is inflammation a useful target for the treatment of metabolic syndrome?

Is inflammation a useful target for the treatment of metabolic

syndrome? PA30035

ANNA MATTHEWS, 2015

Is inflammation a useful target for the treatment of metabolic syndrome? | Anna Matthews

Abstract The focus of this literature review is primarily on the significance of the involvement of

inflammatory cytokines in the two major aspects of metabolic syndrome: obesity and

insulin resistance / type 2 diabetes mellitus (T2DM); and potential novel therapies for the

metabolic syndrome with respect to the inflammatory roles in the associated conditions.

In particular, the effects of TNF-, IL-1 and IL-6 secretion on the metabolic syndrome

are elucidated; as well as T-lymphocytes, oxidative stress and the link to the JNK

pathway. All information used has been collected from articles obtained via Embase, and

cited using EndNote in the Harvard-Bath style. As this is a literature review, data from

original case studies has been used and appropriately referenced.

The findings of the research undertaken suggest that inflammation may indeed be a

useful target for the treatment of the metabolic syndrome, with more and more studies

identifying promising results in the control of glucose homeostasis in recent years. The

main conclusion to be drawn is that inflammatory cytokines TNF-, IL-1 and IL-6 are

likely prospective candidates for new targets in treating the metabolic syndrome, with

some anti-diabetic progress already being observed in anti-inflammatory treatments

such as chloroquine.

Introduction

Metabolic syndrome is a condition that is characterised by differing clusters of three out

of four health abnormalities, depending on which criteria is used. WHO defines the

metabolic syndrome as diagnosis of type 2 diabetes plus any two other risk factors:

including central obesity, hypertension and dyslipidaemia (Yasein et al. 2010); however,

the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III

characterises it as a combination of any three of the above disorders: with the difference

that instead of there being a requirement for diagnosis of type 2 diabetes, impaired

insulin tolerance will suffice, with a fasting blood glucose of 110mg/dL (6.1mmol/L) or

more. The latter explanation seems to be the more generally accepted and so when

discussing Metabolic Syndrome, I will be referring to the NCEP ATP-III classification.

It is becoming an increasing global health issue, as each of the above factors alone carry

a risk of developing cardiovascular disease, and current statistics show approximately

51% of T2DM patients die from CVD and associated complications (Morrish et al. 2001).

Obesity is considered to be a central feature that increases the risk for the development

of metabolic syndrome-associated diseases such as cancer, asthma, sleep apnoea,

osteoarthritis, neurodegeneration and gall bladder disease (Hotamisligil 2006).

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According to Daskalopoulou et al, the treatment of metabolic syndrome outlined by the

NCEP ATP-III focuses on improving the underlying insulin resistance, and this is

managed by modifying lifestyle such as diet and exercise and possibly by drugs;

though monotherapy is often ineffective (Daskalopoulou et al. 2004). Potential drug

therapies include high-dose statins for lowering LDL-C and triglycerides; fibrates for

increasing HDL-C levels to >40mg/dL and thiazolidinediones, as these are thought to

also improve dyslipidaemia and blood pressure (Table 1).

Healthy lifestyle promotion Drug Intervention Small weight loss

Moderate physical activity

Dietary restriction in calorie

intake

Change in dietary composition

Atherogenic dyslipidaemia: Statins; fibrates;

nicotinic acid

Elevated blood pressure: No particular agent is

preferred, although ACE inhibitors and

angiotensin receptor blockers may carry

advantage in patients with metabolic disorders

Insulin resistance and hyperglycaemia:

Metformin; thiazolidinediones; acarbose; orlistat

Table 1 Primary Prevention of Cardiovascular Events associated with Metabolic Syndrome according to

NICE (Paoletti et al. 2006)

Ahmad et al concurs with insulin sensitivity being a main target for treatment of the

symptoms of the abnormalities associated with metabolic syndrome, at least as an initial

step; and goes on to highlight that insulin resistance has been known to exacerbate an

increase in lipids in diabetic patients (Ahmad et al. 2011). This connection suggests that

by targeting insulin resistance, other symptoms may be positively addressed

consequently, such as obesity and hypercholesteraemia. The targets for effective

treatment of the metabolic syndrome are outlined in Table 2:

Table 2 The target levels from therapy for metabolic syndrome (Expert Panel on Detection et al. 2001)

LDL-C

(Main target of therapy for all

high-risk patients)

Patients with Coronary Heart Disease: 2) risk factors: < 130mg/dL

0-1 risk factor: < 160mg/dL

Weight control -10% from baseline

Physical activity 30 45 minutes / day for 3 5 days / week

Treatment of hypertension < 140/90mmHg

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However, the lack of effective drug treatment for tackling the metabolic syndrome as a

whole highlights an obvious clinical need for novel approaches and targets. If we were

to discover a common underlying cause for all the conditions associated with metabolic

syndrome - and target that - we may be able to develop an over-arching treatment, which

would increase patient compliance if taken alone; or improve the effectiveness of current

treatments if used in combination.

There has recently been interest in exploring whether or not there is a connection

between metabolic syndrome and inflammation. I will be reviewing literature on the link

between the immune system and T2DM primarily, as well as the potential benefits of

using anti-inflammatory agents as treatment for metabolic syndrome, which are still being

elucidated. Furthermore, I will discuss the anti-inflammatory aspects of current

treatments and whether these can be isolated and potentially improved into new,

targeted treatments.

The main aspects of metabolic syndrome I will be researching as potential links to

inflammation are T2DM and obesity, as these are the two that are most poorly controlled.

The inflammatory cytokines I will be focussing on are T-cells, IL-1, IL-6, and TNF-

cytokines on the pathogenesis of metabolic syndrome; although there are many to

investigate, and I will make reference to the other inflammatory factors involved without

discussing them in great detail.

Inflammatory Aspects of Insulin Resistance and Obesity

T2DM occurs when insulin resistance is uncompensated for by the pancreatic -cells,

due to a deterioration in -cell function (Maedler et al. 2003). Researching the potential

reasons for -cell dysfunction and death in T2DM produced results linking to

inflammation.

TNF-, IL-1 and IL-6 In 1997, Pickup et al published a study on non-insulin dependent diabetes mellitus

(NIDDM) as a disease of the innate immune system. Three different groups of patients

were used in the study, all similar ages and of the same ethnicity (white European).

