MAP4K4 and IL-6 + Th17 cells play important roles in non-obese type 2 diabetes
Chuang and Tan Journal of Biomedical Science
+ MAP4K4 and IL-6 Th17 cells play important roles in non-obese type 2 diabetes
Huai-Chia Chuang 1
Tse-Hua Tan 0 1
0 Department of Pathology & Immunology, Baylor College of Medicine , Houston, Texas 77030 , USA
1 Immunology Research Center, National Health Research Institutes , 35 Keyan Road, Zhunan 35053 , Taiwan
Obesity is a causal factor of type 2 diabetes (T2D); however, people without obesity (including lean, normal weight, or overweight) may still develop T2D. Non-obese T2D is prevalent in Asia and also frequently occurs in Europe. Recently, multiple evidences oppose the notion that either obesity or central obesity (visceral fat accumulation) promotes nonobese T2D. Several factors such as inflammation and environmental factors contribute to non-obese T2D. According to the data derived from gene knockout mice and T2D clinical samples in Asia and Europe, the pathogenesis of non-obese T2D has been unveiled recently. MAP4K4 downregulation in T cells results in enhancement of the IL-6+ Th17 cell population, leading to insulin resistance and T2D in both human and mice. Moreover, MAP4K4 single nucleotide polymorphisms and epigenetic changes are associated with T2D patients. Interactions between MAP4K4 gene variants and environmental factors may contribute to MAP4K4 attenuation in T cells, leading to non-obese T2D. Future investigations of the pathogenesis of non-obese T2D shall lead to development of precision medicine for non-obese T2D.
Type 2 diabetes; Non-obese type 2 diabetes; Normal-weight type 2 diabetes; Lean type 2 diabetes; MAP4K4; Th17 cells; Visceral fat accumulation
Diabetes directly causes an estimated 1.5 million deaths
in 2012, according to the World Health Organization
(WHO); 90% of diabetes patients have type 2 diabetes
(T2D). Finding ways to combat T2D has been one of the
most important medical challenges for several decades.
T2D is characterized by high blood glucose levels and
insulin resistance, which are caused by impaired insulin
signaling in insulin-targeted tissues including the liver,
muscle, and adipose tissues. Obesity is considered to be
a key cause of T2D. However, 15% of T2D patients in
North America are classified as non-obese (body mass
index, BMI < 30) by WHO criteria, and 50% of those in
Europe and Britain are also non-obese . Even when
the obesity criteria for Asia is adjusted from BMI ≥ 30 to
BMI ≥ 27.5, more than 60% of T2D patients in Asia are
still classified as having non-obese T2D . While BMI >
30 is considered to be morbid obesity, the population of
non-obese T2D in Asia might be underestimated. In
addition, the Obesity in Asia Collaboration also reported
a lower association between increasing BMI and T2D in
Asians compared with that in Caucasians . Thus,
other factors instead of obesity may contribute to the
development of non-obese T2D. Central obesity (visceral
fat accumulation) was thought to be the main cause of
both non-obese and obese T2D ; however, several
recent reports using clinical data or animal models
indicate that central obesity is not associated with
nonobese T2D. Recently, a door has been opened to
understanding of non-obese T2D and will be described below.
Lack of understanding of non-obese T2D
The population of non-obese or lean T2D may be
underestimated around the world. Non-obese T2D
patients show a significantly higher score of “not
accepting diabetes” than obese patients; many slim people do
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not suspect they might have T2D . Notably,
nonobese T2D patients have both an increased risk of heart
disease and a more rapid progression to insulin
treatment compared to obese T2D patients [1, 5, 6].
Furthermore, “non-obese teens are falling prey to T2D,” Asian
Age reported in 2015. We should not ignore that
numerous non-obese or slim people suffer from T2D.
