全身性炎症における高血糖の機序・インスリン抵抗性
As discussed above, it is now apparent that obesity is associated with a state of chronic, low-grade inflammation, particularly in white adipose tissue. How do inflammatory cytokines and/or fatty acids mediate insulin resistance? How do the stresses of obesity manifest inside of cells? In recent years, much has been learned about the intracellular signaling pathways activated by inflammatory and stress responses and how these pathways intersect with and inhibit insulin signaling.
Insulin affects cells through binding to its receptor on the surface of insulin-responsive cells. The stimulated insulin receptor phosphorylates itself and several substrates, including members of the insulin receptor substrate (IRS) family, thus initiating downstream signaling events (32, 33). The inhibition of signaling downstream of the insulin receptor is a primary mechanism through which inflammatory signaling leads to insulin resistance. Exposure of cells to TNF- or elevated levels of free fatty acids stimulates inhibitory phosphorylation of serine residues of IRS-1 (34-36). This phosphorylation reduces both tyrosine phosphorylation of IRS-1 in response to insulin and the ability of IRS-1 to associate with the insulin receptor and thereby inhibits downstream signaling and insulin action (35, 37, 38).
Recently it has become clear that inflammatory signaling pathways can also become activated by metabolic stresses originating from inside the cell as well as by extracellular signaling molecules. It has been demonstrated that obesity overloads the functional capacity of the ER and that this ER stress leads to the activation of inflammatory signaling pathways and thus contributes to insulin resistance (39-41). Additionally, increased glucose metabolism can lead to a rise in mitochondrial production of ROS. ROS production is elevated in obesity, which causes enhanced activation of inflammatory pathways (42, 43).
Several serine/threonine kinases are activated by inflammatory or stressful stimuli and contribute to inhibition of insulin signaling, including JNK, inhibitor of NF-B kinase (IKK), and PKC- (44). Again, the activation of these kinases in obesity highlights the overlap of metabolic and immune pathways; these are the same kinases, particularly IKK and JNK, that are activated in the innate immune response by Toll-like receptor (TLR) signaling in response to LPS, peptidoglycan, double-stranded RNA, and other microbial products (45). Hence it is likely that components of TLR signaling pathways will also exhibit strong metabolic activities.
JNK. The 3 members of the JNK group of serine/threonine kinases, JNK-1, -2, and -3, belong to the MAPK family and regulate multiple activities in development and cell function, in large part through their ability to control transcription by phosphorylating activator protein–1 (AP-1) proteins, including c-Jun and JunB (46). JNK has recently emerged as a central metabolic regulator, playing an important role in the development of insulin resistance in obesity (47). In response to stimuli such as ER stress, cytokines, and fatty acids, JNK is activated, whereupon it associates with and phosphorylates IRS-1 on Ser307, impairing insulin action (36, 39, 48). In obesity, JNK activity is elevated in liver, muscle, and fat tissues, and loss of JNK1 prevents the development of insulin resistance and diabetes in both genetic and dietary mouse models of obesity (47). Modulation of hepatic JNK1 in adult animals also produces systemic effects on glucose metabolism, which underscores the importance of this pathway in the liver (49). The contribution of the JNK pathway in adipose, muscle, or other tissues to systemic insulin resistance is currently unclear. In addition, a mutation in JNK-interacting protein–1 (JIP1), a protein that binds JNK and regulates its activity, has been identified in diabetic humans (50). The phenotype of the JIP1 loss-of-function model is very similar to that of JNK1 deficiency in mice, with reduced JNK activity and increased insulin sensitivity (51). Interestingly, the JNK2 isoform plays a significant nonredundant role in atherosclerosis (52), though apparently not in type 2 diabetes. Recent studies in mice demonstrate that JNK inhibition in established diabetes or atherosclerosis might be a viable therapeutic avenue for these diseases in humans (52, 53).
PKC and IKK. Two other inflammatory kinases that play a large role in counteracting insulin action, particularly in response to lipid metabolites, are IKK and PKC-. Lipid infusion has been demonstrated to lead to a rise in levels of intracellular fatty acid metabolites, such as diacylglycerol (DAG) and fatty acyl CoAs. This rise is correlated with activation of PKC- and increased Ser307 phosphorylation of IRS-1 (54). PKC- may impair insulin action by activation of another serine/threonine kinase, IKKß, or JNK (55). Other PKC isoforms have also been reported to be activated by lipids and may also participate in inhibition of insulin signaling (56).
