scholarly journals Detecting Insulitis in Type 1 Diabetes with Ultrasound Phase-change Contrast Agents

2020 ◽  
Author(s):  
David G. Ramirez ◽  
Awaneesh K. Upadhyay ◽  
Vinh T. Pham ◽  
Mark Ciccaglione ◽  
Mark A Borden ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Contrast Agents ◽  
Cell Mass ◽  
Nod Mice ◽  
Therapeutic Interventions ◽  
Β Cells ◽  
Β Cell ◽  
Diabetes Onset ◽  
Ultrasound Contrast

AbstractType 1 diabetes (T1D) results from immune infiltration and destruction of insulin-producing β-cells within the pancreatic islets of Langerhans (insulitis), resulting in loss of glucose homeostasis. Early diagnosis during pre-symptomatic T1D would allow for therapeutic intervention prior to substantial loss of β-cell mass at T1D onset. There are limited methods to track the progression of insulitis and β-cell mass decline in pre-symptomatic T1D. During insulitis, the islet microvasculature increases permeability, such that sub-micron sized particles can extravasate and accumulate within the islet microenvironment. Ultrasound is a widely deployable and cost-effective clinical imaging modality. However, conventional microbubble contrast agents are restricted to the vasculature. Sub-micron sized nanodroplet (ND) phasechange agents can be vaporized into micron-sized bubbles; serving as a circulating microbubble precursor. We tested if NDs extravasate into the immune-infiltrated islet microenvironment. We performed ultrasound contrast-imaging following ND infusion in NOD mice and NOD;Rag1ko controls, and tracked diabetes development. We measured the biodistribution of fluorescently labeled NDs, with histological analysis of insulitis. Ultrasound contrast signal was elevated in the pancreas of 10w NOD mice following ND infusion and vaporization, but was absent in both the non-infiltrated kidney of NOD mice and pancreas of Rag1ko controls. High contrast elevation also correlated with rapid diabetes onset. In pancreata of NOD mice, infiltrated islets and nearby exocrine tissue were selectively labeled with fluorescent NDs. Thus, contrast ultrasound imaging with ND phase-change agents can detect insulitis prior to diabetes onset. This will be important for monitoring disease progression to guide and assess preventative therapeutic interventions for T1D.SignificanceThere is a need for imaging methods to detect type1 diabetes (T1D) progression prior to clinical diagnosis. T1D is a chronic disease that results from autoreactive T cells infiltrating the islet of Langerhans and destroying insulin-producing β-cells. Overt disease takes years to present and is only diagnosed after significant β-cells loss. As such, the possibility of therapeutic intervention to preserve β-cell mass is hampered by an inability to follow pre-symptomatic T1D progression. There are immunotherapies that can delay T1D development. However identifying ‘at risk’ individuals, and tracking whether therapeutic interventions are impacting disease progression, prior to T1D onset, is lacking. A method to detect insulitis and β-cell mass decline would present an opportunity to guide therapeutic treatments to prevent T1D.

scholarly journals Detecting insulitis in type 1 diabetes with ultrasound phase-change contrast agents

2021 ◽  
Vol 118 (41) ◽  
pp. e2022523118
Author(s):  
David G. Ramirez ◽  
Mark Ciccaglione ◽  
Awaneesh K. Upadhyay ◽  
Vinh T. Pham ◽  
Mark A. Borden ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Phase Change ◽  
Contrast Agents ◽  
Change Agents ◽  
Nod Mice ◽  
Β Cell ◽  
Diabetes Onset ◽  
Ultrasound Contrast ◽  
Pancreatic Islets Of Langerhans