To date, most attention and resources have been
directed toward studying obesity-induced T2D. However,
the pathogenesis of non-obese T2D cannot be readily
revealed using samples from human subjects from North
America due to the small sample sizes of non-obese
T2D patients. It also cannot be demonstrated by the
“gold standard” high-fat-diet (HFD)-fed animal model,
which is not suitable for studying non-obese T2D. In
some cases, studies from Western countries reported
potential risk factors (such as single nucleotide
polymorphisms (SNPs) of insulin receptor substrate 1 (IRS-1))
for T2D ; however, the association between these risk
factors and T2D could not be reproduced using mostly
non-obese T2D patients from Asian countries such as
Turkey , Japan, India, and Taiwan . Thus, it
becomes clear that disease mechanism of non-obese T2D
is different from that of obese T2D [9, 10]. Furthermore,
the cause-effect relationships of the risk factors in
nonobese T2D cannot be demonstrated due to the lack of
relevant non-obese T2D animal models. These
limitations lead to slow progress in our understanding of the
pathogenesis of non-obese T2D.
The controversy of visceral fat accumulation in non-obese
Central obesity as determined by increased visceral fat
accumulation was thought to be a risk of T2D in both
Europeans and Asians . The data derived from 290
second-generation Japanese Americans with a mean age of
61.8 indicate that intra-abdominal fat is only slightly
correlated with the T2D incidence (odds ratio = 1.5), while
the fasting glucose, impaired glucose tolerance (IGT) at
baseline, female sex, or family history of diabetes is
correlated with T2D incidence (odds ratio = 2.3, 3.8, 3.1,
and 1.9, respectively) under the same multivariate model
. In India, both central abdominal fat and visceral fat
accumulation are very slightly correlated with T2D (odds
ratio = 1.001 and 1.011, respectively) .
Over the past decade, it is controversial whether
visceral fat accumulation is the sole explanation for the
high prevalence of non-obese T2D in Asia and Europe
[11, 14]. In earlier studies described above [12, 13], obese
or non-obese individuals from Japan or India were not
subgrouped for analyses; therefore, the very slight
correlation (odds ratio = 1.001, 1.011, or 1.5) between visceral
adiposity and T2D may be due to that the enrolled
individuals also include some obese T2D patients.
Importantly, a clinical study of a consortium of 18,565
European normal-weight/overweight/obese individuals
from eight European countries demonstrates that the
association between insulin resistance and T2D incident
is independent of central obesity (waist circumferences)
and obesity (BMI) . Surprisingly, insulin resistance of
normal-weight T2D subjects is not positively (but
inversely) correlated with central obesity (gynoid fat mass,
measured by dual-energy X-ray absorptiometry (DAX)),
as well as BMI . Consistently, another group also
reported that the BMI, waist circumferences, and fat mass
of non-obese T2D patients from Europe are not
significantly increased compared to control individuals .
Thus, visceral fat accumulation is not associated with
nonobese T2D. In addition, insulin resistance of all the 18,565
enrolled individuals in the above study is correlated with
increased alanine transaminase or γ-glutamyltransferase
levels, suggesting that insulin resistance is associated with
fatty liver (hepatic steatosis) . Moreover, another group
analyzed fat deposition of the lean T2D (BMI = 23) or
obese T2D (BMI = 33) patients from United Kingdom by
magnetic resonance imaging (MRI). They found that
even lean T2D patients have an increased hepatic
steatosis . Collectively, measurement of hepatic
steatosis, instead of BMI, waist circumferences, or body
fat mass, may be a predictor for non-obese or lean
T2D. This concept can be further confirmed in the future
using non-obese (excluding obese) Asian T2D patients. In
addition, the increase of visceral fat accumulation in some
non-obese T2D patients may be a consequence of either
high insulin levels during insulin resistance  or
increased inflammatory responses .
MAP4K4 gene polymorphisms and non-obese T2D
Recently, several groups identified MAP4K4 (also named
HGK; not to be confused with human glucokinase and
human glandular kallikrein, which are named hGK) as a
risk factor for lean T2D. MAP4K4 is a member of the
MAP4K family kinases [20, 21]; MAP4K1  and
MAP4K3  have been reported as important
regulators of T-cell activation [24, 25]. MAP4K4 is required
for cancer cell migration and is associated with cancer
metastasis [26–29]. MAP4K4 also plays an important
role in motility of endothelia cells .
