Background. Obesity promotes a low-grade systemic inflammatory state that may act on the lung to exacerbate asthma. There is little information on the relationship between systemic inflammation and lung function in children and adolescents. Objectives. To explore the relationship among fibrinogen, plasminogen activator inhibitor-1 (PAI-1), lung function in adolescents with the presence of asthma, and/or obesity. Methods. Totally 178 adolescents (boys and girls) were involved; four groups were divided according to their diagnosis: non-obese and non-asthmatic controls (n = 38), non-obese asthmatics (n = 31), obese non-asthmatics (n = 62), obese asthmatics (n = 47). The levels of PAI-1 and fibrinogen were determined in blood samples. The lung function was evaluated with spirometry by measuring forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and forced expiratory flows between 25 and75% (FEF25–75%). Results. Compared to healthy controls, obese adolescents with or without asthma show higher levels of fibrinogen (289.2 ± 61.5, 328.4 ± 54.9, and 324.9 ± 68.9 mg/dL, respectively), PAI-1 (36.0 ± 17.3, 53.2 ± 22.3, and 52.6 ± 24.7 ng/mL, respectively), and the reduced FEV1/FVC ratio (87.7 ± 7.7, 81.6 ± 8.6, and 81.7 ± 6.9, respectively). In the whole studied subjects, FEV1/FVC ratio shows significant inverse correlation with PAI-1 (r = −0.185), fibrinogen (r = −0.157), body mass index (BMI; r = −0.303), insulin(r = −0.198), and HOMA (r = −0.173). In the 78 asthmatic subjects, FVC correlates positively with BMI. Conclusion. Our data demonstrate that the degree of systemic inflammation and the degree of obesity in the whole studied adolescents groups correlate negatively with lung function, suggesting an obstructive pulmonary pattern. Further studies are needed to identify the pathophysiological mechanism for such association.

Background. Hyperuricemia has been associated with an increased risk of endothelial dysfunction (ED), cardiovascular and renal disease. The role of uric acid (UA) on vascular damage is still controversial because previous studies have included patients with other risk factor for ED. Objective. To determine if the treatment with allopurinol improved endothelial function in hyperuricemic patients without other risk factors for ED. Material and methods. In order to gain more insight about the contribution of UA to the ED, we screened 369 apparently healthy male individuals for UA in a period of 9 months. Only 9 patients fulfill the inclusion criteria: UA plasma levels > 7 mg/dL without other risk factors for ED such as hypercholesterolemia, obesity, diabetes and hypertension. Results. Endothelial function, assessed by flow mediated dilatation (FMD) in the brachial artery improved significantly after 30 days of allopurinol treatment (9.6% [6.3–13.3%] vs. 13.7% [11–14.7%], p = 0.036), concomitantly with a decrease of about 45% in the uric acid plasma levels. Other parameters were not modified by allopurinol treatment. Any No significant correlation was found (r = –0.367, p = 0.33) between the ΔUA plasma levels (UA after treatment – UA in basal conditions) and ΔFMD (FMD after treatment – FMD in basal conditions). Conclusions. These results strongly suggest that allopurinol improves flow-mediated vasodilation regardless of uric acid plasma concentrations.

Objectives. We tested the hypothesis that 25-hydroxyvitamin D3 (25OHD) changes during acute inflammation in humans. Methods. Patients with first episode of acute pancreatitis were included. Blood samples were acquired on admission and on days 1, 2, and 14. Results. In total, 73 patients (35 males, median age 59) entered the study. On admission, the distribution of 25-OHD levels was as follows: severely deficient (<13 nmol/L) 23%; deficient (13–25 nmol/L) 20%; insufficient (26–50 nmol/L) 40%; and normal (<50 nmol/L) 17%. There was a significant fall and linear trend in 25OHD, albumin, and hemoglobin from day 0 to day 2. From day 0 to day 2 the drop in 25OHD was 3.1 nmol/L (95% CI 0.59–5.63). The changes from day 0 to day 2 in 25OHD were associated with changes in C-reactive protein (p = 0.02) but not with leukocyte or monocyte count. Conclusions. The 25OHD levels dropped during the first 2 days of acute pancreatitis beyond what was expected based on 25OHD half-life. This study supports our hypothesis that an acute inflammatory condition utilizes 25OHD, but other mechanisms could interfere.