Type 1 diabetes (T1D) results from immune infiltration and destruction of insulin-producing β cells within the pancreatic islets of Langerhans (insulitis). Early diagnosis during presymptomatic T1D would allow for therapeutic intervention prior to substantial β-cell loss at onset. There are limited methods to track the progression of insulitis and β-cell mass decline. During insulitis, the islet microvasculature increases permeability, such that submicron-sized particles can extravasate and accumulate within the islet microenvironment. Ultrasound is a widely deployable and cost-effective clinical imaging modality. However, conventional microbubble contrast agents are restricted to the vasculature. Submicron nanodroplet (ND) phase-change agents can be vaporized into micron-sized bubbles, serving as a microbubble precursor. We tested whether NDs extravasate into the immune-infiltrated islet microenvironment. We performed ultrasound contrast-imaging following ND infusion in nonobese diabetic (NOD) mice and NOD;Rag1ko controls and tracked diabetes development. We measured the biodistribution of fluorescently labeled NDs, with histological analysis of insulitis. Ultrasound contrast signal was elevated in the pancreas of 10-wk-old NOD mice following ND infusion and vaporization but was absent in both the noninfiltrated kidney of NOD mice and the pancreas of Rag1ko controls. High-contrast elevation also correlated with rapid diabetes onset. Elevated contrast was also observed as early as 4 wk, prior to mouse insulin autoantibody detection. In the pancreata of NOD mice, infiltrated islets and nearby exocrine tissue were selectively labeled with fluorescent NDs. Thus, contrast ultrasound imaging with ND phase-change agents can detect insulitis prior to diabetes onset. This will be important for monitoring disease progression, to guide and assess preventative therapeutic interventions for T1D.

scholarly journals Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis and β-cell mass decline in mouse models of type 1 diabetes

2019 ◽  
Author(s):  
David G. Ramirez ◽  
Eric Abenojar ◽  
Christopher Hernandez ◽  
Lucine A. Papazian ◽  
Samantha Passman ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Mouse Models ◽  
Cell Mass ◽  
Nod Mice ◽  
Contrast Enhanced Ultrasound ◽  
Β Cell ◽  
Ultrasound Contrast ◽  
Contrast Enhanced ◽  
Asymptomatic Phase

ABSTRACTType 1 diabetes (T1D) is characterized by the infiltration of autoreactive T-cells into the islet of Langerhans, and depletion of insulin-secreting β-cells. This immune cell infiltration (insulitis) first occurs during an asymptomatic phase of T1D that can take place many years prior to clinical diagnosis. Methods to diagnose insulitis and changes in β-cell mass during this asymptomatic phase are limited, thus precluding early therapeutic intervention. While therapeutic treatments can delay T1D progression, treatment efficacy is limited and widely varying, and a method to track this efficacy is also lacking. During T1D progression, the islet microvasculature increases permeability as a result of insulitis, in both mouse models of T1D and humans with T1D. This increased permeability can allow nanoparticles, such as contrast agents for diagnostic imaging, to access the islet microenvironment. Contrast enhanced ultrasound (CEUS) uses shell-stabilized gas bubbles to provide high acoustic backscatter in vasculature and tissue and is clinically approved. A novel, sub-micron sized ‘nanobubble’ (NB) ultrasound contrast agent has been developed and shown to extravasate and accumulate in tumors, where microvascular permeability is high. To test whether CEUS can be used to measure increased islet microvasculature permeability and indicate the asymptomatic phase of T1D, we applied CEUS measurements with NBs in pre-clinical T1D models. NOD mice and mice receiving an adoptive-transfer of diabetogenic splenocytes showed accumulation of NBs specifically within the pancreatic islets, and only in the presence of insulitis. This accumulation was measured by both ultrasound contrast and histological analysis, and accumulation only occurred for sub-micron sized bubbles. Importantly, accumulation was detected as early as 4w in NOD mice. Thus, CEUS with sub-micron sized NB contrast agent may provide a predicative marker for disease progression early in asymptomatic T1D, as well as monitoring of disease prevention or reversal.

scholarly journals Rotavirus Infection Accelerates Type 1 Diabetes in Mice with Established Insulitis

2008 ◽  
Vol 82 (13) ◽  
pp. 6139-6149 ◽  
Author(s):  
Kate L. Graham ◽  
Natalie Sanders ◽  
Yan Tan ◽  
Janette Allison ◽  
Thomas W. H. Kay ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Nod Mice ◽  
Immune Recognition ◽  
Β Cells ◽  
Β Cell ◽  
Rotavirus Infection ◽  
Diabetes Onset ◽  
Diabetes Development