The risk factor for T2D in Europe was studied using
peripheral blood DNA from the Tübingen Family (TÜF)
cohort (n = 1,769) and the EPIC-Potsdam-derived
prospective case-cohort (n = 2,971) . They found that a
SNP on the MAP4K4 locus (rs11674694) is associated
with increased oral glucose tolerance test (OGTT) glucose
levels, decreased insulin sensitivity, and enhanced risks of
T2D . In a leaner subgroup, this MAP4K4 SNP
(rs11674694) and two other MAP4K4 SNPs (rs13003883
and rs2236936) are also associated with increased plasma
levels of IL-6 but not of TNF-α . Moreover, the
MAP4K4 SNPs (rs2236936 and rs2236935) are associated
with reduced insulin release only in lean subjects (BMI <
25). Consistently, the association of MAP4K4 genetic
variants with T2D using 1,972 samples from Chinese Han
population was also reported; this population is mainly
non-obese individuals (average BMI < 27.5 in both the
T2D subgroup and control subgroup) . The MAP4K4
SNP rs2236935 in the MAP4K4 gene is associated with
T2D. In contrast, the MAP4K4 SNP rs11674694 that
associates with insulin resistance and T2D in European
population is not associated with T2D in Chinese population
. These two results [31, 32] reflect that distinct
MAP4K4 SNPs are associated with T2D in different ethnic
groups. In addition, using genome-wide analysis of DNA
methylation, Yamada et al. reported that the MAP4K4
promoter is hypermethylated in Japanese patients with
atherosclerosis, which is one of the fatal complications
associated with T2D . These reports suggest that
MAP4K4 dysregulation or dysfunction is associated with
Epigenetic regulation of MAP4K4 in non-obese T2D
The pathogenesis of non-obese T2D, by which
MAP4K4deficient inflammatory T cells contribute to T2D, was
recently reported [34, 35]. Normal chow diet-fed
T-cellspecific MAP4K4 conditional knockout (cKO) mice
spontaneously develop T2D . MAP4K4 cKO T cells show
TRAF2 overexpression and IL-6 overproduction. In
adipose tissue of MAP4K4 cKO mice, IL-6 stimulates
adipocytes to further secret the adipokine leptin (Fig. 1) .
Fig. 1 Differentiation of pathogenic IL-6+ Th17 cell in adipose tissue.
MAP4K4 deficiency in T cells results in IL-6 overproduction. These
IL-6-producing T cells infiltrate into adipose tissue. In adipose tissue
microenvironment, IL-6 secreted from IL-6-producing T cells enhances
leptin secretion from adipocytes. Leptin cooperates with IL-6 to
promote Th17 differentiation, leading to development of pathogenic
IL-6+ Th17 cells 
IL-6-overproducing MAP4K4 cKO T cells further
differentiate into pathogenic IL-6+ Th17 cells by a synergistic
effect of leptin and IL-6 in adipose tissue (Fig. 1) .
These pathogenic IL-6+ Th17 cells then circulate to other
insulin-targeted tissues (the liver and muscle), leading to
The clinical significance of MAP4K4-downregulated
IL6+ Th17 cells is validated using purified T cells from T2D
patients. Consistently, MAP4K4 levels are decreased in
peripheral blood T cells from 72% drug-naive T2D
patients in Taiwan . In this study, all the lean T2D
patients display both MAP4K4 downregulation and IL-6
overproduction in T cells . The frequencies of
IL-6producing T cells are correlated with the value of insulin
resistance index . The frequencies of IL-6-producing
T cells can be reduced by ectopically expressed MAP4K4
. These findings suggest that MAP4K4
downregulation in T cells contribute to T2D. Nevertheless, due to the
small sample size, the authors have not demonstrated that
the percentage of obese subjects with MAP4K4
attenuation is lower than that of non-obese subjects in their
study . Moreover, data of demethylation treatment
on the purified T cells from T2D patients demonstrate
that the MAP4K4 downregulation is due to enhanced
methylation on the MAP4K4 promoter . Furthermore,
the methylation frequencies are correlated with OGTT
glucose levels independent of obesity; this correlation is
particularly higher in the patient subgroup with BMI < 23
compared to those in the other two subgroups: 23 ≤ BMI <
27 (overweight) and BMI ≥ 27 (obese) . Taken together,
hypermethylation-mediated MAP4K4 downregulation
frequently occurs in T cells of non-obese T2D patients.
