The Effect of Pioglitazone on Adiposity, Adiponectin and Carotid Artery Intimal Thickness in Obese but Otherwise Healthy Minority Subjects

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Article Information:


Group: 2008
Subgroup: Volume 6, Issue 4, Autumn
Date: December 2008
Type: Original Article
Start Page: 162
End Page: 174

Authors:

  • B Salehian
  • Division of Endocrinology, Metabolism and Molecular Medicine, Charles R Drew University of Medicine and Science, Los Angeles, CA, USA
  • J Bilas
  • Division of Endocrinology, Metabolism and Molecular Medicine, Charles R Drew University of Medicine and Science, Los Angeles, CA, USA
  • V Mahabadi
  • Division of Endocrinology, Metabolism and Molecular Medicine, Charles R Drew University of Medicine and Science, Los Angeles, CA, USA
  • V Aleli
  • Division of Endocrinology, Metabolism and Molecular Medicine, Charles R Drew University of Medicine and Science, Los Angeles, CA, USA
  • K Norris
  • Division of Endocrinology, Metabolism and Molecular Medicine, Charles R Drew University of Medicine and Science, Los Angeles, CA, USA
  • SH Bhasin
  • Division of Endocrinology, Metabolism and Molecular Medicine, Charles R Drew University of Medicine and Science, Los Angeles, CA, USA

      Correspondence:

      Affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Charles R Drew University of Medicine and Science
      City, Province: Los Angeles, CA
      Country: USA
      Tel:
      Fax:
      E-mail: bsalehian@coh.org

Abstract:


We examined the hypothesis that the PPAR Gamma activator, Pioglitazone, has a fat depot specific effect and aimed at determining the ef fects of pioglitazone on changes in total and regional fat distribution, serum adiponectin levels, carotid artery intimal thickness, and subcutaneous adipose tissue histology in otherwise healthy obese men and women from a minority population.

Materials and Methods: This is a doubleblind, randomized, controlled trial, single site study of the minority population in south central Los Angeles. Thirtyfive obese, but otherwise healthy, men and women (waisttohip ratio >0.95 for men and >0.85 in women) were randomly assigned into three groups: Group A: placebo; group B, pioglitazone 30 mg/day, and group C, pioglitazone 45 mg/day, for a duration of 6 months. The primary outcome measures were changes in visceral fat as measured by Computerized Tomography scan (CT Scan) of the abdomen and thigh, body composition by Dual energy Xray Absorptiometry Scan (DXA scan) and carotid artery intimamedia thickness as measured by ultrasound. Serum adiponectin levels and the size and number of adipocytes were also measured.

Results: At baseline, mean age, proportion of female participation, race and ethnicity distribution, blood pressure, Body Mass Index (BMI) and anthropometric measures of subjects in the three groups were not statistically different. After 6 months, we observed significant decrease of intramuscular fat and significant increase of subcutaneous thigh fat in groups B and C as compared to group A. The average carotid artery intimal thickness increased in group A (p<0.01), but not in group B, and decreased in group C (p<0.01). Serum adiponectin levels rose sharply (p<0.001) in the treatment groups only. A significant positive correlation was observed between the change of the adiponectin levels and subcutaneous thigh fat. Conclusion: Results of this study supports the use of pioglitazone in the prevention of stroke and peripheral vascular disease in highrisk populations.

Keywords: Pioglitazone;Subcutaneous fat;Visceral fat;Carotid artery;Intimal thickness; Adiponectin;Adipose tissue

Manuscript Body:


