Expression of CRABP1, GRP, and RERG mRNA in clinically non-functioning and functioning pituitary adenomas.

BACKGROUND: Pituitary tumors account for approximately 10-15% of intracranial neoplasms. AIM: Using the cDNA microarray method, we have previously compared expression under two distinct conditions: a pool of 4 clinically non-functioning pituitary adenomas (NFPA) and a spinal cord metastasis of a non-functioning pituitary carcinoma, in order to gain biological insights into genomic changes of pituitary neoplasias. In the present study, we further investigated the mRNA expression of 3 selected genes previously described as being involved in other neoplasias based on a series of 60 pituitary adenomas: CRABP1 (cellular retinoic acid binding protein 1), GRP (gastrin-releasing peptide), and RERG (Ras-related, estrogen- regulated, growth inhibitor). MATERIAL AND METHODS: The expression of CRABP1, GRP, and RERG was determined by quantitative RT-PCR. RESULTS: A significantly higher content of CRABP1 mRNA was observed in NFPA compared to functioning adenomas, and PRL-secreting adenomas showed a lower expression of this gene compared to normal pituitary. A lower expression of GRP mRNA was detected in NFPA compared to normal pituitary and also to functioning adenomas. RERG mRNA was overexpressed in NFPA in comparison to functioning adenomas and to normal pituitary. Among the functioning adenomas, only the ACTH-secreting adenomas presented a higher expression of RERG mRNA compared to normal pituitary. CONCLUSIONS: The findings of differential expression of CRABP1 in prolactinomas and of RERG in NFPA compared to normal pituitary suggests that retinoic acid and estrogen receptor, respectively, could be involved in the tumorigenesis of these adenomas subtypes. Additional studies are required to further confirm this hypothesis.

Regulation of insulin-like growth factor-I and its receptor in rat aorta after balloon denudation. Evidence for local bioactivity.

Local production of growth factors may play a major role in vascular repair after injury. We examined the regulation of insulin-like growth factor-I (IGF-I) and its specific membrane receptor in balloon-denuded rat aorta. Aortic IGF-I mRNA and radioimmunoassayable IGF-I content increased severalfold after balloon denudation with a peak at 7 d after injury. This coincided with a reciprocal 25% decrease in IGF-I receptor mRNA content and a 40% decrease in total 125I-IGF-I binding. Scatchard analysis indicated a single class of binding sites, with a decrease in receptor number at 7 d compared to control and no change in affinity. By in situ hybridization the predominant site of IGF-I expression in the normal and the denuded vessel wall was the medial smooth muscle cell. After denudation there was a relative decrease in IGF-I receptor mRNA in the medial cells as compared to the neointima, suggesting that the site of IGF-I action was predominantly in the medial layer. These data suggest that local expression and action of IGF-I are significant in the promotion of smooth muscle cell proliferation after arterial injury.

Abundant expression of parathyroid hormone-related protein in primary rat aortic smooth muscle cells accompanies serum-induced proliferation.

Parathyroid hormone-related protein (PTHrP), which is responsible for producing hypercalcemia in patients with humoral hypercalcemia of malignancy, has recently been identified in several normal tissues. Because PTHrP, like parathyroid hormone (PTH), is known to exhibit vasodilatory properties, we investigated the expression and regulation of PTHrP mRNA in cultured rat aortic smooth muscle cells (SMC). We report here that PTHrP mRNA is expressed in SMC and is markedly induced by serum in a time- and concentration-dependent fashion. Addition of 10% fetal calf serum to serum-deprived, confluent cells, resulted in a marked induction of PTHrP mRNA by 2 h with a peak at 4-6 h. PTHrP was detected in SMC by immunocytochemistry and radioimmunoassay of conditioned medium, and was shown to be up-regulated within 24 h after the addition of serum. The serum induction of PTHrP mRNA was blocked by actinomycin D and by cycloheximide indicating the need for protein synthesis to evoke the serum effect on PTHrP gene transcription. In addition, treatment with dexamethasone, which has been previously shown to reduce the constitutive expression of PTHrP in human cancer cells, also blunted the serum induction of PTHrP mRNA in SMC. Treatment of quiescent cells with the serum mitogens platelet-derived growth factor or insulin-like growth factor-I had no effect on PTHrP, whereas the vasoactive peptides endothelin, norepinephrine and thrombin stimulated PTHrP expression. Exogenous addition of recombinant PTHrP-(1-141) had no significant effect on SMC DNA synthesis as measured by [3H]thymidine incorporation. In summary, the abundance of PTHrP mRNA and the characteristics of its regulation in SMC suggest a major role for PTHrP as a local modulator in vascular smooth muscle.

