Current Diabetes Reviews, 2006, 2, 195-211 195

Relationship Between Inflammation, Insulin Resistance and Type 2

Diabetes: ‘Cause or Effect’?

Jerry R. Greenfield1 and Lesley V. Campbell1,2,*

1
Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia
2
Diabetes Centre, St. Vincent’s Hospital, Sydney, Australia

Abstract: Inflammation has been implicated as an important aetiological factor in the development of both insulin
resistance and type 2 diabetes mellitus. This conclusion is predominantly drawn from studies demonstrating associations
between elevated (but ‘normal range’) levels of circulating acute phase inflammatory markers, typified by C-reactive
protein (CRP), and indices of insulin resistance and the development of type 2 diabetes. There is debate as to whether
these associations are independent of body fatness or, rather, an epiphenomenon of obesity, particularly central obesity, a
strong predictor of insulin resistance and type 2 diabetes and an important source of inflammatory cytokines, such as
interleukin-6. Some of this controversy and the inability to draw definitive conclusions from these studies relate to the fact
that most studies measure body fat and its distribution indirectly using anthropometric estimates, such as Body Mass
Index and waist circumference, rather than directly by dual-energy X-ray absorptiometry, computed tomography or
magnetic resonance imaging. Furthermore, use of the term inflammation may be inappropriate when describing mild
elevations of CRP in the ‘normal range’ in the absence of the other changes that characterise classical inflammatory
diseases, such as a reduction in levels (or evidence of consumption) of complement proteins. Debate as to whether obesity
mediates the association between circulating levels of inflammatory markers and insulin resistance can be resolved by
well-designed studies using body fat measured by gold-standard methods. In this review, we present evidence to support
the suggestion that body fat is the primary determinant of circulating inflammatory marker levels in the basal state and
that marginally elevated levels of circulating interleukin-6 and CRP in obesity are a consequence rather than a cause of
insulin resistance. The importance of genetic influences in determining both body fatness and circulating CRP levels will
also be discussed. The review will conclude with a discussion of possible mechanisms linking body fat and insulin
resistance to elevated circulating levels of inflammatory markers, including the possible role of the toll-like family of
immune receptors.

INTRODUCTION reduced levels) of complement proteins, the use of the term

The Metabolic Syndrome, also known as the Insulin
Resistance Syndrome, Syndrome X, Cardiovascular
Dysmetabolic Syndrome and the ‘deadly quartet’, consists of
abdominal or visceral adiposity, insulin resistance,
dyslipidaemia (hypertriglyceridaemia, low high-density
lipoprotein [HDL] cholesterol and a predominance of small,
dense low-density lipoprotein [LDL] cholesterol) and
hypertension [1-5]. While there is debate about the
terminology [6], the importance of identifying and treating
components of the syndrome lies in the associated increased
risk of type 2 diabetes and cardiovascular disease.
The coexistence of type 2 diabetes and atherosclerotic
cardiovascular disease has raised the possibility that
common aetiological mechanisms contribute to their
development. Indeed, a number of authors have recently
suggested that inflammation is a common aetiological factor
unifying these metabolic disorders [7, 8]. However, as
discussed later, in the absence of significantly elevated levels
of circulating acute phase reactants and consumption (ie.
*Address correspondence to this author at the Diabetes and Obesity
Research Program, Garvan Institute of Medical Research, 384 Victoria St,
Darlinghurst, Sydney, Australia; Tel: 61 2 9295 8202; Fax: 61 2 9295 8201;
E-mail: l.campbell@garvan.org.au
inflammation may not be appropriate when describing
mildly raised (but normal range) levels of inflammatory
markers [9].
Recent interest in the hypothesis that inflammation plays
an important aetiological role in the development and
progression of coronary artery disease [10] is derived from
numerous studies demonstrating associations between
baseline levels of inflammatory markers, particularly C-
reactive protein (CRP), and the development of
cardiovascular disease in healthy subjects [11]. This
hypothesis is supported by predominantly in vitro data
reporting that CRP may directly promote pro-atherogenic
processes in vascular cells [12, 13]. Although the risk
attributable to a raised CRP level in humans may be less than
previously reported [11, 14], it nonetheless remains an
independent predictor of cardiovascular mortality and has
been proposed to be a potentially useful additional
prognostic indicator in individuals with intermediate
(Framingham risk score 10 – 20%) 10-year coronary heart
disease risk [15].
However, it remains controversial whether inflammation
(usually represented by an elevated circulating CRP level) is
directly involved in the pathogenesis of insulin resistance
and type 2 diabetes. An alternative hypothesis that will be
discussed is that increased adiposity, itself a predictor of

1573-3998/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd.

196 Current Diabetes Reviews, 2006, Vol. 2, No. 2 Greenfield and Campbell

Fig. (1). Hypothesised relationships between obesity, insulin resistance and pro- and anti-inflammatory cytokines. It has been suggested that
body fat-derived adipocytokines directly promote (interleukin-6 and TNF-α) or protect against (adiponectin) the development of insulin
resistance (panel A). An alternative hypothesis is that increased circulating levels of proinflammatory cytokines, and decreased levels of
antiinflammatory cytokines, are a consequence, rather than a cause, of insulin resistance, primarily driven by increased body fat (panel B).

diabetes risk and a source of inflammatory cytokines,
mediates these associations and interacts with insulin
resistance to raise CRP levels in the circulation [8, 9, 16, 17]
(Fig. 1).
This article will review the evidence for whether
inflammation plays a primary role in the pathogenesis of
insulin resistance and type 2 diabetes and the contribution of
body fat to relationships between CRP and these metabolic
disorders. Furthermore, we will propose possible biological
mechanisms by which body fat and insulin resistance may
lead to elevated circulating levels of inflammatory markers.
Specific attention will be focused on CRP, as it is the most
commonly studied inflammatory marker in relation to
diabetes and cardiovascular risks.
PATHOGENESIS OF INSULIN RESISTANCE AND
TYPE 2 DIABETES MELLITUS – A POSSIBLE
INFLAMMATORY BASIS?
The number of people affected by type 2 diabetes is
predicted to increase from 135 million in 1995 to 300 million
in 2025 [18]. This is largely attributable to increases in the
prevalence of overweight and obesity, typified by developed
countries such as the United States [19], Australia [20] and
the United Kingdom [21]. These disturbing trends have led
to widespread interest in the contributory pathophysiological
mechanisms and, hence, possible interventions, both
pharmacological and non-pharmacological, to prevent or at
least delay the development of these metabolic disorders
[22].
Role of Fatty Acids in the Pathogenesis of Insulin
Resistance and Type 2 Diabetes
Type 2 diabetes is characterised by insulin resistance and
decreased insulin secretion [23]. It is widely accepted that
the accumulation of fatty acids in metabolically active (non-
adipose) tissues, such as muscle and liver, plays a major
aetiological role in insulin resistance, with much research
directed towards the discovery of mechanisms by which lipid
oversupply inhibits insulin action [24-28]. Recent studies
postulate that primary or secondary deposition of muscle
triglyceride and impaired mitochondrial oxidative
phosphorylation explain the early presence of insulin
resistance in genetically predisposed individuals [29].
The major source of fatty acids in the circulation is
adipose tissue. In contrast to peripheral or glutofemoral fat, a
central pattern of fat distribution has been identified as being
particularly adverse with respect to metabolic risk, with
strong relationships reported between increased abdominal
fat and impaired insulin action in humans [30-34]. In
addition to the importance of the amount of fat in the
abdominal region, qualitative differences in adipocyte
biology and fat cell metabolism contribute to the depot-
specific characteristics of central adiposity. In this regard,
omental adipocytes have been shown to be more responsive
to the lipolytic effects of noradrenaline than peripheral
adipocytes in men and women [35, 36]. Increased sensitivity
of omental vs peripheral adipocytes to noradrenaline-
mediated lipolysis is accompanied by resistance of omental
adipocytes to the anti-lipolytic effects of insulin [27, 37, 38].
Inflammation, Insulin Resistance and Type 2 Diabetes Current Diabetes Reviews, 2006, Vol. 2, No. 2 197