Introduction

Pioglitazone is a Peroxisome proliferatoractivated receptor gamma (PPARγ) agonist and has been shown to exert several key metabolic effects. The activation of PPARγ is associated with a depotspecific adipose tissue redistribution,1,2 an increase in serum adiponectin levels,3,4 and an antiinflammatory effect by suppression of the Tumor Necrosis Factor Alpha (TNFα).5 Peroxisome Proliferator Activated Receptor (PPAR) gamma nuclear receptors are mostly expressed in adipose tissue6 compared to skeletal muscle,7 and increase glucose uptake when activated.8
The visceral accumulation of fat is strongly associated with increased risk for cardiovascular disease and type 2 diabetes mellitus. 912 Even in people of nearly normal weight, high levels of central or visceral obesity are associated with increased risk of diabetes, hypertension, and coronary artery disease.13 More recent data suggest that the risk of cerebrovascular disease also increases with a waisttohip ratio >0.95.12 Accumulation of fat in the intraabdominal tissue, particularly those drained by the portal circulation, lead to high portal vein free fatty acid concentrations.14 Free fatty acids interfere and compete with glucose uptake in the liver and muscle and leads to development of hyperinsulinemia, insulin resistance and fatty liver.14 Evidence confirms that PPAR γ activators not only improve insulin sensitivity, but also increase adiponectin;15 it also reduces intraabdominal fat mass by a depotspecific, effect in Zucker rats and in hu16,17mans, and decreases intimal thickness in carotid arteries in patients with type 2 diabetes mellitus.18 Although much is known about the effect of pioglitazone in subjects with type 2 diabetes, the data on the effects of pioglitazone on adipose tissue, adipose depot, and on carotid artery intimal thickness in healthy obese subjects is relatively limited. Furthermore minority populations represent the highest percentage of obese people in US and very limited data is available on this specific target population.19  In this study, we examined the fat depot specific effect of pioglitazone in an obese, but otherwise healthy, minority population; we also examined the effect of pioglitazone on carotid artery intimal thickness and its relationship with adiponectin.

Materials and Methods

Study Design

This is a doubleblind, randomized, controlled trial, single site study of a minority population in south central Los Angeles. Eligible subjects were randomly assigned in a1:1:1 ratio to receive, placebo, 30 and 45 mg pioglitazone respectively, once a day, for a 6month period. The randomization was made by random number (between 1 to 100) generated for each treatment group (e.g. random numbers of 1, 3 7, 9, 34 etc were allotted for enrollees 1, 3, 7, 9 and 34 and they received treatment A; similarly for groups B and C). Each subject, based on their enrollment number, was matched for the treatment number and no attempt was made to match between groups at enrollment. Subjects were between 18 to 55 years old and free of chronic diseases such as diabetes, Chronic Obstructive Pulmonay Diseases (COPD), coronary artery disease, and cancer. Obesity was defined as BMI above ≥ 30 (body weight per kg / height in m2), waisttohip ratio >0.95 in male and >0.85 in females. Subjects with uncontrolled hypertension (blood pressure>159/99 mmHg) were excluded; however, those with stage I hypertension (140159/9099 mm Hg) or those with controlled hypertension (<140/90 mmHg) and on a single antihypertensive medication were eligible to enter into the study. Monthly tablet counts were used to confirm adherence to medications. Research subjects were seen every month and side effects were recorded.
Subjects received diet counseling and were requested to not engage in heavy exercise or sudden change of diet for the 6 month study period. A 3day food record was obtained at baseline and every 2 months till the end of the study to ensure there were no drastic changes in diet. At baseline and at the end of the 6 month study period, body composition was measured by anthropometry and DXA scan. Subcutaneous and visceral fat accumulations were measured by CAT scan of the abdomen obtained transversally, at levels of L1L2, L34, and L5S1, and at midthigh using standard protocol. All scans were read by the same person using sliceomatic software. The display field was used to scale the image pixels for analysis and demarcate regions of interest. Carotid artery intimal thickness was measured at the common carotid artery 2 cm below bifurcation with use of the Holog ultrasound. The average and maximum thickness over the 2 cm length was measured. Average thickness was calculated, based on the 20 measured areas of the lateral wall of each carotid artery. Serum adiponectin levels were measured by ELISA method at baseline and at monthly intervals until the end of the study (AdipoGen), with a coefficient of variation of 4.8%. We calculated the homeostasis model assessment of insulin resistance (HOMAIR) according to the following equation: insulin (U/ml) x fasting glucose (mmol/liter)÷22.5.20 Whole body and regional body composition were evaluated by DXA scanning. The scanners were calibrated by using a soft tissue standard.
Subcutaneous fat biopsies were taken from the abdominal wall and thigh, prior to, and at the end of, the study. Biopsies were performed using 2% lidocaine, with a 0.5 cm incision and use of a skin punch biopsy (medium size), through the incised skin and obtaining fat by scooping from the tissue. A portion of the biopsy was immediately stored at 80C; the remaining tissue was placed in 4.5% formaldehyde for four days, then in concentrated sucrose, followed by embedding in a polyacryl block and sectioned. Cell counts were performed on each sample by a single person (VA). All cells in all available fields were counted in each subject and cell number was adjusted for the square microns. The data from abdomen and thigh were combined.The study was approved by Institutional Review Board committee at Charles R. Drew University.