ABSTRACT Infection modulates type 1 diabetes, a common autoimmune disease characterized by the destruction of insulin-producing islet β cells in the pancreas. Childhood rotavirus infections have been associated with exacerbations in islet autoimmunity. Nonobese diabetic (NOD) mice develop lymphocytic islet infiltration (insulitis) and then clinical diabetes, whereas NOD8.3 TCR mice, transgenic for a T-cell receptor (TCR) specific for an important islet autoantigen, show more rapid diabetes onset. Oral infection of infant NOD mice with the monkey rotavirus strain RRV delays diabetes development. Here, the effect of RRV infection on diabetes development once insulitis is established was determined. NOD and NOD8.3 TCR mice were inoculated with RRV aged ≥12 and 5 weeks, respectively. Diabetes onset was significantly accelerated in both models (P < 0.024), although RRV infection was asymptomatic and confined to the intestine. The degree of diabetes acceleration was related to the serum antibody titer to RRV. RRV-infected NOD mice showed a possible trend toward increased insulitis development. Infected males showed increased CD8+ T-cell proportions in islets. Levels of β-cell major histocompatibility complex class I expression and islet tumor necrosis factor alpha mRNA were elevated in at least one model. NOD mouse exposure to mouse rotavirus in a natural experiment also accelerated diabetes. Thus, rotavirus infection after β-cell autoimmunity is established affects insulitis and exacerbates diabetes. A possible mechanism involves increased exposure of β cells to immune recognition and activation of autoreactive T cells by proinflammatory cytokines. The timing of infection relative to mouse age and degree of insulitis determines whether diabetes onset is delayed, unaltered, or accelerated.

scholarly journals Distinct Roles of β-Cell Mass and Function During Type 1 Diabetes Onset and Remission

Diabetes ◽  
2015 ◽  
Vol 64 (6) ◽  
pp. 2148-2160 ◽  
Author(s):  
Helena Chmelova ◽  
Christian M. Cohrs ◽  
Julie A. Chouinard ◽  
Cathleen Petzold ◽  
Matthias Kuhn ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cell Mass ◽  
Β Cell ◽  
Diabetes Onset ◽  
And Function

Harnessing immune cells to enhance β-cell mass in type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Ercument Dirice ◽  
Rohit N Kulkarni
Keyword(s):  
Type 1 Diabetes ◽  
Mononuclear Cells ◽  
Islet Cells ◽  
Cell Mass ◽  
Cell Loss ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Autoimmune Attack

Type 1 diabetes is characterized by early β-cell loss leading to insulin dependence in virtually all patients with the disease in order to maintain glucose homeostasis. Most studies over the past few decades have focused on limiting the autoimmune attack on the β cells. However, emerging data from patients with long-standing diabetes who continue to harbor functional insulin-producing cells in their diseased pancreas have prompted scientists to examine whether proliferation of existing β cells can be enhanced to promote better glycemic control. In support of this concept, several studies indicate that mononuclear cells that infiltrate the islets have the capacity to trigger proliferation of islet cells including β cells. These observations indicate the exciting possibility of identifying those mononuclear cell types and their soluble factors and harnessing their ability to promote β-cell growth concomitant with autoimmune therapy to prevent the onset and/or halt the progression of the disease.

scholarly journals Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity and Ameliorates Type 1 Diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Geming Lu ◽  
Francisco Rausell-Palamos ◽  
Jiamin Zhang ◽  
Zihan Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Heparan Sulfate ◽  
Dextran Sulfate ◽  
Nod Mice ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties <i>in vitro</i>. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity <i>in vitro</i>. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-γ+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.

scholarly journals Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity and Ameliorates Type 1 Diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Geming Lu ◽  
Francisco Rausell-Palamos ◽  
Jiamin Zhang ◽  
Zihan Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Heparan Sulfate ◽  
Dextran Sulfate ◽  
Nod Mice ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties <i>in vitro</i>. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity <i>in vitro</i>. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-γ+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.

scholarly journals Immune interventions to preserve β cell function in type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 7-13 ◽  
Author(s):  
Mario R Ehlers
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Immune Modulation ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell

Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to destruction of pancreatic β cells, lifelong dependence on insulin, and increased morbidity and mortality from diabetes-related complications. Preservation of residual β cells at diagnosis is a major goal because higher levels of endogenous insulin secretion are associated with better short- and long-term outcomes. For the past 3 decades, a variety of immune interventions have been evaluated in the setting of new-onset T1D, including nonspecific immunosuppression, pathway-specific immune modulation, antigen-specific therapies, and cellular therapies. To date, no single intervention has produced durable remission off therapy in most treated patients, but the field has gained valuable insights into disease mechanisms and potential immunologic correlates of success. In particular, T-cell–directed therapies, including therapies that lead to partial depletion or modulation of effector T cells and preservation or augmentation of regulatory T cells, have shown the most success and will likely form the backbone of future approaches. The next phase will see evaluation of rational combinations, comprising one or more of the following: an effector T-depleting or -modulating drug, a cytokine-based tolerogenic (regulatory T-cells–promoting) agent, and an antigen-specific component. The long term goal is to reestablish immunologic tolerance to β cells, thereby preserving residual β cells early after diagnosis or enabling restoration of β-cell mass from autologous stem cells or induced neogenesis in patients with established T1D.

scholarly journals Effective Destruction of Fas-deficient Insulin-producing β Cells in Type 1 Diabetes

2003 ◽  
Vol 198 (7) ◽  
pp. 1103-1106 ◽  
Author(s):  
Irina Apostolou ◽  
Zhenyue Hao ◽  
Klaus Rajewsky ◽  
Harald von Boehmer
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Type 1 Diabetes ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Β Cells ◽  
Β Cell ◽  
Influenza Hemagglutinin ◽  
Insulin Promoter

In type 1 diabetes, autoimmune T cells cause destruction of pancreatic β cells by largely unknown mechanism. Previous analyses have shown that β cell destruction is delayed but can occur in perforin-deficient nonobese diabetic (NOD) mice and that Fas-deficient NOD mice do not develop diabetes. However, because of possible pleiotropic functions of Fas, it was not clear whether the Fas receptor was an essential mediator of β cell death in type 1 diabetes. To directly test this hypothesis, we have generated a β cell–specific knockout of the Fas gene in a transgenic model of type 1 autoimmune diabetes in which CD4+ T cells with a transgenic TCR specific for influenza hemagglutinin (HA) are causing diabetes in mice that express HA under control of the rat insulin promoter. Here we show that the Fas-deficient mice develop autoimmune diabetes with slightly accelerated kinetics indicating that Fas-dependent apoptosis of β cells is a dispensable mode of cell death in this disease.

scholarly journals Integrated analysis of the pancreas and islets reveals unexpected findings in human male with type 1 diabetes

2021 ◽  
Author(s):  
Rachana Haliyur ◽  
John T Walker ◽  
May Sanyoura ◽  
Conrad V Reihsmann ◽  
Shristi Shrestha ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Genetic Risk Score ◽  
Cell Mass ◽  
Pancreatic Tissue ◽  
Isolated Islets ◽  
Histological Evaluation ◽  
Integrated Analysis ◽  
Β Cells ◽  
Β Cell

Abstract Clinical and pathologic heterogeneity in type 1 diabetes is increasingly being recognized. Findings in the islets and pancreas of a 22-year-old male with 8 years of type 1 diabetes were discordant with expected results and clinical history (islet autoantibodies negative, A1C 11.9%) and led to comprehensive investigation to define the functional, molecular, genetic, and architectural features of the islets and pancreas in order to understand the cause of the donor’s diabetes. Examination of the donor’s pancreatic tissue found substantial, but reduced, β cell mass with some islets devoid of β cells (29.3% of 311 islets) while other islets had many β cells. Surprisingly, isolated islets from the donor pancreas had substantial insulin secretion that is uncommon for type 1 diabetes of this duration. Targeted and whole genome sequencing and analysis did not uncover monogenic causes of diabetes but did identify high-risk HLA haplotypes and a genetic risk score suggestive of type 1 diabetes. Further review of pancreatic tissue found islet inflammation and some previously described α cell molecular features seen in type 1 diabetes. By integrating analysis of isolated islets, histological evaluation of the pancreas, and genetic information, we concluded that the donor’s clinical insulin deficiency was most likely the result autoimmune-mediated β cell loss, but that the constellation of findings was not typical for type 1 diabetes. This report highlights the pathologic and functional heterogeneity that can be present in type 1 diabetes.

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