Pretreatment with Ibuprofen Augments Circulating Tumor Necrosis Factor-α, Interleukin-6, and Elastase during Acute Endotoxinemia

Plasma levels of tumor necrosis factor-α (TNFα), interleukin-1 (IL-1),and interleukin-6 (IL-6) were monitored after intravenous administration of Escherichia coli endotoxin with or without ibuprofen pretreatment to healthy volunteers. Intravenous endotoxin (n = 7) resulted in elevated plasma TNFα concentrations with maximal levelsat 90 min (369 ± 44 pg/ml, P < .001 vs. saline controls, n = 7). The rise in TNF-α was followed by a rise in plasma IL-6 (27 ± 12.8 ng/ml), peaking 30-90 min thereafter. Pretreatment with ibuprofen (n = 6) caused a significant augmentation and temporal shift in cytokine elaboration with maximal TNFα levels(627 ± 136 pg/ml) at 120 min and IL-6 peaks (113 ± 66 ng/ml) at 180 min. In ibuprofen-treated volunteers, the additional increase in TNFα was paralleled by increased levels of circulating elastase. In vitro experiments suggest a causal relationship between these events. Thus, the cyclooxygenaseinhibitor ibuprofen blunts the clinical response to endotoxin but augments circulating cytokine levels and leukocyte degranulatio

Direct medical costs of type 2 diabetes and its complications in Switzerland

Background: This paper analyses the direct medical costs of type 2 diabetes and its complications in Switzerland. Methods: Individual healthcare resource consumption related to type 2 diabetes and its complications was determined retrospectively in 1479 non-incident and non-dying patients over 12 months (1998-1999). Literature-derived attributable risks were used to correct for non-diabetes related macrovascular disease. Results: A total of 111 primary care physicians from 19 cantons throughout Switzerland participated. Their diabetic patients on average had 10.3 consultations per year related to this disease (95% CI: 10.0-10.7). Patients spent on average 2.7 days (95% CI: 2.2-3.3) per year in hospital due to diabetes and diabetes-related complications. Mean annual type 2 diabetes-related direct medical costs per patient amounted to CHF 3,508 / € 2,323 (95% CI: CHF 3,140-3,876 / € 2,080-2,567). They were particularly high in patients with insulin treatment or with complications. After application of attributable risks and a correction for the use of adjuvant materials, costs were CHF 3,324 / € 2,201. Assuming 250,000 patients with type 2 diabetes in Switzerland leads to an estimate of CHF 0.88 billion spent for this disease and its complications in 1998. This represents a share of about 2.2% of the country's total healthcare expenditures. Conclusion: These findings demonstrate the high economic importance of type 2 diabetes and its complications in Switzerlan

Do Sugar-Sweetened Beverages Increase Fasting FGF21 Irrespective of the Type of Added Sugar? A Secondary Exploratory Analysis of a Randomized Controlled Trial.

Human fibroblast growth factor 21 (FGF21) is a multifaceted metabolic regulator considered to control sugar intake and to exert beneficial effects on glucose and lipid metabolism. Elevated serum FGF21 levels are associated with metabolic syndrome, suggesting a state of FGF21 resistance. Further, given the evidence of a hepatic ChREBP and FGF21 signaling axis, it can be assumed that SSBs containing fructose would possibly increase FGF21 concentrations. We investigated the effects of sugar-sweetened beverage (SSB) consumption on fasting FGF21 levels in healthy, lean men, discriminating the effects of glucose, fructose, and their disaccharide sucrose by secondary data analysis from a randomized controlled trial. Seven weeks of daily SSB consumption resulted in increased fasting FGF21 in healthy, lean men, irrespective of the sugar type. Medians of ΔFGF21 between post-SSB intervention values (week 7) and no-intervention period values (IQR) in pg/mL were: glucose 17.4 (0.4-45.8), fructose 22.9 (-8.6-35.1), and sucrose 13.7 (2.2-46.1). In contrast, this change in FGF21 concentration was only 6.3 (-20.1-26.9) pg/mL in the control group. The lack of a fructose-specific effect on FGF21 concentrations is contrary to our assumption. It is concluded that SSB intake may impact FGF21 concentrations and could contribute to the increased FGF21 concentrations observed in subjects suffering from metabolic syndrome that is possibly associated with decreased FGF21 responsiveness

Do Sugar-Sweetened Beverages Increase Fasting FGF21 Irrespective of the Type of Added Sugar? A Secondary Exploratory Analysis of a Randomized Controlled Trial

