**9. Similarities between β-cell failure and death in T1DM and T2DM**

T1DM is considered a chronic autoimmune disease and the major mechanisms responsible βcell death and dysfunction are immune-related. In contrast, the main mechanisms responsible β-cell death and dysfunction in T2DM are related to metabolism. Thus, the convergence points of these two aetiologically-different disorders appear to be the immunological NFκB pathway and, the metabolic ROS/ER stress pathways (Fig. 5).

Islet inflammation in T1DM is characterised by the presence of leukocyte infiltrates [81]. In particular, macrophages and T-cells mediate the destruction of β-cells by phagocytosis, release of cytokines, generating ROS (NO, cytokine-NFκB-dependent [82]) and by activating the granzyme b- and death-receptor-mediated death pathways (Fig. 5). At the biochemical level, production of cytokines such as INF-γ, TNFα and IL-1β act in synergy to promote expression of iNOS and consequently NO, via stimulation of NFκB in mouse islet β-cells [82]. If not regulated, this generation of ROS may impact on ER stress and possibly promote cell death, which has been shown to be an import cell death process in T2DM (Fig. 5). Furthermore, cytokine–mediated activation of β-cell NFκB may result in an autocrine production of similar cytokines by β-cells, amplifying these death signals [76,79]. Another complication that arises with T1DM and immune-mediated reduction of β-cell mass is impaired insulin secretion, which may possibly promote additional hyperglycaemia and dyslipidaemia in these patients. Therefore, and as explained earlier, glucolipotoxicity may follow, along with further cell death that is achieved through mitochondrial- and/or ER-mediated death processes (Fig. 5).

though T2DM is very much a metabolic disease, there are also immunological-related factors that may exacerbate disease progression. NFκB, IL-1β, ER-stress and generation of ROS/RNS are instrumental players in both diseases, and may warrant further investigation with regard

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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**10. β-cell therapies and possible targets for prevention of β-cell failure**

The traditionalistic concept of separate T1 and T2DM syndromes has become clouded with knowledge of the involvement of inflammation in T2DM and the metabolic syndrome in T1DM [108]. It is now apparent that treatment modalities that were specifically designed for one form of diabetes may have application in the other. Exercise, weight loss and diet are the most effective strategies to delay T2DM disease development, but similar strategies have shown

Researchers have targeted TNFα in children with newly diagnosed T1DM and showed that a recombinant TNFR fusion protein preserved c-peptide function, along with enhancing insulin production [82,141]. However, to date, anti-TNFα treatment has failed to improve blood glucose in T2DM patients [90]. Infiltration of cytotoxic T-cells in T1DM has been well charac‐ terised [82]. Therefore, some developing treatment strategies for this precise component of T1DM disease is the generation of T-cell targeted therapy to prevent the destruction of transplanted islets, some of which include introduction of anti-inflammatory Tregs that regulate T-cell activation [89]. Since inflammation has been detected in T2DM, these ap‐ proaches may have similar applications. Directing treatment towards the immunological pathways is quite attractive and recent evidence has suggested that the most promising results involve blockade of IL-1β or NFκB activation [90]. Again, it is noteworthy to highlight that enhanced HSP70 expression has been convincingly demonstrated to protect against obesityinduced insulin-resistance [142], while low HSP70 contents in skeletal muscle of T2DM patients are associated with insulin-resistance [143,144]. Hence, pharmacological (e.g. the hydroxylamine derivative BGP-15, now under clinical trial) as well as physiological (hyper‐ thermic, hot tube) treatments have started to be cogitated as promising therapeutic approaches in T2DM [142,145]. Moreover, physical exercise, which is a powerful antidiabetic intervention, is one of the strongest ways to increase intracellular HSP70 expression in many tissues (for reviews, please see [75,146]), including in pancreatic β-cells (A. Bittencourt et al., manuscript

Elevated IL-1β and reduced IL-1Ra is known to correlate with T1DM, but the recent identifi‐ cation of inflammation in T2DM has meant that the IL-1 receptor antagonist (Anakinra), has been trialed in both T2DM and T1DM patients with successful results [77,140,147]. Here, the agent lowered blood glucose, reduced inflammation, improved insulin-sensitivity and secretion. These reports again illustrate the pivotal role played by IL-1β in mediating DM

Salicylate-derivatives, such as salsalate, are also being used in an anti-inflammatory capacity to inhibit the activation of NFκB, although the precise mechanisms of action are not fully

to development of novel therapies.

significant efficacy in T1DM [108,128].

in preparation).

development, and thus clinical trials continue [90].

In T2DM, hyperglycaemia and dyslipidaemia are critical factors and are generally present in obese individuals with the disease [77]. Consequently, excess glucose and circulating free fatty acids may promote increased ROS production and ER stress by enhancing oxidative phosphorylation and causing a build-up of unfolded proteins in the ER. Elevated ROS and ER stress will activate caspase enzymes via mitochondrial- and ER-mediated death path‐ ways, respectively (Fig. 5). Interestingly, ROS/RNS can also activate and regulate the NFκB stress pathway, which may possibly lead to transcription of genes coding either cytokines or immune cell chemo-attractants (Fig. 5) [98]. Given the spontaneous reactivity of ROS, it is not clear yet exactly how it influences NFκB activation. However, it has been shown to react in a variety of ways promoting stimulation or inhibition of NFκB, with effects depend‐ ent on context [98]. For example, if ROS does promote expression of NFκB-derived cyto‐ kines or immune cell chemo-attractants, these signals may alert nearby macrophages and Tcells to the elevated level of β-cell ROS, and initiate the removal of these damaged cells. Consequently, this could result in immune cell infiltration into pancreatic islets of T2DM patients and possibly β-cell death (Fig. 5).

