N E W S A N D V I E W S

Inflammation as a Sensor of Metabolic Stress in

Obesity and Type 2 Diabetes

Marc Y. Donath
Division of Endocrinology, Diabetes, and Metabolism and Department of Biomedicine, University
Hospital Basel, CH-4031 Basel, Switzerland

t is broadly accepted that the main cause of type 2 dia- ating activation of innate immunity. It is a complex of
I betes is overfeeding. Unclear is how this metabolic stress
is translated into signals leading to defective insulin secre-
several proteins that may activate caspase 1, which cleaves
pro-IL-1␤ to IL-1␤. Activation of IL-1␤ will then induce
tion and action. Increasing evidence points to a role of the itself and a variety of cytokines and chemokines via nu-
innate immune system in sensing changes in nutrient lev- clear factor-␬B. Interestingly, the inflammasome can be
els. This results in an inflammatory process that has been activated by a variety of metabolic disturbance includ-
proposed to contribute to the pathogenesis of type 2 dia- ing uric acid during gout arthritis (9) and cholesterol in
betes (1). At the origin of this process, activation of the atherogenesis (10). In the context of diabetes, it has
IL-1 pathway seems to play a central role. Processing of been shown that glucose and human islet amyloid poly-
pro-IL-1␤ to IL-1␤ is controlled by the inflammasome (see peptide activates the inflammasome in pancreatic islets
below) as a response to sensing danger signals. In this issue (5, 6, 11) and lipopolysaccharide, free fatty acids, and
of Endocrinology, Youm and colleagues (2) demonstrates ceramides in adipose tissues (12–14). All of this assigns
that the inflammasome mediates islet inflammation in- to the inflammasome a role as a sensor of metabolic
duced by high-fat feeding. stress.
Activation of the innate immune system is the first re- The above mentioned studies have convincingly shown
sponse to tissue injury or aggression. It is characterized by the functional role of the inflammasome in insulin resis-
release of cytokines and chemokines and immune cell tance (12–14). With respect to islet inflammation, animal
invasion and is accompanied by functional or structural and clinical studies have shown that reducing IL-1␤ ac-
damage followed by tissue repair or fibrosis. This inflam- tivity improves insulin secretion (7, 8, 15, 16). However,
matory process was originally thought to be caused by it remained to be demonstrated that this involves the in-
microbes or physical damages. However, in some cases, flammasome. In the study by Youm and colleagues (2), it
the innate immune system may attack the body’s own tis- is shown that lack of the NLRP3 inflammasome protects
sues in the absence of an exogenous aggressor, resulting in from the development of islet fibrosis in mice on a high-fat
a sterile inflammatory process, i.e. an autoinflammatory diet. Because fibrosis is an end stage of a chronic inflam-
disease. In the pancreatic islet, metabolic stress may also matory process, it may be assumed that the level of insulitis
elicit such a response. Indeed, glucose, free fatty acids, was decreased, although data on immune cell infiltration
and human islet amyloid polypeptide may induce IL-1␤, are missing in this study. Another weakness of the study is
launching a proinflammatory response impairing insulin the lack of functional insulin secretion tests. However,
production and secretion (3– 6). Accordingly, blocking islet mass and insulin release were improved in the NLRP3
IL-1␤ improves insulin release and glycemia in prediabetic knockout mice on a high-fat diet compared with wild-
and diabetic patients (7, 8). type controls. Therefore, it can be concluded that in-
The question arises of how metabolic stress is sensed by flammasome is most probably a critical mediator of islet
the IL-1 system. The inflammasome is a key factor medi- inflammation in obesity.

ISSN Print 0013-7227 ISSN Online 1945-7170

Printed in U.S.A.
Copyright © 2011 by The Endocrine Society
doi: 10.1210/en.2011-1691 Received August 27, 2011. Accepted August 30, 2011.

For article see page 4039

Endocrinology, November 2011, 152(11):4005– 4006 endo.endojournals.org 4005

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 January 2015. at 23:03 For personal use only. No other uses without permission. . All rights reserved.
4006 Donath News & Views
Thus, unraveling the molecular mechanisms underly-
ing induction of an inflammatory response during obesity
and diabetes assigns to the innate immune system a new
role in detecting metabolic dangers. The inflammasome
appears as the sentinel sensing metabolic stress and alarming
the immune defense in pancreatic islets, insulin-sensitive
tissues, and blood vessels. It is likely that this inflamma-
tory process has protective effects, but eventually, chronic
inflammation will become deleterious. Future studies
should aim at understanding in more detail this process to
develop treatment modalities allowing a targeted use of
antiinflammatory drugs such as IL-1␤ blockers and sal-
salate (7, 17).
Acknowledgments
Address all correspondence and requests for reprints to: Marc
Y. Donath, M.D., University Hospital, Endocrinology, Dia-
betes, and Metabolism, CH-4031 Basel, Switzerland. E-mail:
mdonath@uhbs.ch.
Disclosure Summary: The author has nothing to disclose.
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