Human fibroblast growth factor 21 (FGF21) is a multifaceted metabolic regulator considered to control sugar intake and to exert beneficial effects on glucose and lipid metabolism. Elevated serum FGF21 levels are associated with metabolic syndrome, suggesting a state of FGF21 resistance. Further, given the evidence of a hepatic ChREBP and FGF21 signaling axis, it can be assumed that SSBs containing fructose would possibly increase FGF21 concentrations. We investigated the effects of sugar-sweetened beverage (SSB) consumption on fasting FGF21 levels in healthy, lean men, discriminating the effects of glucose, fructose, and their disaccharide sucrose by secondary data analysis from a randomized controlled trial. Seven weeks of daily SSB consumption resulted in increased fasting FGF21 in healthy, lean men, irrespective of the sugar type. Medians of ΔFGF21 between post-SSB intervention values (week 7) and no-intervention period values (IQR) in pg/mL were: glucose 17.4 (0.4-45.8), fructose 22.9 (-8.6-35.1), and sucrose 13.7 (2.2-46.1). In contrast, this change in FGF21 concentration was only 6.3 (-20.1-26.9) pg/mL in the control group. The lack of a fructose-specific effect on FGF21 concentrations is contrary to our assumption. It is concluded that SSB intake may impact FGF21 concentrations and could contribute to the increased FGF21 concentrations observed in subjects suffering from metabolic syndrome that is possibly associated with decreased FGF21 responsiveness

Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial

Aims The predominance of small dense low-density lipoproteins (sdLDLs) has been associated with increased cardiovascular risk. The effect of ezetimibe on LDL subfraction distribution has not been fully elucidated. This study assessed by gradient gel electrophoresis the effects of ezetimibe alone, simvastatin alone, and their combination on sdLDL subfraction distribution. Methods and results A single-centre, randomized, parallel three-group open-label study was performed in 72 healthy men with a baseline LDL-cholesterol (LDL-C) concentration of 111 ± 30 mg/dL (2.9 ± 0.8 mmol/L). They were treated with ezetimibe (10 mg/day, n = 24), simvastatin (40 mg/day, n = 24), or their combination (n = 24) for 14 days. Blood was drawn before and after the treatment period. Generalized estimating equations were used to assess the influence of drug therapy on LDL subfraction distribution, controlling for within-subject patterns (clustering). We adjusted for age, body mass index, and baseline concentrations of LDL-C and triglycerides. Ezetimibe alone changed LDL subfraction distribution towards a more atherogenic profile by significantly increasing sdLDL subfractions (LDL-IVA +14.2%, P = 0.0216 and LDL-IVB +16.7%, P = 0.039; fully adjusted Wald χ2 test). In contrast, simvastatin alone significantly decreased the LDL-IVB subfraction (−16.7%, P = 0.002). This effect was offset when simvastatin was combined with ezetimibe (LDL-IVB +14.3%, P = 0.44). All three treatments decreased the large, more buoyant LDL-I subfraction, the effects of ezetimibe being the most pronounced (ezetimibe -13.9%, P < 0.0001; combination therapy −7.3%, P = 0.0743; simvastatin −4.6%, P < 0.0001). Conclusion In healthy men, treatment with ezetimibe alone is associated with the development of a pro-atherogenic LDL subfraction profile. Potentially atheroprotective effects of simvastatin are offset by ezetimibe. This study is registered with ClinicalTrials.gov, identifier no. NCT0031799

Milder forms of atherogenic dyslipidemia in ovulatory versus anovulatory polycystic ovary syndrome phenotype