Table 1. Studies of Prospective Associations between C-reactive Protein and other Inflammatory Markers and the Development of
Type 2 Diabetes Mellitus

Risk of development of type 2 diabetes (adjusted Effect of (further) adjustment for adiposity*
Study
for factors other than adiposity in some studies) (and other factors in some studies)

ARIC study [47] OR extreme quartiles factor VII, 1.7; fibrinogen, 1.5; NS except for factor VIII in women
vWF, 1.5 in women (NS in men); factor VIII, 1.4 in
men, 2.2 in women.
ARIC study [48] OR extreme quartiles WBC count, 1.9; low albumin, WBC count and sialic acid: some attenuation;
1.3; fibrinogen, 1.2; sialic acid, 3.7; oromucoid, 7.9; oromucoid: minimally changed; remainder NS
α1-antitrypsin and haptoglobin, NS
Women’s Health Study [49] RR extreme quartiles CRP, 15.7; IL-6, 7.5 RR CRP, 4.2; IL-6 NS
th th
Cardiovascular Health Study [50] OR 75 vs 25 percentile CRP, 2.0; fibrinogen, Minimally changed
albumin, WBC count, platelet count and factor VIIIc
NS
IRAS [51] OR for 1SD increase in CRP, 1.4; fibrinogen, 1.2; CRP, fibrinogen: NS PAI-1: minimally changed
PAI-1, 1.99
th th
Pima Indians [52] RH 90 vs 10 percentile WBC count, 2.7 Minimally changed (after adjustment for percent
body fat)
WOSCOPS [53] HR extreme quintiles CRP, 6.1 Markedly attenuated but statistically significant
Mexico City Diabetes Study [54] OR extreme tertiles CRP, 5.5 (women only; NS in Minimally changed
men)
ARIC study [55] HR extreme quartiles CRP, 2.8; IL-6, 2.5; Only IL-6 remained statistically significant
orosomucoid, 2.3; sialic acid, 1.9
MONICA Augsburg Cohort Study [56] HR extreme quartiles CRP, 2.8 NS
Japanese Americans [57] Results prior to adjustment for adiposity not HR extreme quartiles CRP, 2.8 in men, 3.1 in
presented women
Hoorn Study [58] OR extreme tertiles CRP, 3.0 (men only; NS in No effect but substantially lowered after
women) adjusting for WHR
Pima Indians [59] CRP, IL-6, TNF-α, sE-selectin, CAMs and vWF not NA
significant predictors in Body Mass Index-matched
cases and controls
EPIC-Potsdam cohort [60] OR CRP ≥1.5 vs <1.5 mg/L, 3.5; extreme quartiles IL-6 NS; others markedly attenuated but
IL-6, 7.3; TNF-α, 2.3; IL-1β not a predictor statistically significant
Honk Kong Cardiovascular Risk Factors RR extreme quintiles CRP, 3.9 Attenuated but statistically significant
Prevalence Study [61]
Kuopio Ischaemic Heart Disease Risk Factor OR CRP ≥3.0 vs 0.1-0.99 mg/L, 4.1 Markedly attenuated but statistically significant
Study [62]
Nurses’ Health Study [63] OR extreme quintiles CRP, 7.1; IL-6, 3.3; TNF-αR2, Markedly attenuated but statistically significant
2.6
*Body Mass Index unless otherwise stated. ARIC: Atherosclerosis Risk in Communities Study. CAM: cellular adhesion molecules; CRP: C-reactive protein; EPIC: European
Prospective Investigation into Cancer and Nutrition; HR: hazard ratio; IL-6: interleukin-6; IRAS: Insulin Resistance Atherosclerosis Study; MONICA: Monitoring of Trends and
Determinants in Cardiovascular Disease; NA: not applicable; NS: not significant; OR: odds ratio; RH: relative hazard; RR: relative risk; TNF-αR2: tumour necrosis factor-α receptor
2; vWF: von Willebrand factor; WHR: waist-to-hip ratio; WOSCOPS: West of Scotland Coronary Prevention Study.