Interestingly, an autoimmune element has been reported in obese patients with T2DM, who have presented with elevated circulatory cytokine and acute-phase protein levels [77,87]. A common denominator that may link both T1 and T2DM is IL-1β. Autocrine production of IL-1β by β-cells has been observed in T1DM and in T2DM patients [76,79]. Furthermore, *in vitro* culture of islets from non-diabetic doners in high glucose, caused increased production and secretion of IL-1β, along with subsequent NFκB activation, Fas up-regulation, reduced insulin secretion and β-cell DNA fragmentation [77,78]. Chronic exposure to IL-1β also increases expression of iNOS, and consequently may up-regulate ROS generation and the expression of other pro-inflammatory cytokines like IL-6 and IL-8, which may further poten‐ tiate β-cell failure [78]. These reports clearly demonstrate the inherent link between glucotox‐ icity and the inflammatory processes [77]. In addition, investigators took a step further and showed that exogenous addition of IL-1Ra, the IL-1 receptor antagonist (Anakinra), protected the islets from IL-1β, but also reduced glycated haemoglobin in a small clinical trial of T2DM patients [77,140]. Clinical trials utilising IL-1Ra, still continue [90].

In conclusion, T1 and T2DM are different diseases, but do appear to share some common biochemical ground in terms of disease development. Although T1DM is mostly an autoim‐ mune-related syndrome, elements of metabolic dysregulation are evident. Likewise, even though T2DM is very much a metabolic disease, there are also immunological-related factors that may exacerbate disease progression. NFκB, IL-1β, ER-stress and generation of ROS/RNS are instrumental players in both diseases, and may warrant further investigation with regard to development of novel therapies.

production of cytokines such as INF-γ, TNFα and IL-1β act in synergy to promote expression of iNOS and consequently NO, via stimulation of NFκB in mouse islet β-cells [82]. If not regulated, this generation of ROS may impact on ER stress and possibly promote cell death, which has been shown to be an import cell death process in T2DM (Fig. 5). Furthermore, cytokine–mediated activation of β-cell NFκB may result in an autocrine production of similar cytokines by β-cells, amplifying these death signals [76,79]. Another complication that arises with T1DM and immune-mediated reduction of β-cell mass is impaired insulin secretion, which may possibly promote additional hyperglycaemia and dyslipidaemia in these patients. Therefore, and as explained earlier, glucolipotoxicity may follow, along with further cell death

that is achieved through mitochondrial- and/or ER-mediated death processes (Fig. 5).

patients and possibly β-cell death (Fig. 5).

148 Type 1 Diabetes

patients [77,140]. Clinical trials utilising IL-1Ra, still continue [90].

In T2DM, hyperglycaemia and dyslipidaemia are critical factors and are generally present in obese individuals with the disease [77]. Consequently, excess glucose and circulating free fatty acids may promote increased ROS production and ER stress by enhancing oxidative phosphorylation and causing a build-up of unfolded proteins in the ER. Elevated ROS and ER stress will activate caspase enzymes via mitochondrial- and ER-mediated death path‐ ways, respectively (Fig. 5). Interestingly, ROS/RNS can also activate and regulate the NFκB stress pathway, which may possibly lead to transcription of genes coding either cytokines or immune cell chemo-attractants (Fig. 5) [98]. Given the spontaneous reactivity of ROS, it is not clear yet exactly how it influences NFκB activation. However, it has been shown to react in a variety of ways promoting stimulation or inhibition of NFκB, with effects depend‐ ent on context [98]. For example, if ROS does promote expression of NFκB-derived cyto‐ kines or immune cell chemo-attractants, these signals may alert nearby macrophages and Tcells to the elevated level of β-cell ROS, and initiate the removal of these damaged cells. Consequently, this could result in immune cell infiltration into pancreatic islets of T2DM

Interestingly, an autoimmune element has been reported in obese patients with T2DM, who have presented with elevated circulatory cytokine and acute-phase protein levels [77,87]. A common denominator that may link both T1 and T2DM is IL-1β. Autocrine production of IL-1β by β-cells has been observed in T1DM and in T2DM patients [76,79]. Furthermore, *in vitro* culture of islets from non-diabetic doners in high glucose, caused increased production and secretion of IL-1β, along with subsequent NFκB activation, Fas up-regulation, reduced insulin secretion and β-cell DNA fragmentation [77,78]. Chronic exposure to IL-1β also increases expression of iNOS, and consequently may up-regulate ROS generation and the expression of other pro-inflammatory cytokines like IL-6 and IL-8, which may further poten‐ tiate β-cell failure [78]. These reports clearly demonstrate the inherent link between glucotox‐ icity and the inflammatory processes [77]. In addition, investigators took a step further and showed that exogenous addition of IL-1Ra, the IL-1 receptor antagonist (Anakinra), protected the islets from IL-1β, but also reduced glycated haemoglobin in a small clinical trial of T2DM

In conclusion, T1 and T2DM are different diseases, but do appear to share some common biochemical ground in terms of disease development. Although T1DM is mostly an autoim‐ mune-related syndrome, elements of metabolic dysregulation are evident. Likewise, even
