**8. Pancreatic β-cell failure and death in T2DM**

Failure of pancreatic β-cells is essential in the progression of both T1 and T2DM. The devel‐ opment of T2DM is more gradual than T1, and appears to occur in specific stages. It is dependent on the establishment of insulin-resistance and displays increased degrees of variability in comparison with T1DM. Therefore, determination of the precise mechanisms of T2DM-related cell death remains difficult and, these are still not fully understood.

phosphorylation, ultimately leading to cytochrome *c* release and initiation of mitochondrial-

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

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

147

Lipid accumulation (lipotoxicity) in the ER may also play a significant function in mediating ER stress in β-cells. Obesity is a primary risk factor associated with T2DM, and is accompanied with increased plasma glucose and lipid levels due to high carbohydrate- and fat-based diets [137]. The process by which free fatty acids modulate ER stress is not entirely known [111] but, it has been shown that palmitic acid could deplete ER Ca2+ levels and augment ER morphology and integrity, which may cause activation of ER stress by the mechanisms mentioned above [137,138]. Furthermore, excess fatty acid esterification in the ER, may divert ER machinery and delay the processing and export of proteins in the ER [137]. Since there is a large demand for protein/insulin production in pancreatic islets, β-cells have a highly active and well developed ER. This suggests that β-cells may be more susceptible to ER stress during protein synthesis [109,137]. Given the effects of elevated plasma glucose and lipids in T2DM patients, ER stress could be a vital mechanism facilitating glucotoxicity-, lipotoxicity- or glucolipotoxicity-

Moreover, accumulation of islet amyloid polypeptide (IAPP) may also contribute to β-cell dysfunction and death in a manner similar to that described above [110,111,139]. IAPP precipitates into lethal oligomers inside the ER and like unfolded proteins, activates the ER stress-mediated death pathway [139]. IAPP deposits are present in over 90% of T2DM islets,

In summary, several biochemical mechanisms have been suggested to be responsible for pancreatic β-cell failure and death in T2DM. However, there appears to be significant interplay between the purported pathways and conditions of glucotoxicity-, lipotoxicity- and glucoli‐ potoxicity, which are common in the aetiology of T2DM and require further investigation. Interestingly, from this review there are noteworthy commonalities associated with T1 and T2DM mechanisms of β-cell failure and death. In the following section we will attempt to summarise these, with a view to identifying the potential therapeutic targets that are of interest

post-mortem, indicating a substantial participation in T2DM progression [109,111].

**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

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,

dependent apoptosis [111,135,136].

mediated β-cell failure and death [137].

to the research community.

and, the metabolic ROS/ER stress pathways (Fig. 5).

T2DM patients have a 30-50% reduction in β-cell mass on average post-mortem and the primary candidate pathways leading to β-cell apoptosis are oxidative stress, ER stress, amyloid accumulation, ectopic lipid deposition, lipotoxicity and glucotoxicity [127]. These stresses can all be caused by over-nutrition and neatly connects T2DM to obesity [90]. Glucose, the most important insulin secretatogue, is also the most important regulator of β-cell mass and function [128]. Impaired glucose-tolerance and hyperglycaemia are hallmarks of T2DM and prolonged glucose exposure can promote glucose-desensitisation, decreased insulin secretion and generation of oxidative stress in β-cells [128]. Consequently, glucotoxicity plays a significant part in pancreatic β-cell death in T2DM.

Understandably, excess glucose increases β-cell glucose metabolism and oxidative phosphor‐ ylation. Elevated ETC activity promotes increased superoxide (O2 - ) anion leakage from the mitochondria and may cause oxidative cellular damage [100]. Furthermore, high glucose levels induces NOX activity via NADPH production from metabolism of glucose to pentose, and through the TCA cycle, both leading to increased O2 - output [100]. O2 - can be converted to the less reactive H2O2 via superoxide dismutase, to the highly reactive hydroxyl anion by the ironcatalysed Fenton reaction, or to peroxynitrite (ONOO- ) via reaction with iNOS-derived NO [27,129]. β-cells are considered vulnerable to ROS/RNS generation because they express relatively low levels of antioxidant enzymes, like glutathione and catalase [27,128,129]. These enzymes immediately convert H2O2 to molecular oxygen and water. However, the detrimental combination of reduced activity of antioxidant enzymes, along with ROS/RNS generation can result in oxidative damage to DNA, lipids and proteins, thereby promoting mitochondrialmediated apoptosis. In addition, ROS/RNS can also activate and regulate biochemical stress pathways, such as the NFκB, leading to further negative effects in β-cells [100,101].

Excess glucose can cause increased intracellular calcium, as outlined previously, which may enhance mitochondrial O2 - production, but also deplete ER Ca2+, promoting activation of the ER-stress-mediated death pathway [111,128] alongside unfolded protein response (UPR) (for review, please see [130]). In normal conditions, proteins are synthesised in the ER and are subsequently secreted or routed into a variety of sub-cellular compartments. Howev‐ er, accumulation of native or unfolded proteins within the lumen of the ER can activate caspase enzymes and ultimately promote cell death [131,132]. Reaction of ROS with the ER leads to protein accumulation via dysregulation of the ER oxidative folding pathway [111]. It also results in oxidative activation of Ca2+ release channels in the ER membrane, thereby depleting the ER of Ca2+ [111]. This ER stress activates pro-caspase-12, located on the cytoplasmic side of the ER, in a manner similar to caspase-9 [133,134]. Caspase-12 apopto‐ somes also causes translocation of JNK to the mitochondrial membrane inducing BIM

phosphorylation, ultimately leading to cytochrome *c* release and initiation of mitochondrialdependent apoptosis [111,135,136].

