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Hindawi Publishing CorporationJournal of ObesityVolume 2015, Article ID 291209, 8 pages
Clinical Study
Tissue Factor Expression in Obese Type 2 Diabetic Subjects and
Its Regulation by Antidiabetic Agents
Jing Wang,1,2 Theodore P. Ciaraldi,3,4 and Fahumiya Samad1,2
1 Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA2San Diego Biomedical Research Institute, San Diego, CA 92121, USA3VA San Diego Healthcare System, San Diego, CA, USA4Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Correspondence should be addressed to Fahumiya Samad;
[email protected]
Received 15 November 2014; Revised 17 February 2015; Accepted 19 February 2015
Academic Editor: Aron Weller
Copyright 2015 Jing Wang et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objective. Increased coagulation activation may contribute to the high incidence of cardiovascular complications observed in obeseand type 2 diabetes (T2D) subjects. Although tissue factor (TF), the primary initiator of coagulation is increased in obesity, itsexpression in adipose tissues and its association with metabolic parameters are unclear. We sought to compare TF expression inplasma and adipose tissues of obese subjects with and without T2D, its correlation with metabolic parameters, and regulation inresponse to antidiabetic drugs.
Methods Subjects were recruited from diabetes clinics and adipose tissue was obtained by needlebiopsy of lower subcutaneous abdominal depot. For the intervention study, subjects were randomized into treatment groups withrosiglitazone or metformin for 4 months.
Results. Plasma TF antigen, activity, and adipose TF mRNA were greater in obese T2Dsubjects compared with obese nondiabetics. Plasma TF activity correlated with fasting insulin, glucose, and free fatty acids, (FFAs),and adipose TF mRNA correlated with plasma FFA. Plasma TF activity was reduced by metformin and increased with rosiglitazonetreatment.
Conclusions. Specific diabetes-related metabolic parameters, but not obesity per se, are correlated with TF expression.
Regulation of TF activity by different classes of antidiabetic drugs may relate to protective or adverse cardiovascular outcomes.
TF-FVIIa complex triggers extrinsic coagulation leading toFXa-mediated generation of the downstream coagulation
Obesity is a major risk factor for the development of type
protease thrombin, fibrin deposition, and platelet activation.
2 diabetes (T2D), and clinical studies have established an
Higher plasma concentrations of FVII [3], increased levels
increased incidence of thrombosis and cardiovascular disease
of thrombin and thrombin-antithrombin (TAT) complexes
as a primary cause of mortality in diabetic patients [1, 2]. T2D
[4], and increased circulating monocyte TF procoagulant
is associated with accelerated and premature atherosclerosis
activity [5] are observed in obese subjects. Weight loss
as well as other cardiovascular and thrombotic complica-
in morbidly obese patients significantly reduces thrombin
tions including myocardial infarction, ischemic stroke, and
generation potential [6] and decreases levels of circulating
peripheral vascular disease [1, 2]. While risk factors such
TF, FVII, and prothrombin fragment F1.2, a marker of in vivo
as hypertension and cholesterol are elevated in T2D, these
thrombin formation [7]. Compared with nondiabetic control
only account partially for the cardiovascular burden, and
subjects, T2D patients display signs of hypercoagulability and
emerging evidence suggests that dysregulation of pathways
increased plasma TF procoagulant activity [8, 9], increased
of coagulation is an additional significant mechanism that
abundance of TF-positive microparticles [8, 10], and higher
contributes to increased cardiovascular risk.
TF activity of circulating monocytes [11, 12]. Elevated blood-
TF is the primary initiator of the coagulation pathway
borne or circulating TF correlates with microvascular com-
and is the cell surface receptor for coagulation factors VII
plications and is considered a biomarker for the severity of
and VIIa. Cell surface or microparticle- (MP-) associated
microvascular disease in T2D patients [13, 14].
Journal of Obesity
Whereas plasma TF activity and antigen levels have
Table 1: (a) Metabolic characteristics of subjects and (b) baseline
been shown to be increased in obese subjects as well as
parameters of subjects prior to treatment with metformin or rosigli-
in patients with T2D, whether its expression is higher in
obese diabetics compared with obese nondiabetics is unclear.
This is especially important since all obese subjects are notnecessarily diabetic. In genetically or high fat diet induced
obese mice that are also diabetic, TF activity is increased in
the blood and its activity and gene expression increased in
adipose tissues [15β17]. However, to our knowledge whether
adipose TF expression is similarly induced in obese and
diabetic humans has not been studied. Here, we examined
Fasting glucose (mmol/L)
TF expression in plasma and adipose tissues of obese subjects
Fasting insulin (pmol/L)
with and without diabetes, how its expression correlates with
a number of metabolic parameters, and how its activity isregulated in response to the antidiabetic drugs, metformin,
and rosiglitazone.
