# Insulin Resistance: A Proinflammatory State Mediated

Authors: Fabrizio Montecucco; Sabine Steffens; François Mach
Journal: Mediators of Inflammation
 (2008)

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## Abstract

The dysregulation of the insulin-glucose axis represents the crucial event in insulin resistance syndrome. Insulin resistance increases atherogenesis and atherosclerotic plaque instability by inducing proinflammatory activities on vascular and immune cells. This condition characterizes several diseases, such as type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), obesity, hypertension, dyslipidemia, and other endocrinopathies, but also cancer. Recent studies suggest that the pathophysiology of insulin resistance is closely related to interferences with insulin-mediated intracellular signaling on skeletal muscle cells, hepatocytes, and adipocytes. Strong evidence supports the role of free fatty acids (FFAs) in promoting insulin resistance. The FFA-induced activation of protein kinase C (PKC) delta, inhibitor kappaB kinase (IKK), or c-Jun N-terminal kinase (JNK) modulates insulin-triggered intracellular pathway (classically known as PI3-K-dependent). Therefore, reduction of FFA levels represents a selective target for modulating insulin resistance.


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## Body

## 1. Epidemiology of Insulin Resistance

Historically, the  sweetness of urine
and other body fluids in diabetic patients suggested that glucose had an
important role in the physiopathology of this common disease. Thus, glucose
metabolism and the insulin-glucose axis were the leading fields for scientific
investigations. To emphasize this concept, diabetes was called “mellitus.” Not
only hyperglycaemia is crucial for the diagnosis of diabetes and the development
of clinical complications [1], but also increasing evidence demonstrated the
involvement of insulin in the physiopathology of this disease. In fact,
diabetes is a metabolic disease characterized by hyperglycaemia resulting from either
defects in insulin secretion or insulin properties, or both. In the present
review, we focus on defects of insulin properties, with particular regard to
insulin resistance, which can be defined as a state of reduced responsiveness
to normal circulating levels of insulin. This condition is a feature of various
disorders, such as type 2 diabetes, which may range from predominantly insulin
resistance with relative insulin deficiency to a predominatly secretory defect
of insulin [1]. Insulin resistance is also implicated in impaired glucose
tolerance (IGT) or impaired fasting glucose (IFG), both considered as
“prediabetes” by the Expert Committee on the Diagnosis and Classification of
Diabetes Mellitus [2–4], as well as in obesity, hypertension, dyslipidaemia
(all disorders clustering in the so-called metabolic syndrome) [5], other endocrinopathies
[6], but also in different diseases, such as cancer, infections or rheumatic, and
autoimmune diseases [7–11]. Therefore, given the association between insulin
resistance and different diseases, no epidemiological data are available,
specifically focused on insulin resistance syndrome prevalence or incidence. Furthermore,
only recently (in 1997) the WHO have accepted obesity as an epidemic public
health burden in adults, without evaluating a well-defined method to monitoring
the problem in children [12–15]. Finally, still few clinical studies on Asian
and African cohorts focused on insulin resistance and related diseases have
been published [16–19]. For all these reasons, to better define insulin
resistance epidemiology syndrome requires more investigations. Mechanisms of
insulin resistance remain also unknown. Insulin resistance was initially
recognized as an “allergy” to insulin, with the production of antibodies
anti-insulin [20, 21]. Further investigations showed that metabolism of both nonesterified
fatty acids (NEFA) and free fatty acids (FFAs) was a crucial step in the
development of insulin resistance [22, 23]. On the basis of these new evidences,
Shafrir and Raz suggested in 2003 that diabetes should be now called “lipidus”
instead of “mellitus” [24]. Given the importance of physiological effects of insulin
during atherogenesis [25–27], there is a need to better clarify the complexity
of mechanisms underlying insulin resistance.