In vivo response to growth hormone-releasing peptide-6 in adrenocorticotropin-dependent Cushing's syndrome by lung carcinoid tumor is associated with growth hormone secretagogue receptor type 1a mRNA expression.

GH secretagogues (GHS) have been used for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS) since 1997 due to their ability to increase ACTH and cortisol levels in Cushing's disease. The aim of this study was to correlate ACTH response to GH-releasing peptide-6 (GHRP-6) in vivo with GH secretagogue receptor type 1a (GHSR-1a) mRNA expression in a patient with lung carcinoid tumor. The patient was a 26-yr-old male with diagnosis of ACTH-dependent CS. He presented negative responses to human CRH and desmopressin tests; yet, a significant increase in ACTH after the GHRP-6 test was observed. Sellar magnetic resonance imaging (MRI) showed slight posterior hypointensity, but bilateral petrosal sinus sampling did not show central gradient. Computed tomography (CT) and MRI of thorax/abdomen/cervical were negative and 111In-pentetreotide scintigraphy depicted abnormal uptake on the right lung. The patient was submitted to right thoracotomy for exeresis of lung nodule and hilar lymph node which were characterized as atypical lung carcinoid tumor and he presented clinical and laboratorial remission after surgery. GHSR-1a mRNA expression was studied with real-time quantitative PCR and tumor data were compared with fragments of normal lung and pituitary. There was a higher GHSR-1a expression in the lung carcinoid tumor as compared with normal tissues. The ACTH response to GHRP-6 in a patient with ectopic ACTH production by a lung carcinoid tumor was associated with GHSR-1a expression in the tumor tissue, suggesting an association between GHSR-1a mRNA overexpression and the in vivo response to GHS.

Dissociation between tumor shrinkage and hormonal response during somatostatin analog treatment in an acromegalic patient: preferential expression of somatostatin receptor subtype 3.

INTRODUCTION: About a third of acromegalic patients is resistant to available SS analogs (SA), octreotide (OCT) and lanreotide (LAN). Such resistance is related to reduction of SS receptor (SSTR) density or to a different expression of SSTR subtypes. There are 5 known SSTR subtypes. SSTR2 and SSTR5 are usually expressed in GH-secreting pituitary tumors, and both SA bind preferentially to SSTR2 and, to a lesser extent, to SSTR5. We herein describe an acromegalic patient who presented impressive tumor shrinkage without hormonal normalization during primary therapy with SA. MATERIAL AND METHODS: This 23-yr-old male acromegalic patient was treated with slow-release LAN (LAN-SR), 30 mg every 10 days for six months, followed by OCT-LAR, 30 mg every 28 days for an additional six months with a 75% tumor volume reduction but without GH and IGF-I normalization. Subsequently, he underwent pituitary surgery and expression of SSTR in the removed tumor was performed by real time RT-PCR by the 2-deltaCt method, using GAPDH as internal control. All PCR products were confirmed by automated sequencing. RESULTS: SSTR expression revealed an unusual profile, with almost exclusively expression of SSTR3. CONCLUSIONS: These unusual clinical and receptor subtypes profile suggest an important role of SSTR3 on tumor shrinkage. The low affinity of LAN and OCT for this SSTR subtype could be compensated by its high expression in this GH-secreting pituitary macroadenoma.

Endogenous hyperinsulinemic hypoglycemia: diagnostic strategies, predictive features of malignancy and long-term survival.