Those with four or five of the following were considered to be metabolic syndrome

positive (NIDDM syndrome X positive):

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Hypertriglyceridaemia (VLDL triglyceride > 1.5mmol/L);

Low serum HDL cholesterol ( 160 and/or diastolic pressure >95mmHg

and/or receiving anti-hypertensives);

Coronary heart disease (as assessed by the WHO cardiovascular questionnaire);

Obesity (calculated by BMI > 30kg/m2)

Those with nought or one of the above

features as well as type 2 diabetes mellitus

were considered to be metabolic syndrome

negative (NIDDM syndrome X negative).

Healthy subjects without diabetes acted as a

control group. The results of fasting blood

glucose tests are displayed in Figure 1.

It is evident from these results that the patients

with metabolic syndrome displayed higher levels

of acute-phase immune response, with

increases in C-reactive protein (CRP)

concentrations. Furthermore, a measure of serum IL-6 concentrations in the groups

displayed a significant increase in the NIDDM syndrome X positive group compared with

others (Fig. 2).

It is also useful to note that the scale of the

graph here in Figure 2 is logarithmic: therefore,

the changes are more significant than they may

first appear.

Overall, Pickup et als study provides evidence

that T2DM is associated with increased plasma

levels of the cells and markers associated with

acute immune response (Pickup et al. 1997). As a fairly

early study in this area, the conclusions drawn from it

were merely that inflammation required more research

with regards to T2DM pathogenesis, as it was unclear

whether or not inflammation is the causative agent.

Figure 2 Comparisons of serum

concentrations of IL-6 in non-

diabetics, non-insulin dependent

diabetes mellitus (NIDDM) syndrome

X negative and NIDDM syndrome X

positive. (Pickup et al, 1997)

Figure 1 Serum C-reactive protein levels of

non-diabetic, non-insulin dependent diabetes

mellitus (NIDDM) syndrome X negative and

NIDDM syndrome X positive patient groups

(Modified from Pickup et al, 1997)

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One of the first areas of interest concerning inflammatory mediators in the pathogenesis

of T2DM was the involvement of IL-1 on -cell destruction, initially seen in T1DM.

Two studies on the effect of IL-1 on -cell function in fact precede Pickup et als study.

In 1986, Mandrup-Poulsen deduced that IL-1 appears to play a significant role in the

inhibition of -cell function symbolic of both types of diabetes mellitus (Mandrup-Poulsen

1996). Indeed, a study by

Bendtzen et al showed inhibition

of insulin secretion from the -

cells, followed by destruction,

when rat islets were treated with

IL-1 and cultured for six

days (Bendtzen et al. 1986). The

amount of insulin secretion was

detected via radioimmunoassay

during the six subsequent days

of culture, and the results

showed that with increasing

concentrations of IL-1, insulin

secretion decreased similarly (Fig. 3).

The mechanism of action of IL-1 on -cell function is thought to be via promotion of

Fas-triggered apoptosis by activating NF-B in human islets (Maedler et al. 2003) and

indeed Fas has already been labelled as playing an important role in the pathogenesis

of T1DM. Maedler et al performed a study in 2001 to ascertain whether or not Fas

expression constituted a similar effect in T2DM from hyperglycaemia (Maedler et al.

2001).

The 2001 study was undertaken using islets that were isolated from the pancreases of

eight organ donors who had no previous history of diabetes or metabolic disorder. These

tissues were exposed to elevated glucose concentrations for five days and analysed for

DNA fragmentation, using the dUTP nick-end labelling (TUNEL) technique to identify the

nuclei of the -cells, thus indicating the presence of any degradation that occurred.

TUNEL labels the terminal end of nucleic acids and relies on the presence of nicks in the

DNA, which can be identified by terminal deoxynucleotidyl transferase (TdT). TdT

catalyses the addition of the labelled dUTPs (Gavrieli et al. 1992). The results of the

study were that even when human islets were only transiently exposed to glucose for

three days, the number of proliferating -cells decreased; therefore indicating

involvement of glucose-induced -cell death in T2DM (Fig. 4).

Figure 3 - Comparison between islet-inhibitory and IL-1 effect

regarding insulin levels in rat islets after being cultured with IL-1

for six days. The relationship between IL-1 and insulin levels is

established: increased IL-1 correlated with decreased

insulin. (Bendtzen et al. 1986)

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Figure 4 - Effect of elevated glucose concentrations on human -cell apoptosis: measured using the

TUNEL technique. The cells were isolated from the pancreases of eight heart-beating human cadavers.

Elevated glucose is an important control because T2DM is associated with increased blood glucose levels.

Panel 1 shows the relative number of TUNEL positive -cells per islet after culturing for 5 days in 5.5, 11.1

and 33.3mM glucose or 5.5mM D-glucose + 27.8mM L-glucose normalised to a control of 5.5mM glucose

incubations alone. Panel 2 shows TUNEL-positive -cells per islet during a 10 day culture at 5.5 or

33.3mM glucose. (Maedler et al, 2001)

Maedler et al then went on to study the mechanism involved to identify any potential for

Fas-receptor involvement.

Figure 5 - Glucose effect on stimulating Fas in the -cells of eight human organ donors as assessed by

Western Blotting after culturing the islets in suspension containing 5.5mM, 11.1mM and 3.3mM of glucose

and incubating for 36 hours. Human foreskin fibroblast was used as a positive control for Fas. (Modified

from Maedler et al, 2001)

Fig. 5 shows that glucose has a proportional relationship with expression of Fas and Fas-

ligand. According to Stennicke and Salvesen, the underlying mechanism concerning

apoptosis of -cells is to do with Fas receptor up-regulation, initiated by glucose. More

Fas receptors means more interactions with the constitutively active Fas-ligand on

neighbouring -cells, leading to cleavage of procaspase-8 to caspase-8 and activation

of caspase-3, resulting in DNA fragmentation (Stennicke and Salvesen 2000).

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Fig. 6 supports Stennicke and Salvesens explanation of -cell death, portraying the

effect of increasing glucose concentration on activated caspase 8 and 3.

Addition of an antagonistic anti-Fas antibody ZB4 inhibited the effect of both IL-1 and

glucose on degradation of -cells (Fig. 7)

Figure 7 - Effect of Fas receptor blockade on glucose and IL-1 induced -cell DNA fragmentation in

human islets cultured for 5 days on extracellular-matrix-coated dishes in 5.5 or 33.3mM glucose alone (the

control) or in the presence of interleukin-1 (IL-1), antagonistic Fas antibody ZB4 or both. Results were

normalised to control incubations at 5.5mM glucose alone. (Maedler et al, 2001)

It is evident that the response to both concentrations of glucose are affected similarly by

ZB4, and -cell degradation levels are greatly reduced with ZB4 added to tissue

expressing IL-1 compared to the tissue expressing IL-1 alone. From this, we can deduce

that inhibition of the Fas pathway may be a potential therapeutic target for T2DM, and

success can be gauged by assessing IL-1 expression in the pancreatic islets.