2. Patients and Methods
Human subject protocols were approved by the Committee
on Human Investigation at the University of California, San
Diego (UCSD), and all subjects provided written informed
Fasting glucose (mmol/L)
consent. Subjects were recruited from diabetes clinics and
Fasting insulin (pmol/L)
classified as diabetic or nondiabetic by their response to a
75 g oral glucose tolerance test according to the American
Diabetes Association criteria and classified as obese if their
BMI (kg/m2) > 30 as previously described [18]. Adipose tissue
was obtained by needle biopsy of the lower subcutaneous
For Tables 1(a) and 1(b), data are means Β± SD. TG, triglyceride.
abdominal depot [18]. Other clinical data are summarized in
Table 1(a): βπ < 0.05; ND versus T2D.
Table 1(a). The time from initial diabetes diagnosis to samplecollection ranged from 0.2 to 13 years. None of the subjectshad a history of thromboembolism. All routine laboratory
parameters for subjects in Table 1 were determined using
test values were within 2.5X the upper and lower limits of
standard techniques as previously described [18, 19].
specified normal ranges. A majority of the T2D subjects were
Plasma TF antigen was determined using the IMUBIND
not taking any antidiabetic medications at the time of biopsy
Tissue Factor ELISA kit, and TF procoagulant activity in
and were controlled by diet alone as part of a 6-week washout
plasma was determined using the chromogenic Actichrome
of antidiabetic medications. Of the other T2D subjects, 1 was
TF activity assay according to manufacturer's instructions
on glucovance and 1 was taking rosiglitazone and the other
(American Diagnostica, Stamford, CT). Adipose TF gene
glyburide and metformin at the time of biopsy.
expression was determined by real-time quantitative RT-PCR
In the intervention study (Table 1(b)), subjects were
as previously described [17]. cDNA synthesized from total
excluded if they were previously treated with TZD, treated
RNA was analyzed with gene specific primers (Invitrogen)
with more than one diabetic agent or insulin, had hyper-
and SYBR Green PCR Master mix (PerkinElmer) in an
tension, were pregnant, or had active cardiac disease or
iCycler (Bio-Rad). Relative gene expression levels were cal-
other major illnesses. If applicable, subjects maintained
culated after normalizing to π½-actin using the ΞΞCT method
their blood pressure and lipid-controlling medications. There
(Bio-Rad). Statistical analysis was evaluated using the Graph-
were no differences at baseline between treatment groups
Pad Prism program (Intuitive Software, San Diego, CA).
with regard to duration of diabetes, blood pressure, rou-
The statistical significance of differences within and between
tine laboratory values, or use of blood pressure or lipid-
groups was analyzed by the Student's paired and unpaired
controlling medications. Briefly, after a washout period of
π‘-tests. Correlations were calculated using the Pearson cor-
6 weeks for those participants that were on an antidiabetic
relation. A π value < 0.05 was considered as the level of
treatment, subjects were randomized into a treatment group
with high-dose rosiglitazone (4 mg twice daily) or high-dosemetformin (1,000 mg twice daily) for a period of 4 months
3. Results and Discussion
[19]. To minimize potential side effects, medications wereinitiated below target doses and titrated up over the initial
Although obesity poses a risk for the development of insulin
2 weeks. Both subjects and investigators were blinded to
resistance and T2D, not all obese subjects are diabetic. The
treatment. Blood was collected after 10β12-hour overnight
influence of T2D on tissue factor expression in obese subjects
fast at baseline and 4-month posttreatment. All metabolic
was evaluated in cohorts matched for weight and BMI as
Journal of Obesity
Figure 1: Plasma TF activity (a), antigen (b), and adipose TF mRNA levels (c) in obese T2D subjects compared with obese nondiabetics. Forpanels (a) and (b),
N = 10β13 Β± SD. For panel (c),
N = 6β10 Β± SD. ββπ < 0.01 nondiabetics versus T2D. Clinical characteristics of subjects areindicated in Table 1(a).
indicated in Table 1(a). The body weights (kg) of obese
Table 2: Correlation between TF and metabolic parameters.
nondiabetics and diabetics were 105 Β± 17.3 and 101 Β± 15.9,while their BMIs (kg/m2) were 35.6 Β± 5.6 and 35.6 Β± 7.1,
TF activity TF antigen Adipose TF mRNA
respectively. Fasting levels of plasma glucose, insulin, free
fatty acids (FFAs), and HbA1c were significantly higher in the
obese diabetic cohorts, while no differences were observed
for plasma triglycerides between the two groups. Plasma
TF activity, plasma TF antigen, and adipose TF mRNA
expression were significantly increased in obese diabeticscompared with obese nondiabetics (Figures 1(a)β1(c)).
