**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

149

**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


2. Video feedback (VF)

that the distorted self-perception about performance is one type of negative cognition that maintains social anxiety symptoms in SAD patients and socially anxious individuals. Moreover, previous studies have reported that SAD patients and socially anxious individuals show

There are two subtypes of SAD, the generalized type and the performance only type [12]. Individuals diagnosed with the generalized type experience excessive fear in almost all social situations, including performance and social interactions. Individuals diagnosed with the performance only type experience excessive fear only in performance situations, such as making a presentation in front of the class, with no major anxiety associated with social interaction per se, such as talking with friends or strangers. Furmark et al. reported that individuals with the generalized type exhibit more social distress and impairment [13]. These impairments might include holding a cup firmly, avoiding eye contact, or speaking softly. People with SAD use such safety behaviors to reduce their anxiety, but these behaviors can exclude opportunities to learn what happens in social situations and might cause further anxiety due to decreased coping efficacy. Their physical symptoms might involve displays of physiological arousal in social situations that include shaking, sweating, heart throbbing, and other manifestations of anxious arousal. People with SAD also tend to exaggerate the extent to which these symptoms are visible to others, which leads to more concerns about negative

Many previous studies have indicated that cognitive-behavioral therapy (CBT) techniques are effective in the psychological treatment of SAD [14–16]. According to Rodebaugh et al. [16], typical CBT techniques for the treatment of SAD include exposure, applied relaxation, social skills training, and cognitive restructuring. In a meta-analytic review, they reported that the most recommended treatment component of CBT programs is exposure and cognitive

Video feedback is also included in most CBT treatment programs. After exposure and cognitive restructuring sessions, individuals with SAD try to watch videos of themselves, before receiving cognitive preparation. Clark et al. reported the high efficacy of individual CBT [17]. Their program consisted of developing personal safety behaviors and self-focused attention with patients by shifting the focus of attention to social situations. Based on Clark and Wells' model, patients try to identify the relationship between their own cognition and SAD symptoms on psycho-education sessions. Additionally, video feedback was used to modify distorted self-imagery. Participants try to improve the discrepancy between their negative,

In video feedback sessions, individuals with SAD watch themselves doing actual social tasks, such as public speaking and conversation tasks. They often recognize their performance to be worse than their actual performance. Then, therapists try to improve the discrepancy between subjective and objective perceptions of social performance. For example, Shirotsuki et al. attempted to examine the effects of an individual CBT program that included exposure, cognitive restructuring, and video feedback techniques [18] using video feedback of speech tasks. The results indicated that the program was effective for improving social anxiety symptoms and selfperception during speech tasks, suggesting that individuals with SAD can improve their negative self-perceptions and negative estimations before a speech task. Previous research has also

lower self-ratings than other ratings of their performance [9–11].

66 Cognitive Behavioral Therapy and Clinical Applications

distorted self-images and their objective social performance.

evaluation from others.

restructuring [16].

VF, which is based on the cognitive model of SAD [7], involves providing highly socially anxious individuals and people with SAD with video playback of their social performance following the participation in a social task, such as making a public speech or a one-on-one conversation [37]. Participants then watch the situation using the video recording. It is anticipated that the review of the recording would correct their distorted self-evaluations, including the underestimation of their own social skills [38]. It is suggested that the experience of viewing video recordings of their own social performances would enable socially anxious individuals to correct their underestimation of their social abilities. This, in turn, is expected to lead to reduced symptoms of anxiety when anticipating in future social events [39–41]. Moreover, objective information about the self is expected to result in changes in the negative self-image and lead to confidence about social performance. (See Figure 1 for an illustration of an actual video feedback session).

addition of a pre-VF cognitive preparation phase [39, 40, 43]. In addition, Orr and Moscovitch examined the effect of cognitive review (CR) with video feedback and cognitive preparation (CR) [37]. The results showed that participants in the CP, VF, and CR conditions demonstrated marginally significant reductions in anxiety from Speech 1 to Speech 2. Furthermore, only those who received CP, VF, and CR demonstrated significant improvements in self-perception and performance expectations relative to the only exposure condition. In CR, participants received open-ended questions asking them to provide elaborate written answers (e.g., "How does this feedback make you feel?" or "What is the significance of this feedback to your sense of self?"). However, certain studies have also indicated that neither VF alone nor VF with cognitive preparation succeeded in facilitating significant reductions in social anxiety symptoms above and beyond exposure alone [9, 40, 44]. It is suggested that the null findings pertaining to the reduction of social anxiety in previous VF studies could be at least partially related to the absence of a post-VF review period, during which time participants would be encouraged to elaborate the processing and encoding of feedback information. Orr and Moscovitch indicated that the post-VF review period, which encourages individuals to elaborate, could lead to the processing of new information about themselves and facilitate improvements in self-perception, leading to the subsequent reductions in social anxiety symptoms [37].