Inflammatory IL-6+ Th17 cells and non-obese T2D
High-fat diet (HFD) induces IFN-γ+ T cell population in
mice [36, 37]. Besides IFN-γ+ T cells, inflammatory
macrophages and B cells also contribute to HFD-induced
T2D [37, 38]. Lack of MAP4K4 in T cells results in an
induction of IL-6+ Th17 cell, but not macrophage or B cell,
population in MAP4K4 cKO mice . Unlike IFN-γ+ T
cells, the IL17+ T cell population in mice cannot be
induced by HFD . Notably, MAP4K4-deficient IL-6+
Th17 cells are pathogenic cells causing spontaneous T2D
in T-cell-specific MAP4K4 conditional knockout (cKO)
mice, as well as in healthy recipient mice after adoptive
Consistently, in human drug-naïve T2D patients from
Taiwan, the IL-6+IL17+ T cell population (about 20% of
freshly isolated peripheral blood T cells; without any
stimulation in vitro) is expanded . The frequencies
of the IL-6+IL17+ T cells in T2D patients from Taiwan
are correlated with OGTT glucose levels but not with
BMI or waist circumference . Conversely, IFN-γ+ T
cell population (about 6% of peripheral blood cells;
without any stimulation in vitro) is expanded in T2D
patients from the United States, while IL-17+ T cell
population (only 0.3% of peripheral blood cells; without
any stimulation in vitro) is not enhanced . These
findings indicate that the pathogenic IL-6+IL17+ T cell
population for T2D is not induced by obesity.
Collectively, these results also suggest that IL-6+ Th17 cells and
IFN-γ+ T cells are important causes of non-obese T2D
and obesity-induced T2D, respectively. In addition,
IL17 and IFN-γ levels from T cells of T2D patients from
the Unite States can be induced in vitro by PHA or
antiCD3/CD28 stimulation . The data may suggest that
obese T2D patients under certain pathogenic conditions
(such as infection or pollutant exposure) may induce
non-obese T2D type-responses in addition to obese-type
T2D. Moreover, we cannot rule out that IFN-γ+ T cells
may cross-talk with Th17 cells in T2D patients. Thus, it
is likely that the people with both obesity and MAP4K4
dysfunction may be susceptible to earlier or worse T2D.
Prevention and therapeutic strategies for non-obese T2D
Impaired glucose tolerance (IGT) is a pre-diabetic state.
The frequencies of IL-6-producting T cells from IGT
patients are in between those of T2D and healthy
individuals . This finding suggests that examination of
the IL-6+IL-17+ T cell population or MAP4K4
methylation may provide early diagnosis or even prognosis for
non-obese or lean T2D.
Levels of DNA methylation can be regulated by
environmental factors such as diets, pathogens, toxins, radiation,
environmental hormones, air pollution, and water pH
value. It is well known that air pollution (such as
particulate matter, PM2.5) is associated with prevalence of T2D.
Interestingly, an exposure of ozone-oxidized black carbon
particles induces inflammatory T cell population in the
mediastinal lymph nodes, as well as IL-6 levels in
bronchoalveolar lavage fluids of wild-type mice . Moreover,
T-cell-specific MAP4K4 knockout mice display more
severe lung inflammation than that in wild-type mice
under the ozone-oxidized black carbon exposure .
We propose that interactions between environmental
factors and MAP4K4 polymorphisms/methylation
contribute to MAP4K4 downregulation or inactivation in
T cells, leading to non-obese T2D. Thus, investigating
the relationship between environmental factors and
MAP4K4 expression/dysfunction may help the
prevention of non-obese T2D. In addition, the functional
significance of the SNPs on MAP4K4 needs to be
investigated. It will also be useful to clarify whether
MAP4K4 SNPs and MAP4K4 hypermethylation
coexist or occur independently in non-obese T2D
patients from different countries or different ethnic
groups. Besides MAP4K4, other genes (such as
signaling molecules) and environmental factors that induce
pathogenic IL-6+ Th17 cell population may be also
involved in the pathogenesis of non-obese T2D. It is
Fig. 2 Distinct pathogenic pathways for non-obese T2D and obese T2D. For non-obese T2D, the interaction between environmental factors and
genes on the MAP4K4 gene may enhance methylation of the MAP4K4 promoter, resulting in MAP4K4 downregulation. MAP4K4 downregulation
in T cells subsequently results in overproduction of the proinflammatory cytokines IL-6 and IL-17, leading to insulin resistance of the
insulintargeted cells. In obese T2D, high-fat diet is a cause of obesity and visceral fat accumulation, resulting in overproduction of the proinflammatory
cytokine IFN-γ from T cells [36, 37], the IgG autoantibodies from B cells , and the proinflammatory cytokines TNF-α, IL-1β, IL-6 from macrophages
. Besides macrophages, IL-6 is also produced from adipocytes, hepatocytes, muscle cells, and B cells of high-fat-diet fed mice .
