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Insulin resistance is a major contributor to the pathogenesis of T2DM and plays a key role in associated metabolic abnormalities (see fig. 2 for an overview of the pathological cascade). Insulin resistance occurs when target tissues can no longer sufficiently respond to normal levels of circulating insulin, meaning they harbor a reduced sensitivity to the action of insulin. Subsequently, the pancreas attempts to overcome this reduced response by producing and secreting more insulin in order to promote peripheral glucose uptake, resulting in hyperinsulinemia. An important consequence of increased insulin secretion, is that hIAPP, a 37-amino acid peptide, which is co-secreted with insulin by the pancreatic β-cells, is overproduced and accumulates in the form of plaques. The genes coding for insulin and hIAPP contain similar control elements in their promoter regions, indicating that their β-cell specific expression is likely regulated by the same trans-acting transcription factors (Ashizawa et al., 2004; German et al., 1992; Macfarlane et al., 2000). Furthermore, both precursor forms of insulin and hIAPP are enzymatically cleaved by the prohormone-converting endopeptidases PC2 and PC3 (Marzban et al., 2004; Wang et al., 2001). It has also been shown that under physiological conditions hIAPP is stored in secretory granules in β-cells and is co-secreted with insulin, although the amount of hIAPP is relatively small compared to the amount of insulin (Johnson et al., 1988). Nevertheless, as a consequence of increased insulin production due to insulin resistance, hIAPP is also overproduced and secreted, leading to formation of fibrillar amyloid deposits in the pancreatic islets of Langerhans (Engel et al., 2008). Islet amyloid deposits have been reported in most patients with T2DM and it has been proposed that fibrillar hIAPP induces damage to the β-cell membrane, ultimately leading to β-cell death (Engel et al., 2008).

Additionally, hyperinsulemia causes exaggerated responses in tissues that remain sensitive to insulin. For example, it stimulates the sympathetic nervous system, which may contribute to hypertension (Reaven et al., 1996). In fat cells, insulin inhibits lipid metabolism by decreasing cellular concentrations of cyclic AMP in adipocytes (Dimitriadis et al., 2011). Thus, insulin resistance leads to increased lipolysis with release of fatty acids, leading to dyslipidemia and vascular abnormalities. High free fatty acid concentrations also lead to increased insulin requirement by enhancing glucose output from the liver and reducing glucose uptake in skeletal muscle (Boden, 1999).

Although there is little doubt regarding the importance of genetic factors in T2DM and insulin resistance, it should be recognized that like AD, these disorders are exceedingly heterogeneous. Therefore, most genetic studies have reported diverse results. The candidate gene approach, in attempts to identify a causative factor among the obvious biological candidates for insulin resistance, such as genes involved in pancreatic β-cell function, glucose metabolism or insulin action, has been largely disappointing (Vimaleswaran and Loos, 2010). In most instances, an initial association did not result in identification of conclusive risk factors in subsequent analyses. Currently the most robust single candidate variant is the highly prevalent Pro12Ala polymorphism in the peroxisome proliferator-activated receptor γ (PPARγ) (Lohmueller et al., 2003; Parikh and Groop, 2004). PPARγ is a transcription factor that is activated by fatty acids and is involved in the regulation of adipogenic differentiation. The high risk proline allele of the Pro₁₂Ala PPARγ polymorphism has decreased transcriptional activity and presumably leads to lower insulin sensitivity. In addition to the Pro₁₂Ala PPARγ polymorphism and associated insulin resistance, several findings of positive associations of genomic regions with T2DM have been replicated in one or more studies (McCarthy, 2003). Nevertheless, such findings are generally followed by positional cloning of the causative gene, which to date has not been successful for most regions.

There are several mechanisms that have recently been elucidated to explain how obesity, especially visceral adiposity, leads to insulin resistance and contributes to cardiovascular disease. Obesity can simply be defined as a condition of excessive fat accumulation in adipose tissue, which causes or exacerbates many health problems, both independently and in association with other diseases (Kopelman, 2000). An increased mass of stored triglyceride in insulin target organs, especially in visceral or deep subcutaneous adipose depots, leads to the formation of large adipocytes that are themselves resistant to the ability of insulin to suppress lipolysis. This results in increased release and circulating levels of non-esterified free fatty acids and glycerol, both of which aggravate insulin resistance in skeletal muscle and liver, and can impair insulin action and secretion in pancreatic β-cells. In skeletal muscle, acutely raising plasma free fatty acids reduces insulin stimulated glucose uptake dose-dependently in all individuals irrespective of gender and age (Boden and Chen, 1995; Boden et al., 1994). In addition to excessive storage of fat in adipocytes, accumulation of intramyocellular or intrahepatic lipids is also associated with skeletal muscle and hepatic insulin resistance respectively (Machann et al., 2004; Seppala-Lindroos et al., 2002). It has been shown that free fatty acids stimulate protein kinase C isoforms, which can interrupt the cellular mechanisms of insulin signaling and inhibit glucose transport activity (Griffin et al., 1999). Impaired insulin stimulated glucose transport in skeletal muscle appears to be at least partially responsible for insulin resistance (Cline et al., 1999).