Diagnostic strategies, malignancy predictors and long-term survival were retrospectively evaluated in patients with hyperinsulinemic hypoglycemia (64 insulinomas). Lower median glycemia was 30 (range 20-53) mg/dl [1.6 (1.1-2.9) mmol/l] with concurrent insulin of 48 (13.2-217) microU/ml and 15 (2-46) microU/ml measured by radioimmunoassay (RIA) and immunofluorimetric assay (IFMA), respectively. All patients with insulinomas had a positive prolonged fast within 48 h. Sensitivity of localization methods was: ultrasonography (US) 23%, computed tomography (CT) 28%, magnetic resonance imaging (MRI) 65%, endoscopic US 75%, arteriography 38%, portal venous sampling 67%, selective arterial calcium stimulation 67%, intraoperative US 94% and palpation 92%. Nine patients (14%) had malignant insulinomas. Age at diagnosis (mean+/-SD, 53.8+/-19 vs 39.4+/-16.3 yr; p=0.03), insulin (1372+/-730 vs 785+/-659% (percentage of the method's diagnostic cut-off; 6 and 3 microU/ml for RIA and IFMA, respectively; p=0.007) and C-peptide levels (9.8+/-2.9 vs 3.9+/-2.8 ng/ml (3.2+/-0.9 vs 1.3+/-0.9 nmol/l; p=0.006), and tumor size (6.2+/-4.1 vs 1.5+/-0.6 cm; p=0.0002) were increased in malignant insulinomas. C-peptide level above 6.1 ng/ml (2.0 nmol/l) had a 100% sensitivity and 96% specificity, and tumor size above 2.6 cm yielded a sensitivity of 88% and specificity of 100% in predicting malignancy. Survival of patients with malignant insulinomas was significantly impaired (16 vs 100% at 5 yr; p=0.0000001). The diagnosis of insulinoma can be made within 48 h of fasting. The association between intraoperative US and palpation evidenced the tumor in 95% of the patients. C-peptide and tumor size were reliable malignancy predictors.

Association of single nucleotide polymorphisms in the gene encoding GLUT1 and diabetic nephropathy in Brazilian patients with type 1 diabetes mellitus.

Mesangial cells subject to high extracellular glucose concentrations, as occur in hyperglycaemic states, are unable to down regulate glucose influx, resulting in intracellular activation of deleterious biochemical pathways. A high expression of GLUT1 participates in the development of diabetic glomerulopathy. Variants in the gene encoding GLUT1 (SLC2A1) have been associated to this diabetic complication. The aim of this study was to test whether polymorphisms in SLC2A1 confer susceptibility to diabetic nephropathy (DN) in Brazilian type 1 diabetes patients. Four polymorphisms (rs3820589, rs1385129, rs841847 and rs841848) were genotyped in a Brazilian cohort comprised of 452 patients. A prospective analysis was performed in 155 patients. Mean duration of follow-up was 5.6 ± 2.4 years and the incidence of renal events was 18.0%. The rs3820589 presented an inverse association with the prevalence of incipient DN (OR: 0.36, 95% CI: 0.16 - 0.80, p=0.01) and with progression to renal events (HR: 0.20; 95% CI: 0.03 - 0.70; p=0.009). AGGT and AGAC haplotypes were associated with the prevalence of incipient DN and the AGAC haplotype was also associated with the prevalence of established/advanced DN. In conclusion, rs3820589 in the SLC2A1 gene modulates the risk to DN in Brazilian patients with inadequate type 1 diabetes control.

Pattern of thyrotropin and thyroxine plasma concentrations during the 24-hour sleep-wake cycle in the male rhesus monkey.

The 24-h pattern of the plasma TSH concentration was investigated in five male rhesus monkeys prepared chronically with right atrial catheters and electroencephalogram (EEG) electrodes. The preparation allowed frequent blood sampling (every 15 min), TV monitoring, and EEG recording from the adjacent room for extended periods of time from undisturbed animals. In addition, nap deprivation, 5 h total sleep deprivation, and specific sleep stage deprivation experiments were performed in order to test their influence on the TSH pattern. T4 was also determined in approximately half of the profiles during undisturbed conditions. Both TSH and T4 patterns consisted of low amplitude, high frequency fluctuations which, however, did not exceed the assay variation. TSH showed superimposed higher amplitude spikes at unpredictable times (0-5/24-h). Intra- and interanimal variabilities of both TSH and T4 patterns were high. Power spectral maxima of the TSH time series indicated periodicities between 30-75 min which were not significant. No nyctohemeral difference in the TSH or T4 pattern or their mean concentrations was found, and there was no consistent pattern of a circadian cycle. Independent changes of average TSH and T4 concentrations were seen in 5 of the 16 profiles during undisturbed conditions, under which both hormones were determined. Cross-correlation analysis of the hormonal time series revealed no significant relation between TSH and T4 patterns. The deprivation procedures had no significant influence on the day or nighttime pattern of TSH. Cross-correlation analysis showed no relation between TSH and either activity during the day or sleep stages during the night. It is concluded that in the rhesus monkey, in contrast to man, TSH secretion shows no circadian variation and is not influenced by the sleep-wake cycle.

Interferon-alpha therapy increases type I insulin-like growth factor receptors expression on lymphoid cells from patients with chronic myelogenous leukemia.