## 2. Mechanisms of Insulin Resistance

Insulin is an anabolic essential hormone
for the maintenance of glucose omeostasis, tissue growth, and development [28].
It is well known that insulin is secreted by the pancreatic β cells mainly in response to
increased blood levels of glucose and aminoacids after the meals (extrinsic
rhythm) [29]. In addition, the concentration of insulin in the blood displays
regular variations independently from the food intake [30]. In fact, two
rhythms with periods of 5–10 minutes and 60–120 minutes have
been documented (intrinsic rhythm) [31–33]. The extrinsic rhythm was found
altered in a lot of diseases including gestational diabetes [34], maturity onset
diabetes of the young (MODY) 1 [35, 36], MODY 3 [37], and
Chagas’ disease [38]. Furthermore, an altered plasma insulin secretory response
has been also observed as an effect of aging processes [39]. On the contrary,
the intrinsic rhythm has been found altered in various diseases, such as type 2
diabetes (i.e., MODY 2 as well as maternally inherited
diabetes and deafness (MIDD))
[40, 41], obesity [42], and hypertension [43]. Several genetic and molecular
studies have been performed to investigate the causes of the dysregulated
plasma insulin pattern. Although genetic mutations account for a minor role in
the large part of insulin resistance, an alteration of insulin signal
transduction, which may be due to genetic mutations, could contribute to the
impairment of insulin secretory profile and insulin resistance. Thus, mutations
of glucokinase phosphorylated glucose, hepatic nuclear factor-4 alpha, hepatic
nuclear factor-1 alpha, mitochondrial tRNALeu(UUR), and also insulin receptor
genes have been found [35, 37, 44–46]. For instance, a mutation in the insulin
receptor gene of the pancreatic βcells has been correlated with a
defective insulin-mediated intracellular signal transduction [46]. On the other
hand, obesity and increased FFA levels mediate insulin resistance by inducing a
decreased IRS-1-associated phosphatidylinositol 3-kinase (PI3-K) activity [47].
In line with these findings, it has been shown that insulin resistance was
reversed when obese persons lose weight [48]. However, this weight loss did not
restore normal insulin pulsatiliy in Type 2 diabetes patients [49]. These data
suggest that the defective insulin-mediated intracellular signal transduction is
not the only cause responsible for insulin resistance, and that the molecular
mechanisms of insulin resistance are not completely understood. We will discuss
in the following the potential mechanisms contributing to insulin resistance
which are currently under investigation.


