Autoimmune Aspects of Type 2 Diabetes Mellitus - A Mini-Review

Itariu, Bianca; Stulnig, Thomas M.

doi:10.1159/000356747

Cited by 99 publications

(88 citation statements)

References 67 publications

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“…These cytokines, including TNF-a, IL-6, and IL-1b, may promote insulin resistance in the tissues, where they are produced and further affect more distant sites via circulation such as vessel walls, skeletal and cardiac muscle, kidney, and circulating leukocytes, respectively (8). Further, new data suggest that cytokines such as IL-1R, IL-1b, IL-6, or TNF-a contribute to an islet cell autoimmunity in type 2 diabetes through activation of T cells, B cells, and macrophages, increased expression of b-cell antigens, and subsequent b-cell apoptosis (5).…”

Section: Discussionmentioning

confidence: 99%

“…Novel data further suggest that chronic adipose tissue inflammation and b-cell stress cause an activation of the adaptive immune system as well, which may also participate in the progression of the inflammatory response (5). Autoimmune and inflammatory mechanisms during hyperglycemiainduced glucotoxicity could favor an increased expression of several b-cell antigens, thus increasing b-cell apoptosis through autoantibodies (6).…”

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confidence: 97%

“…Autoimmune and inflammatory mechanisms during hyperglycemiainduced glucotoxicity could favor an increased expression of several b-cell antigens, thus increasing b-cell apoptosis through autoantibodies (6). Such islet autoantibodies are presented in ;10% of subjects with diabetes, which have distinct clinical and phenotypical characteristics compared with patients with type 2 diabetes without signs of autoimmunity (5,7).…”

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confidence: 99%

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Profile of the Immune and Inflammatory Response in Individuals With Prediabetes and Type 2 Diabetes

et al. 2015

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OBJECTIVEThe inflammatory and immune systems are altered in type 2 diabetes. Here, the aim was to profile the immune and inflammatory response in subjects with prediabetes and diabetes in a large population-representative sample. RESEARCH DESIGN AND METHODSIn total, 15,010 individuals were analyzed from the population-based Gutenberg Health Study. Glucose status was classified according to HbA 1c concentration and history of diagnosis. All samples were analyzed for white blood cells (WBCs), granulocytes, lymphocytes, monocytes, platelets, C-reactive protein (CRP), albumin, fibrinogen, and hematocrit. Interleukin-18 (IL-18), IL-1 receptor antagonist (IL-1RA), and neopterin concentrations were determined in a subcohort. RESULTSIn total, 7,584 men and 7,426 women were analyzed (range 35-74 years), with 1,425 and 1,299 having prediabetes and diabetes, respectively. Biomarkers showed varying dynamics from normoglycemic via subjects with prediabetes to subjects with diabetes: 1) gradual increase (WBCs, granulocytes, monocytes, IL-1RA, IL-18, and fibrinogen), 2) increase with subclinical disease only (lymphocytes and CRP), 3) increase from prediabetes to diabetes only (neopterin), and 4) no variation with glucose status (hematocrit). The strongest relative differences were found for CRP, IL-1RA, and fibrinogen concentrations. Several inflammatory and immune markers were associated with the glucose status independent from cardiovascular risk factors and comorbidities, varied with disease severity and the presence of disease-specific complications in the diabetes subcohort. CONCLUSIONSThe inflammatory and immune biomarker profile varies with the development and progression of type 2 diabetes. Markers of inflammation and immunity enable differentiation between the early preclinical and clinical phases of the disease, disease complications, and progression.Type 2 diabetes and its disease-associated complications represent an important and increasing public health burden worldwide (1). Obesity, which leads to metabolic and adipocyte stress, is the most important predisposing factor for type 2 diabetes (2). Obesity-associated insulin resistance, activation of the innate immune system, and chronic increased production of cytokines and adipokines are an

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Section: Discussionmentioning

confidence: 99%

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confidence: 97%

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confidence: 99%

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Profile of the Immune and Inflammatory Response in Individuals With Prediabetes and Type 2 Diabetes

et al. 2015

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“…According to the American Diabetes Association, the disease can be classified into two main types, including type 1 and type 2 diabetes (2). Type 1 diabetes results from a cell-mediated autoimmune attack on β cells, whereas type 2 diabetes is a low-grade, chronic inflammatory disease that shares a common final pathway with type 1 diabetes, in which activation of the nuclear factor κB (NF-κB) signaling pathway causes a reduction in pancreatic β cells (3)(4)(5)(6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor α-induced protein-3 protects zinc transporter 8 against proinflammatory cytokine-induced downregulation

