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It has been suggested that a low grade inflammatory state could predispose for developing insulin resistance and contribute to the development of obesity and type 2 diabetes. Corticosteroid-binding globulin (CBG), the main plasma protein transport for cortisol, has been shown to be negatively regulated by insulin and IL-6, at least in vitro, suggesting that insulin resistance and inflammation may both contribute to decreasing CBG levels. In the present study we measured CBG concentrations in a human healthy population and investigated the relationships of CBG with anthropometric and biochemical markers for inflammation and/or insulin resistance. The data showed that the mean serum CBG level was significantly lower in males (n = 151) than in females (n = 113; 32.5 +/- 9.1 vs. 39.2 +/- 13.9 mg/liter; P < 0.0001). In both sexes serum CBG levels were correlated negatively with age (r = -0.12; P = 0.04), body mass index (r = -0.31; P < 0.0001), waist to hip ratio (WHR; r = -0.39; P < 0.0001), systolic (r = -0.15; P < 0.01) and diastolic (r = -0.15; P = 0.01) blood pressures, and HOMA, an index of insulin resistance (r = -0.12; P = 0.04). In addition, the CBG concentration was negatively associated with serum IL-6 concentrations (r = -0.23; P = 0.017) and with the soluble fraction of TNFalpha receptors, soluble TNF receptor 1 (sTNFR1; r = -0.35; P < 0.0001), and sTNFR2 (r = -0.56; P < 0.0001) in women. A stepwise regression analysis using CBG as an independent variable showed that sex (P < 0.00001), body mass index (P = 0.0002), and HOMA (P = 0.0005), but not systolic blood pressure, diastolic blood pressure, IL-6, sTNFR1, or sTNFR2, constituted significant independent factors that explained 21% of the CBG variance (14%, 2%, and 5%, respectively). In a subsample of 120 men and 68 women, fasting serum free cortisol (calculated as the ratio fasting cortisol/CBG) was significantly associated with WHR (r = 0.24; P = 0.001), systolic (r = 0.18; P = 0.01) and diastolic (r = 0.19; P = 0.007) blood pressures, and HOMA value (r = 0.20; P = 0.005), but not with BMI or age. BMI (P < 0.0001), free cortisol (P = 0.003), and CBG (P = 0.009), but not WHR and age, contributed to 20%, 6%, and 8%, respectively, of HOMA variance in women in a multiple regression analysis. In this model only BMI (P < 0.0001) independently contributed to HOMA variance in men. These findings support the hypothesis that the CBG level is an interesting indicator for both insulin resistance and low grade inflammation. Whether the decrease in CBG levels is genetic by nature or directly associated to increased insulin and/or IL-6 merits further investigation. Nevertheless, because CBG has been shown to be expressed by the adipose tissue, decreased CBG could create locally increased cortisol disposal, with no change in circulating cortisol, and facilitate fat accumulation, insulin resistance, and type 2 diabetes.

Tumor necrosis factor-alpha (TNF-alpha) is increasingly recognized as a key component in the development of insulin resistance and increased blood pressure. In a sample of 368 individuals, the ratio of soluble TNF-alpha receptors (sTNFR2/sTNFR1) correlated positively with systolic and diastolic blood pressure (P < 0.01). This ratio was significantly greater in type 2 diabetic subjects (DM-2) than in type 1 diabetic patients and was greater than in control nondiabetic subjects (P < 0.00001). The TNF-alpha receptor 1 (TNFR1) density in peripheral blood monocytes was similar in DM-2 patients and in nondiabetic subjects. After phorbol 12-myristate 13-acetate, TNFR1 shedding was significantly decreased in DM-2 compared with control subjects, and it was directly associated with insulin sensitivity (r = 0.54, P = 0.03). Serum sTNFR1 concentration was also linked to the vasodilatory response to glyceryltrinitrate (P = 0.01). Conversely, TNF-alpha receptor 2 shedding was negatively associated with insulin sensitivity (r = -0.54, P = 0.03), whereas shedding of L-selectin showed no significant association. After exercise-induced lowering of blood pressure, a parallel decrease in sTNFR2/sTNFR1 was observed in DM-2 patients. Our findings suggest that insulin resistance and blood pressure are linked to altered shedding of TNF-alpha receptors in DM-2. The latter seems reversible and is not genetically determined.

