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Endocrinology 146(10):4189 – 4191
Copyright © 2005 by The Endocrine Society
doi: 10.1210/en.2005-0920
Is Type 2 Diabetes an Autoimmune-Inflammatory
Disorder of the Innate Immune System?
The article by C. T. De Souza et al. (1) in this issue supports
the conclusion that type II diabetes (DMII) is an autoimmune-inflammatory disease. It raises the possibility that
DMII and its complications result from pathological expression of the innate immune system in nonimmune hypothalamic cells, as well as visceral adipocytes, ␤-cells of the pancreas, and vascular endothelium.
Innate immunity is the rapid self-defense response of our
body (2– 4) to an environmental signature molecule that is
perceived as an injuring agent or something foreign, in this
case the hyperlipidemia, rather than a bacterial lipopolysaccharide, viral double-stranded RNA (dsRNA), or CpG sequences in the DNA of infectious agents. The response is
mediated by Toll-like receptors (TLR), and the result is a
cellular gene response that can cause a nonimmune, as well
as an immune, cell to produce a cascade of immunologic
proteins, e.g. cytokines, such as IL-1␤, TNF-␣, and IL-6, which
characterize our inflammatory response (2–12). In atherosclerosis, a disease that is a complication of DMII and, like
DMII, is associated with obesity and hyperlipidemia, the
pathological innate immune response is associated with
overexpression of TLR4 and its signals in vascular endothelial cells and arterial walls (5, 6). A TLR4 knockout improves
disease expression by decreasing the pathological inflammatory response (7).
TLRs in nonimmune cells are now implicated in multiple
autoimmune-inflammatory diseases including, for example,
Hashimoto’s thyroiditis (TLR3 in thyrocytes) (8), colitis
(TLR4 in intestinal epithelial cells) (9, 10), and type 1 diabetes
(TLR3 in pancreatic ␤-cells) (11, 12). In each case, the pathological expression of the TLR in the nonimmune cells is
associated with expression of an autoimmune-inflammatory
disease.
Acquisition of visceral obesity is now recognized as a
significant factor in the development of insulin resistance
and DMII. The hyperlipidemia associated with obesity is a
recognized factor in the development of visceral obesity,
insulin resistance, and DMII. The large visceral fat depots
produce excessive amounts of free fatty acids, adipokines,
and cytokines including TNF-␣ and IL-6 (reviewed in Ref.
13), which can induce insulin resistance (13–15). TNF-␣ can
induce insulin resistance by decreasing serine phosphorylation of the insulin receptor kinase via increases in the supAbbreviations: DMII, Type II diabetes; dsRNA, double-stranded
RNA; HL, hyperlipidemic; IFN, interferon; IR, insulin receptor; IRS, IR
substrate; NF-␬B, nuclear factor-␬B; SOCS, suppressor of cytokine signaling; Stat, signal transducer and activator of transcription; TLR, Tolllike receptor; TRIF/TICAM, TIR domain-containing molecule adapter
inducing IFN-␤/TIR-containing adapter molecule.
Endocrinology is published monthly by The Endocrine Society (http://
www.endo-society.org), the foremost professional society serving the
endocrine community.
pressor of cytokine signaling (SOCS) (16). Additionally,
SOCS-1 and SOCS-3 can bind directly to the insulin receptor
(IR), where SOCS-3 inhibits tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and -2 and SOCS-1 inhibits
tyrosine phosphorylation of IRS-1 only to induce insulin
resistance (17). IL-6 induces insulin resistance by inhibiting
GLUT4 synthesis as well as up-regulating SOCS-3 via activation of signal transducer and activator of transcription(Stat)3 (18, 19).
The study by C. T. De Souza et al. (1) started as an array
analysis of genes modulated by a hyperlipidemic (HL) diet
to determine which genes might be important in the coordination of food intake and energy expenditure, functions
primarily controlled by leptin and insulin. Rats were fed a
high-lipid or a normal diet. At 13 and 16 wk, the hypothalamus was collected and 1176 mRNAs were evaluated. Increases in the IR, leptin receptor, and other genes associated
with proteins important for modulating consumption and
thermogenesis were noted with the HL diet; however, the
authors were more intrigued by the clustering of increased
mRNAs of immune-related proteins.
The HL mice had increased expression of proinflammatory cytokines IL-6, TNF-␣, and IL-1␤ compared with the
control. The HL mice also had increased expression of intermediates involved in the production of proinflammatory
cytokines c-Jun N-terminal kinase and nuclear factor-␬B (NF␬B). Finally, the HL mice also had increased expression of
serine phosphorylation of IR and IRS-2 (key elements of the
insulin-signaling pathway). Interestingly, the IR protein
level in the HL mice was not significantly increased compared with the control mice.
To test the theory that proinflammatory cytokines and
their intermediates were involved with insulin resistance, the
mice were treated with an inhibitor of c-Jun N-terminal kinase (SP600125). Treatment with this compound led to a
lower body mass in the HL mice. SP600125 also reversed the
effect of feeding upon insulin-induced tyrosine phosphorylation of IR and IRS-2, as well as increased insulin-induced
inhibition of spontaneous food intake.
The paper touches on the mechanisms by which a highlipid diet leads to leptin resistance. Leptin resistance occurs
via a similar mechanism as that of insulin resistance, i.e. being
dependent on activated STAT-3 and the immune-related signaling suppressor SOCS-3. The expression of SOCS-3 was
increased in the hypothalamic cells of the HL mice. The HL
mice also showed an inhibition of leptin-induced tyrosine
phosphorylation of STAT-3. In sum, all of the changes seen
in visceral adipocytes in DMII, which are implicated in insulin resistance, leptin resistance, and the development of
DMII, are also noted in the hypothalamic neuronal cell.
