Major advances have been made in understanding the
mechanisms that are involved in the pathogenesis of
type 2 diabetes (T2D)1–5. A decrease in insulin-stimulated
glucose uptake (insulin resistance) is associated with
obesity, ageing and inactivity. The pancreatic islets
respond to insulin resistance by enhancing their cell
mass and insulin secretory activity. However, when the
functional expansion of islet β-cells fails to compensate
for the degree of insulin resistance, insulin deficiency
and ultimately T2D develop. The onset of T2D leads in
turn to the development of its long-term consequences:
macrovascular complications (including athero sclerosis
and amputations) and microvascular complications
(including retinopathy, nephropathy and neuro pathy).
Insulin resistance is typically present throughout the
progression from prediabetes to the later stages of
overt T2D. By contrast, the onset of T2D and its pro-
gression are largely determined by the progressive
failure of β-cells to produce sufficient levels of insu-
lin. Interestingly, many insulin-resistant individuals
do not become diabetic, because their β-cells are able
to compensate for the increased demand for insulin.
Only about one-third of obese, insulin-resistant indi-
viduals actually develop chronic hyperglycaemia and
T2D. The reasons for this heterogeneity are incompletely
understood, although genetics and epigenetics probably
The leading hypothesized mechanisms to explain
insulin resistance and islet β-cell dysfunction in T2D
have been oxidative stress, endoplasmic reticulum stress
(ER stress), amyloid deposition in the pancreas, ectopic
lipid deposition in the muscle, liver and pancreas, and
lipotoxicity and glucotoxicity (BOX 1). All of these stresses
can be caused by overnutrition6–10, although it has been
difficult to determine which mechanism is the most
important in each tissue and in each model or indi-
vidual with T2D. It is noteworthy, however, that each
of these cellular stresses is also thought to either induce
an inflammatory response or to be exacerbated by or
associated with inflammation11–15.
This Review examines recent evidence that implicates
the pathological involvement of the immune system in
T2D, dissects potential underlying mechanisms and
concludes that obesity is associated with inflammation
and that the pathogenesis of T2D can be viewed as an
auto inflammatory disease. We also review the recent results
from clinical trials using anti-inflammatory drugs to
lower blood glucose levels in patients with T2D.
Evidence for T2D as an inflammatory disease
Circulating inflammatory factors in obesity and T2D.
Cross-sectional and prospective studies have described
elevated circulating levels of acute-phase proteins (such
as C-reactive protein (CRP), haptoglobin, fibrinogen,
plasminogen activator inhibitor and serum amyloid A)
and sialic acid, as well as cytokines and chemokines,
in patients with T2D16–19. Furthermore, elevated levels
of interleukin-1β (IL-1β), IL-6 and CRP are predictive
of T2D17,20. Similarly, the serum concentration of IL-1
receptor antagonist (IL-1RA) is elevated in obesity and
prediabetes21, with an accelerated increase in IL-1RA
levels before the onset of T2D19,22,23. The expression
*Clinic of Endocrinology,
Diabetes and Metabolism,
University Hospital Basel,
CH‑4031 Basel, Switzerland.
‡Joslin Diabetes Center,
Harvard Medical School,
One Joslin Place, Boston,
Massachusetts 02215, USA.
14 January 2011
A pathological condition in
which insulin becomes less
effective at lowering blood
(ER stress). A response by the
ER that results in the disruption
of protein folding and the
accumulation of unfolded
proteins in the ER.
The toxic effects of elevated
levels of free fatty acids. These
detrimental effects may be
functional and reversible,
or may lead to cell death.
