Islet Inflammation Impairs the Pancreatic -Cell in Type 2 Diabetes

Division of Endocrinology, Diabetes, and Nutrition, and Center for Integrated Human Physiology, University Hospital of Zürich, Zürich, Switzerland.
Physiology (Impact Factor: 4.86). 12/2009; 24(6):325-31. DOI: 10.1152/physiol.00032.2009
Source: PubMed


Onset of Type 2 diabetes occurs when the pancreatic beta-cell fails to adapt to the increased insulin demand caused by insulin resistance. Morphological and therapeutic intervention studies have uncovered an inflammatory process in islets of patients with Type 2 diabetes characterized by the presence of cytokines, immune cells, beta-cell apoptosis, amyloid deposits, and fibrosis. This insulitis is due to a pathological activation of the innate immune system by metabolic stress and governed by IL-1 signaling. We propose that this insulitis contributes to the decrease in beta-cell mass and the impaired insulin secretion observed in patients with Type 2 diabetes.

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    • "A decrease of inflammatory compounds could be expected for increasing insulin receptor sensitivity and repairing blood sugar taking into cells. According to Donath et al. [17] a decrease of inflammation in pancreatic β cells closely associated with the increase proinsulin synthesis to be insulin and improved insulin sensitivity and pancreatic β cell mass. "
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    ABSTRACT: The pathogenesis of diabetes mellitus involves a low-level inflammatory process due to the increase of blood glucose. In this research, testing of extracted rosella was done on Spraque Dawley rats inducing by streptozotocin. The rats were divided into six groups i.e normal rats (SG), diabetic rats group (DiW, DiR1, DiR2), preventive rats (PR1) and group were diabetic rats given glibenclamide (DiG). Analysis of inflammatory (TNF-α and IL-6) was performed on the spleen of rat using the ELISA technique. The results showed that roselle extract tended to decrease levels of the inflammatory TNF-α in diabetic rats, but could not be able to reduce the levels of IL-6.
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    • "TNF-α and IL-6 have been shown to impair insulin signaling pathways (14), blunting the response of the liver, adipose tissue and skeletal muscle to insulin. Increasing evidence has demonstrated that inflammation is also involved in islet β-cell dysfunction (15). Therefore, the hypothesis that T2D is a chronic low-grade inflammatory disease has arisen (4,5). "
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    ABSTRACT: Type 2 diabetes (T2D) is a common disorder characterized by chronic low-grade inflammation. In the present study, the expression levels of nuclear receptor subfamily 4 group A member 1 (NR4A1) and the correlation with inflammatory cytokine production and free fatty acids (FFAs) in patients with T2D and healthy participants were investigated. NR4A1 expression levels in peripheral blood mononuclear cells (PBMCs) from patients with T2D (n=30) and healthy controls (n=34) were analyzed. In addition, the levels of fasting blood glucose (FBG), fasting plasma insulin (FIN), FFAs, total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) were analyzed, and the homeostasis model assessment (HOMA) was used to estimate the insulin resistance (IR). Additionally, PBMCs from healthy subjects were cultured with or without 250 μM palmitic acid (PA). Levels of NR4A1, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the PBMCs were also analyzed. The basal expression levels of NR4A1, TNF-α and IL-6 were higher in the T2D patients when compared with the controls. In addition, the levels of FFAs, TG and LDL-C, as well as the HOMA-IR, were higher in T2D patients. Furthermore, NR4A1 expression was demonstrated to positively correlate with the HOMA-IR and the levels of FFAs, TNF-α, IL-6, FIN and FBG. Furthermore, 250 μM PA stimulation was shown to increase NR4A1 expression and the secretion of inflammatory cytokines in the cultured PBMCs. Therefore, increased NR4A1 expression levels are correlated with a chronic low-grade inflammatory state and the disorder of lipid metabolism in patients with T2D.
    Experimental and therapeutic medicine 11/2014; 8(5):1648-1654. DOI:10.3892/etm.2014.1958 · 1.27 Impact Factor
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    • "It takes part in autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and type 1 diabetes, but also in metabolic dysregulation [1] with a disturbed secretion associated to type 2 diabetes (T2D) and impaired β-cell function [2], [3]. Indeed in T2D, metabolic stress activates the innate immune system, resulting in a chronic inflammatory state marked by increased cytokines, increased islet-associated macrophages, and β-cell apoptosis [4]–[6]. Surprisingly, IL1-R1 is highly expressed in β-cells [7] which is in line with their high sensitivity to IL-1β. "
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    ABSTRACT: We recently reported that pancreatic islets from pre-diabetic rats undergo an inflammatory process in which IL-1β takes part and controls β-cell function. In the present study, using the INS-1 rat pancreatic β-cell line, we investigated the potential involvement of membrane-associated cholesterol-enriched lipid rafts in IL-1β signaling and biological effects on insulin secretion, β-cell proliferation and apoptosis. We show that, INS-1 cells exposure to increasing concentrations of IL-1β leads to a progressive inhibition of insulin release, an increase in the number of apoptotic cells and a dose-dependent decrease in pancreatic β-cell proliferation. Disruption of membrane lipid rafts markedly reduced glucose-stimulated insulin secretion but did not affect either cell apoptosis or proliferation rate, demonstrating that membrane lipid raft integrity is essential for β-cell secretory function. In the same conditions, IL-1β treatment of INS-1 cells led to a slight further decrease in insulin secretion for low concentrations of the cytokine, and a more marked one, similar to that observed in normal cells for higher concentrations. These effects occurred together with an increase in iNOS expression and surprisingly with an upregulation of tryptophane hydroxylase and protein Kinase C in membrane lipid rafts suggesting that compensatory mechanisms develop to counteract IL-1β inhibitory effects. We also demonstrate that disruption of membrane lipid rafts did not prevent cytokine-induced cell death recorded after exposure to high IL-1β concentrations. Finally, concerning cell proliferation, we bring strong evidence that membrane lipid rafts exert a protective effect against IL-1β anti-proliferative effect, possibly mediated at least partly by modifications in ERK and PKB expression/activities. Our results 1) demonstrate that IL-1β deleterious effects do not require a cholesterol-dependent plasma membrane compartmentalization of IL-1R1 signaling and 2) confer to membrane lipid rafts integrity a possible protective function that deserves to be considered in the context of inflammation and especially T2D pathogenesis.
    PLoS ONE 07/2014; 9(7):e102889. DOI:10.1371/journal.pone.0102889 · 3.23 Impact Factor
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