Figure 6 The effect of differing concentrations of glucose on procaspase-8 and activated caspase-8

expression in the pancreases of eight human organ donors after 36 hours incubation (Modified from

Maedler et al, 2001)

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A study performed by Spranger et al was designed to examine the effect of inflammatory

cytokines on the development of T2DM. The format of the study was a nested case-

control consisting of 27,548 individuals who were free of T2DM at the beginning of the

study. The case subjects were defined as individuals who then developed T2DM within

a 2.3 year follow-up period, and these numbered 192 vs 384 control subjects (Spranger

et al. 2003).

Spranger et al found IL-6 to be an independent predictor of T2DM development after

analysis; however, the increase in TNF- and CRP were found to be insignificant when

adjusting for body mass index (BMI) and waist-to-hip ratio (WHR).

TNF- and IL-1

Odds Ratio 95% Confidence Interval

Reference (low TNF- /

undetectable IL-1)

1 n/a

High TNF- 0.89 0.45 1.73

Undetectable IL-1 0.95 0.54 1.67

Interaction term (high TNF- /

undetectable IL-1)

2.51 0.84 7.57

TNF- and IL-6 Reference

(low TNF- / low IL-6)

1 n/a

High TNF- 1.32 0.68 2.52

High IL-6 2.15 1.12 4.11

Interaction term (both high) 0.7 0.23 2.16

IL-1 and IL-6 Reference

(low IL-6 / undetectable IL-

1)

1 n/a

Undetectable IL-1 0.8 0.43 1.44

High IL-6 1.14 0.55 2.32

Interaction term

(detectable IL-1 / high IL-6)

3.31 1.14 9.87

Table 4 - Interaction between IL- IL-1, IL-6 and TNF- on diabetes risk (Spranger et al, 2003)

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41.0% of case subjects compared to 36.6% of control subjects showed detectable levels

of IL-1, which is not statistically significant. Nevertheless, when taking into

consideration the presence of other cytokines alongside IL-1 expression, it was found

that the combined effects modified the risk of T2DM development (Table 4).

Therefore, the presence of two or more of the inflammatory cytokines IL-1, IL-6 and

TNF- may promote the development of diabetes, and could conceivably suggest a

reason for why traditional Chinese medicines such as Radix Astragali and Radix Ginseng

which have both hypoglycaemic and anti-inflammatory properties are effective at

combating diabetes (Xie and Du 2011).

Dr Paul Lacy first proposed that local generation of cytokines

in the islets may be responsible for -cell damage; although

this was initially only thought to be the case in T1DM (Lacy

1994). However, with increasing studies being undertaken to

examine potential links between inflammation and T2DM, this

pathway was analysed with regards to T2DM pathogenesis.

Westwell-Roper et al performed a study using RMPI cultured

mouse islets to determine whether macrophages are present

and might contribute to islet gene expression. The markers

they looked for in the cells (after 1 and 5 days in RPMI

suspension i.e. media utilising a bicarbonate and buffering

system and alterations in the amount of amino acids and

vitamins) were F4/80 and CD11b. However, their results

indicate that there was little expression of macrophage genes Emr1 and Itgam; and the

-cell genes Pdx1, Ins1 and Ins2 did not change during the culture period either (not

shown).

This indicates that if there is a link to inflammation in T2DM, it is not these genes that are

over-expressed.

Looking at human islet amyloid poplypeptide (hIAPP) in islets, Westwell-Roper et al

discovered that after treating isolated mouse islets with synthetic IAPP for 4 hours, both

hIAPP and the toll-like receptor 2 (TLR2) ligand FSL-1 induced expression of genes that

encode pro-inflammatory cytokines TNF-, IL-1 and IL-6.

Isolating islet macrophages with synthetic hIAPP and rIAPP showed that hIAPP-treated

cells formed amyloid fibrils after 2 hours of exposure; but not rIAPP. Pro-IL-1 was

significantly increased in the hIAPP-treated cells compared with rIAPP-treated cells (Fig.

9). This is proposed to be due to cross-species recognition.

Figure 8 - Levels of macrophage and

-cell genes in mouse islets cultured

in suspension RPMI at 37oC for 1 day

and 5 days respectively. (Westwell-

Roper et al, 2014)

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This is the first evidence to implicate that resident macrophages are the major islet cell

type in which hIAPP stimulates IL-1 synthesis and secretion (Westwell-Roper et al.

2014).

Chawla et al agree that macrophage infiltration into adipose tissues in a state of obesity

is significant: in the adipose tissue of lean mice, only 10-15% of cells express the

macrophage marker F4/80, compared to 45-60% in obese animals (Chawla et al. 2011).

Further regarding inflammatory markers in T2DM, Donath and Shoelson propose that

high glucose intake increases the production of IL-1 (Fig. 10); resulting in further

inflammation of the pancreatic -cells, and impaired insulin secretion.

Figure 9 Effect of human IAPP (hIAPP) and rat IAPP (rIAPP) on stimulating the synthesis and secretion

of IL-1 from pancreatic islets. A: hIAPP or rIAPP was added to bone marrow derived macrophages

following dissolution, and the cells were lysed at the indicated time points for analysis of the expression of

IL-1 by Western Blotting, using an antibody that detects pro-IL-1 and mature IL-1. B: Expression of pro-

IL-1 relative to actin quantified by band densitometry. C: IAPP-induced secretion of IL-1 by BMDMs

and islets evaluated by ELISA after 24 hours. (Modified from Westwell-Roper et al, 2014).

BMDM = Bone Marrow Derived Macrophages.

A

B C

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In 2010, Badawi et al published an article which focuses on the association of

inflammatory mediators and obesity-related insulin resistance. It describes that in the

case of obesity, both animal and human models have shown an increase in adipose

tissues of TNF- and macrophages. In addition, those who have risk factors associated

with T2DM exhibit increased serum levels of pro-inflammatory cytokines than those who

do not (Badawi et al. 25 May 2010). Petersen et al undertook a study concerning the

insulin-resistant offspring of patients with T2DM to examine the mitochondrial activity

and identify whether or not it was impaired in the overweight, insulin-resistant children

compared to lean, insulin-sensitive controls. It was discovered that in insulin-resistant

subjects, the rate of glucose uptake by myocytes stimulated by insulin was around 60%

lower in the insulin-resistant subjects compared to the control. This was associated with

an increase of intra-myocellular lipid content of 80% and a reduction of mitochondrial

phosphorylation of 30% in the insulin-resistant subjects; indicating that insulin resistance

could be due to a defect in mitochondrial oxidative phosphorylation (Petersen et al.

