bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cannabinoid type 1 receptor blockade induces transdifferentiation towards a brown fat phenotype in white adipocytes
Authors: Perwitz N. , Wenzel J. , Wagner I. , Büning J. , Drenckhan M. , Zarse K. , Ristow M. , Lilienthal W. , Lehnert H. , Klein J. 
Published: November 2009

Aim:The endocannabinoid (EC) system is a major component in the control of energy homeostasis. It mediates a positive energy balance via central and peripheral pathways. Blockade of the cannabinoid type 1 receptor induces weight reduction and improves cardiovascular risk factors in overweight patients. Cannabinoid receptor type 1 (CB1R)‐deficient mice are resistant to diet‐induced obesity. The mechanisms responsible for these effects remain only partially elucidated. We hypothesized peripheral effects via direct modulation of adipocyte function to be an integral part of EC action on energy metabolism and insulin sensitivity.Methods:SV40 immortalized murine white and brown adipocytes were used for all experiments. We investigated the effect of CB1R blockade by stimulating the cells acutely and chronically with rimonabant, a selective antagonist for the CB1R, or by knocking down the receptor with small interfering RNA (siRNA). Changes in thermogenic mRNA and protein expression as well as mitochondrial biogenesis and function were assessed by real‐time RT‐PCR, immunoblotting, fluorescent staining techniques, electron microscopy and by measuring oxygen consumption.Results:Acute and chronic blockade of the CB1R with the selective antagonist rimonabant or by siRNA in murine white adipocytes strongly induced the thermogenic uncoupling protein‐1 (UCP‐1). UCP‐1 expression was increased in a time‐ and dose‐dependent manner both at the RNA and protein level. Furthermore, this effect was paralleled by enhanced peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) expression. In accordance with these findings, AMP‐activated protein kinase (AMPK) phosphorylation was also increased after rimonabant treatment. Mitochondria‐specific fluorescent staining demonstrated an augmentation in the number of mitochondria. This was confirmed by electron microscopy images. Moreover, rimonabant treatment enhanced the cytochrome c oxidase activity and increased cellular oxygen consumption.Conclusions:Taken together, our data demonstrate that inhibition of peripheral CB1R action in adipocytes directly promotes transdifferentiation of white adipocytes into a mitochondria‐rich, thermogenic brown fat phenotype. Enhanced thermogenesis and insulin sensitivity may represent a peripheral mechanism contributing to weight loss and improved glucose homeostasis in rimonabant‐treated patients.
Bioengineered skin in diabetic foot ulcers
Authors: Teng Y. J. , Li Y. P. , Wang J. W. , Yang K. H. , Zhang Y. C. , Wang Y. J. , Tian J. H. , Ma B. , Wang J. M. , Yan X. 
Published: November 2009

Objective: Bioengineered skin (BS) has been shown to play an important role in the treatment of diabetic foot ulcers (DFUs). Whether BS in the therapy of DFU can improve the outcomes still remains uncertain. We performed a quantitative meta‐analysis of available randomized controlled trials to determine the effectiveness and safety of BS in the treatment of patients with DFUs. Design and Methods: Comprehensive search strategies of various electronic databases were used for this study to evaluate the effectiveness and safety between BS and conventional treatment (CT) in patients with DFU, and only randomized controlled trials were adopted in our review. Search terms included ‘bioengineered skin’, ‘tissue‐engineering skin’, ‘human‐tissue graft', ‘human‐skin device’, ‘living‐skin equivalent' and ‘diabetic foot', ‘diabetic ulcer’, ‘diabetic wound’. Analysis outcomes included complete wound closure, complications, ulcer recurrence and adverse severe events (ASEs). Results: Seven randomized controlled trials on BS vs. CT were included, and 880 participants met inclusion criteria. Pooled analysis showed a significant effectiveness and safety advantages for BS treatment compared to CT for patients with DFUs. In analysis of complications, only statistically significant difference of infection was noted. And no included trials reported ASEs related to these treatments. Conclusions: Based on the meta‐analysis, patients with DFUs may benefit from the BS because of its high effectiveness and safety and reduced risk for infections in comparison to CT.
Comparison between a basal‐bolus and a premixed insulin regimen in individuals with type 2 diabetes–results of the GINGER study
Authors: Fritsche A. , Larbig M. , Owens D. , Häring H.‐U. ,   on behalf of the GINGER study group
Published: November 2009