Increased lipolysis in omental adipocytes results in increased
release of fatty acids into both the portal vein, which impairs
hepatic insulin extraction, stimulates gluconeogenesis and
enhances triglyceride synthesis, as well as the peripheral
circulation, resulting in impaired insulin-stimulated glucose
uptake [28, 38-40]. It is important to note that the adverse
consequences of increased lipolysis of abdominal adipocytes
are not restricted to the liver and that nonportal drainage
affecting peripheral tissues is also important [41].
Inflammation and CRP
Inflammation in general and CRP in particular have been
implicated as important additional factors in the
pathogenesis of insulin resistance, glucose intolerance and
type 2 diabetes [42-44]. Some authors have even suggested
that the process of inflammation is a component of the
Metabolic Syndrome [45, 46]. These conclusions
predominantly stem from the increasing number of studies
reporting strong prospective associations between circulating
acute phase inflammatory markers, albeit at levels
significantly less than those observed during acute
inflammation, and the development of type 2 diabetes [47-
63] (Table 1). Although various inflammatory ‘markers’
have been studied, including cytokines, chemokines and
acute phase reactants such as interleukin-6, white blood cell
count, albumin, oromucoid, sialic acid, fibrinogen and other
coagulation factors, associations are variable and
inconsistent (Table 1). The most widely studied and pivotal
inflammatory biomarker is CRP, a member of the pentraxin
family of proteins, consisting of five identical polypeptide
198 Current Diabetes Reviews, 2006, Vol. 2, No. 2
Table 2. Heritability of C-Reactive Protein in Twin and Family Studies
Study Population Studied
St. Thomas’ Twin Study [65] 186 postmenopausal twin pairs
Norwegian Twin Panel [66] 78 male and female twin pairs
Elderly twin study [67] 282 elderly twin pairs
NHLBI Family Heart study [68] 924 Caucasian sibling pairs
British Family study [69] 98 British Caucasian families
Diabetic Heart Study [70] 250 families
Japanese American Family Study [71] 68 extended Asian American kindreds
*Adjusted for Body Mass Index. †Formal heritability estimates not calculated as only monozygotic twins were recruited. ‡No difference after adjusting for Body Mass Index.
#Adjusted for duration of diabetes and statin and aspirin use (h2 = 0.49 before adjustment). ¶Adjusted for age, gender, Body Mass Index, smoking, hypertension, diabetes, myocardial
infarction and coronary artery disease and use of CRP lowering medications, oral contraceptives and hormone replacement therapy (h2 = 0.27 before adjustment). ICC: intra-class
correlation coefficient; NHLBI: National Heart, Lung, and Blood Institute.
subunits associated non-covalently in a symmetrical
pentameric configuration [17]. In humans, CRP circulates in
mg/L concentrations, with a median level of 0.8 mg/L, 90th
centile 3 mg/L and 99th centile 10 mg/L in healthy
populations [64]. Hence, levels <3 mg/L are considered
‘normal range’ and levels >10 mg/L are suggestive of
inflammation [12]. Circulating CRP levels are stable over
time making them the most suitable markers of long-term
vascular and metabolic risk [11, 17]. Part of this stability
may relate to the significant heritability of CRP, which has
been investigated in three twin [65-67] and four family [68-
71] studies (Table 2). These studies have found that
approximately 35% of the population variance in circulating
CRP is heritable, even after correcting for Body Mass Index
and other potentially confounding covariates.
THE ROLE OF ADIPOCYTOKINES IN INFLAM-
MATION
Although a number of fat-derived cytokines
(‘adipocytokines’) have been implicated as possible
inflammatory mediators of insulin resistance, the evidence is
predominantly from in vitro studies and animal models [72,
73]. Caution must be exercised in extrapolating from mouse
to man, considering that the main acute phase reactant in
mice is serum amyloid P and that mouse CRP, which
circulates in trace concentrations, only peaks at 2 mg/L at the
height of the animal’s inflammatory response [17, 74]. The
physiological relevance of some of these adipocytokines,
such as tumour necrosis factor (TNF)-α and, particularly,
interleukin-6, to human insulin resistance has not been
established [75, 76].
TNF-α
TNF-α, which has been shown to upregulate interleukin-
6 gene expression [77] and downregulate adiponectin gene
expression [78] in 3T3-L1 adipocytes, attenuates insulin-
mediated suppression of hepatic glucose output and glucose
utilisation in rodents [79]. In contrast, however, there is no
convincing evidence that humans secrete physiologically
significant amounts of TNF-α from adipose tissue [80];
instead, it is thought that TNF-α may have autocrine-
paracrine, rather than endocrine, actions in man [73]. In a
recent study, plasma TNF-α level was unrelated to insulin
sensitivity (by euglycaemic-hyperinsulinaemic clamp) [81].
Greenfield and Campbell
2
Heritability (h ) ICC in Monozygotic Twin Pairs
0.45* 0.54
Not calculated† 0.40
0.20‡ 0.30
0.40 N/A
0.39 N/A
0.40# N/A
0.29¶ N/A
Furthermore, TNF-α inhibition had no effect on insulin
sensitivity in obese patients with [82, 83] and without [84]
type 2 diabetes.
Interleukin-6
Interleukin-6 is a pro-inflammatory cytokine secreted
predominantly from stimulated macrophages, fibroblasts and
vascular endothelial cells [85]. However, in the basal state,
up to 30% of circulating interleukin-6 is derived from
adipose tissue [80]. In addition, elegant studies have recently
shown that strongly exercising muscle releases interleukin-6
in a beneficial glycogen ‘sparing’ manner, increasing hepatic
glucose output, independent of counter-regulatory hormone
production [85].
Although interleukin-6 has been implicated in the
pathogenesis of insulin resistance, data are conflicting [86].
Alternatively, it has been postulated that interleukin-6 may
be upregulated in insulin-resistant muscle as an adaptive
response aimed at reversing impaired glucose uptake and
that interleukin-6 may even be a potential therapeutic agent
in type 2 diabetes [85]. Contrary to evidence that interleukin-
6 interferes with insulin signalling in hepatocyte cell lines
[87], Stouthard et al. reported that incubation of 3T3-L1
adipocytes with interleukin-6 enhanced basal and insulin-
stimulated glucose uptake [88]. In mice, over-expression of
interleukin-6 was found to reduce diabetes risk [89]; in
another study, high-fat fed interleukin-6 deficient mice (with
a targeted null mutation in the interluekin-6 gene) developed
hyperglycaemia and impaired glucose disposal [90]. In
contrast, it was recently reported that interleukin-6 depletion
selectively improved hepatic insulin sensitivity in obese
mice [91].
In vivo studies of the role of interleukin-6 in human
insulin resistance have also yielded conflicting results. In
one study, administration of recombinant human interleukin-
6 to healthy subjects increased glucose levels in a dose-
dependent fashion, without affecting insulin or C-peptide
levels [92]. In contrast, interleukin-6 increased the metabolic
clearance rate of glucose in patients with metastatic renal cell
cancer [93]. In another study, the acute administration of
interleukin-6 to healthy human subjects had no effect on
muscle glucose uptake, whole-body glucose disposal or
endogenous glucose production [94]. Differences in dose and
Inflammation, Insulin Resistance and Type 2 Diabetes
cohort characteristics may partly explain these opposing
findings.
An alternative view is that circulating interleukin-6 level
is more likely to be an index of adiposity rather than a direct
regulator of insulin action in man [81]. Consistent with this
suggestion, a study of Pima Indians found that the inverse
relationship between fasting plasma IL-6 concentration and
insulin sensitivity (by euglycaemic-hyperinsulinaemic
clamp) was attenuated after correcting for percent body fat
[95]. Consistent with this theory, in a study of Body Mass
Index-matched insulin-sensitive controls and insulin-
resistant type 2 diabetic relatives, there was no significant
difference in interleukin-6 (or TNF-α) between the groups,
despite 60% lower rates of glucose infusion and insulin-
stimulated peripheral glucose uptake in the latter group
during hyperinsulinaemic-euglycaemic clamp studies [29].
In a recent study, sustained reduction in free fatty acid levels