2004).

Donath and Shoelson also allude to TNF- having some role to play in obesity and

T2DM, as displayed in Figure 10 above; similarly Xie and Du highlight that the

inflammatory cytokines released during a state of inflammation and/or obesity result in

insulin resistance via activation of the JNK pathway (Xie and Du 2011), which will be

further discussed later.

Figure 10 - Development of

Inflammation in type 2 diabetes. High

glucose intake promotes local

production of inflammatory cytokines,

and a decrease in production of

interleukin-1 receptor antagonist (IL-

1RA), resulting in immune cell

recruitment to the islets and ultimately

tissue inflammation. (Donath and

Shoelson 2011)

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The above evidence suggests that inflammation may well play a part in the pathogenesis

of T2DM: in essence, the cellular stresses indicated in T2DM are thought to either induce

inflammatory response or be associated with inflammation. These include oxidative

stress; ectopic lipid deposition in the muscle, liver and pancreas, lipotoxicity and

glucotoxicity as well as amyloid deposition in the pancreas (Donath and Shoelson 2011).

Kaneto et al propose that oxidative stress is indeed involved in insulin resistance, as

seen in a knock-out study concerning -cell derived cell lines and isolated rat islets

exposed to oxidative stress. The result was a dramatic decrease in insulin gene

expression seen in the knock-out rats (Kaneto et al. 2004) and may be due to activation

of the JNK pathway (Fig. 11). This will be further discussed in The JNK Pathway in

Metabolic Syndrome.

T-lymphocytes and Inflammation in Metabolic Syndrome Many inflammatory cytokines are products of Th2 lymphocytes (such as IL-4 and IL-13).

Fracchia and Walsh propose that activated T lymphocytes require glucose transport via

GLUT1 receptors to accommodate their metabolic demands (Fracchia and Walsh 2015).

Indeed, Caro-Maldonado et al name the main supply of metabolic fuel for lymphocytes

to be glucose, lipids and amino acids all of which are increased in diet-induced

obesity (Caro-Maldonado et al. 2012). It is well known that T-cell activation results in

metabolic reprogramming. Therefore, if levels of glucose, lipids and amino acids are

altered, T-cell production will be affected.

Th1, 2 and 17 cells showed increased proliferation when glucose uptake via GLUT1

transporters was increased; but TReg cells were not affected, as they utilise lipids rather

Figure 11 The proposed effects of Oxidative Stress on

Insulin Resistance. Reactive Oxygen Species (ROS)

have been shown to interfere with cellular signalling

pathways. The JNK pathway in the liver is activated by

ROS, free fatty acids (FFAs) and TNF-. Under obese

diabetic conditions, levels of these factors rise. Serine

phosphorylation of insulin receptor substrate-1 (IRS-1)

inhibits insulin-stimulated tyrosine phosphorylation of the

receptor, resulting in increased insulin resistance and

therefore glucose intolerance. (Kaneto et al, 2004)

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than glucose (Shepherd and Kahn 1999). This indicates that exposure to high levels of

fuels such as glucose, as is evident in obesity, may lead to over-expression of T-

lymphocytes, altering immune response.

Chatzigeorgiou et al portray TNF- and IL-6 in adipocyte interference regarding insulin

signalling locally in the white adipose tissues (WAT) as well as systemically (Table 5).

Lymphocyte subset

Marker Secreted molecules

Classical inflammatory

response

Function in WAT inflammation

CD8+ T-cells CD3

CD8

IFN- Cytotoxic function for

destruction of virus-

infected or cancer

cells

Activation of WAT

macrophages; IFN-

-related WAT

inflammation

Th1 cells CD3

CD4

IL-12R

IFN-

IL-2

Activate

macrophages for

phagocytosis and

pathogen killing

Promotion of WAT

inflammation

through IFN- and

RANTES

Th2 cells CD3

CD4

IL-4

IL-5

IL-10

IL-13

Stimulation of B

cells, promote

humoral antibody

responses &

eosinophil activation

Anti-inflammatory

effects through

activation of IL-10-

producing

macrophages

Table 5 - Lymphocyte subsets and their implicated roles in white adipose tissue (WAT)

inflammation (Chatzigeorgiou et al. 2012)

Chronic Inflammation and Insulin Resistance Konner and Bruning state that the link between obesity, insulin resistance and T2DM has

been extensively researched; and this research has increased our understanding of the

interrelation between them (Konner and Bruning 2011). Inflammation is now considered

to be one of the crucial mechanisms in the development of obesity-associated T2DM

and insulin resistance (Hotamisligil 2006).

There are further, more recent studies that suggest chronic inflammation may be

associated with insulin resistance; and ultimately metabolic syndrome and/or

T2DM (Dregan et al. 2014). One, conducted by Zuliani et al, measures the levels of low

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grade systemic inflammation in subjects with metabolic syndrome compared with healthy

individuals and gave the following results:

38.3% of subjects with metabolic syndrome had high levels of both insulin resistance

(IR) and low grade systemic inflammation (LGSI) compared with 17.6% of healthy

individuals. This shows that although IR and LGSI are not exclusive to metabolic

syndrome, increased levels are indicative of a predisposition to metabolic syndrome.

However, we must question whether or not inflammation is a significant enough

contributing factor to consider anti-inflammatory agents as treatments for metabolic

syndrome. Indeed, only a slightly increased percentage of subjects had LGSI with

metabolic syndrome than without (55% vs 41%). (Zuliani et al. 2015)

A figure outlining the role of inflammatory markers in pathologic conditions from

overweight to T2DM is redacted from Badawi et al (Fig. 12):

Figure 12 - Relationship of inflammatory markers to disease states

FFA = Free fatty acids; TNF- = Tumour necrosis factor ; CRP = C Reactive Protein; LDL = Low density

lipoproteins; HDL = high density lipoproteins; TG = Triglycerides; IGT = Impaired glucose tolerance.

(Badawi et al. 25 May 2010)

This implies that there are many other inflammatory markers related to disease factors

which have the potential to be explored other than those I am discussing in this literature

review.