High-fat-diet-induced B cells recruit macrophages into insulin-targeted tissues and activate T cells for IFN-γ production . TNF-α and
IFN-γ cause insulin resistance . In both non-obese T2D and obese T2D, insulin resistance further induces hepatic and cardiac steatosis
also important to investigate whether other unknown
pathogenic immune cell populations also contribute to
Inhibition of inflammatory T cells may be a useful
approach to treatment of non-obese or lean T2D. Either
IL-6 or IL-17 neutralization improves insulin sensitivity
in diabetic MAP4K4 cKO mice . Several studies
from Japan  and Europe  indicate that
rheumatoid arthritis patients receiving anti-IL-6 receptor
(tocilizumab) treatment also display decreased HbA1c
levels and improved insulin sensitivity. Thus, IL-6 or
IL-17 blockade could be considered as a treatment for
non-obese T2D. In addition, ectopic MAP4K4 expression
or demethylation treatment inhibits IL-6 production in
purified peripheral T cells of T2D patients . Because
MAP4K4 is ubiquitously expressed and MAP4K4
overexpression promotes cancer progression or metastasis
[21, 26], a systemic treatment using MAP4K4 agonists
may not be feasible. Thus, identification of a
T-cellspecific epigenetic regulator of MAP4K4 promoter
methylation may help developing a potential treatment for
non-obese T2D through selective restoration of MAP4K4
in T cells.
Interaction of T2D with rheumatoid arthritis
Rheumatoid arthritis (RA), psoriatic arthritis, or
psoriasis is associated with an increased risk for T2D [43, 44];
conversely, T2D is associated with a significantly
increased risk for RA . The inflammatory cytokines
IL-6 and IL-17 play important roles in the pathogenesis
of RA, psoriatic arthritis, or psoriasis. In addition, IL-6+
Th17 cells are critical pathogenic cells for non-obese
T2D [34, 35]. These findings suggest that the
inflammatory Th17 cells may be common pathogenic cells for
non-obese T2D, RA, psoriatic arthritis, and psoriasis.
Thus, monitoring RA or T2D patients for inflammatory
T cells will help early diagnosis of the other disease.
The pathogenesis of non-obese T2D is overlooked for a
long time due to the myth of the association between
non-obese T2D and visceral fat accumulation. This
misconception has been changed by recent publications
[15, 16]. Inflammatory IL-6+ Th17 cells are pathogenic
cells for non-obese T2D; these pathogenic T cells are
caused by downregulation of MAP4K4 (Fig. 2).
Moreover, the gene variants or enhanced promoter
methylation of MAP4K4 may lead to the downregulation or
even dysfunction of MAP4K4 in T cells. In conclusion,
MAP4K4-downregulated, inflammatory Th17 cells and
obesity contribute to non-obese T2D and obese T2D,
respectively (Fig. 2). Furthermore, both IL-6+ Th17 cells
and obesity may occur in the same individuals, leading
to exacerbated T2D. In addition, inflammatory IL-6+
Th17 cells may be the underlying mechanism
contributing to the association between T2D and other
inflammatory diseases (such as autoimmune arthritis). Now, a
door has been opened to better understanding of
nonobese T2D pathogenesis. The roles of MAP4K4, IL-6+
Th17 cells, and visceral fat accumulation in non-obese
T2D need to be further verified or clarified using
clinical samples from more countries with different ethnic
groups. Future investigations of the interaction between
genes and environmental factors in non-obese T2D
pathogenesis shall lead to development of precision
medicine for non-obese T2D.