### 2.1. Defects on Insulin Signaling

The insulin receptor is considered to
play a critical role in insulin resistance. It is a member of the receptor
tyrosine kinase family [50], composed of two α-subunits and two β-subunits linked together by disulphide bonds. Two isoforms of insulin
receptors are known, exhibiting different affinity for insulin and distribution
within tissues. Although it is tempting to suggest that differences in binding
activity could contribute to insulin resistance, experimental evidence for the involvement
of receptor isoforms or receptor hybrids remains controversial [29]. Apart from
the insulin binding step to its receptor, the receptor intracellular tyrosine
kinase domains (capable of intrinsic kinase activity) have been investigated in
view of their possible implication in insulin resistance. A variety of
scaffolding proteins, including insulin receptor substrate (IRS) proteins, casitas
B lineage lymphoma (Cbl), or Cbl associated protein (CAP), bind to
intracellular receptor sites and become phosphorylated [51–53]. IRS-1 and -2
are considered the most important proteins in regulation of glucose metabolism
[54]. As shown in knockout mouse models, IRS-1 or IRS-2 inactivation causes
insulin resistance [55, 56]. In addition, in vitro experiments showed an
increased serine phosphorylation of IRS by tumor necrosis factor-alpha (TNF-α) or FFA stimulation, thereby causing impaired insulin signal
transduction [54, 57]. Finally, a prolonged exposure to insulin (a typical condition
in hyperinsulinemic patients) may result in a degradation of IRS protein [58].
All together, these data support IRS-1 and IRS-2 as crucial players in the
development of insulin resistance. Furthermore, numerous studies aimed to
identify downstream elements of IRS proteins in the insulin-mediated signal
transduction pathway. As mentioned above, PI3-K is considered the central
mediator [59]. Three different isoforms of this kinase have been identified: Ia,
PI3-K/Akt, capable of generating phosphatidylinositol 4,5-bisphosphate (PIP2)
and phosphatidylinositol 3,4,5-trisphosphate (PIP3); Ib, G protein regulated
kinase; II, incapable of generating PIP2 and PIP3. As shown in Figure 1(a),
activated PI3-K is responsible for the beginning of a complex phosphorylation
cascade, involving the phospholipids PIP2, PIP3, the phosphoinositide-dependent
kinase 1 (PDK1), the protein kinase B (PKB, also called Akt), as well as the
protein kinase C (PKC). Akt mediates the effects of insulin on glucose
transport (GLUT) [60], glycogen synthesis, protein synthesis, lipogenesis, and
suppression of hepatic gluconeogenesis [59]. Once activated, Akt detaches from
the plasma membrane and translocates into the nucleus through a still unknown mechanism
[61], or activates different substrates, such as glycogen synthase kinase-3
(GSK-3) and transcription factors of the Foxo-family [59]. All these proteins
and phospholipids are likely to be implicated in insulin resistance. For
instance, a reduced PI3-K activity has been reported in skeletal muscle and
adipocytes of patients with insulin resistance [62–64]. In addition, Akt
activation has been found reduced in several diseases associated with insulin
resistance [65, 66]. However, Akt involvement in insulin resistance is
controversial, since other studies did not show any alteration of Akt
activation in insulin resistance associated syndromes [67, 68]. On the other
hand, insulin-induced PKC activation has been found altered in type 2 diabetic
[69] or obese [70] patients. Therefore, although other studies are needed, all
these observations suggest that a reduction of insulin-mediated intracellular
signaling is crucial for the establishment of insulin resistance.Figure 1
Lipid signaling interference generates insulin resistance.   (a) Signaling through phosphatidylinositol
3-kinase (PI3-K) is crucial for insulin-mediated glucose transport in
hepatocytes and skeletal muscle cells and for inflammatory protein and hormone
secretion in adipocytes and pancreatic βcells. Free fatty acids (FFAs)
induce a defective insulin-mediated signaling mainly through the activation of protein
kinase C (PKC θ), inhibitor κB kinase (IKK) and c-Jun
N-terminal kinase (JNK). (b) Main cell types involved in the
development of insulin resistance. (c) Main inflammatory cell
populations involved in hyperinsulinemia-induced inflammatory states.Another possible mechanism leading
to insulin resistance might be an upregulation of protein-tyrosine phosphatases
(PTPases), capable of functioning as negative regulators of the insulin-triggered
pathway. Among various proteins, PTP 1B has been shown as a key regulator of
insulin signaling [71–73]. Other phosphatases, such as ectonucleotide
pyrophosphatase phosphodiesterase 1 (ENPP1, also known as PC-1), SH-2-containing
inositol 5′-phosphatase 2 (SHIP2), and phosphatase and tensin homolog deleted
on chromosome 10 (PTEN) have been shown to interfere with insulin sensitivity
[74–76]. Although further investigations are warranted to very verify these
hypotheses, these proteins may represent future potential targets for the
treatment of insulin resistance.


### 2.2. Glucose Metabolism

Glucose uptake into muscle and fat
tissue depends on glucose transporter 4 (GLUT4) expression on the cell
membrane. Insulin reduces glycaemia, mainly by inducing the secretion of this
molecule by muscle and fat cells [77]. However, GLUT4 polymorphisms or mutations
inactivating GLUT4 gene were not associated with insulin resistance [78]. In
addition, GLUT4 concentrations in skeletal muscle of insulin resistant patients
were not reduced [79]. This suggests that alterations in GLUT4 expression are
not a primary cause for the development of insulin resistance. In this context,
the correct functioning of insulin intracellular signalization appears
essential. In fact, GLUT4 upregulation represents the final event of insulin
signaling cascade [80–82]. Among various kinases (Figure 1(a)), Aktβ has been shown to play an essential role. Recently, in vitro and in
vivo studies suggested that PKBβ alterations [83] or disruption [84] are responsible for the reduction
of insulin-induced glucose uptake. Consistent with these data, recent studies
in humans detected a missense mutation in the kinase domain of PKBβ (Akt 2) associated with severe insulin resistance [85]. These data
suggest that insulin signaling also plays crucial role in the regulation
glucose homeostasis.