Cheng¹,

Zhang²,

Chen³

2016

Experimental and Therapeutic Medicine

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Abstract. Zinc transporter 8 (ZnT8) is exclusively expressed in the pancreatic islet and is essential for insulin crystallization, hexamerization and secretion. Tumor necrosis factor α-induced protein-3 (TNFAIP3) is a zinc finger protein that serves a major role in the negative feedback regulation of NF-κB signaling in response to multiple stimuli, and is a central regulator of immunopathology. Although the role of TNFAIP3 in diabetes has been extensively studied, its effect on ZnT8 has not been fully elucidated. The present study aimed to verify whether proinflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β), are able to affect ZnT8 expression in islet cells. In addition, the study aimed to determine the effect of TNFAIP3 overexpression on cytokine-altered ZnT8 activity, considering its effect on NF-κB signaling. Cell-based studies using NIT-1 cells overexpressing TNFAIP3 were used to assess the effect of cytokines on ZnT8 and NF-κB activation, as well as the effect of TNFAIP3 on ZnT8 expression. Western blot analysis and immunofluorescence staining were employed to determine the protein expression and NF-κB activation, respectively. The results indicated that cytokine stimulation led to TNFAIP3 upregulation, ZnT8 downregulation and NF-κB activation. Furthermore, TNFAIP3 overexpression protected ZnT8 from cytokine-induced downregulation. In conclusion, the current results suggest that inflammation or TNFAIP3 dysfunction may be involved in the pathogenesis of diabetes via ZnT8 expression, besides from islet cell apoptosis. In addition, restricting inflammation and enhancing TNFAIP3 expression may exert a positive effect in diabetes prevention, treatment and pancreatic cell transplantation. IntroductionDiabetes, a class of metabolic diseases that are prevalent worldwide affecting 422 million people in 2014 according to the World Health Organization (1), is characterized by hyperglycemia and can cause severe damage to different organs, particularly the eyes, kidneys, nerves, heart and blood vessels. According to the American Diabetes Association, the disease can be classified into two main types, including type 1 and type 2 diabetes (2). Type 1 diabetes results from a cell-mediated autoimmune attack on β cells, whereas type 2 diabetes is a low-grade, chronic inflammatory disease that shares a common final pathway with type 1 diabetes, in which activation of the nuclear factor κB (NF-κB) signaling pathway causes a reduction in pancreatic β cells (3-10).Zinc participates in numerous biological processes, and is essential for the correct processing, storage, secretion, and function of insulin in pancreatic β cells (11-13). Zinc flux is controlled by two types of transporters: The zinc transporter (ZnT; also known as SLC30A) family, and the Zrt-and Irt-like protein (ZIP) family. Typically, the ZnT family regulates Zn 2+ efflux out of the cytoplasm, while the ZIP family regulates Zn 2+ influx into the cytoplasm. Although 10 ZnTs and 14 ZIPs have been identified in mammals, ZnT8 is exclusiv...

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“…The involvement of autoimmune indicates by the persistent presence of the circulating autoantibodies or self-reactive T cells, the lymphocytic infiltration in the target organs. 9,10 Autoantibodies can be formed due to the breakdown in tolerance. For autoantibodies to appear, the autoantigen must become available to the immune system and the immunization event occurred.…”

Section: B I O P H a R M A C E U T I C A L I N S T I T U T Ementioning

confidence: 99%

Autoantibodies in Diabetes Mellitus

Herawati

Susanto

Sihombing

2017

Mol Cell Biomed Sci

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Based on American Diabetes Association (ADA), diabetes can be classified into the following general categories: type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes mellitus (GDM) and specific types of diabetes due to other cause. Obesity is by far the main underlying factor causing T2D and its pathological potential lies in obesity-associated insulin resistance, activation of innate immunity and chronic low-grade inflammation. When tissue inflammation induced, tissue destruction occurs, 'self' antigens, which are generally not accessible to T cells, can be released from the affected tissues and promote autoimmune activation. The 4 major autoantibodies are islet-cell cytoplasmic autoantibodies (ICA), glutamid acid decarboxylase antibody (GADA), islet antigen-2 antibody (IA-2A) and insulin autoantibodies (IAA). In addition, ZnT8A has recently been found to predict T1D. ZnT8 is contained in the islets of Langerhans, with the highest expression is in β cells of the pancreas. ZnT8A measurements simultaneously with GADA, IA-2A and IAA achieve rates of 98% detection for onset level of autoimmune diabetes. Presence of antibodies in T2D also shows the potential serious complications compared with T2D without antibodies. The combination of GADA, IA-2A and ZnT8A can be suggested as the most powerful and cost-effective diagnostic approach in patients with T1D.Keywords: autoantibody, autoimmune, diabetes mellitus, ICA, GADA, IA-2A, IAA, ZnT8A

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Autoimmune Aspects of Type 2 Diabetes Mellitus - A Mini-Review

Cited by 99 publications

References 67 publications

Profile of the Immune and Inflammatory Response in Individuals With Prediabetes and Type 2 Diabetes

Profile of the Immune and Inflammatory Response in Individuals With Prediabetes and Type 2 Diabetes

Tumor necrosis factor α-induced protein-3 protects zinc transporter 8 against proinflammatory cytokine-induced downregulation

Autoantibodies in Diabetes Mellitus

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