  The mechanistic basis for this form of diabetes is not well understood.  In this project we are analyzing the hypothesis that islet inflammation leads to islet amyloid deposition and beta cell failure in patients with CFRD.  Samples from […]

History of the Joslin Medalist Program Joslin first began awarding medals to people with diabetes in 1948 with a 25-year Victory Medal. Believing that proper self-management was the key to minimizing long-term complications, the program was the vision of Elliott P. Joslin, M.D. and served as an incentive for those committed to good, though challenging, […]

Several steps are crucial for induction of type 1 diabetes (T1D); the first is extravasation of CD4+ T lymphocytes from blood vessels into the pancreatic tissue, the second is penetration of the peri-islet basement membrane (BM) surrounding the β-islets, and third the β-cell destruction which leads to appearance of disease symptoms. BMs act to separate […]

Dendritic cells (DCs) play a crucial role in establishing and maintaining the balance between immunity to pathogens and tolerance to self. Whether DCs evoke T cell activation or tolerance in response to antigen presentation is determined by the physiological context in which they differentiate and mature. DC differentiation and inflammatory signalling is abnormal in type […]

The initial overall question to be tested by the collaborative of the Peter Butler laboratory at UCLA and the Mark Atkinson laboratory in Florida was to explore the possibility that the recently described pancreatic duct gland (PDG) compartment of the pancreas might serve as the elusive pancreatic stem cell niche, potentially offering an avenue to […]

(1) To clarify the infiltration of mononuclear cells in exocrine pancreas of Western type 1A diabetes and compare the histological findings to those of Japanese patients (2) To clarify the expressions of the molecules related to innate immunity or viral infection in Western type 1A diabetes and compare the hitological findings to those of Japanese […]

The overall purpose of our research is to understand how changes in extracellular matrix affect insulitis initiation and progression and beta cell destruction in diabetes. Our research focuses on a specific extracellular matrix molecule, hyaluronan, a long chain glycosaminoglycan distributed widely throughout different tissues. Hyaluronan is highly abundant in inflamed tissues and its synthesis is […]

The goal of this proposal is to define the lineage mechanism of ß-cell persistence in type 1 diabetes (T1DM). A few ß-cells often persist in T1DM pancreata. But, the lineage mechanism of ß-cell persistence in T1DM remains poorly understood. Our overarching hypothesis is that ß-cell persistence in T1DM is due to ongoing ß-cell regeneration. Alternatively, […]

Type 1 diabetes is a clinically and pathologically heterogeneous disease. A large subset of individuals with Type 1 diabetes has an autoimmune form of the disease characterized by subtotal loss of beta cells and positivity for islet autoantibodies as well an increase prevalence of DR3 and DR4. We have recently characterized a pathological pattern of beta cell loss […]

During the pathogenesis of Diabetes Mellitus, whether it be type 1 or 2 diabetes, islet cell heterogeneity becomes apparent. This is most commonly seen as a marked variability between the insulin content of some ß-cells versus others. Indeed, some ß-cells have such low insulin content that they appear to be empty. As such, in using […]

Our aim is to assess the protein expression level in conjunction with histological and (sub)cellular localization of the cytokine IL-21, its receptor IL-21R and GLP-1R in normal controls, (pre-)type 1 and type 2 diabetics (with history of incretin treatment for GLP-1R). (adopted by nPOD staff)

The goal of this project is to comprehensively profile the proteins expressed in human pancreas within both the islets and their surrounding environments, and to obtain relative expression levels of pancreatic proteins from different organ donor groups using mass spectrometry based bottom-up and top-down proteomics technologies. Snap-frozen pancreatic tissue sections from organ donor groups with […]

We have previously used Imaging Mass spectrometry (IMS) to identify Insulin within β-cells in the islets of Langerhans. The analysis utilized specially prepared pancreatic sections from the Network of Pancreatic Organ Donors with Diabetes (nPOD). In these studies, a comparative analysis of T1D MS spectra to those of Non-T1D revealed several uniquely expressed proteins between […]

The aim of our study is to develop an imaging agent for in vivo determination of beta-cell mass in humans. Such an imaging agent will not only provide information on progression and management of diabetes but it will also help in monitoring an individual’s response to exercise, diet and anti-diabetic therapy. Unfortunately, there aren’t any […]

In the past we identified Vesicular Monoamine Transporter Type 2 (VMAT2), as a biomarker of beta cell mass that is quantifiable in vivo by Positron Emission Tomography (PET). PET is a tomographic imaging technique providing accurate non-invasive dynamic measurements of regional PET tracer uptake and clearance. These measurements are used to calculate VMAT2 density in […]

In both Type 1 and Type 2 diabetes, there is a gradual loss of pacreatic beta cells with time. The degree of beta cell destruction may be indirectly measured by the appearance of islet-specific components in circulation. For instance, insulin mRNA is increased in circulation in T1D patients before clinical loss of function of transplanted […]