There is increasing evidence that systemic inflammation and insulin resistance constitute interrelated events that contribute to atherosclerosis. We studied the effect of the association between circulating interleukin 6 (IL-6) levels, one of the major mediators of inflammation, and C-reactive protein on insulin resistance and blood pressure in 228 healthy volunteers. The plasma IL-6 concentration was significantly and similarly associated with systolic (SBP) and diastolic (DBP) blood pressure, fasting insulin, and the fasting insulin resistance index (FIRI) in all subjects. When smokers were excluded from the analysis, plasma IL-6 levels correlated with percent fat mass (r = 0.19; P = 0.02), absolute fat mass (r = 0.17; P = 0.03), SBP, DBP, fasting insulin levels, and FIRI. The latter associations persisted after controlling for body mass index (r = 0.15 and r = 0.19; P = 0.02 and P: = 0.0004 for SBP and DBP, respectively; r = 0.24 and r = 0.19, P = 0.004 and P = 0.03, for fasting insulin and FIRI, respectively). Gender and smoking status significantly influenced the results. Although IL-6 levels were significantly associated with fasting insulin and FIRI in men, these significant correlations were not observed in women. Conversely, although IL-6 levels were significantly associated with SBP and DBP in women, these coefficients were not statistically significant in men. All of these associations were lost among smokers and remained significant in nonsmokers. As IL-6 is the major mediator of the acute phase response by hepatocytes and induces the synthesis of C-reactive protein (CRP), we also controlled for the latter. Serum CRP levels correlated significantly with IL-6 in all the subjects, but mainly in nonsmokers and men. Of note was that this significant relationship was lost among smokers. CRP was associated with fasting insulin (r = 0.28; P < 0.0001) and FIRI (r = 0.25; P < 0.0001), but not with SBP or DBP (P = NS), in all subjects. Unlike IL-6, the associations between CRP and these parameters were similar in men and women and in smokers and nonsmokers. For insulin and FIRI they were stronger in women and in nonsmokers. CPR significantly correlated with the WHR only in men (r = 0.22; P = 0.01). Using multiple linear regression in a stepwise manner to predict circulating IL-6 levels, smoking status (P = 0.0059) and FIRI (P = 0.03), but not fat mass or SBP, independently contributed to 11% of its variance in men. When CRP was introduced into the model, the latter (P < 0.0001) and smoking status (P = 0.02), but not FIRI, fat mass, or SBP, contributed to 33% of the variance in IL-6 levels. In women, only SBP (P = 0.04) contributed to 5% of its variance. When CRP was introduced into the model, again only SBP (P = 0.01) contributed to 10% of the variance in IL-6 levels. In 25 of these subjects, insulin sensitivity was determined using the frequently sampled iv glucose tolerance test with minimal model analysis, and circulating IL-6 levels were strongly associated with the insulin sensitivity index (r = -0.65; P < 0.0001). Again, this relationship was even stronger in men (r = -0.75; P < 0.001) and was not significant in women (r = -0.26; P = NS). In all of these subjects, only insulin sensitivity (P = 0.0037), not fat mass, contributed to 21% of the variance of IL-6 levels in a multiple linear regression analysis. In summary, circulating IL-6 levels, by inducing either hypertension in women or insulin resistance in men, constitute a significant proatherogenic cytokine. The mechanisms of these associations should be further investigated.