Type 2 diabetes as an inflammatory
Marc Y. Donath* and Steven E. Shoelson‡
Abstract | Components of the immune system are altered in obesity and type 2 diabetes
(T2D), with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets,
the vasculature and circulating leukocytes. These immunological changes include altered
levels of specific cytokines and chemokines, changes in the number and activation state of
various leukocyte populations and increased apoptosis and tissue fibrosis. Together, these
changes suggest that inflammation participates in the pathogenesis of T2D. Preliminary
results from clinical trials with salicylates and interleukin‑1 antagonists support this notion
and have opened the door for immunomodulatory strategies for the treatment of T2D
that simultaneously lower blood glucose levels and potentially reduce the severity and
prevalence of the associated complications of this disease.
98 | FEBRuARy 2011 | VOLuME 11
© 2011 Macmillan Publishers Limited. All rights reserved
The toxic effects of
detrimental effects may be
functional and reversible, or
may lead to cell death.
A disease resulting from an
attack by the innate immune
system on the body’s own
tissues. By contrast,
autoimmune diseases are
caused by the pathological
activation of adaptive immune
responses. Autoimmune and
have some characteristics in
common, including shared
A macrophage that is activated
by Toll-like receptor ligands
(such as lipopolysaccharide)
and interferon-γ, and that
expresses inducible nitric oxide
synthase, which generates
of IL-1RA is induced by IL-1β and reflects the body’s
response to counterbalance increased IL-1β activity.
Of particular interest is the increased CRP level, which
is currently the best epidemiological biomarker for
T2D-associated cardiovascular disease16–19. Most pro-
inflammatory factors that are present at high levels in
the blood of patients with T2D are IL-1 dependent, and
blocking IL-1 activity has been shown to reduce their
concentrations24–27 (see below).
Elevated levels of circulating IL-1β, IL-6 and acute-
phase proteins in T2D may reflect the activation of
innate immune cells by increased nutrient concentra-
tions, but the levels of these inflammatory markers
may not necessarily reflect the degree of inflammation
in individual tissues. For example, the total volume of
the pancreatic islets is small compared with the blood
volume. Thus, even a high level of islet inflammation is
unlikely to demonstrably contribute to the circulating
levels of these inflammatory factors. By contrast, the
mass of adipose tissue in obese individuals is large, and
can make up over half of the body weight in morbid
obesity. The liver is also a relatively large organ and
is the site for IL-6-induced production of CRP. Thus,
the adipose tissue and the liver may disproportionately
contribute to the circulating levels of inflammatory
markers. Consistent with this, the circulating levels
of inflammatory factors in obese individuals with
prediabetes are similar to the levels in those with overt
diabetes. Furthermore, the levels of circulating CRP or
IL-6 do not predict the efficacy of anti-inflammatory
treatments directed towards insulin secretion or insu-
lin resistance25,28. In summary, degrees of inflammation
vary within individuals and between tissues, and circu-
lating levels of inflammatory factors may not reflect the
severity of inflammation within a specific tissue.
Evidence for inflammation in insulin-sensitive tissues
and islets. The production of tumour necrosis factor
(TNF) by cells in the adipose tissue of obese rodents
provided early evidence of tissue inflammation in the
pathogenesis of insulin resistance and T2D29 (FIG. 1).
Some animal studies30 and several clinical trials using
TNF blockade have failed to demonstrate beneficial
effects on glucose metabolism31–36 (see below). However,
a few small studies conducted with obese individuals or
patients being treated for alternative conditions suggest
that TNF blockers may alter insulin sensitivity or gly-
caemic parameters, indicating that further prospective
studies may be warranted37–40.
Despite the ongoing controversy over whether TNF
blockade improves glycaemic parameters in patients
with T2D, the identification of adipose tissue-derived
TNF has been highly instructive. The source of TNF
in adipose tissue was originally thought to be the adi-
pocytes themselves in response to obesity. However,
this notion has been revised by the discovery of macro-
phages in adipose tissue, and the finding that obes-
ity results in increased numbers of macrophages and
changes in the activation status of these cells. We now
appreciate that adipose tissue macrophages produce
a significant proportion of the inflammatory factors
that are upregulated by obesity41,42. The increase in
the number of macrophages in adipose tissue largely
correlates with the degree of obesity.