Aiming to verify if insulin-like growth factor type I and its receptor (IGF-IR) are implicated on pathophysiology of chronic myelogenous leukemia (CML), we studied 35 patients with CML in chronic phase at diagnosis or during interferon-alpha (IFN-A) or hydroxyurea treatments. Cytometry flow analysis and reverse transcription PCR (RT-PCR) molecular assay for IGF-IR expression on peripheral blood cells from CML patients diagnosed didn't show statistical differences from the control group. Hydroxyurea treated patients had lower expression of IGF-IR in granulocytes, lymphocytes and monocytes (P<0.01). We found statistical higher percentage of T and B lymphocytes positive for IGF-IR on IFN-A treated patients (P<0.001). Also an increase of IGF-IR mRNA expression could be detected in this group when compared with patients in hydroxyurea therapy (P<0.05). Our study suggest that IGF-IR is not directly implicated on CML installation and that the increased expression of IGF-IR on lymphoid cells of IFN-A treated patients could contribute to the immune recognition of malignant cell clone by enhancing immunocompetent cell proliferation and action.

The insulin-like growth factor-I system and hormone replacement therapy.

OBJECTIVE: To determine the effects of hormone replacement therapy on plasma concentrations of free and total insulin-like growth factor (IGF)-I, IGF binding protein (BP)-1, and IGFBP-3. DESIGN: Clinical study. SETTING: Gynecologic clinic at a university hospital. PATIENT(S): Seventy-one postmenopausal women. INTERVENTION(S): Six cycles of four different hormonal replacement therapy regimens: oral conjugated estrogens, transdermal estradiol, oral conjugated estrogens and norethisterone, and transdermal estradiol and norethisterone acetate. MAIN OUTCOME MEASURE(S): Blood samples were collected before and after treatment for measurement of free and total IGF-I, IGFBP-1, and IGFBP-3. RESULT(S): Conjugated estrogen replacement therapy is associated with a decrease in plasma concentration of total IGF-I and increase in concentrations of free IGF-I and IGFBP-1. Transdermal estrogens have no effect on total and free IGF-I and IGFBP-1 concentrations. Oral norethisterone plus conjugated estrogens increased free IGF-I and IGFBP-1 concentrations but did not change IGF-I concentrations. Transdermal conjugated estrogens plus norethisterone acetate increased free IGF-I concentrations but not total IGF-I or IGFBP-1 concentrations. The plasma concentration of IGFBP-3 did not change in any group. CONCLUSION(S): Alterations in total IGF-I concentration can occur depending on the route of hormone replacement therapy administration. Free IGF-I concentrations were elevated in all study groups except that treated with transdermal estrogens.

Analysis of gonadotropin pulsatility in hirsute women with normal menstrual cycles and in women with polycystic ovary syndrome.

OBJECTIVE: To study the relation between plasma gonadotropin pulsatility, androgen levels, and estrogen levels in patients with polycystic ovary syndrome (PCOS), in hirsute women with normal menstrual cycles, and in healthy women. DESIGN: Prospective study. SETTING: University medical center-based cellular and molecular endocrinology laboratory. PATIENT(S): Eight healthy women (group 1), 9 hirsute women with normal menstrual cycles (group 2), and 19 women with PCOS (group 3). INTERVENTION(S): Plasma concentrations of LH and FSH were measured by RIA every 15 minutes for 12 hours. MAIN OUTCOME MEASURE(S): Rhythmic parameters of 12-hour LH and FSH secretion. RESULT(S): Rhythmic parameters of 12-hour LH secretion were significantly higher in patients with PCOS (group 3) than in controls (group 1) or in hirsute women with normal menstrual cycles (group 2). The frequency of LH pulses was statistically higher in patients with PCOS (group 3) than in controls (group 1). Statistically significant correlations were found when the frequency of LH pulses was plotted against basal LH concentrations and rhythmic parameters of 12-hour LH secretion. CONCLUSION(S): Luteinizing hormone pulse amplitude was higher in patients with PCOS than in hirsute women with normal menstrual cycles or in healthy women. The LH pulse frequency was increased only in patients with PCOS compared with healthy women and not in hirsute women with normal menstrual cycles.

The source(s) of estrogen production in hirsute women with polycystic ovarian disease as determined by simultaneous adrenal and ovarian venous catheterization.