**8. Pancreatic β-cell failure and death in T2DM**

146 Type 1 Diabetes

part in pancreatic β-cell death in T2DM.

enhance mitochondrial O2

through the TCA cycle, both leading to increased O2

catalysed Fenton reaction, or to peroxynitrite (ONOO-

Failure of pancreatic β-cells is essential in the progression of both T1 and T2DM. The devel‐ opment of T2DM is more gradual than T1, and appears to occur in specific stages. It is dependent on the establishment of insulin-resistance and displays increased degrees of variability in comparison with T1DM. Therefore, determination of the precise mechanisms of

T2DM patients have a 30-50% reduction in β-cell mass on average post-mortem and the primary candidate pathways leading to β-cell apoptosis are oxidative stress, ER stress, amyloid accumulation, ectopic lipid deposition, lipotoxicity and glucotoxicity [127]. These stresses can all be caused by over-nutrition and neatly connects T2DM to obesity [90]. Glucose, the most important insulin secretatogue, is also the most important regulator of β-cell mass and function [128]. Impaired glucose-tolerance and hyperglycaemia are hallmarks of T2DM and prolonged glucose exposure can promote glucose-desensitisation, decreased insulin secretion and generation of oxidative stress in β-cells [128]. Consequently, glucotoxicity plays a significant

Understandably, excess glucose increases β-cell glucose metabolism and oxidative phosphor‐

mitochondria and may cause oxidative cellular damage [100]. Furthermore, high glucose levels induces NOX activity via NADPH production from metabolism of glucose to pentose, and

less reactive H2O2 via superoxide dismutase, to the highly reactive hydroxyl anion by the iron-

[27,129]. β-cells are considered vulnerable to ROS/RNS generation because they express relatively low levels of antioxidant enzymes, like glutathione and catalase [27,128,129]. These enzymes immediately convert H2O2 to molecular oxygen and water. However, the detrimental combination of reduced activity of antioxidant enzymes, along with ROS/RNS generation can result in oxidative damage to DNA, lipids and proteins, thereby promoting mitochondrialmediated apoptosis. In addition, ROS/RNS can also activate and regulate biochemical stress

Excess glucose can cause increased intracellular calcium, as outlined previously, which may

the ER-stress-mediated death pathway [111,128] alongside unfolded protein response (UPR) (for review, please see [130]). In normal conditions, proteins are synthesised in the ER and are subsequently secreted or routed into a variety of sub-cellular compartments. Howev‐ er, accumulation of native or unfolded proteins within the lumen of the ER can activate caspase enzymes and ultimately promote cell death [131,132]. Reaction of ROS with the ER leads to protein accumulation via dysregulation of the ER oxidative folding pathway [111]. It also results in oxidative activation of Ca2+ release channels in the ER membrane, thereby depleting the ER of Ca2+ [111]. This ER stress activates pro-caspase-12, located on the cytoplasmic side of the ER, in a manner similar to caspase-9 [133,134]. Caspase-12 apopto‐ somes also causes translocation of JNK to the mitochondrial membrane inducing BIM

pathways, such as the NFκB, leading to further negative effects in β-cells [100,101].


output [100]. O2



) anion leakage from the


) via reaction with iNOS-derived NO

ylation. Elevated ETC activity promotes increased superoxide (O2

T2DM-related cell death remains difficult and, these are still not fully understood.

Lipid accumulation (lipotoxicity) in the ER may also play a significant function in mediating ER stress in β-cells. Obesity is a primary risk factor associated with T2DM, and is accompanied with increased plasma glucose and lipid levels due to high carbohydrate- and fat-based diets [137]. The process by which free fatty acids modulate ER stress is not entirely known [111] but, it has been shown that palmitic acid could deplete ER Ca2+ levels and augment ER morphology and integrity, which may cause activation of ER stress by the mechanisms mentioned above [137,138]. Furthermore, excess fatty acid esterification in the ER, may divert ER machinery and delay the processing and export of proteins in the ER [137]. Since there is a large demand for protein/insulin production in pancreatic islets, β-cells have a highly active and well developed ER. This suggests that β-cells may be more susceptible to ER stress during protein synthesis [109,137]. Given the effects of elevated plasma glucose and lipids in T2DM patients, ER stress could be a vital mechanism facilitating glucotoxicity-, lipotoxicity- or glucolipotoxicitymediated β-cell failure and death [137].

Moreover, accumulation of islet amyloid polypeptide (IAPP) may also contribute to β-cell dysfunction and death in a manner similar to that described above [110,111,139]. IAPP precipitates into lethal oligomers inside the ER and like unfolded proteins, activates the ER stress-mediated death pathway [139]. IAPP deposits are present in over 90% of T2DM islets, post-mortem, indicating a substantial participation in T2DM progression [109,111].

In summary, several biochemical mechanisms have been suggested to be responsible for pancreatic β-cell failure and death in T2DM. However, there appears to be significant interplay between the purported pathways and conditions of glucotoxicity-, lipotoxicity- and glucoli‐ potoxicity, which are common in the aetiology of T2DM and require further investigation. Interestingly, from this review there are noteworthy commonalities associated with T1 and T2DM mechanisms of β-cell failure and death. In the following section we will attempt to summarise these, with a view to identifying the potential therapeutic targets that are of interest to the research community.