In the commercial Actichrome TF activity assay (Ameri-
can Diagnostica) plasma samples are directly incubated with
FVIIa, FX, and a chromogenic substrate for FXa. A limitation
of this assay is that the values obtained tend to be somewhat
overestimated. However, regardless of the absolute levels of
βπ < 0.05, ββπ < 0.01, βββπ < 0.001 for TF (activity, antigen or adipose
TF activity, we believe that, on a relative basis, the observation
mRNA) versus indicated metabolic parameters.
that plasma TF activity is higher in obese T2D relative toobese nondiabetics is relevant. In the plasma, TF exists in theform of microparticles shed from apoptotic or activated cells,
Since metabolic changes observed in T2D may contribute
as well as an alternately spliced soluble form of TF. It should
to elevated TF expression, we determined the correlation
be noted that the TF activity and antigen assays used did not
of TF expression with a number of metabolic parameters.
discriminate between these various forms of TF but rather
As indicated in Table 2, no significant correlations were
measured total plasma TF.
observed for plasma TF activity and antigen with either BMI
Journal of Obesity
Fasting glucose (mmol/L)
Fasting insulin (pmol/L)
Fasting insulin (pmol/L)
Figure 2: Correlations between (a) plasma TF activity levels and plasma fasting glucose, (b) plasma TF activity and fasting insulin, (c)plasma TF antigen and fasting insulin, (d) plasma TF activity and plasma free fatty acid (FFA), (e) plasma TF antigen and plasma FFA, and(f) adipose TF mRNA and plasma FFA. Correlations were calculated using the Pearson correlation. A π value < 0.05 was considered as thelevel of significance.
or weight suggesting that obesity per se may not contribute to
and FFA (Table 2, Figure 2). Interestingly adipose TF mRNA
elevated TF activity. Alternately, TF activity was significantly
was correlated only with plasma FFA (Table 2, Figure 2(f)).
correlated with fasting glucose, insulin, and free fatty acid
Hyperinsulinemia is associated with insulin resistance
(FFA), while TF antigen was correlated with fasting insulin
and T2D, and insulin administration has been demonstrated
Journal of Obesity
to increase circulating TF in healthy and T2D subjects [9,
were observed in metformin-treated T2D patients and in
20] and in obese insulin-resistant and diabetic mice, insulin
prediabetics on statin and metformin therapy [27]. To directly
increases both circulating and adipose TF expression [15, 16].
determine in vivo efficacy of metformin on suppressing
Microparticles shed from activated monocytes are important
coagulation, we determined the effect of metformin on TF
sources of blood-borne TF. Compared with normal mono-
activity in obese T2D subjects. Baseline characteristics of
cytes, insulin-resistant T2D monocytes express more TF and
the treatment group are summarized in Table 1(b). Four-
shed MP with a higher TF levels in response to insulin [11].
month high-dose metformin treatment led to a moderate
TF expression is negatively regulated by phosphoinositide 3-
insignificant reduction of plasma TF activity (Figures 3(a)
kinase signaling [21], suggesting that downregulation of this
and 3(e)). Out of eight patients that were followed, six
pathway as a consequence of insulin resistance may favor TF
showed a reduction in TF activity, while in two of the
upregulation in T2D [11]. Our study indicating that plasma
subjects TF activity was modestly increased (Figure 3(b)).
TF activity and antigen are correlated with insulin levels is
These small decreases in TF activity observed in 75% of the
consistent with these previous data and suggests that the
patients however may be clinically relevant as such changes
compensatory hyperinsulinemia that accompanies insulin
in hemostatic factors including factor VIIa have been shown
resistance and T2D may contribute to the observed increase
to determine cardiovascular risk [28].