### 2.3. Inflammatory Molecules

Recent evidence suggests that
inflammation might be crucial for the development of insulin resistance [86]. Proinflammatory
cytokines and acute-phase reactants are positively correlated with insulin
resistance in metabolic syndrome patients [87]. Among these soluble mediators, interleukin
(IL)-1 and IL-1 receptor antagonist (RA) have been implicated in the
development of insulin resistance in humans [88, 89] and in rodents [90, 91]. IL-1RA
is anaturally occurring cytokine and a member of the IL-1 family
whose only function is to prevent a biologic response to IL-1 [92]. In
humans, the blockade of IL-1 with IL-1 RA improves glycaemia and beta-cell
secretory function and reduces markers of systemic inflammation [93].
Accordingly, IL-1 has been shown to induce insulin resistance mainly by
inhibiting insulin-mediated signaling [94, 95]. Thus, IL-1 has to be considered
as an important factor involved in insulin resistance. TNF-α and IL-6 are also of particular interest, because of their increased
expression in adipose tissue and their capacity to induce insulin resistance [96].
Further evidence for the link between TNF-α and insulin resistance was provided by a study using blocking anti-TNF-α antibodies in obese rodents or TNF-α knockout obese mice [97]. In these animals, a reduced insulin
resistance was obtained by the suppression of TNF-α. The possible molecular mechanism of TNF-α-induced insulin resistance may involve IRS-1 [98]. Surprisingly, the
infusion of anti-TNF-α antibody in humans did not affect insulin resistance. Further
investigations are needed to better understand these opposite results obtained in
human and mice. On the other hand, the role of IL-6 in insulin resistance is
also controversial. IL-6 interferes with the metabolism of both adipose and
skeletal muscle tissues [99, 100], but has also a positive effect on skeletal
muscle cell insulin sensitivity [101]. In addition, IL-15 has been shown to
play a possible role in myocyte-adipocyte crosstalk, but only few studies are
published at present to better clarify its role in insulin resistance [102]. Moreover,
it is now established that hormones from adipose tissue hormones contribute to insulin
resistance. For instance, leptin has been shown to reverse insulin resistance
in mice with congenital lipodystrophy [103]. Administration of leptin to
patients with lipodystrophy can increase the body fat content and reverse
insulin resistance [104]. Resistin, a new adipocyte hormone [105], may be another
important link between increased fat mass and insulin resistance [106]. Resistin
decreases insulin-dependent glucose transport in vitro and increases fasting
blood glucose concentrations and hepatic glucose production in vivo [106–109].
Similarly, the reduction of adiponectin could contribute to insulin resistance.
Very recently, adiponectin has been showed as an anti-inflammatory and
immunomodulatory molecule [110, 111]. In humans, adiponectin levels correlate
with insulin sensitivity. Mice deficient in adiponectin are insulin resistant
[112] and the administration of adiponectine to obese and insulin resistant
mice has been shown to improve insulin sensitivity [113–115]. In addition,
inflammatory mediators such as the proinflammatory chemokine monocyte
chemotactic protein-1 (MCP-1) are believed to play a role in the pathogenesis
of insulin resistance. Recent in vitro evidence suggests that MCP-1 induces
insulin resistance in both adipocytes and skeletal muscle cells [116]. Finally,
retinol-binding protein (RBP)-4 and tissue inhibitors of metalloproteinases (TIMP)-1
were recently described to contribute to insulin resistance in vivo, but the
underlying mechanism remains unclear [117–119]. In conclusion, at the present
state of knowledge, insulin resistance has to be defined as a complex syndrome
involving not only glucose and lipids, but also several proinflammatory
molecules.