Video Feedback Techniques Used in Social Anxiety Disorders

http://dx.doi.org/10.5772/intechopen.71278

69

It has been suggested that the negative interpretation bias in social situations and social information might interfere with the effectiveness of video feedback in SAD. Certain studies have reported the effects of negative interpretations on social anxiety symptoms. Foa et al. found that individuals with social phobia rated negative social events as more probable and costly than nonclinical anxious controls [45]. Stopa and Clark showed that patients with generalized social phobia were more likely to interpret ambiguous social events negatively and to catastrophize in response to unambiguous, mildly negative events relative to other anxiety disorder groups or a nonpatient control group [46]. Constans et al. reported that socially anxious individuals showed a less positive interpretation of ambiguous interpersonal events [47]. In summary, the interpretation bias regarding social situations seen in individuals

with social anxiety is characterized by more negative and less positive cognitions.

It is possible that socially anxious individuals negatively evaluate their appearance on video. This negative interpretation could interfere with the effectiveness of video feedback. In addition, SAD patients may also lack positive interpretations about their appearance on video. Therefore, it is possible that SAD patients and high socially anxious individuals interpret their video as more negative and less positive. However, the relationship between negative and positive interpretations of their appearance on video and social anxiety symptoms has not

Based on the above considerations, Shirotsuki et al. examined differences in efficacy between video only (VW) and video with cognitive interventions (VW + CI) [44]. They divided participants into a video only group (VW group) and a video with cognitive intervention group (VW + CI group). Only VW + CI group was instructed to watch a video of their speech

3. Cognitive biases in SAD

been investigated to date.

Warnock-Parkes et al. [42] suggested five broad categories of interference that results from video feedback [43]: (a) reexperiencing feelings when watching the video, (b) selectively searching for behaviors that could be interpreted negatively, (c) discounting the accuracy of the video image, (d) mistaking safety behaviors for social deficits, and (e) reactivating habitual patterns of self-criticism. Warnock-Parkes et al. [42] suggested that patients with social anxiety disorder have these processing biases that would make it difficult for them to see the videos differently from their habitual negative self-perception. It is important to reduce processing biases to identify the effects of video feedback.

Several studies have reported that video feedback techniques improve distorted selfperceptions when used as a psychological intervention for social anxiety [9, 11, 39]. Rapee and Hayman showed that high and low socially anxious individuals improved their distorted self-perceptions after video feedback [9]. Harvey et al. demonstrated that 7 min of cognitive preparation before video feedback enhanced the effect of video feedback on distorted selfperceptions [39]. Rodebaugh also reported that cognitive preparation enhanced selfperceptions about speech performance [11]. On the other hand, Smits et al. failed to find any difference between exposure and exposure with video feedback [40]. They suggested that their technique might have targeted probability bias by providing performance feedback, which interferes with the necessary reappraisal of cost bias.

Orr and Moscovitch summarized previous VF studies [37]. They described that experimental research on social anxiety and VF has typically examined the efficacy of VF on its own (i.e., with neither a pre-VF preparation phase nor a post-VF review phase) [37, 41] or only with the

Figure 1. Image of the state of actual video feedback.