BMI: Body mass index; DAX: Dual-energy X-ray absorptiometry; HFD: High-fat
diet; IGT: Impaired glucose tolerance; MAP4K4 cKO: T-cell-specific MAP4K4
conditional knockout; MAP4K4: MAP kinase kinase kinase kinase 4; OGTT: Oral
glucose tolerance test; RA: Rheumatoid arthritis; SNP: Single nucleotide
polymorphism; T2D: Type 2 diabetes
This work was supported by grants from the National Health Research
Institutes, Taiwan (IM-105-PP-01 and IM-105-SP-01, to T.-H. T.). T.-H. T. is a
Taiwan Bio-Development Foundation (TBF) Chair in Biotechnology.
Availability of data and materials
Data and materials related to this work are available upon request.
Consent for publication
All authors approve the manuscript for publication.
1. Vaag A , Lund SS . Non-obese patients with type 2 diabetes and prediabetic subjects: distinct phenotypes requiring special diabetes treatment and (or) prevention? Appl Physiol Nutr Metab . 2007 ; 32 : 912 - 20 .
2. Huxley R , James WP , Barzi F , Patel JV , Lear SA , Suriyawongpaisal P , Janus E , Caterson I , Zimmet P , Prabhakaran D , et al. Ethnic comparisons of the cross-sectional relationships between measures of body size with diabetes and hypertension . Obes Rev . 2008 ;9 Suppl 1: 53 - 61 .
3. Chan JC , Malik V , Jia W , Kadowaki T , Yajnik CS , Yoon KH , Hu FB . Diabetes in Asia: epidemiology, risk factors, and pathophysiology . JAMA . 2009 ; 301 : 2129 - 40 .
4. Miyawaki Y , Iwahashi H , Okauchi Y , Sudo Y , Fujiwara Y , Omote Y , Imagawa A , Shimomura I. Differences in emotional distress among inpatients with type 1, obese type 2, and non-obese type 2 diabetes mellitus . Intern Med . 2015 ; 54 : 2561 - 7 .
5. Brunetti P. The lean patient with type 2 diabetes: characteristics and therapy challenge . Int J Clin Pract Suppl . 2007 ; 153 : 3 - 9 .
6. Coleman NJ , Miernik J , Philipson L , Fogelfeld L. Lean versus obese diabetes mellitus patients in the United States minority population . J Diabet Complications . 2014 ; 28 : 500 - 5 .
7. Jellema A , Zeegers MP , Feskens EJ , Dagnelie PC , Mensink RP. Gly972Arg variant in the insulin receptor substrate-1 gene and association with type 2 diabetes: a meta-analysis of 27 studies . Diabetologia . 2003 ; 46 : 990 - 5 .
8. Arikoglu H , Aksoy Hepdogru M , Erkoc Kaya D , Asik A , Ipekci SH , Iscioglu F. IRS1 gene polymorphisms Gly972Arg and Ala513Pro are not associated with insulin resistance and type 2 diabetes risk in non-obese Turkish population . Meta Gene . 2014 ; 2 : 579 - 85 .
9. George AM , Jacob AG , Fogelfeld L. Lean diabetes mellitus: An emerging entity in the era of obesity . World J Diabetes . 2015 ; 6 : 613 - 20 .
10. Perry JR , Voight BF , Yengo L , Amin N , Dupuis J , Ganser M , Grallert H , Navarro P , Li M , Qi L , et al. Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases . PLoS Genet . 2012 ; 8 : e1002741 .
11. Ma RC , Chan JC. Type 2 diabetes in East Asians: similarities and differences with populations in Europe and the United States . Ann N Y Acad Sci . 2013 ; 1281 : 64 - 91 .
12. Boyko EJ , Fujimoto WY , Leonetti DL , Newell-Morris L. Visceral adiposity and risk of type 2 diabetes: a prospective study among Japanese Americans . Diabetes Care . 2000 ; 23 : 465 - 71 .
13. Anjana M , Sandeep S , Deepa R , Vimaleswaran KS , Farooq S , Mohan V. Visceral and central abdominal fat and anthropometry in relation to diabetes in Asian Indians . Diabetes Care . 2004 ; 27 : 2948 - 53 .
14. Hearst A. You don't look diabetic: diabetes in non-obese south Asians-is there a molecular or genetic basis for Increased insulin resistance? Clinical Correlations . 2011 . http://www.clinicalcorrelations.org/?p= 4694 .
