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Figure 1
Metabolism and immunity are closely linked. Both
overnutrition and undernutrition have implications for
immune function. Starvation and malnutrition can suppress
immune function and increase susceptibility to infections. Obesity
is associated with a state of aberrant immune activity and
increasing risk for associated inflammatory diseases, including
atherosclerosis, diabetes, airway inflammation, and fatty liver
disease. Thus, optimal nutritional and metabolic homeostasis is an
important part of appropriate immune function and good health.
Table 1
Factors that mediate the intersection of metabolism
and immunity
Figure 2
Lipids and inflammatory mediators: integration of
metabolic and immune responses in adipocytes and macrophages
through shared mechanisms. Under normal conditions, adipocytes
store lipids and regulate metabolic homeostasis, and macrophages
function in the inflammatory response, although each cell type has
the capacity to perform both functions. In obesity, adipose tissue
becomes inflamed, both via infiltration of adipose tissue by
macrophages and as a result of adipocytes themselves becoming
producers of inflammatory cytokines. Inflammation of adipose
tissue is a crucial step in the development of peripheral insulin
resistance. In addition, in proatherosclerotic conditions such as
obesity and dyslipidemia, macrophages accumulate lipid to
become foam cells. Adipocytes and macrophages share common
features such as expression of cytokines, FABPs, nuclear hormone
receptors, and many other factors. As evidenced by genetic loss-
of-function models, adipocyte/macrophage FABPs modulate both
lipid accumulation in adipocytes and cholesterol accumulation in
macrophages, as well as the development of insulin resistance and
atherosclerosis. PPAR and LXR pathways oppose inflammation
and promote cholesterol efflux from macrophages and lipid storage
in adipocytes.
PKC and IKK. Two other inflammatory kinases that play a large role
in counteracting insulin action, particularly in response to lipid
metabolites, are IKK and PKC-. Lipid infusion has been
demonstrated to lead to a rise in levels of intracellular fatty acid
metabolites, such as diacylglycerol (DAG) and fatty acyl CoAs. This
rise is correlated with activation of PKC- and increased Ser307
phosphorylation of IRS-1 (54). PKC- may impair insulin action by
activation of another serine/threonine kinase, IKK, or JNK (55).
Other PKC isoforms have also been reported to be activated by lipids
and may also participate in inhibition of insulin signaling (56).
Figure 3
Nutrient and pathogen sensing or response systems
have important overlapping features, and their modulation by
obesity or infection can lead to overlapping physiological
outcomes. For example, the chronic inflammation of obesity leads
to elevated plasma lipid levels and the development of insulin
resistance, eventually resulting in fatty liver disease,
atherosclerosis, and diabetes. Infection typically leads to a more
transient and robust inflammatory response and short-term
hyperlipidemia that aids in the resolution of the infection. In some
circumstances of chronic infection, however, insulin resistance,
diabetes, and atherosclerosis can result.
Why inflammation?
Conclusions
Figure 4
Model of overlapping metabolic and inflammatory
signaling and sensing pathways in adipocytes or macrophages.
Inflammatory pathways can be initiated by extracellular mediators
such as cytokines and lipids or by intracellular stresses such as ER
stress or excess ROS production by mitochondria. Signals from all
of these mediators converge on inflammatory signaling pathways,
including the kinases JNK and IKK. These pathways lead to the
production of additional inflammatory mediators through
transcriptional regulation as well as to the direct inhibition of
insulin signaling. Other pathways such as those mediated through
the SOCS proteins and iNOS are also involved in inflammation-
mediated inhibition of insulin action. Opposing the inflammatory
pathways are transcription factors from the PPAR and LXR families,
which promote nutrient transport and metabolism and antagonize
inflammatory activity. More proximal regulation is provided by
FABPs, which likely sequester ligands of these transcription factors,
thus promoting a more inflammatory environment. The absence of
FABPs is antiinflammatory. The cell must strike a balance between
metabolism and inflammation. In conditions of overnutrition, this
becomes a particular challenge, as the very processes required for
response to nutrients and nutrient utilization, such as
mitochondrial oxidative metabolism and increasing protein
synthesis in the ER, can induce the inflammatory response. IR,
insulin receptor.
Review
iabetologia
June 2005, Volume 48, Issue 6, pp 10381050
Authors
Authors and affiliations
H. KolbEmail author
T. Mandrup-Poulsen
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1. 1.
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4. 4.
Review
First Online:
30 April 2005
DOI: 10.1007/s00125-005-1764-9
180Citations
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Abstract
Subclinical, low-grade systemic inflammation has been observed in patients with type 2
diabetes and in those at increased risk of the disease. This may be more than an
epiphenomenon. Alleles of genes encoding immune/inflammatory mediators are associated
with the disease, and the two major environmental factors the contribute to the risk of type 2
diabetesdiet and physical activityhave a direct impact on levels of systemic immune
mediators. In animal models, targeting of immune genes enhanced or suppressed the
development of obesity or diabetes. Obesity is associated with the infiltration and
proinflammatory activity of macrophages in adipose tissue, and immune mediators may be
important regulators of insulin resistance, mitochondrial function, ectopic lipid storage and
beta cell dysfunction or death. Intervention studies targeting these pathways would help to
determine the contribution of an activated innate immune system to the development of type
2 diabetes.
