Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies

Center for Type 1 Diabetes Research, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
Physiological Reviews (Impact Factor: 27.32). 01/2011; 91(1):79-118. DOI: 10.1152/physrev.00003.2010
Source: PubMed


Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.

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    • "Type 1 diabetes mellitus (T1DM) is an autoimmune disease leading to beta cell destruction and lowered insulin production [1]. Insulin administration, as the standard treatment strategy for type 1 diabetes, cannot exactly mimic the physiologic secretion of insulin in the body [2]. "
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    ABSTRACT: Type 1 diabetes mellitus (T1DM) is an autoimmune disorder that leads to beta cell destruction and lowered insulin production. In recent years, stem cell therapies have opened up new horizons to treatment of diabetes mellitus. Among all kinds of stem cells, mesenchymal stem cells (MSCs) have been shown to be an interesting therapeutic option based on their immunomodulatory properties and differentiation potentials confirmed in various experimental and clinical trial studies. In this review, we discuss MSCs differential potentials in differentiation into insulin-producing cells (IPCs) from various sources and also have an overview on currently understood mechanisms through which MSCs exhibit their immunomodulatory effects. Other important issues that are provided in this review, due to their importance in the field of cell therapy, are genetic manipulations (as a new biotechnological method), routes of transplantation, combination of MSCs with other cell types, frequency of transplantation, and special considerations regarding diabetic patients’ autologous MSCs transplantation. At the end, utilization of biomaterials either as encapsulation tools or as scaffolds to prevent immune rejection, preparation of tridimensional vascularized microenvironment, and completed or ongoing clinical trials using MSCs are discussed. Despite all unresolved concerns about clinical applications of MSCs, this group of stem cells still remains a promising therapeutic modality for treatment of diabetes.
    Full-text · Article · Nov 2015 · Journal of Diabetes Research
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    • "Over time, pancreatic b-cells fail to compensate for the increased insulin demand due to loss of key b-cell functions such as glucose-stimulated insulin secretion (GSIS), in concert with a gradual depletion of b-cell mass [2]. In contrast, T1D, which often manifests during childhood, is a result of selective autoimmune destruction of the pancreatic b-cells, leading to insulin deficiency [3]. The mechanisms linking glucose metabolism and insulin secretion in the b-cell are still incompletely understood, as are the mechanisms of b-cell dysfunction and death. "
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    ABSTRACT: Metabolomics, the characterization of the set of small molecules in a biological system, is advancing research in multiple areas of islet biology. Measuring a breadth of metabolites simultaneously provides a broad perspective on metabolic changes as the islets respond dynamically to glucose or environmental stressors. As a result, metabolomics has the potential to provide new mechanistic insights into islet physiology and pathophysiology. Here we summarize advances in our understanding of islet physiology and the etiologies of type-1 and type-2 diabetes derived from metabolomics studies. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Archives of Biochemistry and Biophysics
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    • "Pancreatic í µí»½-cell damage is the fundamental pathogenesis of type 1 diabetes, which is mediated by an autoimmune and inflammatory process[1]. Disruption of pancreatic í µí»½cells leading to islet dysfunction and reduced í µí»½-cell mass is also implicated in type 2 diabetes[2]. "
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    ABSTRACT: Oxidative stress is implicated in the pathogenesis of pancreatic β-cell dysfunction that occurs in both type 1 and type 2 diabetes. Nuclear factor E2-related factor 2 (NRF2) is a master regulator in the cellular adaptive response to oxidative stress. The present study found that MIN6 β-cells with stable knockdown of Nrf2 (Nrf2-KD) and islets isolated from Nrf2-knockout mice expressed substantially reduced levels of antioxidant enzymes in response to a variety of stressors. In scramble MIN6 cells or wild-type islets, acute exposure to oxidative stressors, including hydrogen peroxide (H2O2) and S-nitroso-N-acetylpenicillamine, resulted in cell damage as determined by decrease in cell viability, reduced ATP content, morphology changes of islets, and/or alterations of apoptotic biomarkers in a concentration- and/or time-dependent manner. In contrast, silencing of Nrf2 sensitized MIN6 cells or islets to the damage. In addition, pretreatment of MIN6 β-cells with NRF2 activators, including CDDO-Im, dimethyl fumarate (DMF), and tert-butylhydroquinone (tBHQ), protected the cells from high levels of H2O2-induced cell damage. Given that reactive oxygen species (ROS) are involved in regulating glucose-stimulated insulin secretion (GSIS) and persistent activation of NRF2 blunts glucose-triggered ROS signaling and GSIS, the present study highlights the distinct roles that NRF2 may play in pancreatic β-cell dysfunction that occurs in different stages of diabetes.
    Full-text · Article · May 2015 · Oxidative medicine and cellular longevity
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