15. Scott RA , Fall T , Pasko D , Barker A , Sharp SJ , Arriola L , Balkau B , Barricarte A , Barroso I , Boeing H , et al. Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity . Diabetes . 2014 ; 63 : 4378 - 87 .
16. Rajkovic N , Zamaklar M , Lalic K , Jotic A , Lukic L , Milicic T , Singh S , Stosic L , Lalic NM . Relationship between obesity, adipocytokines and inflammatory markers in type 2 diabetes: relevance for cardiovascular risk prevention . Int J Environ Res Public Health . 2014 ; 11 : 4049 - 65 .
17. Levelt E , Pavlides M , Banerjee R , Mahmod M , Kelly C , Sellwood J , Ariga R , Thomas S , Francis J , Rodgers C , et al. Ectopic and visceral fat deposition in lean and obese patients with type 2 diabetes . J Am Coll Cardiol . 2016 ; 68 : 53 - 63 .
18. Chakrabarti P , Kandror KV . Adipose triglyceride lipase: a new target in the regulation of lipolysis by insulin . Curr Diabetes Rev . 2011 ; 7 : 270 - 7 .
19. Tilg H , Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis . Hepatology . 2010 ; 52 : 1836 - 46 .
20. Yao Z , Zhou G , Wang XS , Brown A , Diener K , Gan H , Tan TH. A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway . J Biol Chem . 1999 ; 274 : 2118 - 25 .
21. Chuang HC , Wang X , Tan TH . MAP4K family kinases in immunity and inflammation . Adv Immunol . 2016 ; 129 : 277 - 314 .
22. Hu MC , Qiu WR , Wang X , Meyer CF , Tan TH . Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade . Genes Dev . 1996 ; 10 : 2251 - 64 .
23. Diener K , Wang XS , Chen C , Meyer CF , Keesler G , Zukowski M , Tan TH , Yao Z. Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase . Proc Natl Acad Sci U S A . 1997 ; 94 : 9687 - 92 .
24. Shui JW , Boomer JS , Han J , Xu J , Dement GA , Zhou G , Tan TH . Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell-mediated immune responses . Nat Immunol . 2007 ; 8 : 84 - 91 .
25. Chuang HC , Lan JL , Chen DY , Yang CY , Chen YM , Li JP , Huang CY , Liu PE , Wang X , Tan TH . The kinase GLK controls autoimmunity and NF-κB signaling by activating the kinase PKC-θ in T cells . Nat Immunol . 2011 ; 12 : 1113 - 8 .
26. Collins CS , Hong J , Sapinoso L , Zhou Y , Liu Z , Micklash K , Schultz PG , Hampton GM. A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase . Proc Natl Acad Sci U S A . 2006 ; 103 : 3775 - 80 .
27. Qiu MH , Qian YM , Zhao XL , Wang SM , Feng XJ , Chen XF , Zhang SH . Expression and prognostic significance of MAP4K4 in lung adenocarcinoma . Pathol Res Pract . 2012 ; 208 : 541 - 8 .
28. Liang JJ , Wang H , Rashid A , Tan TH , Hwang RF , Hamilton SR , Abbruzzese JL , Evans DB , Wang H. Expression of MAP4K4 is associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma . Clin Cancer Res . 2008 ; 14 : 7043 - 9 .
29. Zhao Y , Li F , Zhang X , Liu A , Qi J , Cui H , Zhao P. MicroRNA-194 acts as a prognostic marker and inhibits proliferation in hepatocellular carcinoma by targeting MAP4K4 . Int J Clin Exp Pathol . 2015 ; 8 : 12446 - 54 .
30. Vitorino P , Yeung S , Crow A , Bakke J , Smyczek T , West K , McNamara E , Eastham-Anderson J , Gould S , Harris SF , et al. MAP4K4 regulates integrinFERM binding to control endothelial cell motility . Nature . 2015 ; 519 : 425 - 30 .
31. Sartorius T , Staiger H , Ketterer C , Heni M , Machicao F , Guilherme A , Grallert H , Schulze MB , Boeing H , Stefan N , et al. Association of common genetic variants in the MAP4K4 locus with prediabetic traits in humans . PLoS One . 2012 ; 7 : e47647 .