### 2.4. Lipids and Insulin Resistance

Lipid abnormalities, such as
increased circulating free fatty acids, are frequently associated with insulin
resistance [120]. Lipid metabolism induces insulin resistance through a well-known cascade of events. The excessive fat intake causes an increased influx of
triglycerides into the blood and an excess of plasma levels of FFAs, which
induce insulin resistance, with consequent hyperglycaemia. The increased levels
of glucose stimulate pancreatic βcells to secrete more and more insulin,
generating hyperinsulinemia, which further triggers the elevation of triglycerides
and closes the vicious circle [121]. When insulin secretion is not sufficient
and elevated glucose levels prevail,
diabetes becomes overt. Defective
insulin secretion is a result of chronic exposure to elevated levels of fatty
acids, which inhibits insulin gene expression by functioning as true toxic
agents for pancreatic βcells [122]. “Lipotoxicity” depends
on the interference with insulin-mediated intracellular signaling in various
cell types (Figure 1). In particular, FFAs have been shown to activate PKC θ(Figure 1(a)), which not only
interferes with insulin signaling (by inducing insulin resistance), but also is
implicated in promoting proatherogenic mechanisms, such as endothelial
dysfunction, growth, migration, and apoptosis of  vascular smooth muscle cells,
induction of adhesion molecules and oxidized low-density lipoprotein uptake of oxidized low-density lipoprotein by monocyte-derived macrophages [123]. Furthermore, it was recently
shown that FFAs induce insulin resistance in muscle through the activation of inhibitor
κB kinase (IKK) and c-Jun N-terminal kinase (JNK) (Figure 1(a)) [124]. Therefore,
FFAs induce insulin resistance in hepatocytes and skeletal muscle cells through
the activation of different kinases (Figures 1(a) and 1(b)). Both FFAs from
plasma and those released from stored triglycerides activate second messangers,
which alter insulin signaling [125]. FFAs are also involved in modulating
insulin production by pancreatic β-cells and cytokine secretion by hepatocytes, adipocyte, muscle cells,
and inflammatory cells (Figure 1(c)). This strongly supports FFA as important
proatherosclerotic agents.


## 2.1. Defects on Insulin Signaling

The insulin receptor is considered to
play a critical role in insulin resistance. It is a member of the receptor
tyrosine kinase family [50], composed of two α-subunits and two β-subunits linked together by disulphide bonds. Two isoforms of insulin
receptors are known, exhibiting different affinity for insulin and distribution
within tissues. Although it is tempting to suggest that differences in binding
activity could contribute to insulin resistance, experimental evidence for the involvement
of receptor isoforms or receptor hybrids remains controversial [29]. Apart from
the insulin binding step to its receptor, the receptor intracellular tyrosine
kinase domains (capable of intrinsic kinase activity) have been investigated in
view of their possible implication in insulin resistance. A variety of
scaffolding proteins, including insulin receptor substrate (IRS) proteins, casitas
B lineage lymphoma (Cbl), or Cbl associated protein (CAP), bind to
intracellular receptor sites and become phosphorylated [51–53]. IRS-1 and -2
are considered the most important proteins in regulation of glucose metabolism
[54]. As shown in knockout mouse models, IRS-1 or IRS-2 inactivation causes
insulin resistance [55, 56]. In addition, in vitro experiments showed an
increased serine phosphorylation of IRS by tumor necrosis factor-alpha (TNF-α) or FFA stimulation, thereby causing impaired insulin signal