There is growing evidence that memory T cells are associated with a variety of autoimmune conditions, including type 1 diabetes (T1D). While autoreactive T cells are detected in both patients and healthy control subjects, CD45RO+ memory autoreactive T cells are usually found in patients but not in controls. Our own studies in several pancreas transplant […]

Pancreatic lymph nodes (PLN) are the central location for the autoimmune response that leads to type 1 diabetes (T1D), yet no histological studies of this crucial step in pathogenesis of human diabetes exist. In this study, we request sections from T1D and matched control PLN to allow us to follow up our preliminary observations showing […]

Growing evidence suggests inflammation as a major underlying mechanism in the pathogenesis of type 2 diabetes mellitus (T2DM). Supporting the involvement of the immune system in T2DM, cross-sectional and prospective studies have associated elevated circulating levels of acute-phase proteins. Furthermore, clinical studies have demonstrated that anti-inflammatory drugs may improve glycaemia. Morphological and therapeutic intervention studies […]

Insulin-specific B lymphocytes play an important role in development of autoimmunity in Type 1 Diabetes (T1D). Since potentially offensive autoreactive cells are silenced by mechanisms of immune tolerance, participation of insulin-binding B cells (IBCs) in T1D must reflect escape from this silencing. Examining this question, we found that those IBCs bearing antigen receptors with high […]

Type 1 diabetes (T1D) has devastating effects on the health and quality of life of those affected. Several studies have associated the proinflammatory cytokine IL‐18 with an increased risk of T1D. Significantly higher IL-18 cytokine levels are seen in individuals at high risk for developing disease, increased serum levels of IL‐18 have been observed in […]

The majority of human T cell antigens relevant to T1D have been defined using algorithms which predict high affinity peptide binding to MHC.   However, direct evidence showing that these antigens are presented to T cells by human islets and APCs in T1D patients has not been established for the vast majority of these peptides.  A […]

Maternal microchimerism (MMc) is acquired by an infant during pregnancy and these cells are maintained in some individuals for decades.  Encountering maternal antigens during pregnancy represents the first immunological challenge for the fetus although maternal cells are protected from detection by induction of suppressive fetal regulatory T cells. In type 1 diabetes increased levels of […]

1. To test the hypothesis that vascular endothelial cells in the pancreas of recent-onset diabetic patients have increased expression of VEGF receptors (VEGF-R). 2. To examine the expression of VEGF or VEGF-R on islet-invading CD4+ T lymphocytes. 3. To examine the utility of TCR repertoire between different T cell subsets as a marker of T1D […]

Our group is studying T cell phenotype and antigen presentation and recognition by T cells in T1D, with three main objectives. (i) The characterization of role of T cells involved in immunoregulation, i.e. regulatory T cells (nTregs or iTregs) and NKT cells. We are studying the mechanisms of regulation by analyzing the role of soluble […]

Migration of lymphocytes from blood vessels into pancreatic lymph nodes (PanLNs) and pancreas is critical for the development of islet inflammation and beta cell destruction in type 1 diabetes (T1D). Adhesion of lymphocytes to the luminal surface of blood vessel endothelia in PanLNs and pancreas is an important step in this migration. However, the adhesion […]

Interleukin-15 (IL-15) is a pro-inflammatory cytokine that promotes the activation and maintenance of natural killer (NK) and CD8 (+) T-effector memory (T-EM) cells. In patients with type 1 diabetes, elevated serum levels of IL-15 have been reported. Using an assay developed in the lab, we demonstrated that the serum sIL-15Rα levels were significantly higher in […]

In Type 1 Diabetes (T1D), the complex interplay of immune cells shifts the balance in favor of the development of lymphocytes, that attack structures of our own body: autoimmunity. These attacks resulting in an inflammation in the pancreas and, eventually, to the destruction of insulin producing beta cells. Cytokines are small proteins that are released […]

Tyrosine kinase inhibitors (TKis) effectively limit autoimmunity in animal models and are under clinical study in RA, MS and psoriasis. Recent studies in NOD mice have demonstrated proof-of-principal for promiscuous PTK blockade, using inhibitors initially developed to inhibit oncogenic pathways in cancer. Our recent work has shown that the selective Syk inhibitor R788 limits diabetes […]

One of the major questions we still don’t have an answer to is why some people who are genetically predisposed for development of T1D don’t progress and why others do. In addition, why there are different timings for the progression of this disease (i.e. why are some faster than others).  Our thoughts are that these […]

We have identified type 1 diabetes (T1D)-associated differential DNA methylated variable positions (T1D-MVPs) in CD14+ from peripheral blood mononuclear cells (PBMCs) from monozygotic (MZ) twins discordant for T1D (Rakyan V et al.; Plos Genetics 2011). We aim to determine the role of T1D-associated MVPs in the mechanisms that underpin immune dysfunction in T1D. We have therefore […]