Background: Interleukin 6 (IL-6) is thought to play important roles in the development of reactive thrombocytosis caused by inflammation by its stimulatory effect on megakaryocytopoiesis. A G/C polymorphism of the IL-6 gene at position -174 has been found to be associated to different transcription rates. Specifically, subjects with the CC genotype showed lower plasma IL-6 levels compared with GC or GG subjects. Given this difference in transcription rates of IL-6 we speculated on different platelet count according to this IL-6 polymorphism., Methods: The G/C polymorphism of the IL-6 gene at position -174, serum IL-6 concentration and platelet count were prospectively analyzed in 59 (25 women) consecutive healthy subjects., Results: Subjects who were homozygotes for the C allele at position -174 of the IL-6 gene (Sfa NI genotype) showed significantly lower platelet count than carriers of the G allele, despite similar age, sex, body mass index and proportion of smokers (205400 +/- 44088 vs 239818 +/- 60194, p = 0.047). This was in parallel to differences in peripheral white blood cell count (5807 +/- 1671 vs 6867 +/- 1192 x 10(9)/ml, p = 0.01)., Conclusion: This is the first description, to our knowledge, of a genetical influence on basal platelet counts, which appears to be partially dependent on a polymorphism of the IL-6 gene, even in the absence of inflammation.

Background: Iron-dependent free radicals formation has been related to greater damage in cerebral ischemia. The authors analyzed whether increased body iron stores were associated with early neurologic worsening and excitatory amino acid release in patients with acute ischemic stroke., Methods: Ferritin, total iron, and glutamate concentrations in plasma and CSF were measured on admission in 100 consecutive patients with a cerebral infarction of <24 hours' duration. The authors diagnosed progressing stroke when the Canadian Stroke Scale score decreased one or more points between admission and 48 hours. Cranial CT was performed on admission and repeated on days 4 to 7 of hospitalization., Results: Ferritin concentrations in plasma (median 391, range 119 to 500 versus 148, 21 to 399 ng/mL) and in CSF (17.4, 6.8 to 82, versus 4.8, 0.6 to 14 ng/mL) were significantly higher in the 45 patients with subsequent progressing stroke than in those with nonprogressing stroke (p < 0.001). There was a positive correlation between ferritin and glutamate concentrations in plasma (r = 0.81, p < 0.001) and CSF (r = 0.64, p < 0.001). Plasma ferritin concentrations >275 ng/mL in plasma (OR, 33.5; 95% CI, 4.7 to 235) and >11 ng/mL in CSF (OR, 11.4; 95% CI, 3. 1 to 41) were independently and significantly related to early neurologic worsening. The effect was reduced by >60% after controlling for glutamate concentrations, but remained significant., Conclusions: High plasma and CSF ferritin concentrations within the first 24 hours from the onset of ischemic stroke are associated with early neurologic deterioration. Increased body iron stores may contribute to stroke progression by enhancing the cytotoxic mechanisms in cerebral ischemia.

Background: A direct relationship between body mass index (BMI), visceral adipose tissue, insulin levels and growth hormone-binding protein (GHBP) activity has consistently been reported. It was recently described that GHBP directly depends on serum leptin levels. Since leptin co-varies with insulin secretion and/or sensitivity, we aimed to study the influence of these variables on plasma GHBP activity., Subjects: In order to isolate the effects of obesity per se from those of insulin secretion, three groups of subjects were prospectively studied: 14 lean, 10 obese and nine obese subjects with glucose intolerance., Measurements: The percentage of body fat was measured through bioelectric impedance. Insulin sensitivity and secretion were determined through a frequently sampled intravenous glucose tolerance test with minimal model analysis. Serum leptin was measured by radioimmunoassay. GHBP activity was determined by the high performance liquid chromatography-gel filtration method., Results: Plasma GHBP activity was found to correlate with BMI (r = 0. 65, P < 0.0001), fat mass (r = 0.51, P = 0.003), waist circumference (r = 0.64, P < 0.0001), waist-to-hip ratio (r = 0.42, P = 0.01), insulin sensitivity (SI, r = - 0.61, P = 0.0001), insulin secretion (expressed as the acute insulin response to intravenous glucose, AIRg) (r = 0.48, P = 0.006) and leptin concentration (r = 0.49, P = 0.004). The associations with SI (r = - 0.42, P = 0.02) and AIRg (r = 0.38, P = 0.03) persisted even after controlling for fat mass. Since insulin secretion and insulin sensitivity usually covary in glucose tolerant subjects (an increased insulin secretion is necessary to compensate a decreased insulin sensitivity), we constructed a multiple linear regression to predict GHBP activity. In this model, SI (P = 0.005), AIRg (P = 0.02) and SD score-leptin (P = 0.03) independently contributed to 34, 10 and 8% of the variability in serum GHBP activity., Conclusions: Our results suggest that plasma GHBP activity is simultaneouslly influenced by insulin secretion and sensitivity and leptin. Perhaps leptin, through increased insulin secretion, might induce GHBP/GH secretion, explaining the normal to high insulin-like growth factor (IGF)-I levels found in overnutrition.