Keywords
CRP
C-reactive protein
FasL
Fas ligand
FLIP
ICAM
MCP-1
NF-B
nuclear factor-B
PAI-1
RANTES
regulated upon activation normal T cell expressed and secreted
SOCS
Introduction
Type 2 diabetes is caused by the failure of beta cells to compensate for insulin
resistance. Inflammatory or immunological factors are implicated in both
insulin resistance and beta cell failure, and this review will consider evidence
suggesting that these might be linked by a common mechanism.
Table 1
Acute-phase proteins
-1 Acid glycoprotein Haptoglobin
CRP Fibrinogen
Systemic cytokines/chemokines
IL-10 MIF
IL-1+IL-6 MCP-1
IL-18 RANTES
TAFI PAI-1
Fig. 1
Elevated systemic levels of CRP (a) and IL-6 (b) in type 2 diabetes.
Comparison of patients with type 2 diabetes (n=152) with non-diabetic
control subjects matched for age and sex (n=77) from a population-based
sample. Modified after Mller et al. [218] Boxand whisker plots show the
10th, 25th, 50th (median), 75th and 90th percentiles
Leucocyte count
Orosomucoid
Fibrinogen
Sialic acid
Serum albumin
IL-6
Study Age at Number Follow- Incident Immunological
entry of up for diabetes risk factor
(years) subjects diabetes (n)
Japanese male office 3559 2,953 6 years 154 (263 Leucocyte count
worker study [15] IFG)
(IRAS) [16]
[21] IL-6
CRP
Table 3
Animal models that prove the link between inflammatory/immune genes and
type 2 diabetes
Inflammatory/immune defects that cause insulin resistance or type 2 diabetes in mice on a high-
caloric diet
Environmental factors seem to act via two major targets. One is the
processing of glucose, fatty acids and other metabolites, as regulated by
insulin and other hormones in the majority of tissues, and the other is beta
cell function. The resulting insulin resistance and impaired insulin secretion
precede the onset of hyperglycaemia by many years, if not decades [45, 46].
The hypothesis of an immune origin of type 2 diabetes is based on the
concept that immune inflammatory mediators are responsible for the effects
of these environmental factors on insulin resistance and beta cell function.
As depicted in Fig. 2, the metabolic concept of the pathogenesis of diabetes
considers that tissue function is directly affected by the toxic effect of excess
glucose, NEFA and triglycerides, probably mediated by increased oxidative
stress. The immunological concept assumes that the production of
proinflammatory immune mediators is an essential step in glucotoxicity and
lipotoxicity. Conversely, anti-inflammatory immune mediators such as IL-10
would be expected to counteract glucotoxicity and lipotoxicity.
Fig. 2
In animal models, both insulin resistance and diabetes can result from
diverse genetic defects affecting the function of individual organs, including
liver, fat, muscle, islet and neuronal tissue [4767]. However, as described
above, insulin resistance may also result from defects in various
inflammatory/immune genes (Table 3). What mediates the effects of
environmental factors on insulin resistance? There are indications that
dietary effects may be immune mediated and that monocytes, endothelial
cells and other cell types respond to elevated concentrations of glucose or
NEFA by releasing inflammatory mediators, such as PAI-1, IL-6, TNF-,
soluble ICAM-1, prostaglandins, MCP-1 and IL-1 [6875].
Fig. 3
A model for inflammatory beta cell dysfunction and apoptosis in (pre) type 2
diabetes. Metabolic stressors can cause beta cell dysfunction via increased
cytokine action or reduced cytokine antagonist action, and increased free
radical production. A reduced expression of the Fas/FasL signalling inhibitor
FLIP may accelerate this phenomenon. Toxic actions may be enhanced by
products of metabolically stressed endothelial cells and by increased systemic
levels of beta cell toxic immune mediators. IL-1 Ra IL-1 receptor
antagonist; ROS reactive oxygen species; EC endothelial cells
Immune or inflammatory?
Intervention studies
The classical treatment modalities for type 2 diabetes are diet and exercise
for weight reduction, and pharmacological intervention by oral
hypoglycaemic drugs or insulin, all of which affect the inflammatory state.
Weight reduction and/or physical exercise markedly reduce circulating levels
of inflammatory mediators such as CRP and IL-6 (Table 4), a response that
probably indicates the remission of macrophage-mediated inflammation in
adipose tissue as a consequence of altered fat cell metabolism. It could be
argued that the remission of systemic low-grade inflammation by lifestyle
changes is an epiphenomenon, but, once again, genetic studies imply a causal
relationship. For example, it was reported by the Finnish Diabetes
Prevention Study that the protective effect of lifestyle changes was associated
with polymorphisms in the promoters of the genes encoding TNF- and IL-6
[160].
Table 4
Inflammatory mediators whose concentrations are reduced by weight loss and/or physical
exercise [190207]
CRP, TNF-, soluble TNF- receptor 2, IL-6, IL-18, MCP-1, PAI-1, t-PA, soluble ICAM-1,
soluble VCAM-1, P-selectin
Sulphonylurea: TNF-
Metformin: CRP