The focus of our Breakthrough T1D Autoimmunity Center is to create and study a humanized mouse model of Type 1 diabetes. The approach that we are developing involves use of immune deficient (γc-/-) mice with “knock-in” of human cytokine and other genes that are needed for optimal reconstitution with human cells. In addition, we have created transgenic mice that […]

As with many autoimmune diseases, T1D is initiated by some unknown inciting event (or events) that results in the appearance of disease-relevant biomarkers.  Serum autoantibodies to islet antigens or changes in whole blood gene expression that appear before the onset of glucose intolerance can serve as biomarkers to identify pre-diabetic individuals. As we enter the […]

One of the primary characteristics of Type 1 Diabetes (T1D) is the presence of autoantibodies directed to self-antigens expressed in the pancreatic islets, specifically those associated with the insulin secretory machinery. Although T1D is well characterized as a T-cell mediated disease, a mechanistic role of islet autoantibodies generated during the progression of T1D have not […]

Aire+ cells were readily identified by immuno-staining in both PN and nPLN sections. Like in mouse, human eTACs were relatively rare but localized outside the B-cell follicles and stained with the hallmark “nuclear speckling” pattern. Furthermore, the eTACs were ubiquitously positive for MHC class II but lacked high expression of CD11c, calling into question their […]

Our project entitled humoral immunity investigates several serological aspects of Type 1 Diabetes (T1D). Our group also serves as the ELISA autoantibody core wherein we oversee the screening laboratories and together with the University of Colorado maintain quality assurance and control for this program. However we also conduct research into additional aspects of autoantibodies from […]

Despite improvement in insulin delivery, maintaining tight control of glucose homeostasis continues to be a challenge that results in bouts of severe hypoglycemia and hyperglycemia and serious long term complications in many patients. Therefore, developing an immunotherapy for type 1 diabetes (T1D) remains a major goal. Reaching this goal requires detailed knowledge of the diabetogenic […]

An altered balance between pathogenic and regulatory pathways in autoimmunity has been hypothesized and at times demonstrated in peripheral blood of patients with type 1 diabetes. However, our knowledge in humans at the sites of the autoimmune attack (i.e., the pancreas) is scanty. Studies generated in our lab. demonstrate that FOXP3+ T regulatory (Treg) cells, […]

Our understanding of type 1 diabetes (T1D) has been advanced greatly by studies carried out using mice and rats. However, rodents are not humans and progress in the understanding of the pathogenesis of T1D in humans has been impeded by the a lack of assays that permit the direct in vivo analysis of diabetogenic human […]

To determine the specificities and frequencies of islet autoreactive CD8 T-cells in pancreas draining lymph nodes, control lymph nodes, spleen and/or peripheral blood from diabetic and non-diabetic organ donors, we used the Diab-Q-kit, a nanotechnology that allows the direct detection of circulating autoreactive CD8 T-cells against an array of islet-epitopes simultaneously, reducing the needs of […]

Type 1A Diabetes mellitus (T1D) is a predominantly T cell mediated autoimmune endocrine disease. Both CD4+ and CD8+ T cells reactive to diabetic autoantigens can be identified at low frequency in the peripheral blood of diabetic subjects and their at-risk relatives, but the extent to which these peripheral responses reflect those in the pancreatic draining […]

nPOD participated in the ImmunoChip consortium, that was established to design a cost effective genotyping array in order to fine map well established GWAS reported risk loci in immunologically related human diseases, including type 1 diabetes.

We hypothesize that the alterations seen in diabetic BM are a major cause of impaired homeostasis in other vascular beds. Main objectives (1) to obtain a deeper insight into the cellular and vascular composition of diabetic BM using IHC, flow cytometry, and expressional studies (2) to determine whether BM microangiopathy is associated to poor metabolic control and increased susceptibility […]

Type 1 diabetes (T1D) represents a major public health burden demanding innovative treatment strategies. Mesenchymal stem cells (MSC) have profound immunomodulatory effects. Numerous clinical trials have focused on the immunomodulatory capacity of MSC to treat various immune-mediated diseases.  We were amongst the first to show the protective effects of allogeneic MSC in autoimmune diabetes in […]

Despite advances in understanding the pathogenesis of diabetic retinopathy (DR), the nature and time course of the molecular changes associated with DR remain incompletely understood. We propose to investigate the mechanism of bone marrow (BM) failure in diabetes and test diverse therapeutic approaches to correct BM and bone marrow progenitor cell (BMPC) dysfunction in order […]

Beta-cell apoptosis contributes to loss of β-cells and decreases in β-cell function in both types 1 and 2diabetes mellitus. It is therefore important to understand the mechanisms underlying β -cell apoptosis if this process is to be prevented or delayed. Our hypothesis is that the group VIA Ca2+-independent phospholipase A2 (iPLA2 β) participates in β […]

Characterization of expression of novel anti-diabetes targets in pancreas of Type 1 and Type 2 diabetics.