by acipimox, an inhibitor of lipolysis, significantly enhanced
hepatic and muscle insulin sensitivity, without affecting
weight (and presumably fat mass) or plasma levels of TNF-α
and interleukin-6 [96]. Furthermore, there was no
relationship between whole body glucose disposal and
plasma levels of these cytokines before and after treatment
[96]. Taken together, these results suggest that the amount of
body fat is an important determinant of circulating
interleukin-6 level and that body fat, when measured
accurately, largely accounts for the association between
increased circulating interleukin-6 and insulin resistance.
Adiponectin
Adiponectin, also referred to as apM1 (adipose most
abundant gene transcript 1), Acrp 30 (adipocyte
complement-related protein of 30 kDa), adipoQ and GBP28
(gelatin binding protein of 28 kDa) is a large, abundant
collagen-like protein secreted exclusively from adipocytes
[97, 98]. Adiponectin, the secretion of which is inhibited by
TNF-α and interleukin-6 [73], is reported to have insulin-
sensitising, anti-atherosclerotic and anti-inflammatory
properties [99], the latter mediated, possibly, through down-
regulation of CRP production and synthesis [100]. In
contrast to most other adipocytokines, plasma adiponectin
concentration is paradoxically inversely associated with total
body and abdominal fat and reduced in obesity, due, most
likely, to the strong and independent association between
adiponectin levels and insulin sensitivity [101-103]. Perhaps
paradoxically, there is some evidence to suggest that omental
fat may be a more important determinant of circulating
adiponectin levels than subcutaneous abdominal fat, as
adiponectin secretion from human omental (but not
subcutaneous) adipocytes increased with decreasing Body
Mass Index and following incubation with insulin and/or
insulin-sensitising drugs such as rosiglitazone (a
thiazolidinedione) [104]. However, it should be noted that
adiponectin circulates in two main forms – a low molecular
weight trimer-dimer (hexamer) and a higher-order high
molecular weight (HMW) complex, comprising two or three
hexamers [99, 105]. Measuring these distinct complexes,
specifically the ratio of HMW-to-total adiponectin, has been
proposed to reflect changes in insulin sensitivity better than
total levels in some situations, such as with thiazolidinedione
therapy [99, 106].
Current Diabetes Reviews, 2006, Vol. 2, No. 2 199
Circulating adiponectin levels are directly associated
with insulin sensitivity (measured by the euglycaemic-
hyperinsulinaemic clamp), even after adjusting for percent
body fat [102]. A possible role for decreased adiponectin in
the pathogenesis of insulin resistance was provided by a
study by Hotta et al. in Rhesus monkeys, which reported that
plasma levels of adiponectin decreased in parallel with the
development of insulin resistance [107]. Furthermore,
circulating adiponectin levels are lower in healthy subjects
who develop type 2 diabetes compared to those who do not
[108, 109]. Vionnet et al. recently mapped a diabetes
susceptibility locus to human chromosome 3q27 [110], a
region where the gene encoding adiponectin is located [111].
Polymorphisms in the adiponectin gene ACDC have been
reported to be associated with type 2 diabetes in a Japanese
population [111]; however, this was not replicated in a recent
study of Pima Indians [112].
Receptors for adiponectin have recently been identified;
adiponectin receptor 1 (AdipoR1), although expressed
ubiquitously, is most abundant in muscle and has high-
affinity for globular and low affinity for full-length
adiponectin [113]. In contrast, adiponectin receptor 2
(AdipoR2) is predominantly expressed in liver and has
intermediate affinity for both globular and full-length
adiponectin [113]. This differential receptor expression may
account for tissue-specific effects of various isoforms of
circulating adiponectin.
In obese and lipoatrophic insulin-resistant mice,
treatment with adiponectin (particularly globular
adiponectin) has been shown to improve insulin sensitivity
and to enhance suppression of insulin-mediated hepatic
glucose output, reduce hepatic and skeletal muscle
triglyceride content and increase fatty acid oxidation in
muscle [114, 115]. Although the mechanisms by which
adiponectin exerts these actions are debated, there is
evidence to suggest that increased tyrosine phosphorylation
of the insulin receptor in muscle, activation of adenosine
monophosphate (AMP)-activated protein kinase in muscle
and liver, increased activity of peroxisome proliferator
activated receptor (PPAR)-α and increased expression of
genes encoding proteins involved in fatty acid transport and
oxidation (e.g. CD-36 and fatty acid transport protein-1) may
be involved [116, 117].
Despite this evidence in animals, similar studies using
infused adiponectin have not been published in humans.
Therefore, a definitive role for adiponectin in human insulin
resistance remains uncertain. Against adiponectin being an
important factor in human insulin resistance, we [9] and
others [29] reported that insulin-sensitive and insulin-
resistant relatives of subjects with type 2 diabetes, with
similar Body Mass Index values, had similar levels of
circulating adiponectin. In another study, although plasma
adiponectin was correlated with insulin-stimulated non-
oxidative glucose disposal in a study of type 2 diabetic first-
degree relatives, levels did not change following acipimox
treatment, despite a significant improvement in insulin action
[96]. Until adiponectin is shown to have direct favourable
effects on insulin sensitivity in man, the possibility that low
circulating adiponectin levels are a consequence rather than
cause of insulin resistance cannot be excluded.
200 Current Diabetes Reviews, 2006, Vol. 2, No. 2
ADIPOSITY IS AN IMPORTANT DETERMINANT OF
CIRCULATING INFLAMMATORY MARKERS AND
THEIR RELATIONSHIP WITH TYPE 2 DIABETES
RISK
There is widespread debate as to whether associations
between inflammatory markers and type 2 diabetes are
independent of body fatness or, rather, an epiphenomenon of
obesity, particularly central obesity, which is a strong
predictor of insulin resistance and type 2 diabetes [30] and
an important source of inflammatory cytokines [80]. Some
of this controversy, together with the inability to draw
definitive conclusions from most studies, relates to the fact
that body fat and its distribution are usually measured
indirectly using anthropometric estimates, such as Body
Mass Index, waist circumference and waist-to-hip ratio
[118]. The inaccuracy of anthropometric surrogates as
measures of central abdominal fat stores was illustrated by a
recent study, which failed to detect a difference in waist
circumference and waist-to-hip ratio between subjects with
and without type 2 diabetes, despite a significant difference
in visceral fat area measured by magnetic resonance imaging
[119].
The question as to whether obesity mediates the
association between circulating levels of inflammatory
markers and insulin resistance and type 2 diabetes can only
be resolved by studies which measure body fat directly using
more accurate techniques, such as dual-energy X-ray
absorptiometry, computed tomography (CT) and magnetic
resonance imaging (MRI). CT and MRI represent ‘gold-
standard’ methods for measuring visceral fat and have been
validated against cadaveric studies in humans [120, 121].
Dual-energy X-ray absorptiometry, which is commonly used
to measure bone mineral density in clinical practice, is an
accurate, rapid and validated technique for measuring body
fat mass and its distribution. Dual-energy X-ray
absorptiometry not only quantifies adipose tissue depots, but
also includes fat content within other tissues such as muscle.
Dual-energy X-ray absorptiometry is associated with
minimal radiation exposure and provides an accurate
measure of total body and central abdominal adiposity, but
does not measure intra-abdominal and subcutaneous
abdominal fat depots independently [122]. However,
distinguishing intra-abdominal from subcutaneous
abdominal fat may be less important than previously
thought, as there is evidence that subcutaneous abdominal fat
(perhaps deep subcutaneous abdominal fat in particular
[123]) has a similar or even stronger relationship with
directly-measured insulin sensitivity than intra-abdominal fat
[124-126]. Indeed, it has been suggested that because the
amount of subcutaneous abdominal fat is large in