Initial studies are beginning to characterize the
macrophage subtypes in the adipose tissue under dif-
ferent conditions, including in lean or obese animals
and individuals43,44, following rapid weight loss45, and
in lipodystrophy (a condition of adipose tissue loss that
is paradoxically associated with insulin resistance and
T2D)46. Similar to resident macrophages in other tissues,
adipose tissue macrophages adapt to their environment;
for example, their genomic and proteomic expression
profiles are highly distinct from those of resident mac-
rophages in other tissues (H. Shapiro, J. Lee and S.E.S.,
unpublished observations). Furthermore, the genomic
profile of adipose tissue macrophages from lean mice
differed from the profile of macrophages that had been
recently recruited to adipose tissue during the induction of
diet-induced obesity. The recently recruited macrophages
have a classically activated, pro-inflammatory phenotype
(M1-type macrophages; expressing TNF and inducible
nitric oxide synthase) compared with the alternatively
activated phenotype (M2-type macrophages; expressing
yM1 (also known as CHI3L3), arginase 1 and IL-10)
of the resident adipose tissue macrophages from lean
mice43. The authors proposed that during the progression
to obesity, adipose tissue is associated with a phenotypic
switch in macrophages from a M2 to a M1 phenotype
and that these M1-type macrophages contribute to the
Box 1 | Potential pathogenic mechanisms in type 2 diabetes
Several mechanisms have been described to explain impaired insulin secretion and
function in type 2 diabetes (T2D). Interestingly, each of these mechanisms, except for
amyloid deposition, is thought to have a role in both insulin resistance and islet β‑cell
failure. Although listed separately, these mechanisms are strongly linked and
contribute to tissue inflammation.
Glucotoxicity. Hyperglycaemia per se impairs insulin secretion116,117 and induces β‑cell
death81. Of note, small changes in glucose concentrations, which are apparent years
before overt T2D, are toxic for β‑cells7. In vivo studies performed in patients with type 1
diabetes118 and in rat models of the disease119 have demonstrated that chronic
hyperglycaemia also promotes insulin resistance.
Lipotoxicity. Similar to glucose, long‑chain free fatty acid levels in the plasma are often
increased in states of insulin resistance, impairing β‑cell secretory function120,121 and
inducing β‑cell apoptosis122,123 and insulin resistance124. Interestingly, saturated fatty
acids seem to be particularly toxic, whereas mono‑unsaturated fatty acids are
protective, and the combination of elevated glucose and free fatty acids has a
potentiating effect on T2D (glucolipotoxicity)125. Lipotoxicity may act through the
circulation or locally by ectopic tissue lipid deposition126.
Oxidative stress. Several cell stressors (including glucose in particular) lead to the
generation of reactive oxygen species127. β‑cells have very low levels of antioxidative
enzymes and are therefore particularly vulnerable to oxidative stress. Oxidative stress is
also central to the development of insulin resistance128,129.
Endoplasmic reticulum stress. In response to insulin resistance, β‑cells dramatically
increase insulin production. The flux of proteins through the endoplasmic reticulum
(ER) of β‑cells is quite high under physiological conditions and any further increase is
expected to tilt the balance towards ER stress10,130,131. ER stress is also thought to have a
role in insulin resistance132.
Amyloid deposition. Islet amyloid deposits are found in the islets of most patients with
T2D. However, it remains unclear whether aggregation of human islet amyloid
polypeptide is a cause or consequence of β‑cell failure133.
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The authors wish to thank their scientific collaborators who
have contributed so much to these studies, in particular
A. Goldfine, J. Lee, D. Mathis, K. Maedler, P. Halban,
T. Mandrup‑Poulsen, J. Ehses and M. Boni‑Schnetzler.
Competing interests statement
The authors declare competing financial interests: see web
version for details.
All lInks ARe AcTIve In The onlIne PDf
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