The therapeutic treatment of type 1 and type 2 diabetes mellitus (T1DM, T2DM) has vastly improved over the past decades; however complete normalization of glucose remains elusive without proper functioning pancreatic β cells. Truly, sustained and effective treatment of T1DM and T2DM must involve retaining/replacing the function of pancreatic β cells. To this end, we […]

To confirm and publish our preliminary observations (Diabetes 55 (supplement 1):64-OR, 2006) suggesting that humans with Type 1 Diabetes Mellitus have a marked and islet-selected loss of their sympathetic nerves, similar to that we have observed in animal models of autoimmune diabetes. If true such a defect may contribute to the impaired glucagon response to […]

ORIGINAL: This research seeks immunohistochemical evidence of beta cell oxidative and nitrosative stress during various stages of T1D and whether such stressors are also present preceding and during the early onset of the disease. Antibodies to nitrotyrosine, a marker of peroxynitrite-mediated cell damage and to 8-hydroxy-2-deoxyguanosine (a marker of DNA oxidation) are being employed in […]

In rodents and humans, the rate of beta cell proliferation declines rapidly after birth; formation of the islets of Langerhans begins perinatally and continues after birth. We tested whether increased levels of E-cadherin during islet formation mediate the decline in beta cell proliferation rate by contributing to a reduction of molecules that mediate cell replication. In vitro, a […]

We cloned a genetic modifier of T2D in obese mice. The gene, Ildr2, encodes a molecule that plays a role in both lipid metabolism and cellular responses to stress.  Animals with lower levels of expression of this gene has reduced number of insulin producing cells in the pancreas, and, ultimately went on to develop mild diabetes.  How […]

The aim of this study is to determine how CFTR mutations affect beta cell performance, and whether their effect is direct (cell-autonomous), or indirect, by affecting other cell types/physiological processes with secondary consequences for beta cell function and viability. It is likely that any mechanistic insights obtained from the study of this specific etiology of […]

12/15-lipoxygenase (12/15-LO) is an enzyme responsible for the metabolism of arachidonic acid to pro-inflammatory responses by immune cells in a variety of tissues, including pancreatic islets and fat tissues.  Our extensive research has shown that type 1-like diabetes development is significantly diminished in the absence of 12/15-lipoxygenase.  By using 12/15-LO deficient C57BL/6 mice, we were […]

Recent evidence suggests that beta cell dedifferentiation is a key early mechanism that underlies the pathogenesis of type 2 diabetes (T2D) [1]. This includes the loss of transcriptional regulators of beta cell function as well as other critical components of beta cell function. The study further suggests that beta cell dedifferentiation and acquisition of progenitor markers precedes […]

Recent decades have seen an incredible growth in the prevalence of diabetes. While it is important to pursue multiple therapeutic strategies, harnessing the regenerative capacity of islet β-cells to increase an individual’s insulin secretion capacity is among the promising approaches. Recently, discovery-oriented unbiased chemical screening led to the identification of the metabolic enzyme adenosine kinase […]

ORIGINAL: We have been interested in the mechanisms by which beta-cells regenerate in diabetes. Our laboratory is interested in how beta -cells regenerate under normal and pathophysiological conditions, with the goal of developing new therapies for diabetes that result in an increased number of those cells. There are two possible mechanisms for endogenous regeneration: beta-cell […]

It is well accepted that compromised ß-cell function is an integral part of diabetes development.  Several recent studies, mostly using complex genetic mouse models, have supported the notion that a change in the ß-cell state or identity due to varying insults causes diabetes in the absence of ß-cell death.  Our work has focused on the […]

Our work aims to understand the defects were deficiencies in the pancreatic beta cells of diabetics. We use a number of molecular methods, including but not limited to single cell RNA sequencing, to characterize the molecular phenotypes of islet cells.

ORIGINAL PROJECT: Established different skin fibroblast cell lines, both from control and T1D nPOD donors. Graciously offered this as a resource available to current nPOD investigators. ADDENDUM: The pancreata of nPOD cases are some of the best characterized type 1 diabetes cases. The availability of beta cells from stem cells would greatly enhance this resource […]

Diabetes is associated with β-cell dysfunction. But it remains unclear whether the latter results from reduced β-cell number or function. Purpose of this study is to investigate the hypothesis that β-cell failure is the result of β-cell dedifferentiation, rather than apoptosis or degranutaion. Transcription factor FoxO1 integrates β-cell proliferation with adaptive β-cell function. The rationale […]