**4. Immune-like characteristics of β-cells and response to cytokines**

The pathophysiology of pancreatic islets in T1 and T2DM is characterised by an inflammatory process that includes immune cell infiltration, presence of apoptotic cells, expression of cytokines or adipokines and even amyloid deposits [76]. Although the aetiology of T1DM differs from T2DM, a common feature of both is an immune system-mediated destruction of pancreatic β-cells, ultimately leading to pancreatic dysfunction and reduced β-cell mass. However, the immunological-mediated attack does not solely originate from invading macrophages and/or cytokines produced by T-lymphocytes, as initially occurs in early stage T1DM. In fact, it also stems from local production of pro-inflammatory cytokines by the pancreatic β-cells themselves. The similarity between pancreatic β-cells and immune cells is an intriguing characteristic. Both can release and respond to cytokines; their function is dependent on changes in concentration of ROS/RNS and they both express high levels of proinflammatory proteins such as NFκB, iNOS, NOX and TLR's. Pancreatic β-cells have been shown to express biologically active cytokines like the pro-inflammatory cytokine IL-1β in hyperglycaemic conditions [77,78]. Due to their potent effects, cytokine production is strin‐ gently regulated. Control mechanisms include down-stream activation/processing (conver‐ sion of pro-IL-1β to IL-1β by inflammasomes), and co-expression of binding proteins/ antagonists (like the IL-1 receptor antagonist, IL-1Ra), that regulate cytokine bio-reactivity [76]. However, expression of the biologically active form of IL-1β was evident in pancreatic β-cells, indicating that similar to immune cells, these cells possess the necessary cellular machinery to allow expression of immunologically active cytokines [77]. Autocrine production of IL-1β, has been correlated with autoimmune destruction of β-cells in T1DM and is also associated with glucotoxicity in the pathogenesis of T2DM patients [76,79]. IL-1β elicits its potent cytotoxic effects through activation of NFκB, and a subsequent initiation of the extrinsic cell-death pathway [78]. Additionally, chronic exposure to IL-1β results in increased iNOS expression, and consequently excess NO production. High levels of NO inhibit mitochondrial ATP synthesis and up-regulate the expression of pro-inflammatory genes in β-cells, which may potentiate β-cell failure [78].

β-Cells also express NOX in large quantities, and utilise controlled NOX-derived ROS to drive mitogenic signalling and proliferation [27]. However, during hyperglycaemia or dyslipidae‐ mia as occurs in T2DM, levels of NOX-derived ROS may increase and overwhelm antioxidant defences, leading to mitochondrial dysfunction, DNA oxidation, lipid peroxidation and β-cell

The Impact of Inflammation on Pancreatic β-Cell Metabolism, Function and Failure in T1DM and T2DM…

http://dx.doi.org/10.5772/55349

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These reports illustrate the immune-like characteristics of pancreatic β-cells and clearly demonstrate the ability of these cells to not only respond to cytokines, but to be capable of producing endogenous cytokines in an autocrine fashion. This suggests that the immune system plays an integral part in progression of DM and may offer potential therapeutic targets. However, to develop immune-related treatments, more research is required into understand‐