transduction [54, 57]. Finally, a prolonged exposure to insulin (a typical condition
in hyperinsulinemic patients) may result in a degradation of IRS protein [58].
All together, these data support IRS-1 and IRS-2 as crucial players in the
development of insulin resistance. Furthermore, numerous studies aimed to
identify downstream elements of IRS proteins in the insulin-mediated signal
transduction pathway. As mentioned above, PI3-K is considered the central
mediator [59]. Three different isoforms of this kinase have been identified: Ia,
PI3-K/Akt, capable of generating phosphatidylinositol 4,5-bisphosphate (PIP2)
and phosphatidylinositol 3,4,5-trisphosphate (PIP3); Ib, G protein regulated
kinase; II, incapable of generating PIP2 and PIP3. As shown in Figure 1(a),
activated PI3-K is responsible for the beginning of a complex phosphorylation
cascade, involving the phospholipids PIP2, PIP3, the phosphoinositide-dependent
kinase 1 (PDK1), the protein kinase B (PKB, also called Akt), as well as the
protein kinase C (PKC). Akt mediates the effects of insulin on glucose
transport (GLUT) [60], glycogen synthesis, protein synthesis, lipogenesis, and
suppression of hepatic gluconeogenesis [59]. Once activated, Akt detaches from
the plasma membrane and translocates into the nucleus through a still unknown mechanism
[61], or activates different substrates, such as glycogen synthase kinase-3
(GSK-3) and transcription factors of the Foxo-family [59]. All these proteins
and phospholipids are likely to be implicated in insulin resistance. For
instance, a reduced PI3-K activity has been reported in skeletal muscle and
adipocytes of patients with insulin resistance [62–64]. In addition, Akt
activation has been found reduced in several diseases associated with insulin
resistance [65, 66]. However, Akt involvement in insulin resistance is
controversial, since other studies did not show any alteration of Akt
activation in insulin resistance associated syndromes [67, 68]. On the other
hand, insulin-induced PKC activation has been found altered in type 2 diabetic
[69] or obese [70] patients. Therefore, although other studies are needed, all
these observations suggest that a reduction of insulin-mediated intracellular
signaling is crucial for the establishment of insulin resistance.Figure 1
Lipid signaling interference generates insulin resistance.   (a) Signaling through phosphatidylinositol
3-kinase (PI3-K) is crucial for insulin-mediated glucose transport in
hepatocytes and skeletal muscle cells and for inflammatory protein and hormone
secretion in adipocytes and pancreatic βcells. Free fatty acids (FFAs)
induce a defective insulin-mediated signaling mainly through the activation of protein
kinase C (PKC θ), inhibitor κB kinase (IKK) and c-Jun
N-terminal kinase (JNK). (b) Main cell types involved in the
development of insulin resistance. (c) Main inflammatory cell
populations involved in hyperinsulinemia-induced inflammatory states.Another possible mechanism leading
to insulin resistance might be an upregulation of protein-tyrosine phosphatases
(PTPases), capable of functioning as negative regulators of the insulin-triggered
pathway. Among various proteins, PTP 1B has been shown as a key regulator of
insulin signaling [71–73]. Other phosphatases, such as ectonucleotide
pyrophosphatase phosphodiesterase 1 (ENPP1, also known as PC-1), SH-2-containing
inositol 5′-phosphatase 2 (SHIP2), and phosphatase and tensin homolog deleted
on chromosome 10 (PTEN) have been shown to interfere with insulin sensitivity
[74–76]. Although further investigations are warranted to very verify these
hypotheses, these proteins may represent future potential targets for the
treatment of insulin resistance.