Introduction: The beta 3-Adrenergic receptor (beta 3AR) and leptin are molecules involved in the regulation of energy balance. Recently, a mutation in the beta 3AR gene (Trp64Arg) has been reported to be associated with features of insulin resistance, weight gain and early onset of Type 2 Diabetes Mellitus. The aim of this study was to determine the frequency and clinical characteristics of the Trp64Arg mutation in the beta 3AR gene in Type 2 diabetic patients, its relationship with leptin levels, and its role in microangiopathic complications., Subjects and Methods: 187 Type 2 diabetic patients and 100 unrelated non-diabetic subjects were studied. There was no difference between the diabetic and nondiabetic subjects in the frequency of the Trp64 and Arg64 alleles (92.5% vs. 92.3% and 7.5% vs. 7.7%, respectively). Type 2 diabetic patients were divided into two groups according to the presence (n = 27) or absence of the mutation (n = 160)., Results: Mutation of the beta 3AR gene was not associated with any differences either in the clinical and metabolic parameters or microangiopathic complications. Type 2 diabetic patients carrying the Arg64 allele tended to have a lower diabetes duration, but this was not statistically significant. Plasma leptin levels were not different according to the beta 3AR genotype., Conclusions: The Trp64Arg mutation is not a major determinant of Type 2 diabetes and its microangiopathic complications. Moreover, this mutation was not clinically relevant in leptin regulation.

Background and Purpose: Although iron-mediated mechanisms are important in experimental brain injury after carotid occlusion, their clinical role in acute ischemic stroke has not been determined. We evaluated the influence of iron stores, measured as serum ferritin, on the outcome of acute cerebral infarct., Methods: Admission and fasting glycemia, glycosylated hemoglobin, serum cortisol, serum ferritin, and 24-hour urinary free cortisol levels were measured on the first day of hospitalization in 67 patients admitted with an acute ischemic stroke of less than 24 hours' duration. Patients were classified into two groups according to their Canadian Stroke Scale (CSS) score on day 30: good outcome group (alive and CSS score > 7 points) and poor outcome group (dead or CSS score < or = 7 points)., Results: Thirty-three patients (49%) had good outcome and 34 (51%) poor outcome. Fasting glycemia (P = .001), serum cortisol (P < .001), and urinary free cortisol (P = .001) but not admission glycemia and glycosylated hemoglobin had higher levels in patients with poor outcome. Serum ferritin values were greater in the poor outcome group (218 +/- 156 micrograms/L versus 133 +/- 125 micrograms/L; P = .004), and a correlation between ferritin values and degree of worsening or improvement of the CSS score on day 30 was found (P = .002). Serum cortisol (odds ratio [OR], 6.7; 95% confidence interval [CI], 1.7 to 26), fasting glycemia (OR, 5.4; 95% CI, 1.2 to 24), and serum ferritin (OR, 4.6; 95% CI, 1.1 to 19) were independently related to poor outcome in a logistic regression analysis., Conclusions: High serum ferritin levels within the first 24 hours of hospitalization for an acute ischemic stroke are related to a poor prognosis, independent of the stress response. More research is needed to determine the origin of increased serum ferritin levels and the therapeutic implications.

The computed tomographic (CT) findings in five patients with tuberculous Addison's disease were evaluated. All patients had extra-adrenal tuberculosis. Two patients had enlarged adrenal glands with calcifications at the times of diagnosis. Follow-up CT from 4 to 30 months showed a progressive decrease in the size of adrenal glands from bilateral enlargement to small calcified glands and provides a clue to the etiology of Addison's disease and proper therapy.