32. Li TT , Qiao H , Tong HX , Zhuang TW , Wang TT . Association of common genetic variants in mitogen-activated protein kinase kinase kinase kinase 4 with type 2 diabetes mellitus in a Chinese Han population . Chin Med J (Engl) . 2016 ; 129 : 1179 - 84 .
33. Yamada Y , Nishida T , Horibe H , Oguri M , Kato K , Sawabe M. Identification of hypo- and hypermethylated genes related to atherosclerosis by a genomewide analysis of DNA methylation . Int J Mol Med . 2014 ; 33 : 1355 - 63 .
34. Chuang HC , Sheu WH , Lin YT , Tsai CY , Yang CY , Cheng YJ , Huang PY , Li JP , Chiu LL , Wang X , et al. HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance . Nat Commun . 2014 ; 5 : 4602 .
35. Chuang HC , Wang JS , Lee IT , Sheu WH , Tan TH . Epigenetic regulation of HGK/MAP4K4 in T cells of type 2 diabetes patients . Oncotarget . 2016 ; 7 : 10976 - 89 .
36. Winer S , Chan Y , Paltser G , Truong D , Tsui H , Bahrami J , Dorfman R , Wang Y , Zielenski J , Mastronardi F , et al. Normalization of obesity-associated insulin resistance through immunotherapy . Nat Med . 2009 ; 15 : 921 - 9 .
37. Nishimura S , Manabe I , Nagasaki M , Eto K , Yamashita H , Ohsugi M , Otsu M , Hara K , Ueki K , Sugiura S , et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity . Nat Med . 2009 ; 15 : 914 - 20 .
38. Winer DA , Winer S , Shen L , Wadia PP , Yantha J , Paltser G , Tsui H , Wu P , Davidson MG , Alonso MN , et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies . Nat Med . 2011 ; 17 : 610 - 7 .
39. Jagannathan-Bogdan M , McDonnell ME , Shin H , Rehman Q , Hasturk H , Apovian CM , Nikolajczyk BS . Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes . J Immunol . 2011 ; 186 : 1162 - 72 .
40. Jin M , Chu H , Li Y , Tao X , Cheng Z , Pan Y , Meng Q , Li L , Hou X , Chen Y , et al. MAP4K4 deficiency in CD4(+) T cells aggravates lung damage induced by ozone-oxidized black carbon particles . Environ Toxicol Pharmacol . 2016 ; 46 : 246 - 54 .
41. Ogata A , Morishima A , Hirano T , Hishitani Y , Hagihara K , Shima Y , Narazaki M , Tanaka T. Improvement of HbA1c during treatment with humanised antiinterleukin 6 receptor antibody, tocilizumab . Ann Rheum Dis . 2011 ; 70 : 1164 - 5 .
42. Ursini F , Russo E , Letizia Hribal M , Mauro D , Savarino F , Bruno C , Tripolino C , Rubino M , Naty S , Grembiale RD. Abatacept improves whole-body insulin sensitivity in rheumatoid arthritis: an observational study . Medicine (Baltimore) . 2015 ; 94 :e888.
43. Solomon DH , Love TJ , Canning C , Schneeweiss S. Risk of diabetes among patients with rheumatoid arthritis, psoriatic arthritis and psoriasis . Ann Rheum Dis . 2010 ; 69 : 2114 - 7 .
44. Su CC , Chen Ie C , Young FN , Lian Ie B. Risk of diabetes in patients with rheumatoid arthritis: a 12-year retrospective cohort study . J Rheumatol . 2013 ; 40 : 1513 - 8 .
45. Lu MC . Yan ST , Yin WY , Koo M , Lai NS : Risk of rheumatoid arthritis in patients with type 2 diabetes: a nationwide population-based case-control study . PLoS One . 2014 ; 9 : e101528 .
46. Donath MY , Shoelson SE . Type 2 diabetes as an inflammatory disease . Nat Rev Immunol . 2011 ; 11 : 98 - 107 .
47. DeFuria J , Belkina AC , Jagannathan-Bogdan M , Snyder-Cappione J , Carr JD , Nersesova YR , Markham D , Strissel KJ , Watkins AA , Zhu M , et al. B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile . Proc Natl Acad Sci U S A . 2013 ; 110 : 5133 - 8 .