comparison with other fat compartments (e.g. intra-
abdominal fat), it may constitute the most metabolically
active fat depot influencing insulin sensitivity [124, 126].
In a number of studies [47-49, 51, 53, 55, 56, 58, 60-63],
controlling for adiposity and other metabolic factors
markedly attenuated, to the point of insignificance in some
studies [47, 48, 51, 55, 56], the association between
inflammatory markers and type 2 diabetes risk (Table 1).
Furthermore, in a study of Pima Indians, in which cases
Greenfield and Campbell
(who developed diabetes) and controls (who did not develop
diabetes) were matched for age, gender and adiposity (albeit
estimated by Body Mass Index and waist circumference),
basal CRP levels were not associated with the risk of type 2
diabetes [59]. However, the use of indirect anthropometric
estimates of body fatness in the majority of these studies
must limit conclusions regarding the role of obesity in the
relationship between CRP and type 2 diabetes. Persistence of
a significant relationship after adjusting for surrogate
measures of body size does not indicate that relationships
between CRP and type 2 diabetes are exclusive of body
fatness. This question can only be resolved using direct
adiposity measures. This important issue of residual
confounding and its clinical implications has been discussed
elsewhere in detail [127].
Although CRP is primarily secreted by the liver in
response to stimulation by pro-inflammatory cytokines,
particularly interleukin-6, a recent report suggested that CRP
mRNA may be expressed in adipose tissue itself [100]. As
discussed later in the review, in the basal state, 25 – 30% of
total systemic interleukin-6 is derived from adipose tissue
[80]. Therefore, it is biologically plausible that adiposity is
an important, and perhaps the primary, determinant of
inflammatory cytokine production in healthy individuals and
that increased body fat accounts for the strong association
between basal CRP and subsequent risk of type 2 diabetes.
Of note, production rates of interleukin-6 in omental fat are
up to three times that of subcutaneous adipose tissue [128].
Furthermore, recent evidence suggests that in addition to
adipocytes, macrophages in fat may account for a significant
proportion of inflammatory cytokine production [129].
In order to investigate the specific role of adiposity in
determining circulating CRP levels, we recently investigated
the relationship between total body and central abdominal fat
(measured by dual-energy X-ray absorptiometry) and
circulating levels of CRP in healthy female twins [130]. As
already mentioned above, approximately 35% of the
population variance in circulating CRP is heritable [65-71].
Furthermore, our group has reported that genetic factors
explain up to 60 – 70% of the population variance in central
abdominal fat [131-133]. Of note, some of this genetic
influence is shared with total body fat [132]. Therefore it is
important to control for genetic factors when examining the
relationship between adiposity and circulating CRP levels.
The main finding of our study was that levels of CRP were
strongly related to total body and central abdominal fat. CRP
was also associated with other components of the Metabolic
Syndrome, including blood pressure, HDL cholesterol and
triglyceride levels. In order to determine whether these
relationships persisted after controlling for genetic
influences, we: (i) examined relationships between intra-pair
differences in CRP and these variables; and (ii) in
monozygotic twins discordant for body fatness or lipid
values, compared CRP levels in twins with the higher values
of these Metabolic Syndrome components with CRP levels
in twins with the lower values of these Metabolic Syndrome
components. In both analyses, CRP was consistently related
to total body fat, central abdominal fat, HDL cholesterol and
triglyceride levels, independent of genetic, age, gender and
environmental effects.
Inflammation, Insulin Resistance and Type 2 Diabetes
Few other studies have examined the relationship
between CRP levels and direct measures of adiposity. Using
dual-energy X-ray absorptiometry, we and others have
demonstrated significant associations between CRP and total
body fat [9, 134-145] and trunk fat [144-146]. Two
subsequent studies [9, 134], both from our group, confirm
our finding of a strong relationship between circulating
levels of CRP and central abdominal fat, a stronger
determinant of insulin resistance than total body or trunk fat
[30]. Our results are consistent with studies that report
associations between CRP and abdominal fat measured by
CT [137, 138, 140, 143, 147, 148]. However, these studies
are limited by the use of single-slice scanning, which, as we
have reported, may result in misclassification when ranking
or ordering subjects based on abdominal adiposity [122].
Taken together, these studies highlight the importance of
body fat in determining circulating CRP levels and indicate
that its confounding effect must be properly accounted for in
future studies.
ADIPOSITY VS INSULIN RESISTANCE IN
DETERMINING CIRCULATING LEVELS OF
INFLAMMATORY MARKERS
Controversy exists as to the relative importance of body
fat and the closely related phenotype, insulin sensitivity, in
determining circulating levels of inflammatory markers. In
particular, it is unclear whether insulin resistance is
associated with increased CRP levels in the absence of
increased adiposity. Most of the studies investigating this
question are limited by the use of indirect measures of body
fatness and insulin sensitivity. The evidence investigating
this question is summarised in the following paragraphs.
Body Fat Mediates the Relationship between CRP Levels
and Insulin Sensitivity
Some studies have found that insulin resistance is not
associated with levels of inflammatory markers in the
circulation, despite strong and significant relationships
between CRP levels and Body Mass Index and waist
circumference [149, 150]. Other studies suggest that
adiposity mediates or confounds the inverse relationship
between CRP and insulin sensitivity. For example,
controlling for Body Mass Index, waist circumference [151]
or total body fat measured by dual-energy X-ray
absorptiometry [144] eliminated associations between CRP
and components of the Metabolic Syndrome. Consistent with
these results, in a study using direct measures of insulin
sensitivity (euglycaemic-hyperinsulinaemic clamp) and
adiposity (dual-energy X-ray absorptiometry and CT), the
relationship between CRP and insulin-stimulated glucose
disposal was attenuated in premenopausal women, and was
eliminated in postmenopausal women, by covarying for total
body or intra-abdominal fat [140]. This is supported by two
other studies, in which the inverse relationship between CRP
and insulin sensitivity became non-significant after adjusting
for total fat mass [152, 153]. In a study of Pima Indians,
although percentage total body fat (by dual energy X-ray
absorptiometry) and insulin-stimulated glucose disposal (by
euglycaemic-hyperinsulinaemic clamp) explained 71% of the
total variance in circulating CRP levels, adiposity was the
2
dominant factor (r = 0.51 and 0.20 respectively) [141]. In
Current Diabetes Reviews, 2006, Vol. 2, No. 2 201
the Insulin Resistance Atherosclerosis Study, the association
between low insulin sensitivity (as determined by the
frequently sampled intravenous glucose tolerance test) and
higher CRP levels was considerably attenuated after
adjusting for waist circumference alone [154].
In contrast to the above reports, in a study of healthy
women with a wide range of body fatness, central fat and
insulin resistance (albeit estimated by waist circumference
and homeostasis model assessment [HOMA] respectively)
were both independently associated with CRP level [155].
Similarly, percent total body fat (by dual-energy X-ray
absorptiometry) and insulin resistance (by HOMA) were
independent predictors of CRP in a study of subjects with
varying degrees of glycaemia [135], although it should be
noted that HOMA is an unreliable measure of insulin
resistance in subjects with glucose intolerance [156]. While
differences in cohort size and characteristics may explain
some of the disparity between studies, imprecision in the
methods used to measure adiposity and insulin sensitivity in
some of these studies is very likely to have contributed
[127].
Reductions in CRP Levels Following Weight Loss are