Outcome Measures

The primary outcome measurements were the change in the ratios of visceraltosubcutaneous fat in the abdomen and in the thigh, and common carotid artery intimamedia thickness, 2 cm below carotid bifurcation. The visceral and subcutaneous fat in abdomen and thigh was adjusted for each subject’s body mass index (BMI), by dividing the sum of the surface of the target adipose tissue (visceral abdomen, intramuscular thigh, subcutaneous thigh etc..) to the subject’s BMI. The secondary outcome measure was changes in serum adiponectin levels.

Statistical Analysis

All data are presented as mean±standard error of mean. Comparison within groups A, B and C was performed by analysis of variance at baseline and after the end of the study period. The comparison between each group (before and at the end of the study period) was performed by the student paired ttest. Data were examined for normal distribution, prior to any statistical comparison. Multiple regression analysis at baseline, and during the study, was used to examine correlation between serum adiponectin levels and changes of fat depots and carotid artery intimal thickness. Adipose tissue surface area, both visceral and subcutaneous, was measured and adjusted for the individual’s BMI (surface divided by BMI). For nonparametric variables, Chi square test was used, with p<0.05 being considered significant. Excel and SPSS software was used for graphs and statistical analysis. The sample size was based on the percent change in visceral fat cross sectional area, the primary outcome during the study. A sample size of 56 subjects (including 25% drop rate) provided 85% power to detect a 10% change in visceral fat measured.

Results

Characteristics of Patients

Out of the 47 subjects that entered the study, 7 subjects withdrew after the first screening, and an additional 3 were lost at 9 patients in group C.one week, one month, and two months after At baseline, there were no significant difthe first followup respectively. One patient ferences among the three groups in terms of was excluded from the study due to engaging age, the proportion of female participation, in heavy exercise and losing over 20 pounds, race and ethnicity distribution, (except other and another patient because of heavy alcohol races participation), their blood pressure, fat abuse and interruptive behavior. distribution measured by DXA and CT scan,At the end of the study period, we had carotid artery intimal thickness, serum adipocomplete pairs of tests for 35 subjects; 11 panectin levels and adipocyte number per field tients in group A, 15 patients in group B, and measured.

Table 1. Characteristics of patients at randomization according to treatment group

 

Characteristic

Group A
Group B Group C P Value
Number
11 15 9  
 Age (YearM±SEM)
 41.9±3  41.8± 2.5  41.5± 3.7  0.75
 Female sex (%)
 8 (88.8)  11(73)  6(66)  0.25
 AA race (%)
 45  40  33  0.25
 Latina (o)s (%)
 55  33  55  0.25
 Other races (%)
 0  27  12  0.01
 BMI (kg/m2) (1825)

 38.2±1.2  39.9± 1.7  40.61± 1.7  0.82
 Abdominal circumference (cm)
 114.4±2.3  120.9± 3  124.3±5.4  0.29
  In females (< 80 cm)
 115.8±3.1  118.4± 3.7  121.6± 6.7  0.73
  In males (<94 cm)

 110±1.2  127.7±3.3  130.5± 9.7  0.35
 Waist to Hip ratio
 0.93±0.01  0.95± 0.01  0.96± 0.02  0.61
  In females (<0.95)

 0.92±0.02  0.94± 0.01  0.93± 0.03  0.96
  In males (<100 cm)

 0.96±0.02  1.01± 0.01  1.0± 0.02  0.49
 Right arm A circumference (cm)

 38.9±0.9  39.3± 0.7  42.2± 1.86  0.11
 Left arm Circumference (cm)
 39±1.04  39.3± 0.7  41.8± 2.1  0.28
 Left anterior arm fat thickness (mm)
 25±3.3  33.7± 2.1  29.7± 2.3  0.08
 Left posterior arm fat thickness (mm)
 32.25±4.2  38.25± 1.7  35.06± 3.0  0.33
 Suprailiac fat thickness (mm)
 30.6±2.8  36± 2.1  37.5± 3.1  0.19
 Fasting blood glucose (70110 mg/dL)
 78.3±2.68  90.4±2.2  84.4±3.21  0.01
         between A &B
 HOMA Index (IR)

 3.52±1.97  4.5±1.7  3.35±1.3  0.42
 HOMA Beta cells index (%)  48±9.89  45.8±6  64.3±13  0.30
 Total body fat by DXA (%)

 43±2.4  41.2±1.25  41±2.7  0.76
 Trunk fat by DXA (%)
 40.8±1.7  39.1±0.9  38.5±2.6  0.63
 Lower extremities fat by DXA (%)