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The JNK Pathway and Metabolic Syndrome A study by Kaneto et al addressed the involvement of the JNK pathway in the

development of insulin resistance. Obesity was induced both in a control group of mice

with wild type JNK and knock-out mice lacking JNK. When the mice were placed on a

high-fat diet, the obese wild type mice developed mild hyperglycaemia but the blood

glucose levels in obese JNK-KO mice were significantly lower. These results indicate

that the knock-out mice were able to avoid obesity-induced hyperglycaemia, and so the

JNK pathway must play a role in insulin resistance. Fig. 13 proposes a potential

mechanism for this pathway, with the suggestion that oxidative stress may induce

nucleocytoplasmic translocation of PDX-1 through activation of the JNK pathway,

resulting in -cell dysfunction found in both types of diabetes.

Nguyen et al found that FFA treatment impaired insulin signalling in mice via decreased

GLUT-4 translocation when compared to mice not injected with FFAs (Fig. 14).

This was due to inhibition of

phosphorylation of key

downstream components such

as IRS-1 in 3T3-L1 adipocytes

that were used as an in vitro

model system (Fig. 15).

Figure 13 - Possible mechanism for impaired

-cell function under hyperglycaemic

conditions in rodents. Pancreatic and

duodenal homeobox 1 (PDX-1, a.k.a. insulin

promotor factor 1) is translocated from the

nuclei to the cytoplasm in response to

oxidative stress, which in turn can be caused

by hyperglycaemia seen in diabetes.

Translocation results in lower levels of PDX-1

in the nucleus, which is detrimental to

pancreatic development as it is necessary for

-cell maturation. (Kaneto et al, 2004)

Figure 14 Free Fatty Acid (FFA) treatment effect on impaired

insulin signalling in mice, measured via decreased GLUT-4

translocation using secreted TNF-. (Nguyen et al. 2005)

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Figure 15 Effects of Insulin Receptor Substrate 1 (IRS-1) from various tissues of obese rats on insulin

stimulated insulin resistance autophosphorylation (Hotamisligil et al. 1996)

It was also shown that inhibitory serine phosphorylation of insulin receptor substrate

(IRS)-1 is responsible for both TNF- and free fatty acid (FFA) induced insulin resistance

(as alluded to above when discussing Nguyens study); and this phosphorylation was

markedly increased in obese wild type mice compared to lean wild type mice and JNK-

KO mice. This demonstrates that the absence of JNK1 leads to an enhancement of IRS-

1 due to lack of phosphorylation (Kaneto et al. 2004).

Anti-Inflammatory Effects of Current Treatments of Metabolic Syndrome

Statins and ACE Inhibitors Two medications used for control of the hypercholesteraemic and hypertensive aspects

of Metabolic Syndrome were assessed for anti-inflammatory activity when used in

combination. The study was performed by Han et al and compared the decrease in

atheroma size when treated with a rosuvastatin and ramipril combination and

rosuvastatin alone.

The study revealed that the anti-inflammatory effect observed was an important factor

for the change in atheroma volume, suggesting that anti-inflammatory mechanisms can

be elucidated by combining a statin with an ACE inhibitor. Although this study was

designed to explore the effect of this combination of therapies on reducing the size of

atheromas, the underlying conditions associated with development of atheromas are

also seen in metabolic syndrome, and so the benefits seen in metabolic syndrome when

statins and ACE inhibitors are used for the individual aspects of the condition may

actually be due, in part, to the anti-inflammatory effect seen in this case of polypharmacy.

The proposed mechanism of effect of the combined therapy of a statin and an ACE

inhibitor is one similar to that of methotrexate: ACE inhibitors decrease the amount of

reactive oxygen species, which as we discussed earlier, may contribute to the

development of insulin resistance seen in metabolic syndrome; and statins exert a variety

of effects other than reducing low density cholesterol.

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According to Marini et al, the pathophysiology of the anti-inflammatory effects of statins

reside in the inhibition of hydroxymethylglutaryl CoA (HMG CoA) reductase, in turn

decreasing the production of isoprenoid intermediates farnesyl-PP and geranylgeranyl-

PP (Marini et al. 2014) and therefore decreasing inflammation.

Blanco-Colio et al clarify the anti-inflammatory and immunomodulatory effects of such

HMG CoA reductase inhibitors in Table 6.

In essence, the anti-inflammatory effects of statins in combination with the anti-ROS

effects of ACE inhibitors may be responsible for some therapeutic benefit when used in

metabolic syndrome, and HMG CoA reductase inhibitors could potentially be an area of

research to go into regarding novel treatments for the metabolic syndrome.

Thiazolidinediones Thiazolidinediones are peroxisome proliferator-activated receptor (PPAR-) agonists

that can be used in patients with insulin resistance or T2DM as well as kidney failure.

According to Szeto and Li, induction of PPAR- results in an inhibition of inflammatory

cytokines being produced by macrophages (Szeto and Li 2008).

Indeed, Jiang et al demonstrated the inhibition of TNF- release by troglitazone in a

study using monocytes prepared from unrelated donors, using PMA- and okadaic acid-

induced cytokine synthesis to establish the effects (Jiang et al. 1997).

The result was a clear decrease in expression of the pro-inflammatory cytokine TNF-

in lipopolysaccharides when troglitazone is added to the monocyte, as established via

ELISA.

As we have already elucidated, TNF- plays a significant role in the pathogenesis of

obesity and T2DM in particular, which are prominent features of the metabolic syndrome.

This group of anti-diabetic agents, thiazolidinediones, appears to have more than just a

hypoglycaemic effect contributing to its therapeutic mechanism of action.

Anti-Inflammatory Effects Immunomodulatory Effects Adhesion molecules Proliferation of lymphoid cells

Chemoattractant proteins Natural Killer activity

Pro-inflammatory transcription factors Major histo-compatibility class II

antigens

Inflammatory serum markers Organ rejection

Table 6 Immunomodulatory and anti-inflammatory effects of 3-hydroxy-3-methyl-glutaryl CoA reductase

(HMG-CoA reductase) inhibitors (Blanco-Colio et al. 2003)

17


Biguanides According to Lockwood, therapeutic metformin concentrations of 25M have

chloroquine-mimetic anti-lysosomal action (which will be discussed later): in a study

performed by Lockwood on rat heart cells, 25M of metformin alone caused a 20-25%

inhibition of total protein degradation (reducing ROS and pro-inflammatory cytokine

release) (Fig. 17A). This action was completely stopped by prior addition of chloroquine,

indicating that the proteolysis inhibited by metformin is due to the same lysosomal

subcomponent as is the target for chloroquine (Lockwood 2010).

Metformins anti-inflammatory effects may contribute to its efficacy in the treatment of

insulin resistance / T2DM in metabolic syndrome.