More Closely Related to Changes in Adiposity Than
Changes in Insulin Sensitivity
Although weight loss has been shown to lead to a
reduction in circulating CRP levels in obese subjects
following caloric restriction [143, 157-161] or bariatric
surgery [162-165], relatively few studies have
simultaneously measured changes in fat mass, insulin
sensitivity and CRP. A recent study raised the possibility that
Body Mass Index and macronutrient composition may
modify the CRP response to a weight-loss diet [166],
although the results are preliminary and require
confirmation.
In a study of weight loss following gastric surgery,
reductions in CRP levels paralleled the decrease in Body
Mass Index but were unrelated to changes in insulin
sensitivity [163]. Similarly, in a recent diet-induced weight
loss study, reductions in CRP were significantly related to
the amount of weight lost, but were not correlated with the
change in insulin sensitivity [167]. In a study of weight loss
induced by diet and exercise in overweight and obese
postmenopausal women, although changes in total fat,
visceral fat, CRP and interleukin-6 were inversely related to
the improvement in insulin sensitivity in univariate analysis,
only visceral fat and levels of interleukin-6 were significant
predictors of the change in insulin sensitivity in stepwise
multiple regression analysis [168]. In other words, CRP was
not an independent predictor of weight loss-induced
improvements in insulin sensitivity, independent of
adiposity.
Subjects Concordant for Body Fat but Discordant for
Insulin Sensitivity Have Similar Levels of Circulating
CRP
Using bioelectrical impedance analysis to measure body
fat, Romano et al. recently reported that obese insulin-
resistant subjects had higher CRP levels than obese insulin-
sensitive subjects [169]. However, in the same study, the
202 Current Diabetes Reviews, 2006, Vol. 2, No. 2
latter group of subjects (mean fat mass 38.1 ± 8.6 kg) had
higher CRP levels than lean individuals with similar insulin
sensitivity (mean fat mass 19.2 ± 5.3 kg), implicating
adiposity as the main determinant of CRP. Although two
studies found that obese insulin-resistant subjects had higher
CRP levels than insulin-sensitive subjects ‘matched’ for
Body Mass Index [135, 157], no conclusion can be made
from these studies regarding the relative influence of insulin
sensitivity and body fat on CRP concentrations, as no direct
or true measure of body fat was performed [118].
Furthermore, the use of the modified insulin suppression test
to measure insulin sensitivity in one of these studies [157]
limits the applicability of these results, considering that
glucose recovery following insulin injection is dependent on
a number of factors including insulin dose, the extent of the
counter-regulatory hormone response and adiposity itself.
In a recent study of obese postmenopausal women, which
used direct measures of body fat (dual-energy X-ray
absorptiometry and single-slice CT), levels of CRP,
interleukin-6 and TNF-α were similar in insulin-resistant
subjects with the Metabolic Syndrome and insulin-sensitive
subjects without the Metabolic Syndrome, a consequence,
most likely, of the fact that the groups had similar amounts
of total body and subcutaneous abdominal fat [170]. Using a
similar design, a study comparing inflammatory markers in
premenopausal women with and without polycystic ovary
syndrome (PCOS), matched for Body Mass Index, found that
the relatively insulin-resistant PCOS group had similar CRP
levels to relatively insulin-sensitive controls [171]. In the
whole group, controlling for Body Mass Index significantly
attenuated the inverse relationship between insulin
sensitivity and CRP level. In contrast, controlling for insulin
sensitivity had no effect on the relationship between Body
Mass Index and CRP levels. Consistent with this result, in
another study of women with PCOS, the relationship
between insulin resistance (estimated by HOMA) and CRP
level was attenuated after adjusting for Body Mass Index
[172]. Finally, controlling for Body Mass Index greatly
attenuated associations of PCOS and CRP with carotid
intima-media wall thickness, raising the possibility that these
associations are also mediated by increased body fatness
[173].
IS INFLAMMATION ASSOCIATED WITH INSULIN
RESISTANCE IN THE ABSENCE OF OBESITY?
Taken together, the studies described above suggest that
body fat is the primary determinant of circulating CRP levels
in the basal state and increase the likelihood that marginally
elevated levels of circulating CRP in insulin resistance are
mediated by increased body fat. However, it is still not clear
whether inflammation is a mediator of insulin resistance in
obesity, or, rather, whether levels of pro-inflammatory
cytokines and inflammatory markers, such as interleukin-6
and CRP, are increased in obese subjects as a consequence of
insulin resistance [42].
At the height of an inflammatory response, circulating
CRP levels may rise up to 10,000 fold [17]. CRP activates
the classical complement pathway by binding to C1q,
leading to the activation of the terminal membrane attack
complex, C5 – C9 [174]. Hence, during an inflammatory
Greenfield and Campbell
process, complement is usually consumed and circulating
levels are expected to be reduced. Although insulin
resistance and type 2 diabetes are often described as
inflammatory diseases, the use of the term ‘inflammation’
may be inappropriate in the context of mildly elevated CRP
levels (within the ‘normal range’) and normal complement
protein levels. The reported association between minimally
elevated CRP levels and type 2 diabetes does not necessarily
implicate inflammation in the aetiology of insulin resistance
and type 2 diabetes.
To further explore this question, we recently studied
relationships between insulin sensitivity (by euglycaemic-
hyperinsulinaemic clamp), total body and abdominal obesity
(by dual-energy X-ray absorptiometry and MRI
respectively), inflammatory mediators (CRP and
adiponectin) and circulating levels of complement proteins
(C3, C4, C1q, Factor B and Factor D) in 19 normoglycaemic
normolipidaemic non-obese first-degree relatives of type 2
diabetic subjects (REL) and 22 Body Mass Index-matched
controls with no known family history of type 2 diabetes
(CON) [9]. Despite similar body fat measures, REL were
20% less insulin sensitive than CON subjects (Table 3).
However, REL and CON had comparable, ‘normal range’
levels of CRP, adiponectin and proteins of both the classical
(C1q and C4) and alternative (C3, factors B and D)
complement pathways (Table 3) [9]. In other words, there
was no evidence of inflammation (ie. elevated CRP levels
and complement consumption) in the REL group, despite
significantly lower insulin sensitivity.
In analyses including the whole group, CRP was directly
related to measures of total body and central abdominal fat
and inversely associated with insulin sensitivity and
adiponectin levels (Table 4) [9]. CRP levels were related to
levels of acute-phase components of the alternative pathway
(Factor B and C3) but not Factor D, a non-acute phase
alternative pathway component. Of the classical complement
pathway components, CRP was significantly associated with
C1q only (Table 4). In multiple regression analysis with
glucose infusion rate as the dependent variable, CRP was not
significantly related to insulin sensitivity, independently of
total body fat. Similar results were found when total body fat
was replaced by either central abdominal fat or subcutaneous
abdominal fat [9].
In summary, our results suggest that, in the absence of
obesity, insulin resistance is not associated with the
recognised processes of inflammation and that the use of the
term may be need to be revised when referring to
associations between circulating inflammatory markers,
insulin resistance and type 2 diabetes.
POSSIBLE PATHOPHYSIOLOGICAL MECHANISMS
LINKING BODY FAT AND INSULIN RESISTANCE
TO ELEVATED CIRCULATING LEVELS OF
INFLAMMATORY MARKERS
Although the pathophysiological links between adiposity
and insulin resistance and elevated levels of systemic
inflammatory markers remain unknown, possible
mechanisms include: (1) cytokine production by adipocytes
and immune cells within adipose tissue; (2) chronic over-
stimulation of the immune response by toll-like receptors
Inflammation, Insulin Resistance and Type 2 Diabetes Current Diabetes Reviews, 2006, Vol. 2, No. 2 203