 44±1.9  41.8±1.3  43.3±2.5  0.70
 Visceral BMI adjusted abdominal fat (mm2/BMI)

 2058±74.8  2330±205  2375±264  0.58
 Intramuscular BMI adjusted thigh fat (mm2/BMI)  521±40  445±37  437±56  0.40
 SubQ BMI adjusted thigh fat (mm2/BMI)

 332±22  401±15  470±38  0.25
 Visceral / total subQ fat ratio (adjusted)

 0.51±0.02  0.56±0.02  0.54±0.02  0.46
 IM/subQ fat ratio

 1.35±0.15  1.06±0.09  0.99±0.16  0.19
 Adiponectin levels (μg/mL)

 6.0±1.2  6.8±1.1  9.1±4.1  0.73
 Carotid artery intimal thickness (mm)
 0.73±0.01  0.79±0.02  0.80± 0.02  0.32
 Adipocyte numbers

 62±7.7  60±4.5  57±5.6  0.81

 

A; For all reference range please refer to http://www.kidney.org/PROFESSIONALS/kdoqi/guidelinesupdates/nut
appx07a.html and AR Frisancho New standards of weight and body composition by frame size and height for as
sessment of nutritional status of adults and the elderly. American Journal of Clinical Nutrition, Vol 40, 808819,1984; Group A received placebo, Group B received pioglitazone 30 mg once a day, and Group C received pioglitazone 45 mg a day.

Table 1 summarizes characteristics of the 35 subjects who completed the study. The mean age of subjects was 42±1.8 years; 75% were female, 45% were selfreported black and 42% Latinos and 12% were Asian or Caucasians. There was no significant difference between groups A, B, and C among variables measured (Table 1).

Changes during the Study Period

pared to group A. Visceral fat, measured by CAT scan, decreased in groups B and C, compared to group A, but not at a statistically significant level. However, in the thigh, there were significant increases in subcutaneous fat in group C compared to group A (Fig.1) and significant decrease in the intramuscular fat (Fig. 2). The ratio of intramuscular fat to subcutaneous fat was significantly different in group C compared to group A (Fig. 3). We did not observe any statistically significant change in the ratio of visceral to subcutaneous fat after 6 months of therapy between groups.

 

 

Fig. 1. Comparison of subcutaneous fat surface in the thigh as measured by square millimeters, obtained by midtight CAT scan at baseline and after 6 months treatment with placebo (group A), with pioglitazone 30 mg daily (group B), and with pioglitazone 45 mg daily (group C)
* Denotes P<0.05 within groups by Analysis of Variance

 

 

Fig. 2. Comparison of intramuscular fat surface as measured by square millimeters, obtained by midthigh CAT scan at baseline and after 6 months treatment with placebo (group A), with pioglitazone 30 mg daily (group B), and with pioglitazone 45 mg daily (group C)
* Denotes P<0.05 between groups by paired ttest and subscript a denotes p=0.05 by analysis of variance within groups A and C after the treatment

 

 

Fig. 3. Comparison of the mean of BMI adjusted intramuscular / subcutaneous fat ratio, obtained by midthigh CAT scan at baseline and after 6 months treatment with placebo (group A), with pioglitazone 30 mg daily (group B), and with pioglitazone 45 mg daily (group C)
* Denotes P<0.05 between Group by paired ttest and subscript a denotes p<0.05 by analysis of variance within Group C compared to group B and A

 

The serum levels of adiponectin at baseend of the study period the adiponectin levels line were not different within groups. At the in group A was 4.8±0.9 g/mL (p=NS within group A), in group B 12.0±2.6 (P<0.03 withtin from baseline were statistically significant in group B) and in group C 16.0±6.8 g/mL within groups by analysis of variance (Table2).

Table 2. Mean serum adiponectin levels at baseline and after 6 months treatment with placebo (group A), with pioglitazone 30 mg daily (group B), and with pioglitazone 45 mg daily (group C)

 

Group  Adiponectin μg/mL P between groups after therapy P within groups
Baseline After Therapy    
 A  6.0±1.2†
 4.8±0.9
 0.73 (A Vs B&C)  0.2
 B  6.8±1.1
 12.0±2.6
 0.10 (B Vs A)  0.03
 C  9.1±4.1
 16.0±6.8  0.3 (C Vs A)  0.04

† mean±SD

Multiple linear regression analysis showed statistically significant correlation between the levels of serum adiponectin at baseline and subcutaneous fat in the thigh, the intramuscular fat, and the ratio of intramuscular to subcutaneous fat (Multiple r=0.97, P<0.01) but not with visceral fat.A positive correlation was also observed with the change in subcutaneous fat in thigh and change in serum adiponectin levels (r=0.61; P=0.032) during the study period.Carotid artery intimal thickness increased by an average of 30 micron in group A, remained unchanged in group B, and decreased by 30 microns in group C. Within group analysis using paired Student’s ttest, indicated significant changes in group C only (Fig. 4).