Background. Fibroblast growth factor (FGF)-21 has been recently characterized as a potent metabolic regulator, but the physiological role of FGF-21 remains poorly understood. This study was designed to investigate serum FGF-21 levels in type 2 diabetes mellitus (T2DM) patients and explore the correlations between its serum levels and various cardiometabolic parameters in humans. Methods. Fifty-four newly diagnosed patients with T2DM (NDDM), 54 subjects with long duration of T2DM (LDDM), that is, more than 5 years, and 35 normal controls participated in this study. Fasting serum FGF-21 levels were measured using ELISA kits. The anthropometric parameters, glucose, glycosylated hemoglobin A1c, lipids, insulin, and high-sensitive C-reactive protein (hsCRP) levels were also measured in fasting status. Results. Serum FGF-21 levels were significantly higher in patients with NDDM and LDDM than in controls (361.80 ± 140.28 pg/mL and 351.17 ± 133.44 pg/mL vs. 185.89 ± 59.29 pg/mL, both p < 0.01), but there was no difference in serum FGF-21 levels between NDDM and LDDM. Fasting serum FGF-21 was found to correlate positively and significantly with age, waist-to-hip ratio, systolic blood pressure, fasting plasma glucose, glycosylated hemoglobin A1c, homeostasis model assessment (HOMA) of insulin resistance, and hsCRP, but negatively with HOMA of β-cell insulin secretion. Furthermore, multiple regression analyses showed that fasting insulin, HOMA of insulin resistance, low-density lipoprotein cholesterol, and hsCRP were independent factors influencing serum FGF-21 levels. Logistic regression analyses demonstrated that serum FGF-21 was significantly associated with T2DM. Conclusions. Serum FGF-21 levels were significantly increased in patients with T2DM. They may play a role in the pathogenesis of T2DM.

Introduction. We previously demonstrated increases in β-adrenergic receptor (β-AR) density in rat liver, in association with increased β-AR-mediated stimulation of glucose output in rat hepatocytes, during senescent aging. We therefore hypothesized that pharmacologic β-adrenergic stimulation might induce insulin resistance and glucose output in liver of aging rats in vivo. Methods. In this study, pancreatic clamps were performed on young adult (4-month-old) and senescent (24-month-old) Fischer 344 male rats by infusing somatostatin (3 μg/kg/min) at time 0 to inhibit insulin secretion, and then infusing insulin (1 mU/kg/min) to replace basal insulin concentrations. At time 0 rats also received either the β-AR agonist isoproterenol (100 ng/kg/min) or saline (control). After 120 min the insulin infusion rate was increased to 4 mU/kg/min for an additional 120 min. Tritiated glucose was infused throughout the study to measure glucose turnover rates. Results and Conclusion. The results of the pancreatic clamp studies demonstrated that under saline control conditions hepatic glucose production (HGP) was suppressed during hyperinsulinemia in both young and old rats, with a trend toward reduced insulin sensitivity in the older animals. Isoproterenol infusion impaired insulin-induced suppression of HGP in both age groups. The results suggest that β-AR stimulation by isoproterenol increases HGP and acutely induces hepatic insulin resistance in both young and old rats. A similar role for β-adrenergic-mediated hepatic insulin resistance in aging humans would suggest a novel therapeutic target for the treatment or prevention of glucose dysregulation and diabetes developing with advancing age.