To determine the significant source(s) of estrogen production in women with polycystic ovarian disease (POD), 12 women underwent selective adrenal and ovarian vein catheterization, with simultaneous peripheral blood samplings for determination of cortisol, androstenedione (delta 4A), testosterone, estrone (E1), and estradiol (E2). Ovarian vein E2 gradients were observed in 11 of the 12 patients with a mean of 13.4, whereas adrenal blood samples did not demonstrate significant E2 gradients. Seven of 8 patients exhibited ovarian secretion of E1, with a mean gradient of 13.6 times that of peripheral blood, whereas 4 of the 8 adrenal samples showed E1 gradients. The mean value was 1.4 times peripheral levels. No significant correlations were found between peripheral E1 levels and body weight or degree of adiposity, nor was there a relationship between obesity and E1/delta 4A molar ratio in peripheral blood. The subjects with the highest ovarian delta 4A levels had a significant correlation between peripheral delta 4A and E1. Therefore, our data indicate a significant contribution of ovarian E1 secretion to the peripheral E1 pool in addition to the extraglandular conversion of delta 4A to E1. There was general lack of correlation between peripheral E1 concentrations and plasma E2, and these relationships versus body size suggest that the major source of E2 in women with POD was ovarian secretion.

Short- and long-term gliclazide effects on pancreatic islet cell function and hepatic insulin extraction in non-insulin-dependent diabetes mellitus.

Nine non-obese males with non-insulin-dependent diabetes mellitus (NIDDM) were evaluated before and after 3 and 12 months (6 patients) treatment with the second generation hypoglycemic sulfonylurea: gliclazide. They underwent an oral glucose tolerance test, intravenous glucose and arginine tests measuring plasma insulin and C-peptide responses. Pre-hepatic insulin production and insulin delivery to peripheral tissues were calculated by deconvolution techniques and hepatic extraction of insulin estimated. An improvement was observed in the beta-cell function of the patients on gliclazide treatment: reduction of fasting plasma glucose associated with a progressive increase in C-peptide level but insulin levels decreased at 12 months, suggesting an increase in hepatic insulin extraction at this time. In the same way, while plasma glucose values after oral and i.v. glucose were greatly reduced at 3 and 12 months treatment, insulin did not change but C-peptide levels increased significantly at 12 month treatment. While the prehepatic insulin secretion rate increased progressively on gliclazide during all glucose challenges, the fractional hepatic insulin extraction fell after 3 and increased at 12 month treatment, with opposite changes in insulin delivered to peripheral tissues. Thus the insulinogenic effect of gliclazide could be masked during long-term administration by a concomitant effect of gliclazide which increases hepatic extraction of insulin. The maintenance of the responsiveness to the non-glucose secretagogue, arginine, as evaluated by the C-peptide levels, before and after correction of hyperglycemia, suggested improvement of beta-cell sensitivity to glucose after sulfonylurea treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of fat distribution on the pharmacokinetics of cortisol in obesity.

OBJECTIVE: Patients with predominantly upper body obesity are at greater risk for developing diabetes mellitus, hyperlipidemia, hypertension, and cardiovascular disease. Little is known about the mechanisms involved in the regulation of regional body distribution. It has been accepted that the accumulation of fat into adipose tissue depends on regional metabolic regulation of adipocytes and that glucocorticoids play a role in this mechanism. The aim of the present study is to investigate how the pharmacokinetics of cortisol correlate to intraabdominal and subcutaneous fat distribution in obese patients. METHODS: A group of 24 obese patients (13 males and 11 females) were submitted to a CT scan for intraabdominal and subcutaneous fat area evaluation. A 30-min cortisol infusion (0.25 mg/kg) was administered and plasma cortisol was measured over 6 hours. RESULTS: Patients with larger intraabdominal fat areas were found to have a higher cortisol clearance than those with lower intraabdominal fat areas. Cortisol clearance (both, absolute and body-weight corrected) showed a statistically significant correlation with intraabdominal fat area, either expressed by waist-hip ratio or obtained by computerized tomography. CONCLUSIONS: These findings indicate a more effective clearance capability for cortisol in patients with central obesity resulting in lowered cortisol plasma levels despite an increased cortisol secretion observed in this patient group.

Expression of neurotensin and its receptors in pituitary adenomas.