IKKß can impact on insulin signaling through at least 2 pathways. First, it can directly phosphorylate IRS-1 on serine residues (34, 57). Second, it can phosphorylate inhibitor of NF-B (IB), thus activating NF-B, a transcription factor that, among other targets, stimulates production of multiple inflammatory mediators, including TNF- and IL-6 (58). Mice heterozygous for IKKß are partially protected against insulin resistance due to lipid infusion, high-fat diet, or genetic obesity (59, 60). Moreover, inhibition of IKKß in human diabetics by high-dose aspirin treatment also improves insulin signaling, although at this dose, it is not clear whether other kinases are also affected (61). Recent studies have also begun to tease out the importance of IKK in individual tissues or cell types to the development of insulin resistance. Activation of IKK in liver and myeloid cells appears to contribute to obesity-induced insulin resistance, though this pathway may not be as important in muscle (62-64).
Other pathways. In addition to serine/threonine kinase cascades, other pathways contribute to inflammation-induced insulin resistance. For example, at least 3 members of the SOCS family, SOCS1, -3, and -6, have been implicated in cytokine-mediated inhibition of insulin signaling (65-67). These molecules appear to inhibit insulin signaling either by interfering with IRS-1 and IRS-2 tyrosine phosphorylation or by targeting IRS-1 and IRS-2 for proteosomal degradation (65, 68). SOCS3 has also been demonstrated to regulate central leptin action, and both whole body reduction in SOCS3 expression (SOCS3+/–) and neural SOCS3 disruption result in resistance to high-fat diet–induced obesity and insulin resistance (69, 70).
Inflammatory cytokine stimulation can also lead to induction of iNOS. Overproduction of nitric oxide also appears to contribute to impairment of both muscle cell insulin action and ß cell function in obesity (71, 72). Deletion of iNOS prevents impairment of insulin signaling in muscle caused by a high-fat diet (72). Thus, induction of SOCS proteins and iNOS represent 2 additional and potentially important mechanisms that contribute to cytokine-mediated insulin resistance. It is likely that additional mechanisms linking inflammation with insulin resistance remain to be uncovered.
As discussed above, it is now apparent that obesity is associated with a state of chronic, low-grade inflammation, particularly in white adipose tissue. How do inflammatory cytokines and/or fatty acids mediate insulin resistance? How do the stresses of obesity manifest inside of cells? In recent years, much has been learned about the intracellular signaling pathways activated by inflammatory and stress responses and how these pathways intersect with and inhibit insulin signaling.
Insulin affects cells through binding to its receptor on the surface of insulin-responsive cells. The stimulated insulin receptor phosphorylates itself and several substrates, including members of the insulin receptor substrate (IRS) family, thus initiating downstream signaling events (32, 33). The inhibition of signaling downstream of the insulin receptor is a primary mechanism through which inflammatory signaling leads to insulin resistance. Exposure of cells to TNF- or elevated levels of free fatty acids stimulates inhibitory phosphorylation of serine residues of IRS-1 (34-36). This phosphorylation reduces both tyrosine phosphorylation of IRS-1 in response to insulin and the ability of IRS-1 to associate with the insulin receptor and thereby inhibits downstream signaling and insulin action (35, 37, 38).
Recently it has become clear that inflammatory signaling pathways can also become activated by metabolic stresses originating from inside the cell as well as by extracellular signaling molecules. It has been demonstrated that obesity overloads the functional capacity of the ER and that this ER stress leads to the activation of inflammatory signaling pathways and thus contributes to insulin resistance (39-41). Additionally, increased glucose metabolism can lead to a rise in mitochondrial production of ROS. ROS production is elevated in obesity, which causes enhanced activation of inflammatory pathways (42, 43).
Several serine/threonine kinases are activated by inflammatory or stressful stimuli and contribute to inhibition of insulin signaling, including JNK, inhibitor of NF-B kinase (IKK), and PKC- (44). Again, the activation of these kinases in obesity highlights the overlap of metabolic and immune pathways; these are the same kinases, particularly IKK and JNK, that are activated in the innate immune response by Toll-like receptor (TLR) signaling in response to LPS, peptidoglycan, double-stranded RNA, and other microbial products (45). Hence it is likely that components of TLR signaling pathways will also exhibit strong metabolic activities.