Aim: To compare the efficacy and safety of an intensified insulin regimen, using insulin glargine (glargine) once daily and pre‐meal insulin glulisine (glulisine) (basal‐bolus), with a conventional therapy, using premixed insulin (premix) twice daily. Methods: This 52‐week, open‐label, randomized, multinational, multicentre trial included 310 subjects with type 2 diabetes (T2D) on premix, with or without metformin, who were randomized to a basal‐bolus regimen with glargine and glulisine (n = 153; mean ± s.d. age 60.2 ± 7.5 years; HbA1c 8.6 ± 0.8%; weight 87.0 ± 15.1 kg; T2D duration 12.8 ± 5.8 years) or twice‐daily premix (n = 157; age 60.9 ± 7.8 years; HbA1c 8.5 ± 0.9%; weight 84.3 ± 15.0 kg; T2D duration 12.5 ± 6.8 years). The primary endpoint was change in HbA1c from baseline to endpoint. Results: Mean decrease in baseline‐to‐endpoint HbA1c for basal‐bolus vs. premix was −1.31 vs. −0.80% (difference: −0.476%; 95% Cl: −0.714, −0.238; p = 0.0001, ancova). More subjects reached HbA1c ≤ 7.0% in the basal‐bolus group than in the premix group [68 (46.6%) vs. 43 (27.9%); p = 0.0004], while they also experienced significantly lower mean ± s.d. daytime (−2.7 ± 2.3 vs. −2.3 ± 2.5 mmol/l; p = 0.0033) and postprandial (−3.1 ± 2.6 vs. −2.5 ± 2.8 mmol/l; p < 0.0001) blood glucose. Endpoint daily insulin doses were 98.0 ± 48.7 vs. 91.3 ± 44.3 IU (p = 0.2104); mean weight gain was +3.6 ± 4.0 vs. +2.2 ± 4.5 kg (p = 0.0073). Mean number of overall hypoglycaemic events with basal‐bolus and premix was 13.99 and 18.54 events/patient year, respectively (difference: −3.90; 95% CI: −10.40, 2.60; p = 0.2385). Conclusions: An intensified basal‐bolus regimen using glargine/glulisine results in a significantly superior glycaemic control vs. premix therapy in a population with long‐standing insulin‐treated T2D, with no increase in the rates of hypoglycaemia.
Tanshinone IIA pretreatment protects myocardium against ischaemia/reperfusion injury through the phosphatidylinositol 3‐kinase/Akt‐dependent pathway in diabetic rats
Authors: Zhang Y. , Wei L. , Sun D. , Cao F. , Gao H. , Zhao L. , Du J. , Li Y. , Wang H. 
Published: November 2009

Aim: Diabetes Mellitus (DM) is widely acknowledged to increase the risk of cardiovascular death, which warrants the use of aggressive primary prevention strategies. The aim of the present study was to investigate the pretreatment effects of tanshinone IIA (TSN), a traditional Chinese medicine, on myocardial infarct size, apoptosis, inflammation and cardiac functional recovery in diabetic rats subjected to myocardial ischaemia/reperfusion (I/R). Methods: Streptozocin (STZ) induced diabetic rats (n = 80) were randomized to receive TSN, TSN plus wortmannin [a phosphatidylinositol 3‐kinase (PI3K) inhibitor] or saline. They were exposed to a 30‐min ischaemia by ligation of the left coronary artery except for the sham group. Haemodynamics, infarct size and myocardial apoptosis were examined 3 h after reperfusion. The effects of TSN on Akt and NF‐κB phosphorylation and the expression of tumour necrosis factor‐alpha (TNF‐α) and interleukin‐6 (IL‐6) in cardiac tissues were examined. Results: Our results revealed that TSN administration significantly reduced myocardial infarct size (0.252 ± 0.038 vs. 0.327 ± 0.027, p < 0.05), improved left ventricular ejection fraction (LVEF) (0.774 ± 0.058 vs. 0.716 ± 0.054, p < 0.05), decreased myocardial apoptotic death (0.114 ± 0.026 vs. 0.191 ± 0.023, p < 0.05) compared with I/R group. Western blot analysis showed that TSN treatment enhanced Akt phosphorylation and inhibited NF‐κB phosphorylation in cardiac tissues. Moreover, pretreatment with wortmannin abolished the beneficial effects of TSN: a reduction of infarct size, a decrease in LVEF, inhibition of myocardial apoptosis and Akt phosphorylation, enhancement of NF‐κB phosphorylation and an increase of cytokine production including TNF‐α and IL‐6 after I/R injury in diabetic rats. Conclusions: This study indicates that TSN pretreatment reduces infarct size and improves cardiac dysfunction after I/R injury in diabetic rats. This was accompanied with decreased cardiac apoptosis and inflammation. The possible mechanism responsible for the effects of TSN is associated with the PI3K/Akt‐dependent pathway.
Twelve weeks treatment with the DPP‐4 inhibitor, sitagliptin, prevents degradation of peptide YY and improves glucose and non‐glucose induced insulin secretion in patients with type 2 diabetes mellitus
Authors: Aaboe K. , Knop F. K. , Vilsbøll T. , Deacon C. F. , Holst J. J. , Madsbad S. , Krarup T. 
Published: November 2009