Figure 17 Results from a study performed on rat heart cells. A) Percent inhibition of perfused myocardial

protein degradation by 25M metformin; B) Synergy of metformin anti-proteolytic action by Zn2+ (Lockwood

2010)

It also appears that Zn2+ has synergistic activity when combined with metformin, with

regards to the proteolytic effect (Fig. 21B). This could show promise as a novel treatment

for the inflammation associated with T2DM or insulin resistance in metabolic syndrome:

metformin and zinc.

18


Effects of Anti-Inflammatory Treatments on T2DM

Interleukin-1 Receptor Antagonist A study published in the New England Journal of Medicine in 2007 by Larsen et al

contains evidence that interleukin-1 receptor antagonist (IL-1RA) is reduced in the

pancreatic islets of patients with T2DM.

Larsen et als study involved a double-blind, parallel-group trial where 34 of 70 patients

with T2DM received 100mg of a recombinant human IL-1RA (Anakinra) via

subcutaneous injection once a day for 13 weeks; and the remaining 36 patients received

a placebo.

Figure 18: Changes in glycated haemoglobin and fasting plasma glucose levels during the study whereby

100mg of recombinant human IL-1RA (Anakinra) was injected into human subjects once a day for 13

weeks. (Larsen et al, 2007)

Fig. 18 depicts the difference in glycated haemoglobin levels from baseline and 13 weeks

from the study beginning in the Anakinra group and the placebo group.

19


The results were a reduction of 0.33 percentage point in the Anakinra group; and an

increase of 0.13 percentage point in the placebo group a difference of 0.46 percentage

point between groups (95% confidence interval 0.01 0.90 and p = 0.03).

With regards to -cells (Fig. 19), function was increased in the group receiving Anakinra,

and decreased in the group receiving placebo.

Figure 19 - -cell function differences observed during the study whereby 100mg of recombinant human

IL-1RA (Anakinra) was injected into human subjects once a day for 13 weeks. (Larsen et al, 2007)

Furthermore, Fig. 20 displays that hs-CRP and IL-6 levels were consistently and

significantly decreased in women who had developed T2DM and were receiving

Anakinra compared to placebo (Larsen et al. 2007).

Figure 20 - Markers of Systemic Inflammation observed during the study whereby 100mg of recombinant

human IL-1RA (Anakinra) was injected into human subjects once a day for 13 weeks (Larsen et al, 2007)

20


Put together, these results indicate that the ILRA Anakinra both decreases inflammatory

markers CRP and IL-6 and improves the symptoms of T2DM with regards to -cell

function, glycated haemoglobin and fasting plasma glucose (Fig. 22, 23 and 24).

However, neither changes in the baselines of CRP or IL-6 correlated with the change in

glycated haemoglobin levels. This suggests that reduced systemic inflammation does

not play a large part in improved insulin secretion; however, it may prevent -cell

destruction and promote its regeneration in T2DM.

Targeting hIAPP with Clodronate Westwell-Roper et al treated isolated mouse islets with clodronate-containing liposomes

to assess the contribution of macrophages to hIAPP-induced inflammation of the islets;

and found, via immunostaining, that clodronate reduced the number of F4/80 positive

islet cells as well as macrophage markers in IAPP, but not -cell markers (Fig.

21) (Westwell-Roper et al. 2014).

This was due to phagocyte depletion mediated by clodronate, which in turn prevented

the expression of pro-inflammatory cytokines normally initiated by hIAPP.

Figure 21 Effect of treatment with clodronate-containing liposomes (CLOD-lip; 1mg/mL clodronate) on

expression of inflammatory genes by IAPP in isolated 12-week-old mice compared to control liposomes

(PBS-lip) for 36 hours. Results assessed by RT-qPCR. (Westwell-Roper et al 2014)

21


Anti-TNF- As discussed previously, the study by Hotamisligil in 1993 (using rodents) was one of

the first that demonstrated the link between TNF- and insulin resistance (Hotamisligil et

al. 1993). Since then, according to Donath, the results have been repeated in a large

number of animal models (Donath 2014).

A double-blind clinical trial by Ofei et al was designed to examine any effect of a

recombinant-engineered human TNF--neutralising antibody (CDP571) on blood sugar

control, in obese patients who are diabetic but not insulin dependent. This was a

relatively short and small study, involving

only 21 patients over a 2-week period

receiving intravenous (IV) injections of

either CPD571 5mg/kg or normal saline.

The results from this study indicate that

TNF- neutralisation over a short period of

time had no effect on treating insulin

resistance in obese NIDDM patients (Ofei

et al. 1996).

However, a more recent and prolonged

study performed in 2010 by Stanley et al

focused on the link between obesity and

TNF- in forty patients with metabolic syndrome but without diabetes. The randomised

clinical trial included administration of either: the anti-TNF- drug Etanercept 50mg twice

weekly for 3 months followed by 50mg once weekly for three months; or a placebo.

The results showed significant improvement in fasting blood glucose in the patients who

took Etanercept compared to placebo (Fig. 22).

At the start of the trial, five of the Etanercept group and four of the placebo group had a

fasting blood glucose of at least 100mg/dL. Three of the five receiving Etanercept and

one of the four receiving the placebo had normalised fasting glucose after six months

administration (Stanley et al. 2011).

These results imply that anti-TNF- treatments have only been proven to be effective for

metabolic syndrome-related insulin resistance when used long-term.

Figure 22 - Effect of twice-weekly injections of 50mg

Etanercept for three months followed by once weekly

for three months on fasting glucose in obese patients

with metabolic syndrome compared to placebo

(Stanley et al 2011)

22


Hydroxychloroquine Chloroquine is used against various inflammatory conditions, such as rheumatoid

arthritis (RA) (Joint Formulary Committee, 2013). Its mechanism of action is via

interference with vacuolar transport; swelling lysosomal vesicles and making them more

alkaline. However, it is little known that chloroquine has anti-diabetic actions, and was

proposed for use in diabetes but cast aside due to safety issues (Lockwood 2010). Its

hypoglycaemic activity was demonstrated in a controlled trial performed by Wasko et al,

where hydroxychloroquine was administered to patients with RA and they were

monitored for development of T2DM, against patients with RA not receiving

hydroxychloroquine; and the results showed improvement in the hydroxychloroquine

group (the number of reports of incident diabetes were 54 patients from 1808 in the

hydoxychloroquine group vs 171 from 3097 in the control group) (Wasko et al. 2007).

After adjusting for time and confounding factors, it was distinguished that the relative risk

of developing diabetes was 0.23 when the patient had 4 years of treatment with

hydroxychloroquine compared to without (Fig. 23).