in plasma TF expression in these patients. A significant cor-
Thiazolidinediones (TZDs) that act through the nuclear
relation was also observed between TF activity and glucose,
and this is in line with data indicating that hyperglycemia
(PPARπΎ) are potent insulin sensitizers and highly effective
in healthy volunteers and T2D increases TF procoagulant
oral medications for T2D [29]. However, clinical trials have
activity [9] and improved glycemic control reduces circulat-
indicated that the TZD and rosiglitazone (Avandia) lead to a
ing TF [22]. Importantly, combined hyperinsulinemia and
high risk of myocardial infarction and cardiovascular disease
hyperglycemia produced an additive increase in TF activity
leading to their withdrawal [29]. While the reason for its
[20], suggesting that the presence of these two conditions
adverse cardiovascular side effects is not fully understood,
that often occur concurrently in T2D may contribute to the
in vitro studies have demonstrated that rosiglitazone upreg-
observed increase in TF and procoagulant activity in thesepatients.
ulated the expression of procoagulant TF bearing MP byhuman monocytes/macrophages [30]. To determine if
In this study, the metabolic parameter that showed the
rosiglitazone regulates TF activity in vivo, we measured
strongest correlation with plasma TF activity and antigen and
plasma TF activity in a cohort of obese T2D subjects at
the only correlate associated with adipose TF expression was
baseline and after 4 months of rosiglitazone treatment.
FFA (Table 2, Figure 2(f)). Obesity is associated with a dyslipi-demia that in part is manifested as increased circulating FFA.
A significant increase in TF activity was observed after
Increased adipose lipolysis due to insulin resistance is a pri-
rosiglitazone treatment compared with baseline levels
mary mechanism leading to elevated FFA in the plasma and
(Figures 3(c) and 3(e)). Of the 10 patients that were studied,
in the local microenvironment of obese T2D patients. FFA
7 of them showed an increase and 3 showed a decrease
activates toll-like receptor- (TLR-) mediated signaling, and in
in plasma TF activity (Figure 3(d)). To our knowledge,
monocytes induction of TF expression has been shown to be
this is the first in vivo demonstration where rosiglitazone
dependent on the coordinated activation of TLR-dependent
induces TF activity in human subjects which may potentially
nuclear factor-π
B (NF-π
B) and Jun N-terminal kinase (JNK)
contribute to the adverse cardiovascular outcomes with this
signaling pathways [21]. It is tempting to speculate that FFAs
drug. The mechanism for rosiglitazone-mediated increase in
could similarly increase TF expression in adipocytes and
TF activity is unclear and is not related to metabolic measures
adipose tissue macrophages via TLR-mediated activation of
of insulin sensitivity as these were markedly improved in
NF-π
B and JNK signaling cascades. A role for FFA in TF
rosiglitazone-treated patients [19]. Despite their side effects,
induction was confirmed by our finding that TF expression
TZDs are still considered to have therapeutic value due to
in adipocytes is increased by palmitate (Samad, unpublished
their superior antidiabetic effects. Since increased TF activity
observation), the most abundant plasma FFA in obesity.
was not observed in all rosiglitazone-treated subjects, it is
Metformin, a member of the biguanide family, is one of
tempting to speculate that measures of TF activity could be
the most commonly used antidiabetic drugs and is highly
a useful indicator to identify patients that may be at risk for
effective in lowering blood glucose and improving peripheral
developing cardiovascular disease in response to TZDs.
insulin sensitivity in patients with T2D [23]. In addition,
In conclusion, our study shows that plasma and adipose
increasing studies indicate that metformin reduces the risk
TF expression is increased in obese T2D compared to obese
of diabetes-associated atherothrombotic disease independent
nondiabetic subjects and significantly correlated with FFA.
of its antihyperglycemic effect [24]. A limited number of
Regulation of TF activity by different classes of antidiabetic
in vitro and clinical studies have suggested that the cardio-
drugs may relate to protective or adverse cardiovascular
protective effects of metformin may be related to beneficial
effects on pathways of fibrinolysis and hemostasis. In vitrostudies show that metformin suppresses TF expression in
Conflict of Interests
human monocytes and reduces thrombin activity and fibrinpolymerization [25, 26]. Modest reductions of VIIa activity
The authors state that they have no conflict of interests.
Journal of Obesity
Figure 3: Plasma TF activity at baseline and following treatment with metformin ((a), (b), and (e)) and rosiglitazone ((c), (d), (e)). The π₯-axisnumbers (1β8) in Figure 3(b) and (1β10) in Figure 3(d) represent each patient and are not identical as these are subjects from two treatmentsstudies. For metformin-treated subjects in panels (a), (b), and (e):
N = 8 Β± SD. For rosiglitazone-treated subjects in panels (c), (d), and (e):
N = 10 Β± SD. βπ < 0.05, baseline versus rosiglitazone. Baseline clinical characteristics of subjects are indicated in Table 1(b).
Journal of Obesity
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