This has potential, but far-reaching implications, by possibly relating DMII to autoimmune-inflammatory diseases
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Endocrinology, October 2005, 146(10):4189 – 4191
associated with overexpression of TLRs and TLR signaling.
The overexpression is seen in nonimmune cells and results
in the production of cytokines and chemokines that can be
activated through the TNF receptor-associated factor-6/
NF-␬B and interferon (IFN) regulatory factor-3/type 1 IFN
signal pathway, which together increase IL-6 and phosphorylate STAT-3. In short, pathological expression of TLR/TLR
signaling when evident in nonimmune cells can result in IL-6
and Stat-3 activation of Socs genes and cause insulin/leptin
resistance as well as produce TNF-␣ and IL-1, which are also
implicated in insulin resistance.
TLRs are a family of 10 known cell-surface receptors related to IL-1 receptors (2– 4). They protect mammals from
pathogenic organisms, such as viruses, by generating an
innate immune response to products of the pathogenic organism (2– 4). The innate immune response increases genes
for several inflammatory cytokines and costimulatory molecules; it is critical for the development of antigen-specific
adaptive immunity, both humoral and cell mediated (2– 4).
TLRs are present in most monocytes, macrophages, or immune cells; TLR3, which mediates a potent antiviral response
(2– 4), is present primarily on dendritic cells in humans, e.g.
antigen presenting cells, which process and then present
antigenic peptides to lymphoid cells in lymphoid organs
(2– 4).
The TLRs signal through adaptor molecules that bind to
the cytoplasmic portion of the TLR. TLR3 and TLR4, for
example, which recognize dsRNA or lipopolysaccharide, respectively, have either two adaptor molecules (TLR4),
MyD88 and TIR domain-containing molecule adapter inducing IFN-␤/TIR-containing adapter molecule (TRIF/TICAM)-1 (2– 4), or one (TLR3), TRIF/TICAM-1, which links to
two separate signal pathways. In the case of dsRNA binding
to TLR3, the TRIF/TICAM bypasses MyD88 and activates
TNF receptor-associated factor, which then activates NF-␬B,
MAPK, and various cytokines that direct an inflammatory
response. In a separate interaction, TRIF/TICAM-1 activates
IRF-3 and causes the synthesis and release of the type I IFNs
and chemokines such as IFN-inducible protein 10. The type
I IFN can induce a positive feedback loop, further up-regulating TLR3, or can interact with other cells, a phenomenon
closely linked to the antiviral gene defense program. The
type 1 IFN can induce a secondary, or delayed, activation of
NF-␬B signaling to reinforce its actions. In recent work, the
TLR and signal system have been recognized in nonimmune
cells by different groups (3–12, 20 –22). TLR pathological
expression on nonimmune cells is now recognized as a potential cause of humoral and cell-based autoimmune/inflammatory diseases (3–12, 20 –22) wherein the noxious environmental event or infectious agent attacks a nonimmune
rather than the immune cell. The immune cell becomes a
bystander response (20 –22).
The question is: how do proinflammatory cytokines released from nonimmune cells in innate immunity (possibly
via TLRs) tie in with the receptors for leptin and insulin? The
receptors for leptin and insulin share a common pathway.
After the receptors bind their respective ligand, Stat-3 is
activated by phosphorylation. The activated Stat-3 will then
up-regulate socs-3 gene expression. Subsequently, by means
of feedback inhibition, SOCS-3 works to block the binding of
Kohn et al. • News & Views
insulin and leptin to their receptor, causing resistance. As
previously shown, activation of TLRs (particularly TLR3 and
TLR4) leads to a cascade of interactions that initiates the
activation of NF-␬B and IRF-3. Activated NF-␬B then induces
the transcription of proinflammatory cytokines IL-6 and
TNF-␣ as well as others. The important link between the two
pathways is that IL-6 then acts to phosphorylate STAT-3,
leading to the insulin and leptin resistance.
The link between obesity and disease is not completely
clear. The paper by De Souza et al. (1) helps to strengthen the
role of proinflammatory cytokines and their intermediates as
being important in the disease process, particularly in diseases such as DMII. By pointing out the association between
a high-fat diet and the increased inflammation in the hypothalamus, many new areas of treatment and research could
be explored. This paper also raises questions for further
study, such as: what is the link between a high-lipid diet and
a proinflammatory status in the hypothalamus? and if nonimmune cells such as the hypothalamus and adipose tissue
can become proinflammatory, what other cells in the body
act in the same way? A very glaring aspect of the paper is to
emphasize that nonimmune cells can cause the release of
proinflammatory cytokines that can lead to insulin and leptin
resistance. This begs further research in this exciting but
fledgling area and could open the door to exciting ideas in
research and treatment.
Leonard D. Kohn, Brian Wallace, Frank Schwartz, and
Kelly McCall
Edison Biotechnology Institute
and Ohio University College of Osteopathic Medicine
Ohio University
Athens, Ohio 45701
Acknowledgments
Received July 21, 2005. Accepted July 22, 2005.
Address all correspondence and requests for reprints to: Leonard D.
Kohn, Edison Biotechnology Institute, Building 25, The Ridges, Ohio
University, Athens, Ohio 45701. E-mail: [email protected].
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Endocrinology is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the
endocrine community.