Table 3. Cohort Characteristics and Biochemical Variables in Relatives of Type 2 Diabetic Subjects (REL) and Healthy Controls
(CON)

Variable REL CON P-value

Age (y) 30.7 ± 1.6 31.3 ± 1.6 0.80

Weight (kg) 73.4 ± 4.1 73.7 ± 3.5 0.90
2
Body Mass Index (kg/m ) 25.8 ± 1.1 24.3 ± 0.8 0.29
Waist (cm) 80.0 ± 3.2 78.7 ± 2.6 0.76
Waist-to-hip ratio 0.79 ± 0.02 0.82 ± 0.02 0.38
Total body fat (kg)* 25.5 ± 2.5 20.9 ± 2.0 0.15
Fat free mass (FFM, kg)* 47.7 ± 2.6 52.9 ± 2.9 0.20
Central abdominal fat (kg)* 1.39 ± 0.15 1.21 ± 0.13 0.37
Subcutaneous abdominal fat (L)† 2.23 ± 0.29 1.69 ± 0.25 0.17
Visceral abdominal fat (L)† 0.59 ± 0.07 0.61 ± 0.11 0.88
Fasting plasma glucose (mmol/L) 5.0 ± 0.1 4.9 ± 0.1 0.35
2-hr post-challenge glucose (mmol/L)‡ 5.8 ± 0.2 5.2 ± 0.3 0.12
Fasting plasma insulin (mU/L) 10.6 ± 0.8 8.5 ± 0.9 0.08
Glucose infusion rate (µmol/min/kgFFM) 51.8 ± 3.9 64.9 ± 4.6 0.04
Fasting total cholesterol (mmol/L) 4.08 ± 0.22 4.19 ± 0.18 0.71
Fasting HDL cholesterol (mmol/L) 0.89 ± 0.07 0.90 ± 0.06 0.93
Fasting triglycerides (mmol/L) 0.81 ± 0.11 0.68 ± 0.05 0.27
Fasting non-esterified fatty acids (mmol/L) 0.46 ± 0.04 0.42 ± 0.05 0.58
C-reactive protein (mg/L) 1.55 ± 0.23 1.68 ± 0.46 0.33
Adiponectin (µg/mL) 14.6 ± 1.7 15.1 ± 1.4 0.82
C1q (mg/L) 103 ± 4 101 ± 2 0.67
C4 (mg/l) 218 ± 15 217 ± 16 0.96
C3 (g/L) 1.21 ± 0.07 1.05 ± 0.05 0.06
Factor B (mg/L) 263 ± 17 227 ± 13 0.10
Factor D (µg/mL) 1.39 ± 0.09 1.33 ± 0.06 0.58
*by dual-energy X-ray absorptiometry; †by magnetic resonance imaging in n=36 subjects (scans unavailable in one CON subject due to claustrophobia and
four REL subjects due to technical difficulties); ‡following 75 g oral glucose tolerance test. Copyright © 2004 American Diabetes Association. Reprinted from
[9] with permission from the American Diabetes Association.

(TLR); (3) an inherited acute phase ‘hyper-responsiveness’
in obese subjects; (4) loss of insulin-mediated inhibition of
cytokine-stimulated CRP production in insulin resistance;
and (5) mitochondrial dysfunction. Each of these
mechanisms will be discussed briefly below.
Cytokine Production by Adipose Tissue
Adipose tissue has been reported to produce
approximately 30% of systemic interleukin-6 in healthy
subjects [80]. Recent studies have demonstrated that
inflammatory cytokines originate not only from adipocytes,
but also from immune cells, specifically macrophages,
within adipose tissue [129]. Earlier evidence that cells other
than adipocytes may produce inflammatory cytokines in
human adipose tissue was provided by Fried et al. who
observed that only 10% of total tissue production of
interleukin-6 by adipose tissue could be attributed to
adipocytes [128]. A series of elegant and detailed studies
recently demonstrated that the number of macrophages in
adipose tissue increases with increasing obesity and that
macrophages are responsible for a significant proportion of
inflammatory cytokine production from fat tissue [175, 176].
However, the factors that attract macrophages to adipose
tissue, and the specific factors that stimulate these immune
cells to produce inflammatory cytokines in obesity, remain
to be determined [129].
Toll-Like Receptors
Emerging evidence for a possible role of TLRs,
specifically TLR-4, may be relevant to this discussion. This
group of recently discovered pattern-recognition receptors,
10 of which have been described in humans, provide a
potential crucial link between innate immunity and
atherogenesis [177]. It is possible that stimulation of
204 Current Diabetes Reviews, 2006, Vol. 2, No. 2 Greenfield and Campbell

Table 4. Simple Linear Regression Analyses between C-reactive Protein Levels and Adiposity Measures, Metabolic Variables,
Adiponectin and Complement Proteins in Relatives of Type 2 Diabetic Subjects and Healthy Controls

Variable r-value P-value

Age (y) 0.12 0.45

Weight (kg) 0.34 0.03
2
Body Mass Index (kg/m ) 0.41 0.008
Waist (cm) 0.36 0.02
Waist-to-hip ratio 0.12 0.46
Total body fat (kg)* 0.35 0.03
Fat free mass (kg)* 0.15 0.35
Central abdominal fat (kg)* 0.43 0.005
Subcutaneous abdominal fat (L)† 0.59 0.0002
Visceral abdominal fat (L)† 0.38 0.02
Fasting plasma glucose (mmol/L) 0.32 0.045
2-hr post-challenge glucose (mmol/L)‡ 0.03 0.88
Fasting plasma insulin (mU/L) 0.26 0.11
Glucose Infusion Rate (µmol/min/kgFFM) -0.33 0.04
Fasting total cholesterol (mmol/L) 0.22 0.17
Fasting HDL cholesterol (mmol/L) -0.20 0.21
Fasting triglycerides (mmol/L) 0.39 0.01
Fasting non-esterified fatty acids (mmol/L) 0.17 0.30
Adiponectin (µg/mL) -0.34 0.03
C1q (mg/L) 0.34 0.03
C4 (mg/L) 0.30 0.06
C3 (g/L) 0.41 0.009
Factor B (mg/L) 0.43 0.005
Factor D (µg/mL) 0.10 0.56

*by dual-energy X-ray absorptiometry; †by magnetic resonance imaging in n = 36 subjects (scans unavailable in one CON subject due to claustrophobia and
four REL subjects due to technical difficulties); ‡following 75 g oral glucose tolerance test. Copyright © 2004 American Diabetes Association. Reprinted from
[9] with permission from the American Diabetes Association.

macrophages in fat to produce inflammatory cytokines is the
result of TLR-4 activation. Stimulation of TLR-bearing
immune cells is known to directly regulate innate immune
genes, resulting in the secretion of pro-inflammatory
cytokines and chemokines, including interleukin-6 [178,
179].
Although the specific ligands that trigger this immune
cascade in adipose tissue remain uncertain, lipoproteins may
be important candidates. Reports that oxidized LDL
(oxLDL) and mildly oxidized (minimally modified) LDL
(mmLDL) are possible endogenous ligands for TLR-4 [177-
179], raise the possibility that this modified lipoprotein, or
related lipid moieties, may contribute to the production of
pro-inflammatory cytokines in obesity. Although absolute
LDL concentration is often ‘normal’ in obesity, relationships
between insulin resistance, a component of the Metabolic
Syndrome, and LDL cholesterol level have been reported
[32]. Furthermore, qualitative changes in LDL size and
density, associated with hypertriglyceridaemia and low HDL
concentrations in the Metabolic Syndrome, increase its
sensitivity to atherogenic oxidative modification [180].
Binding of these modified lipoproteins to TLR-4 on
macrophages may be a potential mechanism stimulating
cytokine production in obesity, particularly central obesity.
Acute Phase ‘Hyper-Responsiveness’
Polymorphisms in the TLR gene are associated with
reduced circulating levels of pro-inflammatory cytokines, a
diminished response to endotoxin-derived lipopoly-
saccharide (LPS), and greater susceptibility to acute bacterial
infection, but relative protection from atherosclerosis [178,
181]. On the other hand, it could be hypothesised that acute
phase ‘hyper-responsiveness’, due to increased sensitivity of
the TLR to exogenous ligands such as LPS, and, eventually,
to some endogenous ligands, results in excessive cytokine
and chemokine production. Indeed, it has been suggested
Inflammation, Insulin Resistance and Type 2 Diabetes Current Diabetes Reviews, 2006, Vol. 2, No. 2 205