## 2.2. Glucose Metabolism

Glucose uptake into muscle and fat
tissue depends on glucose transporter 4 (GLUT4) expression on the cell
membrane. Insulin reduces glycaemia, mainly by inducing the secretion of this
molecule by muscle and fat cells [77]. However, GLUT4 polymorphisms or mutations
inactivating GLUT4 gene were not associated with insulin resistance [78]. In
addition, GLUT4 concentrations in skeletal muscle of insulin resistant patients
were not reduced [79]. This suggests that alterations in GLUT4 expression are
not a primary cause for the development of insulin resistance. In this context,
the correct functioning of insulin intracellular signalization appears
essential. In fact, GLUT4 upregulation represents the final event of insulin
signaling cascade [80–82]. Among various kinases (Figure 1(a)), Aktβ has been shown to play an essential role. Recently, in vitro and in
vivo studies suggested that PKBβ alterations [83] or disruption [84] are responsible for the reduction
of insulin-induced glucose uptake. Consistent with these data, recent studies
in humans detected a missense mutation in the kinase domain of PKBβ (Akt 2) associated with severe insulin resistance [85]. These data
suggest that insulin signaling also plays crucial role in the regulation
glucose homeostasis.


## 2.3. Inflammatory Molecules

Recent evidence suggests that
inflammation might be crucial for the development of insulin resistance [86]. Proinflammatory
cytokines and acute-phase reactants are positively correlated with insulin
resistance in metabolic syndrome patients [87]. Among these soluble mediators, interleukin
(IL)-1 and IL-1 receptor antagonist (RA) have been implicated in the
development of insulin resistance in humans [88, 89] and in rodents [90, 91]. IL-1RA
is anaturally occurring cytokine and a member of the IL-1 family
whose only function is to prevent a biologic response to IL-1 [92]. In
humans, the blockade of IL-1 with IL-1 RA improves glycaemia and beta-cell
secretory function and reduces markers of systemic inflammation [93].
Accordingly, IL-1 has been shown to induce insulin resistance mainly by
inhibiting insulin-mediated signaling [94, 95]. Thus, IL-1 has to be considered
as an important factor involved in insulin resistance. TNF-α and IL-6 are also of particular interest, because of their increased
expression in adipose tissue and their capacity to induce insulin resistance [96].
Further evidence for the link between TNF-α and insulin resistance was provided by a study using blocking anti-TNF-α antibodies in obese rodents or TNF-α knockout obese mice [97]. In these animals, a reduced insulin
resistance was obtained by the suppression of TNF-α. The possible molecular mechanism of TNF-α-induced insulin resistance may involve IRS-1 [98]. Surprisingly, the
infusion of anti-TNF-α antibody in humans did not affect insulin resistance. Further
investigations are needed to better understand these opposite results obtained in
human and mice. On the other hand, the role of IL-6 in insulin resistance is
also controversial. IL-6 interferes with the metabolism of both adipose and
skeletal muscle tissues [99, 100], but has also a positive effect on skeletal
muscle cell insulin sensitivity [101]. In addition, IL-15 has been shown to
play a possible role in myocyte-adipocyte crosstalk, but only few studies are
published at present to better clarify its role in insulin resistance [102]. Moreover,
it is now established that hormones from adipose tissue hormones contribute to insulin
resistance. For instance, leptin has been shown to reverse insulin resistance
in mice with congenital lipodystrophy [103]. Administration of leptin to
patients with lipodystrophy can increase the body fat content and reverse
insulin resistance [104]. Resistin, a new adipocyte hormone [105], may be another
important link between increased fat mass and insulin resistance [106]. Resistin
decreases insulin-dependent glucose transport in vitro and increases fasting
blood glucose concentrations and hepatic glucose production in vivo [106–109].
Similarly, the reduction of adiponectin could contribute to insulin resistance.
Very recently, adiponectin has been showed as an anti-inflammatory and
immunomodulatory molecule [110, 111]. In humans, adiponectin levels correlate
with insulin sensitivity. Mice deficient in adiponectin are insulin resistant
[112] and the administration of adiponectine to obese and insulin resistant
mice has been shown to improve insulin sensitivity [113–115]. In addition,
inflammatory mediators such as the proinflammatory chemokine monocyte
chemotactic protein-1 (MCP-1) are believed to play a role in the pathogenesis
of insulin resistance. Recent in vitro evidence suggests that MCP-1 induces
insulin resistance in both adipocytes and skeletal muscle cells [116]. Finally,
retinol-binding protein (RBP)-4 and tissue inhibitors of metalloproteinases (TIMP)-1
were recently described to contribute to insulin resistance in vivo, but the
underlying mechanism remains unclear [117–119]. In conclusion, at the present
state of knowledge, insulin resistance has to be defined as a complex syndrome
involving not only glucose and lipids, but also several proinflammatory
molecules.


## 2.4. Lipids and Insulin Resistance

Lipid abnormalities, such as
increased circulating free fatty acids, are frequently associated with insulin
resistance [120]. Lipid metabolism induces insulin resistance through a well-known cascade of events. The excessive fat intake causes an increased influx of
triglycerides into the blood and an excess of plasma levels of FFAs, which
induce insulin resistance, with consequent hyperglycaemia. The increased levels
of glucose stimulate pancreatic βcells to secrete more and more insulin,
generating hyperinsulinemia, which further triggers the elevation of triglycerides
and closes the vicious circle [121]. When insulin secretion is not sufficient
and elevated glucose levels prevail,
diabetes becomes overt. Defective
insulin secretion is a result of chronic exposure to elevated levels of fatty
acids, which inhibits insulin gene expression by functioning as true toxic
agents for pancreatic βcells [122]. “Lipotoxicity” depends
on the interference with insulin-mediated intracellular signaling in various
cell types (Figure 1). In particular, FFAs have been shown to activate PKC θ(Figure 1(a)), which not only
interferes with insulin signaling (by inducing insulin resistance), but also is
implicated in promoting proatherogenic mechanisms, such as endothelial
dysfunction, growth, migration, and apoptosis of  vascular smooth muscle cells,
induction of adhesion molecules and oxidized low-density lipoprotein uptake of oxidized low-density lipoprotein by monocyte-derived macrophages [123]. Furthermore, it was recently
shown that FFAs induce insulin resistance in muscle through the activation of inhibitor
κB kinase (IKK) and c-Jun N-terminal kinase (JNK) (Figure 1(a)) [124]. Therefore,
FFAs induce insulin resistance in hepatocytes and skeletal muscle cells through
the activation of different kinases (Figures 1(a) and 1(b)). Both FFAs from
plasma and those released from stored triglycerides activate second messangers,
which alter insulin signaling [125]. FFAs are also involved in modulating
insulin production by pancreatic β-cells and cytokine secretion by hepatocytes, adipocyte, muscle cells,
and inflammatory cells (Figure 1(c)). This strongly supports FFA as important
proatherosclerotic agents.