addition of a pre-VF cognitive preparation phase [39, 40, 43]. In addition, Orr and Moscovitch examined the effect of cognitive review (CR) with video feedback and cognitive preparation (CR) [37]. The results showed that participants in the CP, VF, and CR conditions demonstrated marginally significant reductions in anxiety from Speech 1 to Speech 2. Furthermore, only those who received CP, VF, and CR demonstrated significant improvements in self-perception and performance expectations relative to the only exposure condition. In CR, participants received open-ended questions asking them to provide elaborate written answers (e.g., "How does this feedback make you feel?" or "What is the significance of this feedback to your sense of self?"). However, certain studies have also indicated that neither VF alone nor VF with cognitive preparation succeeded in facilitating significant reductions in social anxiety symptoms above and beyond exposure alone [9, 40, 44]. It is suggested that the null findings pertaining to the reduction of social anxiety in previous VF studies could be at least partially related to the absence of a post-VF review period, during which time participants would be encouraged to elaborate the processing and encoding of feedback information. Orr and Moscovitch indicated that the post-VF review period, which encourages individuals to elaborate, could lead to the processing of new information about themselves and facilitate improvements in self-perception, leading to the subsequent reductions in social anxiety symptoms [37].


**Meet the editor**

Dr. Leonid A. Kosyachenko is professor of National University of Chernivtsi, Ukraine. After receiving his Doctor of Sciences Degree in Physics and Mathematics in 1983, he founded and became a head of Optoelectronics Department – the first department of this kind at Ukrainian universities. About twenty of his pupils have performed work to obtain the degrees of Candidate

(Ph.D.) and Doctor of Sciences. His research interests have been in physics and technology of solar cells, semiconductor X-ray and γ-ray detectors, light-emitting and photosensitive devices. He is author (co-author) of several books and numerous scientific articles; presented reports at international scientific conferences and meetings in Germany, Italy, England, Japan, China, Greece, Spain, Belgium, Russia. He was the leader of several collaborative projects with the institutions of Russia, Belorussia and is one of the leaders of the long-term projects of the European Commission. Prof. L.A. Kosyachenko is a member of the Ukrainian Physical Society and the guest editor of journal "Solar Energy Materials and Solar Cells".

Contents

**Preface IX**

Chapter 1 **Effects of Optical Interference**

**and Annealing on the Performance of**

Chunfu Zhang, Hailong You, Yue Hao, Zhenhua Lin and Chunxiang Zhu

K. Boubaker, M. Amlouk and A. Amlouk

Chapter 3 **Flexible Photovoltaic Textiles for Smart Applications 43**

Chapter 2 **A New Guide to Thermally Optimized**

M. Benhaliliba, C.E. Benouis,

Chapter 4 **Dilute Nitride GaAsN and InGaAsN Layers**

Chapter 5 **Organic-Inorganic Hybrid Solar Cells:**

Chapter 6 **Relation Between Nanomorphology and**

Zoran Stević and Vesna Grekulović

Almantas Pivrikas

Seishi Abe

Malina Milanova and Petko Vitanov

Mukesh Kumar Singh

**Polymer/Fullerene Bulk Heterojunction Solar Cells 1**

**Doped Oxides Monolayer Spray-Grown Solar Cells: The Amlouk-Boubaker Optothermal Expansivity**

**Grown by Low-Temperature Liquid-Phase Epitaxy 69**

**State of the Art, Challenges and Perspectives 95**

**Performance of Polymer-Based Solar Cells 121**

Chapter 7 **One-Step Physical Synthesis of Composite Thin Film 149**

Chapter 8 **Cuprous Oxide as an Active Material for Solar Cells 167**  Sanja Bugarinović, Mirjana Rajčić-Vujasinović,

Yunfei Zhou, Michael Eck and Michael Krüger

**AB 27**


Chalcogenides - Preparation and Applications

*Edited by Dhanasekaran Vikraman*

Published in London, United Kingdom

Chalcogenides - Preparation and Applications http://dx.doi.org/10.5772/intechopen.98001 Edited by Dhanasekaran Vikraman

#### Contributors

Ho Soonmin, Immanuel Kodaikanal, Mohanraj Kumar, Rakesh K. Sonker, Pronoy Nandi, Mohamed Amine Ghebouli, Brahim Ghebouli, A. Kryuchyn, V.V. Petrov, V.M. Rubish, M.L. Trunov, Devappa S. Lamani, Akrajas Ali Umar, Nurul Ain Abd Malek, Nabilah Alias, Abang Annuar Ehsan, Pramoda K. Nayak, Nilanjan Basu, Vishal K. Pathak, Laxman Gilua, Madhavi Jonnalagadda, Varishetty Madhu Mohan, VishnuBhotla Prasad, Prince Sharma, Veerpal Singh Awana, Mahesh Kumar

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