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

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

Journal of Investigative Medicine ◽

10.1136/jim-d-15-00196 ◽

2016 ◽

Vol 64 (1) ◽

pp. 14-20 ◽

Cited By ~ 2

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.

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

10.1101/2020.10.28.359687 ◽

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.

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Immune interventions to preserve β cell function in type 1 diabetes

Journal of Investigative Medicine ◽

10.1097/jim.0000000000000227 ◽

2016 ◽

Vol 64 (1) ◽

pp. 7-13 ◽

Cited By ~ 11

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.

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A focus on the role of Pax4 in mature pancreatic islet β-cell expansion and survival in health and disease

Journal of Molecular Endocrinology ◽

10.1677/jme-07-0134 ◽

2007 ◽

Vol 40 (2) ◽

pp. 37-45 ◽

Cited By ~ 35

Author(s):

Thierry Brun ◽

Benoit R Gauthier

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Pancreatic Islet ◽

Cell Expansion ◽

Cell Mass ◽

Cell Physiology ◽

Β Cells ◽

Β Cell

Blood glucose homeostasis is achieved by the regulation of insulin and glucagon secretion from the pancreatic islet β- and α-cells. Diabetes mellitus, which comprises a heterogeneous group of hyperglycaemic disorders, results mainly from inadequate mass and function of islet β-cells. Autoimmune destruction of β-cells causes type 1 diabetes, while type 2 is characterized by impaired insulin secretion and is often associated with diminished insulin action on its target tissues. Interestingly, similar to type 1 diabetes, a gradual loss of β-cell mass is observed in type 2 diabetes often requiring insulin therapy. Understanding the molecular mechanism that governs β-cell mass plasticity may provide a means to develop strategies to countera,ct β-cell death while increasing replication. Of particular interest is the islet-specific transcription factor paired box4 (Pax4) that was previously shown to be indispensable for the establishment of the β-cell lineage during development. However, recent accumulating evidence now suggest that Pax4 is also crucial for mature β-cell expansion and survival in response to physiological cues and that mutations or polymorphisms are associated with both type 1 and type 2 diabetes. In contrast, aberrant expression of Pax4 confers protection against apoptosis to insulinomas, whereas it promotes cell growth in lymphocytes. This review summarizes promising new published results supporting the important function of Pax4 in mature islet β-cell physiology and its contribution to pathophysiology when deregulated.

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Use of a systems biology approach to understand pancreatic β-cell death in Type 1 diabetes

Biochemical Society Transactions ◽

10.1042/bst0360321 ◽

2008 ◽

Vol 36 (3) ◽

pp. 321-327 ◽

Cited By ~ 35

Author(s):

Decio L. Eizirik ◽

Fabrice Moore ◽

Daisy Flamez ◽

Fernanda Ortis

Keyword(s):

Cell Death ◽

Type 1 Diabetes ◽

Systems Biology ◽

Gene Networks ◽

Nuclear Factor Κb ◽

Signal Transducer ◽

Trial And Error ◽

Β Cells ◽

Β Cell

Accumulating evidence indicates that β-cells die by apoptosis in T1DM (Type 1 diabetes mellitus). Apoptosis is an active gene-directed process, and recent observations suggest that β-cell apoptosis depends on the parallel and/or sequential up- and down-regulation of hundreds of genes controlled by key transcription factors such as NF-κB (nuclear factor κB) and STAT-1 (signal transducer and activator of transcription 1). Understanding the regulation of these gene networks, and how they modulate β-cell death and the ‘dialogue’ between β-cells and the immune system, will require a systems biology approach to the problem. This will hopefully allow the search for a cure for T1DM to move from a ‘trial-and-error’ approach to one that is really mechanistically driven.

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Towards a Curative Therapy in Type 1 Diabetes: Remission of Autoimmunity, Maintenance and Augmentation of β Cell Mass

Novartis Foundation Symposia - Defining Optimal Immunotherapies for Type 1 Diabetes ◽

10.1002/9780470697405.ch14 ◽

2008 ◽

pp. 146-158 ◽

Cited By ~ 11

Author(s):

Frank Waldron-Lynch ◽

Matthias von Herrath ◽

Kevan C. Herold

Keyword(s):

Type 1 Diabetes ◽

Cell Mass ◽

Diabetes Remission ◽

Β Cell ◽

Curative Therapy

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Nonlinear Analysis for a Type-1 Diabetes Model with Focus on T-Cells and Pancreatic β-Cells Behavior

Mathematical and Computational Applications ◽

10.3390/mca25020023 ◽

2020 ◽

Vol 25 (2) ◽

pp. 23

Author(s):

Diana Gamboa ◽

Carlos E. Vázquez ◽

Paul J. Campos

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Cell Population ◽

Closed Loop ◽

Pancreatic Β Cell ◽

Activated Macrophages ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

Type-1 diabetes mellitus (T1DM) is an autoimmune disease that has an impact on mortality due to the destruction of insulin-producing pancreatic β -cells in the islets of Langerhans. Over the past few years, the interest in analyzing this type of disease, either in a biological or mathematical sense, has relied on the search for a treatment that guarantees full control of glucose levels. Mathematical models inspired by natural phenomena, are proposed under the prey–predator scheme. T1DM fits in this scheme due to the complicated relationship between pancreatic β -cell population growth and leukocyte population growth via the immune response. In this scenario, β -cells represent the prey, and leukocytes the predator. This paper studies the global dynamics of T1DM reported by Magombedze et al. in 2010. This model describes the interaction of resting macrophages, activated macrophages, antigen cells, autolytic T-cells, and β -cells. Therefore, the localization of compact invariant sets is applied to provide a bounded positive invariant domain in which one can ensure that once the dynamics of the T1DM enter into this domain, they will remain bounded with a maximum and minimum value. Furthermore, we analyzed this model in a closed-loop scenario based on nonlinear control theory, and proposed bases for possible control inputs, complementing the model with them. These entries are based on the existing relationship between cell–cell interaction and the role that they play in the unchaining of a diabetic condition. The closed-loop analysis aims to give a deeper understanding of the impact of autolytic T-cells and the nature of the β -cell population interaction with the innate immune system response. This analysis strengthens the proposal, providing a system free of this illness—that is, a condition wherein the pancreatic β -cell population holds and there are no antigen cells labeled by the activated macrophages.

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