## 3. Role of Insulin Resistance in Atherosclerotic Plaque Instability

The development of atherosclerotic
plaques is dependent on the interaction of multistep biochemical processes that
lead to the plaque formation, maturation, and complication [126]. Plaque
instability, rupture, and thrombosis are crucial events in the acute artery
occlusion, which causes dramatic ischemic consequences in the heart, brain, and
also peripheral tissues. Insulin resistance is considered to be a pivotal event
in the increased risk of plaque instability through different pathways [127, 128].
High concentrations of insulin directly increase proinflammatory activities of
leukocytes, which are involved in atherosclerotic plaque instability. In
particular, insulin directly increases neutrophil and monocyte in vitro migration in response to
chemokines secreted in atherosclerotic plaques [129, 130]. Insulin could also
favor atherosclerotic plaque necrosis by accelerating macrophage death [131].
Furthermore, insulin induces in vivo production of matrix metalloproteinase-9 (MMP-9),
which is responsible for plaque instability and rupture [132–134]. The
pharmacologic or behavioral treatments to reduce insulin resistance have been
shown to inhibit MMP-9 secretion [126, 135, 136]. On the other hand, insulin
could also induce a serious atherothrombotic state, by increasing platelet
resistance to antiaggregating agents [137] and production of procoagulatory
factors, such as plasminogen activator inhibitor-1 (PAI-1), factor VII, factor
XII, fibrinogen, and tissue plasminogen activator [126]. These evidences
strongly support an emerging role of insulin in plaque instability and rupture.
Further investigations are needed to better clarify the specific roles and the
interactions of insulin and lipids on inflammatory cells.


## 4. Conclusion Remarks

In
the last years, the standard definition of insulin resistance has been shifted
from a traditional “glucocentric” to a new “lipocentric” view [138]. Several
soluble mediators are involved in the development of insulin resistance,
through generating insulin signaling dysfunction. Among these, FFAs have to be
considered as proatherosclerotic agents, capable of interfering with insulin signaling
and provoking insulin resistance. New and selective therapies contrasting FFA
effects may be promising targets for the treatment of insulin resistance. A
possible promising strategy capable of reducing the consequences of excessive
lipolysis and reorient FFA flux toward adipose tissue might be represented by
peroxisome proliferator-activated receptor (PPAR)-α and -γ agonists [139]. PPAR-γ agonists have been recently shown to regulate trygliceride lipase in
adipocytes in vitro and in vivo [140]. Furthermore, PPAR-γ has been shown as crucial in the control of differentiation of human
monocytes in M2 macrophages, the subset of macrophages resident in
atherosclerotic plaques with anti-inflammatory activity [141]. In vivo studies have also demonstrated that PPAR-γ agonists treatment in patients with type 2 diabetes
mellitus is associated with a reduction in plasma NEFA levels [142–145]. However, two recent important
clinical studies have shown an increase of acute cardiovascular outcomes
induced by treatment with thiazolidinediones (PPAR-γ agonists) [146, 147]. On the other hand, although PPAR-α has been shown to have vascular and metabolic beneficial effects, the
activity of PPAR-α agonists on lipid metabolism is still controversial [148, 149]. Therefore, further trials are
needed to recommend the use of these pharmacological agents for reducing lipid-mediated
insulin resistance.



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*Source: 767623-2008-06-30.xml*