In addition, a major conceptual advance in the field of obesity induced insulin resistance was made by the discovery that obesity gives rise to a state of chronic low-grade inflammation with evidence of increased infiltration of macrophages into the adipose tissue (Oliver et al., 2010). These adipose tissue macrophages have been shown to produce many pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6). Both cytokines have been implicated in the development of insulin resistance and the pathophysiology of T2DM and obesity (Weisberg et al., 2003), either by directly reducing insulin sensitivity through the insulin-signaling pathway (Peraldi et al., 1996), or via activation of nuclear factor-κB (NF-κB) causing downregulation of GLUT4 and IRS-1 (Lumeng et al., 2007). It is therefore hypothesized that the adipose tissue macrophages may directly contribute to insulin resistance observed in obesity. Consistently, in obese subjects, adipose tissue macrophage content is higher in visceral adipose tissue than in subcutaneous adipose tissue, in agreement with the hypothesis that visceral fat plays a more prominent role in insulin resistance (Cancello et al., 2006). Also, increased adiposity negatively correlates with production of adiponectin, an insulin-sensitizing hormone that is thought to decrease hepatic gluconeogenesis and increase lipid oxidation in muscle (Arita et al., 1999; Tomas et al., 2002).  

            As glucose levels rise as a consequence of peripheral insulin resistance, hyperglycemia, and over time, glucose toxicity follows. Hyperglycemia has been associated with the formation of large amounts of reactive oxygen species in β-cells, resulting in impaired signaling processes and ultimately irreversible cellular damage (Leibowitz et al., 2010). Reactive oxygen species have long been thought to result from enhanced interleukin-lβ (IL-lβ) and NFκB activity, which have been implicated in the induction of β-cell damage and dysfunction in T2DM (Eizirik et al., 1996; Flodstrom et al., 1996). IL-1β initiates signal transduction by binding to interleukin 1 receptor type I (IL-1R1) on the β-cell. Subsequent events involve the recruitment of several effector proteins, including interleukin 1 receptor accessory protein (IL-1RAcP), adaptor protein myeloid differentiation primary response gene 88 (MyD88), interleukin-1 receptor-associated kinase (IRAK)-4, and preformed Tollip/IRAK-1 complexes that reside in the cytoplasm, allow­ing IRAK-1 to interact with TNF-receptor-associated factor 6 (TRAF6) (Maedler et al., 2009). IRAK1/TRAF6 dissociates from the receptor complex and binds to TGF-β activated kinase 1 (TAK1) at the membrane. In turn TRAF6/TAK1 are translocated to the cytosol where TRAF6 is ubiquitinated, allowing TAK1 to become activated (Frobose et al., 2006). TAK1 phosphorylates the IκB kinase (IKK) complex, which subsequently phosphorylates IκB itself. IκB is an inhibitory protein that retains NFκB in the cytoplasm. However, once phosphorylated, IκB dissociates from its complex with NFκB, allowing NFκB to translocate to the nucleus and initiate transcription of its target genes such as iNOS, resulting in production of NO, a toxic reactive radical (Maedler et al., 2009). Interestingly, the overall aberrant effects of IL-1β signaling include reduced AKT signaling (Storling et al., 2005) and desensitization of the insulin receptor (Emanuelli et al., 2004), altogether resulting in high levels of β-cell stress, ensuing in dysfunction and sustained pro-apoptotic output signals.

These data suggest a role for IL-1β in the pathogenesis of type 2 diabetes; however, the events that lead to higher concentrations of active, secreted IL-1β in this disease remain unclear. Interestingly, it has been shown that hIAPP can induce inflammasome activation and thereby increase IL-1β production by lipopolysaccharide (LPS)-primed macrophages or dendritic cells, whereas this association was not found for the non-amyloidogenic rat form of hIAPP (Masters et al., 2010). They further reported that in NLRP3-deficient bone marrow dendritic cells, the production of mature IL-1β in response to hIAPP was completely abrogated, indicating that this effect was dependent on the NLRP inflammasome. This multiprotein complex consists of the NLR protein NLRP3, the adapter ASC (apoptosis-associated speck-like protein containing a caspase-recruit­ment domain) and pro-caspase-1. The general consensus is that maturation and release of IL-1β requires two distinct signals: the first signal leads to synthesis of pro-IL-1β and other components of the inflammasome, such as NLRP3 itself; the second signal results in the assembly of the NLRP3 inflammasome, caspase-1 activation and IL-1β secretion (Gross et al., 2009). Masters and colleagues furthermore reported that the concentrations of TNF and IL-6 were not altered by the presence of IAPP, which indicated that there was a specific effect on IL-1β production and not a general increase in the production of proinflammatory cytokines (Masters et al., 2010).