Is Diabetes Mellitus a Continuous Spectrum?
ABSTRACT Diabetes mellitus has been historically divided into type 1 and type 2 diabetes, with type 1 being an autoimmune disease and type 2 being primarily a metabolic disease.
The current diabetes classification scheme needs to be reevaluated because of the accumulating evidence of immune system involvement in the pathophysiology of type 2 diabetes.
There are similarities and differences between type 1 and type 2 diabetes with regard to pathogenesis, pathophysiology, and genetics. We propose a resolution to the dilemma of the current classification scheme.
- SourceAvailable from: PubMed Central
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- "During the progression of the disease, autoimmune-mediated apoptosis of beta cells leads to a continuous reduction of insulin secretion and beta cell mass (5). Some phenotypic T2DM subjects also present markers of autoimmunity and these are correlated with beta cell function, suggesting a possible role of immune system in the pathogenesis of T2DM (4,40,41). Reports have indicated that about 10% of individuals with T2DM have diabetes-specific autoantibodies, but the percentage is higher in younger-age and in leaner groups (42). More recent data indentified T2DM subjects with islet-reactive T cell responses (with or without autoantibodies) and these were correlated with a lower beta cell function (41). "
ABSTRACT: Diabetes is a complex, heterogeneous condition that has beta cell dysfunction at its core. Many factors (e.g. hyperglycemia/glucotoxicity, lipotoxicity, autoimmunity, inflammation, adipokines, islet amyloid, incretins and insulin resistance) influence the function of pancreatic beta cells. Chronic hyperglycaemia may result in detrimental effects on insulin synthesis/secretion, cell survival and insulin sensitivity through multiple mechanisms: gradual loss of insulin gene expression and other beta-cell specific genes; chronic endoplasmic reticulum stress and oxidative stress; changes in mitochondrial number, morphology and function; disruption in calcium homeostasis. In the presence of hyperglycaemia, prolonged exposure to increased free fatty acids result in accumulation of toxic metabolites in the cells (“lipotoxicity”), finally causing decreased insulin gene expression and impairment of insulin secretion. The rest of the factors/mechanisms which impact on the course of the disease are also discusses in detail. The correct assessment of beta cell function requires a concomitant quantification of insulin secretion and insulin sensitivity, because the two variables are closely interrelated. In order to better understand the fundamental pathogenetic mechanisms that contribute to disease development in a certain individual with diabetes, additional markers could be used, apart from those that evaluate beta cell function. The aim of the paper was to overview the relevant mechanisms/factors that influence beta cell function and to discuss the available methods of its assessment. In addition, clinical considerations are made regarding the therapeutical options that have potential protective effects on beta cell function/mass by targeting various underlying factors and mechanisms with a role in disease progression.Biochemia Medica 10/2013; 23(3):266-80. DOI:10.11613/BM.2013.033 · 2.40 Impact Factor
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- "IL-17A is a well-known pro-inflammatory cytokine involved in autoimmune diseases. Importantly, mounting evidence collected over the past decade indicates that the etiology of T2D includes an autoimmune component that initiates an inflammation affecting pancreatic islet β cells [8,28-32], which provides new insight into the mechanism and potential treatment of insulin resistance through immune modulation. Recent clinical studies showed the increase of circulating Th17 cells and IL-17 production in T2D patients  and obese patients . "
ABSTRACT: The prevalence of type 2 diabetes (T2D) is increasing worldwide and creating a significant burden on health systems, highlighting the need for the development of innovative therapeutic approaches to overcome immune dysfunction, which is likely a key factor in the development of insulin resistance in T2D. It suggests that immune modulation may be a useful tool in treating the disease. In an open-label, phase 1/phase 2 study, patients (N = 36) with long-standing T2D were divided into three groups (Group A, oral medications, n = 18; Group B, oral medications + insulin injections, n = 11; Group C having impaired beta-cell function with oral medications + insulin injections, n = 7). All patients received one treatment with the Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates mononuclear cells from the whole blood, briefly co-cultures them with adherent cord blood-derived multipotent stem cells (CB-SCs), and returns the educated autologous cells to the patient's circulation. Clinical findings indicate that T2D patients achieve improved metabolic control and reduced inflammation markers after receiving Stem Cell Educator therapy. Median glycated hemoglobin (HbA1C) in Group A and B was significantly reduced from 8.61% +/- 1.12 at baseline to 7.25% +/- 0.58 at 12 weeks (P = 2.62E-06), and 7.33% +/- 1.02 at one year post-treatment (P = 0.0002). Homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) demonstrated that insulin sensitivity was improved post-treatment. Notably, the islet beta-cell function in Group C subjects was markedly recovered, as demonstrated by the restoration of C-peptide levels. Mechanistic studies revealed that Stem Cell Educator therapy reverses immune dysfunctions through immune modulation on monocytes and balancing Th1/Th2/Th3 cytokine production. Clinical data from the current phase 1/phase 2 study demonstrate that Stem Cell Educator therapy is a safe approach that produces lasting improvement in metabolic control for individuals with moderate or severe T2D who receive a single treatment. In addition, this approach does not appear to have the safety and ethical concerns associated with conventional stem cell-based approaches.Trial registrationClinicalTrials.gov number, NCT01415726.BMC Medicine 07/2013; 11(1):160. DOI:10.1186/1741-7015-11-160 · 7.28 Impact Factor
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- "Diabetes is classified as a group of chronic metabolic disorders that are characterized by elevated blood glucose levels due to the insufficient production of insulin and/or peripheral insulin resistance . The strict division into type 1 and type 2 diabetes based on an autoimmune etiology versus a primarily metabolic pathology, respectively, has been challenged over the last few years  and it has recently been suggested that a continuous spectrum of diabetic disorders exist . Classical type 2 diabetes is a heterogeneous cluster of disorders, whereby both lifestyle and genetic factors play a role in its pathogenesis . "
ABSTRACT: Insulin resistance in skeletal muscle tissues and diabetes-related muscle weakness are serious pathophysiological problems of increasing medical importance. In order to determine global changes in the protein complement of contractile tissues due to diabetes mellitus, mass-spectrometry-based proteomics has been applied to the investigation of diabetic muscle. This review summarizes the findings from recent proteomic surveys of muscle preparations from patients and established animal models of type 2 diabetes. The potential impact of novel biomarkers of diabetes, such as metabolic enzymes and molecular chaperones, is critically examined. Disease-specific signature molecules may be useful for increasing our understanding of the molecular and cellular mechanisms of insulin resistance and possibly identify new therapeutic options that counteract diabetic abnormalities in peripheral organ systems. Importantly, the biomedical establishment of biomarkers promises to accelerate the development of improved diagnostic procedures for characterizing individual stages of diabetic disease progression, including the early detection of prediabetic complications.Journal of nutrition and metabolism 02/2012; 2012:893876. DOI:10.1155/2012/893876