Figure 23 - Probability of developing type 2 diabetes mellitus (T2DM) in rheumatoid arthritis (RA) patients

according to hydroxychloroquine use (Wasko et al 2007)

This implies that the anti-inflammatory drug chloroquine can have a beneficial effect on

the prevention of T2DM development; in turn suggesting that the inflammatory aspect of

T2DM is worth targeting for therapy.

23


Conclusions

Role of Inflammation in Metabolic Syndrome With regards to the role of inflammation in metabolic syndrome, there appears to be

significant evidence that this may be the case.

As determined by Stennicke and Salvesen, Fas receptor upregulation by glucose plays

a role in -cell death: and addition of an anti-Fas antibody to pancreatic cells has already

exhibited positive effects on reducing -cell apoptosis. The benefit of this therapy is that

effectiveness is independent of glucose concentration, which also indicates that Fas

receptor may be over-expressed in patients with metabolic syndrome and could be a

cause of insulin resistance rather than just over-consumption of glucose.

A plethora of studies, including Spranger et al, elucidate that inflammatory cytokines are

increased in T2DM, in particular IL-6 and TNF-.

Lacy also highlighted the effect that the increased infiltration of macrophages into

adipose tissue has on cytokine secretion, and ruled out pathways that are not involved;

and consequently the outcome of hIAPP on cytokine secretion and activation has also

been addressed. 30-50% more obese mice express the IL-1 secreting macrophage

F4/80 than lean mice, which indicates that the problems associated with obesity (seen

in Fig. 1) must be in some part due to increased inflammation: and indeed, as Badawi et

al discovered, patients with T2DM risk factors exhibited increased serum levels of

inflammatory cytokines than patients without. Linking this to the fact that Fas receptor

and IL-1 are upregulated in T2DM; TNF-, FFA and IL-6 levels increased in obesity;

and low grade systemic inflammation combined with insulin resistance noted in patients

with metabolic syndrome, the evidence points to inflammation as a propagator of

metabolic syndrome development.

The evidence of links between anti-inflammatory and anti-diabetic effects of current

treatments such as statins, ACE inhibitors, biguanides and thiazolidinediones further

support this. Furthermore, the evidence of effectiveness of anti-inflammatory treatments

insofar on glucose homeostasis (for example Anakinra, the IL-1R antagonist) conveys

insulin resistance to be a result of inflammation rather than vice versa.

24


Potential Future Targets The notable potential targets for novel treatments focusing on inflammation include Fas

receptors; IL-1; IL-6; TNF-; hIAPP and IL-1R, as all have been consistently indicated

in increased risk of the conditions associated with metabolic syndrome.

The main issue involved with developing such therapies is expense, but taking into

account the cost of treating all the individual components of the metabolic syndrome

separately, plus the eventual cost of consequential heart failure / cancer / liver failure

may just equate.

In conclusion, inflammation does appear to link together the conditions associated with

metabolic syndrome to a fairly significant extent, and so appears to be a reasonable

target for addressing the symptoms involved as a whole. It is an option worth exploring.

25


References

Joint Formulary Committee, 2013. British National Formulary. 66 ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain. Ahmad, M., Hassan, S., Hafeez, F. & Jajja, A., 2011. Prevalence of Various Components of Metabolic Syndrome in our Younger Population. Pakistan Journal of Physiology, 7(2), pp. 46-49. Badawi, A., Klip, A., Haddad, P., Cole, D.E., Garcia Bailo, B., El-Sohemy, A. & Karmali, M., 25 May 2010. Type 2 diabetes mellitus and inflammation: Prospects for biomarkers of risk and nutritional intervention. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, (3), pp. 173-187. Bendtzen, K., Mandrup-Poulsen, T., Nerup, J., Nielsen, J.H., Dinarello, C.A. & Svenson, M., 1986. Cytotoxicity of human pl 7 interleukin-1 for pancreatic islets of Langerhans. Science, (232), pp. 1545-1547. Blanco-Colio, L.M., Tunon, J., Martin-Ventura, J.L. & Egido, J., 2003. Anti-inflammatory and immunomodulatory effects of statins. Kidney Int, 63(1), pp. 12-23. Caro-Maldonado, A., Gerriets, V.A. & Rathmell, J.C., 2012. Matched and mismatched metabolic fuels in lymphocyte function. Seminars in Immunology, 24(6), pp. 405-413. Chatzigeorgiou, A., Karalis, K.P., Bornstein, S.R. & Chavakis, T., 2012. Lymphocytes in obesity-related adipose tissue inflammation. Diabetologia, 55(10), pp. 2583-2592. Chawla, A., Nguyen, K.D. & Goh, Y.P.S., 2011. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol, 11(11), pp. 738-749. Daskalopoulou, S.S., Mikhailidis, D.P. & Elisaf, M., 2004. Prevention and Treatment of the Metabolic Syndrome. Angiology, 55(6), pp. 589-603. Donath, M. & Shoelson, S., 2011. Type 2 diabetes as an inflammatory disease. Nature Reviews: Immunology, (11), pp. 98-107. Donath, M.Y., 2014. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov, 13(6), pp. 465-476. Dregan, A., Charlton, J., Chowienczyk, P. & Gulliford, M.C., 2014. Chronic inflammatory disorders and risk of type 2 diabetes mellitus, coronary heart disease, and stroke : A population-based cohort study. Circulation, 130(10), pp. 837-844. Expert Panel on Detection, -., Evaluation and Treatment of, -. & High Blood Cholesterol in Adults, -. 2001. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA, 285(19), pp. 2486-2497. Fracchia, K.M. & Walsh, C.M., 2015. Metabolic mysteries of the inflammatory response: T cell polarization and plasticity. International Reviews of Immunology, 34(1), pp. 3-18. Gavrieli, Y., Sherman, Y. & Ben-Sasson, S.A., 1992. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. The Journal of Cell Biology, 119(3), pp. 493-501. Hotamisligil, G.S., 2006. Inflammation and metabolic disorders. Nature, 444(7121), pp. 860-867. Hotamisligil, G.S., Peraldi P Fau - Budavari, A., Budavari A Fau - Ellis, R., Ellis R Fau - White, M.F., White Mf Fau - Spiegelman, B.M. & Spiegelman, B.M., 1996. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science, 271(5249), pp. 665-668.