Fig. (2). Acute phase ‘hyper-responsiveness’ hypothesis. Increased levels of a broad range of inflammatory markers in obese individuals,
typified by C-reactive protein (CRP), are a function of obesity-driven cytokine production due to genetically determined immune hyper-
responsiveness. It is important to note that the amount of body fat, as well as its distribution, are also under significant genetic control. CRP:
C-reactive protein; hsp60: heat shock protein 60; LPS: lipopolysaccharide; mmLDL: minimally modified low-density lipoprotein; TLR: toll-
like receptor.

that the normally protective process of binding of LPS to
lipoproteins, which buffers its toxicity, is ‘overcome’ by
chronic stimulation, making LDL immunogenic and toxic to
endothelial cells [86]. Whilst hyper-responsiveness to
bacterial infection, together with an enhanced ability to store
fat, may have conferred a ‘survival advantage’ over many
centuries, it could be expected to be potentially detrimental
in a modern, obese, sedentary population, particularly in
relation to endothelial function and cardiovascular risk. Very
recent evidence suggests that the immune response to LPS is
largely genetically determined, with heritability estimates of
0.53 for TNF-α, 0.57 for interleukin-6 and 0.86 for
interleukin-1β [182]. Using factor analysis, it has been
shown that obesity, albeit estimated by anthropometric
estimates, clusters with inflammatory markers [183],
suggesting that obesity and circulating levels of
inflammatory markers may be mechanistically linked and
influenced by common genetic factors. In other words,
increased levels of a broad range of inflammatory markers in
obese individuals may be a function of genetically
determined immune hyper-responsiveness, stimulated by any
of a variety of putative ligands related to increased adiposity,
itself under significant genetic control. This hypothesis is
illustrated in Fig. (2).
Impaired Anti-Inflammatory Effect of Insulin
As discussed, although the evidence presented in this
review argues that body fat may be the primary stimulus for
cytokine production in individuals with the Metabolic
Syndrome, the closely related phenotype, insulin resistance,
is likely to play an important mediating role in obesity.
Insulin has been reported to have anti-inflammatory
properties, including suppression of cytokine-mediated
acute-phase protein gene expression [184] and reduction in
intranuclear factor κB, reactive oxygen species, plasma
soluble intercellular adhesion molecule-1, monocyte
chemoattractant protein-1 and plasminogen activator
inhibitor-1 [185]. This has led to the notion that insulin may
have ‘anti-inflammatory’ properties [86, 186, 187] and hence
that insulin resistance increases levels of inflammatory
markers by attenuating this effect [165]. We therefore
suggest that increased levels of CRP are likely to be a
consequence, and not necessarily the cause, of insulin
resistance. Consistent with previous suggestions [188], these
results increase the likelihood that circulating CRP levels are
a balance between adipose tissue-derived interleukin-6-
mediated up-regulation of hepatic CRP production and the
‘anti-inflammatory’ or suppressive effect of insulin on the
liver, which is impaired in insulin-resistant subjects.
This hypothesis is illustrated in Fig. (3). In scenario (a),
in non-obese insulin-sensitive subjects, there is minimal
stimulation of hepatic CRP production by interleukin-6 due
to relatively low levels of body fat; hence circulating levels
of CRP are in the low-normal range. In scenario (b), in non-
obese insulin-resistant subjects, although insulin inhibition
of interleukin-6-mediated hepatic CRP production is
206 Current Diabetes Reviews, 2006, Vol. 2, No. 2 Greenfield and Campbell

Fig. (3). Hypothesised interaction between stimulation of hepatic C-reactive protein (CRP) production by fat-derived interleukin-6 and
insulin-mediated inhibition of this process in insulin-sensitive and insulin-resistant obese and non-obese subjects. The thickness of the arrows
relate to the quantity of interleukin-6 (IL-6) or CRP secreted from fat and the liver respectively. The width of the T-bar indicates the degree of
inhibition by insulin of hepatic CRP production. Copyright © 2004 American Diabetes Association. Reprinted from [9] with permission from
the American Diabetes Association.

impaired due to insulin resistance, CRP levels remain in the
low-normal range because of minimal stimulation of CRP
secretion by interleukin-6. In scenario (c), in obese insulin-
sensitive subjects, the tendency for CRP levels to be up-
regulated in proportion to body fatness is somewhat
attenuated by insulin, and hence circulating levels are
relatively normal. In scenario (d), the same positive stimulus
to CRP secretion exists; however, because inhibition of CRP
production by insulin is impaired, CRP levels are in the
high-normal range.
Mitochondrial Dysfunction
It has been argued that insulin resistance is more
important than insulin deficiency in mediating the acute
phase response [189]. As discussed earlier, it has been
postulated that muscle triglyceride accumulation and
impaired mitochondrial activity accompany insulin
resistance early in its development in genetically predisposed
subjects [29]. It is interesting to note that heat shock protein
60 (hsp60), a mitochondrial ‘housekeeping’ protein, is
released into the extracellular space by impaired
mitochondrial metabolism [190]. Hsp60 is an endogenous
ligand of TLR-4, which activates proinflammatory gene
targets [179] (Fig. 2). Therefore, mitochondrial dysfunction
may be a potential unifying pathomechanism linking insulin
resistance with increased levels of inflammatory markers,
causing lipid accumulation in muscle and being one of the
possible precedents of hsp60-induced TLR-4-mediated
cytokine release.
CONCLUDING REMARKS
In conclusion, there is a significant body of evidence to
suggest that the relationship between inflammatory markers
and both insulin resistance and the development of type 2
diabetes is mediated by increased adiposity. Although
inflammation has been purported to induce insulin
resistance, contrary evidence suggests that in the absence of
increased adiposity, insulin resistance per se is not
associated with systemic elevation of CRP and reduced
complement protein levels. As insulin has anti-inflammatory
properties, it is possible that levels of inflammatory markers
can be mildly increased in insulin resistance as a
consequence of impaired suppression of cytokine-stimulated
hepatic CRP production. Recent evidence that TLRs are
possible mediators of the inflammatory response and that
macrophages are responsible for a significant proportion of
cytokine production in adipose tissue have provided
biologically plausible mechanisms for these associations.
Inflammation, Insulin Resistance and Type 2 Diabetes
Given the evidence presented in this review, it is imperative
that future studies both consider and control for the
confounding effect of body fat when formulating
mechanistic hypotheses regarding inflammatory markers and
metabolic disease. Failure to properly adjust for adiposity, in
part a consequence of the use of indirect estimates of body
fat in some studies [191, 192], must limit the validity of their
findings.
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Received: 02 August, 2005 Revised: 30 September, 2005
Current Diabetes Reviews, 2006, Vol. 2, No. 2 211
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Accepted: 14 October, 2005