BACKGROUND Dyslipidemia is common in women with polycystic ovary syndrome (PCOS) but its prevalence in different PCOS phenotypes is still largely unknown. METHODS We measured plasma lipids and lipoproteins in 35 anovulatory PCOS (age: 25 ± 6 years, BMI: 28 ± 6 kg/m2), 15 ovulatory PCOS (age: 30 ± 6 years, BMI: 25 ± 3 kg/m2) and 27 healthy women (controls) age- and BMI-matched with ovulatory PCOS. PCOS was diagnosed by the presence of clinical or biologic hyperandrogenism associated with chronic anovulation and/or polycystic ovaries at ultrasound. In women with normal menses chronic anovulation was indicated by low serum progesterone levels (<9.54 nmol/l) during midluteal phase (days 21-24) in two consecutive menstrual cycles. RESULTS Total cholesterol, triglycerides and low-density lipoprotein (LDL)-cholesterol levels increased and high-density lipoprotein (HDL)-cholesterol decreased from controls to ovulatory and then to anovulatory PCOS (all P < 0.05). Levels of lipoprotein(a) (Lp(a)) and small, dense LDL increased (P < 0.0001 for both) and LDL size reduced (P < 0.005) between groups. Insulin resistance (by HOMA) showed a positive correlation with triglycerides and small, dense LDL and an inverse correlation with HDL-cholesterol and LDL size (P < 0.05 for all) in both PCOS phenotypes. No significant correlations were found with testosterone levels. At multivariate analysis, insulin resistance was independently associated with HDL-cholesterol and small, dense LDL in both PCOS phenotypes and with triglyceride concentrations in ovulatory PCOS only. CONCLUSIONS Women with ovulatory PCOS showed milder forms of atherogenic dyslipidemia than anovulatory PCOS and this seemed to be related to the extent of insulin resistance. Future prospective studies are needed to assess the relative contribution of such alterations on cardiovascular ris

Atherogenic forms of dyslipidaemia in women with polycystic ovary syndrome

OBJECTIVE: Dyslipidaemia is very common in patients with polycystic ovary syndrome (PCOS) but, beyond plasma lipids, atherogenic lipoprotein (Lp) and apolipoprotein (apo) alterations are still ill defined. DESIGN: We measured concentrations of apoB, Lp(a) and small, dense low-density lipoprotein (LDL) in 42 patients with PCOS [age: 28 +/- 7 years, body mass index (BMI): 27 +/- 5 kg/m(2)] vs. 37 age- and BMI-matched healthy controls. METHODS: Elevated Lp(a) levels considered were those > 30 mg/dl while elevated apoB concentrations were those > 100 g/l. RESULTS: Polycystic ovary syndrome showed increased triglycerides levels (p = 0.0011) and lower high-density lipoprotein (HDL)-cholesterol concentrations (p = 0.0131) while total- and LDL cholesterol were similar. PCOS also showed smaller LDL size (p = 0.0005), higher levels of total small, dense LDL (p < 0.0001), higher concentrations of Lp(a), as considered as absolute values (p = 0.0143) and log-transformed (p = 0.0014), while no differences were found in apoB levels. Elevated Lp(a) concentrations were found in 24% of PCOS, while elevated apoB levels were relatively uncommon (14%). Spearman correlation analysis revealed that Lp(a) concentrations were weakly correlated only with HDL-cholesterol levels (r = -0.378, p = 0.0431). In addition, 36% of patients with PCOS with normal plasma lipid profile showed elevated levels of Lp(a), apoB or small, dense LDL. CONCLUSIONS: Atherogenic Lp abnormalities may be found in one-third of women with PCOS who have a normal lipid pattern. Future prospective studies are needed to test to which extent such atherogenic forms of dyslipidaemia may contribute to the increased cardiovascular risk in young women with PCOS

Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets

Erratum / Corrigendu

Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine induced cell death

Pancreatic β-cells depend on the well-balanced regulation of cytosolic zinc concentrations, providing sufficient zinc ions for the processing and storage of insulin, but avoiding toxic effects. The zinc transporter ZnT8, encoded by SLC30A8, is a key player regarding islet cell zinc homeostasis, and polymorphisms in this gene are associated with altered type 2 diabetes susceptibility in man. The objective of this study was to investigate the role of ZnT8 and zinc in situations of cellular stress as hypoxia or inflammation. Isolated islets of wild-type and global ZnT8-/- mice were exposed to hypoxia or cytokines and cell death was measured. To explore the role of changing intracellular Zn2+ concentrations, wild-type islets were exposed to different zinc concentrations using zinc chloride or the zinc chelator N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN). Hypoxia or cytokine (TNFα, IFNγ, IL1β) treatment induced islet cell death, but to a lesser extent in islets from ZnT8-/- mice, which were shown to have a reduced zinc content. Similarly, chelation of zinc with TPEN reduced cell death in wild-type islets treated with hypoxia or cytokines, whereas increased zinc concentrations aggravated the effects of these stressors. This study demonstrates a reduced rate of cell death in islets from ZnT8-/- mice as compared to wild-type islets when exposed to two distinct cellular stressors, hypoxia or cytotoxic cytokines. This protection from cell death is, in part, mediated by a reduced zinc content in islet cells of ZnT8-/- mice. These findings may be relevant for altered diabetes burden in carriers of risk SLC30A8 alleles in man