Objective: Erythropoietin (EPO) is a cytokine that regulates the proliferation, differentiation, and survival of erythroid progenitor cells. EPO has recently been demonstrated to have a tissue-protective role by mediating anti-apoptotic signals through the erythropoietin receptor (EPOR) in various tissues, including brain, liver, and heart. We have previously examined pancreatic β-cell line NIT-1 cells for the expression of EPOR by real-time PCR and determined that these cells were protected by EPO against cytokine-induced apoptosis. The precise underlying anti-apoptotic mechanisms in pancreatic β-cells are poorly understood. The purpose of this study is to examine erythropoietin receptor expression in the NIT-1 pancreatic beta-cell line and the intracellular pathway related with its anti-apoptosis effect in NIT-1 cells. Methods: we examined the expression of EPOR by western blot. We investigate the role of erythropoietin in the survival of these cells, and whether the PI3K/AKT pathway is involved in this protective process. Results: NIT-1 cells expressed EPOR and, in the presence of certain cytokines, exposure of NIT-1 cells to recombinant human erythropoietin (rhEPO) significantly improved the impaired insulin secretion and inhibited cytokine-induced apoptosis. RhEPO caused a rapid activation of Akt and increased expression of Bcl-2. The protective anti-apoptotic effect of rhEPO was significantly abolished by a specific phosphatidylinositol 3-kiniase (PI3K) inhibitor, LY294002. Conclusions: Our findings indicate that EPOR is expressed in pancreatic β-cell line NIT-1 cells and suggest that EPO may act as a survival factor requiring the PI3K/Akt pathway.

Objective. The aim was to characterize the transfer of the insulin analog glargine across the placenta using the placental perfusion model. Methods. Placentas were obtained and selected cotyledons were cannulated and dually perfused. Glargine, 50 mU/L (n = 2) and 200 mU/L (n = 1), and a reference marker, antipyrine (50 μg/mL), were added to the maternal circulation. Samples were taken from the maternal and fetal compartments. Results. Glargine was not detected in the fetal compartment. In the maternal compartment, the steady state concentration was 50% lower than the starting concentration. Conclusions. Glargine probably does not cross the human placenta. Reduced maternal steady state concentrations may suggest insulin uptake by the placenta.

Background and aims. Enhanced release of triglycerides (TG) by the liver is implicated in the pathogenesis of the metabolic syndrome. The aim of the study was to evaluate whether a primary elevation in hepatic glucose utilization (HGU), as induced by an acute rise in circulating glucose values during physiological hyperinsulinemia, promotes TG synthesis in spite of the reduction in free fatty acids (FFA) levels. Methods. Glucose dose–response studies were conducted in anesthetized pigs using positron emission tomography (PET) to quantify HGU during fasting euglycemic conditions (EF), and under two-step hyperglycemic hyperinsulinemia (1st-HH +3.0, 2nd-HH +6.0 mmol/L over EF glucose values). Liver biopsies were obtained in three animals to evaluate the relationship between glucose exposure and hepatic fat content. Results. Plasma glucose levels were progressively increased in the two-step studies, and otherwise stable within every hour of PET scanning. HGU increased almost fivefold with raising glucose levels, from 0.033 ± 0.009 in EF to 0.149 ± 0.043 in 1st-HH, p = 0.02, and to 0.138 ± 0.050 μmol/min/g in 2nd-HH, p = 0.03. Circulating TG concentrations increased by 50 and 100% in the two hyperglycemic conditions (p = 0.03 2nd-HH vs. EF), in spite of a 70% suppression in plasma FFA levels. The hepatic TG content paralleled the glucose loads. Plasma γ-glutamyl transferase (γ-GT) was increased by 17% (p < 0.05). Conclusions. A short-term elevation in circulating glucose levels within the physiological postprandial range was sufficient to increase HGU, resulting in a significant synthesis and release of TG by the liver, which was accompanied by an acute rise in γ-GT and liver fat content.

Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms representing <5% of all pancreatic malignancies with an estimated incidence of 1–1.5 cases/100,000. PNETs are broadly classified as either functional or nonfunctional. Functional PNETs include insulinomas, gastrinomas, vasoactive intestinal peptideomas, glucagonomas, and somatostatinomas. The clinical manifestations associated with these tumors are the result of excessive hormonal secretion and action. The functional nature of these tumors makes pancreatic hormone testing critical not only for initial diagnosis but also for follow-up, because they are important tumor markers. Nonfunctional PNETs typically remain clinically silent until a substantial mass effect occurs. Although the majority of PNETs occur sporadically, it is important to recognize that these tumors may be associated with a variety of familial syndromes and in many cases genetic testing of PNET patients is warranted. This article familiarizes the reader with the clinical presentation and the biochemical, radiologic, and genetic testing indicated for diagnosis and follow-up of patients with PNET.

This article refers to:Placental Transfer of the Insulin Analog Glargine in the Ex Vivo Perfused Placental Cotyledon Model