T1DM is exclusively an autoimmune form of DM, and islet inflammation is characterised by the presence of leukocyte infiltrates that include B-cells, T-cells, macrophages and Natural Killer (NK) cells [81]. Macrophages play a critical role since they phagocytose apoptotic and necrotic β-cells, as well as produce ROS and cytokines (TNFα, INF-γ and IL-1β), that can promote β-cell death, which leads to patient insulin-dependence. However, effector CD4 helper and CD8-cytotoxic T-cells represent the predominant pancreatic infiltrate for this disease, and recent evidence has suggested that T1DM progression may be dependent on a precarious equilibrium between migration and activation of effector and regulatory T-cells (Treg) [82]. An important element in T1DM disease development is the generation of autor‐ eactive effector T-cells that kill pancreatic β-cells through expression of Fas, lytic granules and cytokines such as INF-γ [82]. Research into formation of these autoimmune cell types is still at an early stage, and it was only definitively shown in 2012, that autoreactive effector cytotoxic-CD8 T-cells were indeed present in T1DM human pancreatic islets [81]. Furthermore, the means by which these "homicidal" immune cells are generated and go on to attack β-cells is still not fully understood. However, part of the process is believed to involve dendritic cell migration to draining lymph nodes following antigen presentation, and stimulation of autoreactive T-cell differentiation [82,83]. T-cells sub-sets such as Th1, Th2 and Th17 are thus formed and they express the necessary weaponry that is responsible for β-cell death in T1DM [82], this being exacerbated by strong psychological stress [84], one of the possible triggering factors for the onset of T1DM (for review, please see [85]). Additionally, T-cell–mediated release of INF-γ and TNFα can up-regulate expression of pro-apoptotic proteins (Bim and PUMA) leading to β-cell death, along with promoting recruitment and clearance of damagedcells by macrophages [77,86]. On the other hand, in normal individuals, activity of these autoimmune cells is normally controlled by Treg cells and it is the failure to control the action of effector T-cells that result in autoimmune disease. The mechanisms by which Treg cells prevent autoimmune attack is also not fully elucidated, but they are thought to prevent cytotoxic action of T-cells by use of contact inhibition and release of soluble signalling factors, such as IL-10 and TGFβ (transforming growth factorβ) [82]. It is also unclear whether the

ing the mechanisms of islet inflammation in both T1 and T2DM.

**5. Islet inflammation in T1DM and T2DM**

death.

Similar to macrophages and dendritic cells, β-cells also express TLR's that normally function to regulate the immune system [80]. TLR's interact with a wide variety of pathogenrelated molecules, including lipopolysaccharide (LPS), a component of bacterial cell walls. This allows phagocytosis of microbes before infection can be established. However, in βcells, it is believed that TLR's play a role in insulin-resistance and inflammation in T2DM. TLR2 and TLR4 have been suggested as receptors for fatty acids, and may alter insulin signalling during dyslipidaemia. We have shown that β-cells express a range of TLR's and could indeed respond to LPS via TLR's, and this interaction decreased insulin exocytosis accordingly [80]. However, glutamine restored insulin release. Glutamine can also regu‐ late pro-inflammatory gene expression in mononuclear cells [11,80]. Glutamine also upregulates nuclear factor of activated T cells (NFAT), and thus promotes β-cell growth, while suppressing β-cell death. Mutations in NFAT-dependent genes have been demonstrated to result in hereditary forms of T2DM [11]. Moreover, as discussed above, glutamine can enter HBP thus regulating GSK-3β activity and HSP70 expression which promotes anti-inflamma‐ tion and cytoprotection [53,54].

Pancreatic β-cells are also reported to express other cytokines, including IL-6, IL-8, granulocyte colony-stimulating factor (G-CSP) and MIP-1 (macrophage inflammatory protein-1) that not only induce apoptotic β-cell death, but also signal patrolling macrophages, enhancing islet immune cell infiltration [76]. Macrophages, monocytes, neutrophils and dendritic cells perform their function by engulfing invading foreign matter including bacteria or dead cells, and degrade them using super oxide (O2 - ) generated from plasma membrane-bound NOX [27]. β-Cells also express NOX in large quantities, and utilise controlled NOX-derived ROS to drive mitogenic signalling and proliferation [27]. However, during hyperglycaemia or dyslipidae‐ mia as occurs in T2DM, levels of NOX-derived ROS may increase and overwhelm antioxidant defences, leading to mitochondrial dysfunction, DNA oxidation, lipid peroxidation and β-cell death.

These reports illustrate the immune-like characteristics of pancreatic β-cells and clearly demonstrate the ability of these cells to not only respond to cytokines, but to be capable of producing endogenous cytokines in an autocrine fashion. This suggests that the immune system plays an integral part in progression of DM and may offer potential therapeutic targets. However, to develop immune-related treatments, more research is required into understand‐ ing the mechanisms of islet inflammation in both T1 and T2DM.