 

Fig. 4. Comparison of the mean of carotid artery intimal thickness at 2 cm below carotid bifurcation measured by use of ultrasound at baseline and after 6 months treatment with placebo (group A) pioglitazone 30 mg daily (group B), and pioglitazone 45 mg daily (group C)
* Denotes P<0.05 within groups by paired ttest

 

 

Fig. 5. Comparison of the number of adipocytes at baseline from subcutaneous adipose tissue from abdomen and thigh (A1T1) counted per each field with X20 magnification and after 6 months treatment with placebo(group A), with 30 mg pioglitazone a day (group B), and with 45 mg pioglitazone (group C) a day.
* Denotes significant difference between groups by analysis of variance. No significant difference was observed before treatment and was only observed after the treatment.

The change in subcutaneous fat was concomitant with the histological changes seen in groups B and C. The number of adipocytes increased in group A, with no changes in groups B and C. Analysis of variance demonstrated significant difference in terms of the numbers of adipocytes in groups B and C, compared to group A (Fig.5). From a histological point of view, the adipose tissue membranes became straighter and less convoluted in groups B and C, but not in group A, where no morphological changes were seen (Fig. 6). Also, in groups B and C, the large adipocytes became larger on an average, possibly masking the number/field of any new, small adipocytes.

Discussion

In the present study of minority obese, but otherwise healthy, subjects (primarily African Americans and Latinos), we observed that 45 mg of pioglitazone daily, for 6 months, increases subcutaneous fat in the thigh, while it concomitantly decreases the intramuscular fat in this region; it also decreases carotid artery intimal thickness and increases adiponectin levels. Changes in intramuscular fat, subcutaneous fat, and visceral fat were also correlated with adiponectin levels.
Visceral fat differs significantly from peripheral fat depots in its metabolic activity and hormonal regulation. For instance, compared to the peripheral fat compartment, visceral fat has a greater turnover rate, a higher blood flow, higher density of lipolytic betaadrenergic, glucocorticoid, androgen receptors and has higher expression of GLUT4 than peripheral fat cells.21 Furthermore PPARgamma mRNA levels were significantly higher in visceral adipose tissue in obese subjects compared to lean subjects, indicating that relative PPARgamma expression is increased in omental fat in obesity.22

 

 

 

Fig. 6Comparison of adipose tissue of the thigh in a 45 year old female before (panels A) and after six months therapy with 45 mg/day pioglitazone (B) and from a 42 year old male (panels C before and D after 6 months treatment with 30 mg/day of pioglitazone)