The neurotensin (NT) produced in the hypothalamus and in pituitary gonadotrophs and thyrotrophs participates in neuroendocrine regulation. Recently, the involvement of this peptide in normal and neoplastic cell proliferation has been postulated. In the present study, we evaluated the expression of NT and its receptors (NTR1, 2 and 3) in a series of 50 pituitary adenomas [11 growth hormone (GH)-, eight prolactin (PRL)-, four adrenocorticotrophic hormone (ACTH)- and 27 nonfunctioning adenomas]. NT mRNA expression was significantly higher in functioning compared to nonfunctioning adenomas and with normal pituitary. Nonfunctioning pituitary adenomas showed lower expression of NT mRNA than normal pituitary. In the immunohistochemical study of functioning adenomas, NT was colocalised with GH, PRL and ACTH secreting cells. In nonfunctioning adenomas, the NT immunoreactivity intensity was variable among the samples. NTR3 mRNA expression was observed in all examined samples and was higher in the adenomas, both functioning and nonfunctioning, compared to normal pituitary. By contrast, NTR1 and NTR2 mRNA were not detected in either pituitary adenomas or normal tissue. The higher expression of NTR3, as well as the expression of NT by tumoural corticotrophs, lactotrophs and somatotrophs, which are cells types that do not express this peptide in the normal pituitary, suggests that NT autocrine and/or paracrine stimulation mediated by NTR3 may be a mechanism associated with the tumourigenesis of functioning adenomas.

Metallothionein isoform 3 gene is differentially expressed in corticotropin-producing pituitary adenomas.

In order to search for candidate genes related to pituitary adenoma aggressiveness, the present investigation was intended to compare the mRNA expression profile from a pool of four nonfunctional pituitary adenomas (NFPA) with a spinal cord metastasis of a nonfunctional pituitary carcinoma (MNFPC). The metallothionein isoform 3 (MT3) gene was differentially expressed in nonfunctional adenomas in comparison to the metastasis of nonfunctional carcinoma. A microarray dataset comprising 19,881 probes was employed for comparing expression profiles of a spinal cord metastasis of a nonfunctional pituitary carcinoma with a pool of four nonfunctional pituitary adenomas. RT-qPCR confirmed the microarray findings and was used to investigate MT3 mRNA gene expression in tumor samples of a series of 52 different pituitary adenoma subtypes comprising 10 corticotropin (ACTH)-producing, 18 growth hormone (GH)-producing, 8 prolactin (PRL)-producing, and 16 nonfunctional adenomas. Microarray data analysis by GeneSifter program unveiled Gene Ontology terms related to zinc ion-binding activity closely related to MT3 function. MT3 mRNA expression was statistically significantly higher in ACTH-producing pituitary adenomas and in nonfunctional pituitary adenomas in comparison to the other pituitary adenoma subtypes. The more abundant expression of this gene in ACTH-producing pituitary adenomas suggests that MT3 could be related to distinct pituitary cell lineage regulating the activity of some transcription factor of importance in hormone production and/or secretion.

Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome.

Visceral adipose tissue (VAT) imaged by computed tomography (CT) or magnetic resonance imaging (MRI) is associated with the metabolic syndrome features, being morphologically and functionally different from subcutaneous adipose tissue (SAT). Insulin effect is lower and catecholamine effect higher in visceral adipose tissue, with its metabolites and its secretions draining through portal system, partially at least, to the liver. Thus, visceral cells transfer and release fatty acids more extensively, have increased glucocorticoid and reduced thiazolidinedione responses, produce more angiotensinogen, interleukin-6 and plasminogen activator inhibitor-1, and secrete less leptin and adiponectin than SAT. Furthermore, there are regional differences in the intrinsic characteristics of the preadipocytes, with those of SAT presenting greater differentiation and fat cell gene expression but less apoptosis than that of VAT. All features contribute to the morbidity associated with increased VAT. To evaluate the relationship between VAT and components of the metabolic syndrome, 55 non-diabetic women, 11 lean (VAT < 68 cm 2) and 44 obese were studied. The obese with VAT within the normal range (VAT < or = 68 cm 2) had higher BMI, WHR, BP and resistance to FFA suppression during oGTT in comparison to the lean controls. The obese with VAT > 68 cm 2 compared to those with VAT < or = 68 cm 2 had similar body mass index (BMI) but significantly higher in vivo homeostasis model assessment for insulin resistance (HOMA IR ) results and triglycerides. By pooling all data, correlation analysis indicated that VAT contributes more to insulin resistance (HOMA IR ) than SAT does, but not when insulin-suppressed plasma free fatty acids during oral glucose tolerance test as an index of insulin resistance are taken into consideration.