26


Hotamisligil, G.S., Shargill Ns Fau - Spiegelman, B.M. & Spiegelman, B.M., 1993. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science, 259, pp. 87-91. Jiang, C., Ting At Fau - Seed, B. & Seed, B., 1997. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Letters to Nature, 391, pp. 82-86. Kaneto, H., Kawamori, D., Nakatani, Y., Gorogawa, S.-i. & Matsuoka, T.-a., 2004. Oxidative Stress and the JNK Pathway as a Potential Therapeutic Target for Diabetes. Drug News & Perspectives, 17(7), p. 447. Konner, A.C. & Bruning, J.C., 2011. Toll-like receptors: linking inflammation to metabolism. Trends in Endocrinology and Metabolism, 22(1), pp. 16-23. Lacy, P.E., 1994. The intraislet macrophage and type 1 diabetes. Mt Sinai J Med, 61, pp. 170-174 Larsen, C.M., Faulenbach, M., Vaag, A., Vlund, A., Ehses, J.A., Seifert, B., Mandrup-Poulsen, T. & Donath, M.Y., 2007. Interleukin-1Receptor Antagonist in Type 2 Diabetes Mellitus. New England Journal of Medicine, 356(15), pp. 1517-1526. Lockwood, T.D., 2010. The lysosome among targets of metformin: new anti-inflammatory uses for an old drug? Expert Opinion on Therapeutic Targets, 14(5), pp. 467-478. Maedler, K., Sergeev, P., Ris, F., Oberholzer, J., Joller-Jemelka, H.I., Spinas, G.A., Kaiser, N., Halban, P.A. & Donath, M.Y., 2003. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. Journal of Clinical Investigation, 110(6), pp. 851-860. Maedler, K., Spinas, G.A., Lehmann, R., Sergeev, P., Weber, M., Fontana, A., Kaiser, N. & Donath, M.Y., 2001. Glucose Induces -Cell Apoptosis Via Upregulation of the Fas Receptor in Human Islets. Diabetes, 50(8), pp. 1683-1690. Mandrup-Poulsen, T., 1996. The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia, (39), pp. 1005-1029. Marini, M.G., Sonnino, C., Previtero, M. & Biasucci, L.M., 2014. Targeting Inflammation: Impact on Atherothrombosis. Journal of Cardiovascular Translational Research, 7, pp. 9-18. Morrish, N.J., Wang Sl Fau - Stevens, L.K., Stevens Lk Fau - Fuller, J.H., Fuller Jh Fau - Keen, H. & Keen, H., 2001. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia, 44(2), pp. 14-21. Nguyen, M.T.A., Satoh, H., Favelyukis, S., Babendure, J.L., Imamura, T., Sbodio, J.I., Zalevsky, J., Dahiyat, B.I., Chi, N.-W. & Olefsky, J.M., 2005. JNK and Tumour Necrosis Factor-alpha Mediate Free Fatty Acid-induced Insulin Resistance in 3T3-L1 Adipocytes. The Journal of Biological Chemistry, 280, pp. 35361-35371. Ofei, F., Hurel, S., Newkirk, J., Sopwith, M. & Taylor, R., 1996. Effects of an Engineered Human AntiTNF- Antibody (CDP571) on Insulin Sensitivity and Glycemic Control in Patients With NIDDM. Diabetes, 45(7), pp. 881-885. Paoletti, R., Bolego, C., Poli, A. & Cignarella, A., 2006. Metabolic Syndrome, Inflammation and Atherosclerosis. Vascular Health and Risk Management, 2(2), pp. 145-152. Petersen, K.F., Dufour S Fau - Befroy, D., Befroy D Fau - Garcia, R., Garcia R Fau - Shulman, G.I. & Shulman, G.I., 2004. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. New England Journal of Medicine, 350(7), pp. 664-671.

27


Pickup, J.C., Mattock, M.B., Chusney, G.D. & Burt, D., 1997. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia, 40, pp. 1286-1292. Shepherd, P.R. & Kahn, B.B., 1999. Glucose Transporters and Insulin Action Implications for Insulin Resistance and Diabetes Mellitus. New England Journal of Medicine, 341(4), pp. 248-257. Spranger, J., Kroke A Fau - Mohlig, M., Mohlig M Fau - Hoffmann, K., Hoffmann K Fau - Bergmann, M.M., Bergmann Mm Fau - Ristow, M., Ristow M Fau - Boeing, H., Boeing H Fau - Pfeiffer, A.F.H. & Pfeiffer, A.F., 2003. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes, 52(3), pp. 812-817. Stanley, T.K., Zanni, M.V., Johnsen, S., Rasheed, S., Makimura, H., Lee, H., Khor, V.K., Ahima, R.S. & Grinspoon, S.K., 2011. TNF-alpha Antagonism with Etanercept Decreases Glucose and Increases the Proportion of High Molecular Weight Adiponectin in Obese Subjects with Features of the Metabolic Syndrome. J Clin Endocrinol Metab, 96(1), pp. E136-E150. Stennicke, H.R. & Salvesen, G.S., 2000. Caspase-controlling intracellular signals by protease zymogen activation. Biochimica et Biophysica Acta, 1477, pp. 299-306. Szeto, C.-C. & Li, P.K.-T., 2008. Antiproteinuric and anti-inflammatory effects of thiazolidinedione (Review Article). Nephrology, 13(1), pp. 53-57. Wasko, M.C., Hubert Hb Fau - Lingala, V.B., Lingala Vb Fau - Elliott, J.R., Elliott Jr Fau - Luggen, M.E., Luggen Me Fau - Fries, J.F., Fries Jf Fau - Ward, M.M. & Ward, M.M., 2007. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA, 298(2), pp. 187-193. Westwell-Roper, C.Y., Ehses Ja Fau - Verchere, C.B. & Verchere, C.B., 2014. Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1beta production and beta-cell dysfunction. Diabetes, 16(5), pp. 1698-1711. Xie, W. & Du, L., 2011. Diabetes is an inflammatory disease: evidence from traditional Chinese medicines. Diabetes, Obesity and Metabolism, (13), pp. 289-301. Yasein, N., Ahmad, M., Matrook, F., Nasir, L. & Froelicher, E.S., 2010. Metabolic syndrome in patients with hypertension attending a family practice clinic in Jordan. Eastern Mediterranean Health Journal, 16(4), pp. 375-379. Zuliani, G., Morieri, M.L., Volpato, S., Maggio, M., Cherubini, A., Francesconi, D., Bandinelli, S., Paolisso, G., Guralnik, J.M. & Ferrucci, L., 2015. Insulin resistance and systemic inflammation, but not metabolic syndrome phenotype, predict 9 years mortality in older adults. Atherosclerosis, 235(2), pp. 538-545.

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is inflammation a useful target for the treatment of metabolic syndrome?

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