Pioglitazone is known as an insulin sensitizer; while facilitating glucose disposal, it increases hepatic sensitivity to insulin (decreased glucose output by the liver under insulin effect) and decreases free fatty acid in serum, simultaneously facilitating its use/deposition by adipose tissue.23 The concomitant effects of pioglitazone on intramuscular fat and adiponectin levels, and their significant correlations, suggest a possible direct role of adiponectin on fat utilization in the muscle.
While facilitating more room for fatty acid deposition24 in adipose tissue, pioglitazone prevents free fatty acids from competing with glucose at the muscular level. However, as we and others have observed, pioglitazone increases the level of adiponectin,which is a hormone with several key effects on glucose and lipid metabolism. Adiponectin activates carnitine palmitoyltransferase1, malonylCoA decarboxylase, and mediumchain acylCoA dehydrogenase in the hepatocytes, 27 theoretically facilitating betaoxidation of fatty acids in the liver.28 It also activates carnitine palmitoyl transferase III and acetylCoA carboxykinase in muscle mitochondria,29 thereby accelerating glucose utilization in the Krebs cycle In hepato3031cytes, adiponectin suppresses glucose6phosphatase and phosphoenolpyruvate carboxykinase, as well as inhibiting gluconeogenic pathways independent of insulin. Hence, on the one hand, adiponectin facilitates entrance of free fatty acids into both adipocytes and hepatocytes and betaoxidation of free fatty acids in the mitochondria of the muscles and hepatocytes by enhancing fuel metabolism, and on the other, it also facilitates conversion of excess calories into fat32 as shown by the larger adipose tissues in our biopsy samples. The association observed between adiponectin and intramuscular fat (or with the ratio of intramuscular fat and subcutaneous fat) suggests the importance of better metabolism of fuel in obese subjects who are in excess of their reserve. It seems that pioglitazone not only increases the reservoir location for the triglycerides, but also facilitates their catabolism in the muscle through adiponectin, as observed in our study, with decreases in intramuscular fat. It is known that PPAR gamma agonists increase flux of fatty acids into adipocytes in rats by virtue of fatty acid transport protein genePPAR gamma response element.33 Sequestration of lipid in adipose tissue takes place, while wholebody resting or postprandial fat oxidation does increase in rats and humans,34 by increasing the uncoupling protein 2 expression however, not necessarily, causing weight loss but, rather, weight gain may be compensated by eating more; the reason for increases in food consumption is not yet understood during obesity.35Pioglitazone is also known to inhibit proliferation, hypertrophy, and migration of vascular smooth muscle cells (VSMC) induced by growth factors.36 These processes are crucial in the development of vascular remodeling, atherosclerosis, and diabetic organ complications. One important finding of our study is the decrease of intimal thickness in carotid arteries. Pioglitazone is known to decrease inflammatory cytokines secreted by macrophages thereby decreasing inflammatory processes leading to atherosclerosis.37 Also the fact that pioglitazone induced an increased apoptosis of macrophages suggests that the same phenomena might take place in carotid artery intima thus explaining rapid regression of carotid artery intimal thickness. The intimal thickness of carotid arteries has been shown as one of the best predictors of coronary artery disease and stroke.40 In our study, we saw an average decrease of carotid artery intimal thickness of 30 microns in subjects given 45 mg pioglitazone daily for 6 months. Whether this also implies decrease of intimal thickness, particularly in the lower extremities is not known, but theoretically it could be rapidly effective in alleviating ischemic limbs and be beneficial in terms of macrovasculopathy in diabetic subjects; in the same context, family members of a subject with history of stroke may benefit not only from aspirin but also from pioglitazone in delaying progression of the carotid artery atherosclerosis or cerebrovascular events.Surprisingly, a significant inverse relationship was observed between visceral fat measured by CAT scan and carotid artery intimal thickness. Taking into account the dynamic nature of adipose deposition, there seems to be a 20 to 30 year lapse between the start of visceral fat accumulation and development of advanced carotid artery atherosclerosis. Thus, it could be that at an early phase of metabolic syndrome, the accumulation of fat in abdomen is beneficial for preventing accelerated atherosclerosis. These vascular effects of pioglitazone provide additional mechanisms by which treatment of patients with visceral obesity using these agents might reduce cardiovascular risk.

Regarding study limitations, our study has a small sample size and hence limited power analysis. Further studies are clearly needed to address the role of pioglitazone in prevention of peripheral vascular disease in diabetic subjects and also in prevention of stroke in high risk obese subjects.A study of retroperitoneal fat pads in Zucker rats demonstrated an increase in adipocyte size and number, due to combined differentiating effect and an increase in biosynthesis of triglycerides.41 We were unable to confirm this observation, since the number of adipocytes per field was decreased and although they were larger, they also had a less convoluted membrane.
The recent observation of the decrease in number of macrophages in the adipose tissue due to increase in apoptosis induced by pioglitazone highlights the role played by adipose tissue in secreting TNFalpha and its consequences which is insulin resistance.These data provide a rationale for the use of PPARγ activators combined with physical activity for the treatment of visceral obesity and its hallmark, the insulin resistance.In conclusion, pioglitazone in healthy obese minority subjects was associated with redistribution of fat from intramuscular to subcutaneous fat depot and decline in carotid artery intimal thickness, all associated and correlated with changes in serum adiponectin levels. This study also suggests the use of pioglitazone, as an adjunct, in prevention of stroke and peripheral vascular disease in highrisk populations.

Acknowledgment

We would like to express our appreciation to Bernard Delacruz, PhD, for editing the manuscript, Ken Chiu, MD for his critical review of the manuscript, and Mayer Davidson, MD for his incredible support during the study. This study was supported by research gants from RCMINCRR (RR14616004, RR03026 and RR11145), and NIDDK (DK 49296 and DK 59627).

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