JNK. The 3 members of the JNK group of serine/threonine kinases, JNK-1, -2, and -3, belong to the MAPK family and regulate multiple activities in development and cell function, in large part through their ability to control transcription by phosphorylating activator protein–1 (AP-1) proteins, including c-Jun and JunB (46). JNK has recently emerged as a central metabolic regulator, playing an important role in the development of insulin resistance in obesity (47). In response to stimuli such as ER stress, cytokines, and fatty acids, JNK is activated, whereupon it associates with and phosphorylates IRS-1 on Ser307, impairing insulin action (36, 39, 48). In obesity, JNK activity is elevated in liver, muscle, and fat tissues, and loss of JNK1 prevents the development of insulin resistance and diabetes in both genetic and dietary mouse models of obesity (47). Modulation of hepatic JNK1 in adult animals also produces systemic effects on glucose metabolism, which underscores the importance of this pathway in the liver (49). The contribution of the JNK pathway in adipose, muscle, or other tissues to systemic insulin resistance is currently unclear. In addition, a mutation in JNK-interacting protein–1 (JIP1), a protein that binds JNK and regulates its activity, has been identified in diabetic humans (50). The phenotype of the JIP1 loss-of-function model is very similar to that of JNK1 deficiency in mice, with reduced JNK activity and increased insulin sensitivity (51). Interestingly, the JNK2 isoform plays a significant nonredundant role in atherosclerosis (52), though apparently not in type 2 diabetes. Recent studies in mice demonstrate that JNK inhibition in established diabetes or atherosclerosis might be a viable therapeutic avenue for these diseases in humans (52, 53).
PKC and IKK. Two other inflammatory kinases that play a large role in counteracting insulin action, particularly in response to lipid metabolites, are IKK and PKC-. Lipid infusion has been demonstrated to lead to a rise in levels of intracellular fatty acid metabolites, such as diacylglycerol (DAG) and fatty acyl CoAs. This rise is correlated with activation of PKC- and increased Ser307 phosphorylation of IRS-1 (54). PKC- may impair insulin action by activation of another serine/threonine kinase, IKKß, or JNK (55). Other PKC isoforms have also been reported to be activated by lipids and may also participate in inhibition of insulin signaling (56).
IKKß can impact on insulin signaling through at least 2 pathways. First, it can directly phosphorylate IRS-1 on serine residues (34, 57). Second, it can phosphorylate inhibitor of NF-B (IB), thus activating NF-B, a transcription factor that, among other targets, stimulates production of multiple inflammatory mediators, including TNF- and IL-6 (58). Mice heterozygous for IKKß are partially protected against insulin resistance due to lipid infusion, high-fat diet, or genetic obesity (59, 60). Moreover, inhibition of IKKß in human diabetics by high-dose aspirin treatment also improves insulin signaling, although at this dose, it is not clear whether other kinases are also affected (61). Recent studies have also begun to tease out the importance of IKK in individual tissues or cell types to the development of insulin resistance. Activation of IKK in liver and myeloid cells appears to contribute to obesity-induced insulin resistance, though this pathway may not be as important in muscle (62-64).
Other pathways. In addition to serine/threonine kinase cascades, other pathways contribute to inflammation-induced insulin resistance. For example, at least 3 members of the SOCS family, SOCS1, -3, and -6, have been implicated in cytokine-mediated inhibition of insulin signaling (65-67). These molecules appear to inhibit insulin signaling either by interfering with IRS-1 and IRS-2 tyrosine phosphorylation or by targeting IRS-1 and IRS-2 for proteosomal degradation (65, 68). SOCS3 has also been demonstrated to regulate central leptin action, and both whole body reduction in SOCS3 expression (SOCS3+/–) and neural SOCS3 disruption result in resistance to high-fat diet–induced obesity and insulin resistance (69, 70).
Inflammatory cytokine stimulation can also lead to induction of iNOS. Overproduction of nitric oxide also appears to contribute to impairment of both muscle cell insulin action and ß cell function in obesity (71, 72). Deletion of iNOS prevents impairment of insulin signaling in muscle caused by a high-fat diet (72). Thus, induction of SOCS proteins and iNOS represent 2 additional and potentially important mechanisms that contribute to cytokine-mediated insulin resistance. It is likely that additional mechanisms linking inflammation with insulin resistance remain to be uncovered.
アクセス
トータル
ランキング