Aim: To examine the effects of 12 weeks of treatment with the DPP‐4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non‐glucose induced insulin secretion during a hyperglycaemic clamp, in patients with type 2 diabetes. Method: A double‐blinded, placebo‐controlled study over 12 weeks in which 24 patients with T2DM were randomized to receive either sitagliptin (Januvia) 100 mg qd or placebo as an add‐on therapy to metformin. In week 0, 1 and 12 patients underwent a meal test and a 90‐min 20 mM hyperglycaemic clamp with 5 g of l‐arginine infusion. Main outcome measure was postprandial total glucagon‐like peptide 1 (GLP‐1) concentration. Additional measures were insulin and C‐peptide, glycaemic control, intact and total peptide YY (PYY) and glucose‐dependent insulinotropic polypeptide (GIP), and intact glucagon‐like peptide 2 (GLP‐2) and GLP‐1. Results: All patients [sitagliptin n = 12, age: 59.5 (39–64) years, HbA1c: 8.0 (7.3–10.0)%, BMI: 33.2 (29.3–39.4); placebo n = 12, age: 60 (31–72) years, HbA1c: 7.7 (7.1–9.8)%, BMI: 30.7 (25.7–40.5)] [median (range)] completed the trial. Sitagliptin treatment improved glycaemic control, had no effect on total GLP‐1, GIP or intact GLP‐2, but reduced total PYY and PYY3‐ 36, and increased PYY1‐ 36 and intact incretin hormones. Sitagliptin improved first and second phases of beta cell secretion and maximal secretory capacity. All effects were achieved after 1 week. No significant changes occurred in the placebo group. Conclusion: The postprandial responses of total GLP‐1 and GIP and intact GLP‐2 were unaltered. PYY degradation was prevented. Glucose and non‐glucose induced beta cell secretion was improved. There was no difference in responses to sitagliptin between 1 and 12 weeks of treatment.
Pharmacokinetics following continuous subcutaneous insulin infusion of insulin aspart with or without initial subcutaneous bolus
Authors: Petersen S. B. , Kildegaard J. , Nielsen F. S. , Søndergaard E. , Parkner T. , Laursen T. , Lauritzen T. , Skyggebjerg O. , Christiansen J. S. 
Published: November 2009

Aim: To evaluate time to steady state insulin concentration (Css) following continuous subcutaneous insulin infusion (CSII) of insulin aspart (IAsp) with or without an initial s.c. bolus. Methods: In random order 10 healthy volunteers were given a basal insulin infusion rate (0.5 U/h) for 8 h with or without an initial s.c. bolus (1.4 U). Serum IAsp was measured until 3 h after infusion was stopped. Results: An overshoot of IAsp was seen before Css was achieved following an initial bolus of insulin as compared to no bolus. The apparent half‐life (t½) with or without bolus did not differ (p = 0.15). Time to steady state (Tss) was evaluated in two ways: (1) Tss defined as the first point within an interval of Css± 2 × CV was 233 vs. 166 min with and without a bolus respectively (p = 0.068). (2) A t‐test was performed for each concentration‐time point vs. mean Css, and the first point with no significance was defined, Tss. This gave 208 (p = 0.09) and 178 min (p = 0.24) with and without bolus respectively. Mathematical modelling suggests that an ideal mean bolus should be 0.89 U, and that this bolus dose may result in a shorter Tss. Conclusion: A bolus of 1.4 U resulted in an overshoot of serum IAsp before Css and a longer period before Css is achieved. Mathematical modelling suggests that a mean bolus of 0.89 U would result in a faster achievement of Css compared to no bolus
Leptin‐based glycopeptide induces weight loss and simultaneously restores fertility in animal models
Authors: Kovalszky I. , Surmacz E. , Scolaro L. , Cassone M. , Ferla R. , Sztodola A. , Olah J. , Hatfield M. P. D. , Lovas S. , Otvos L. 
Published: November 2009

Aim: To design, manufacture and test a second generation leptin receptor (ObR) agonist glycopeptide derivative. The major drawback to current experimental therapies involving leptin protein is the appearance of treatment resistance. Our novel peptidomimetic was tested for efficacy and lack of resistance induction in rodent models of obesity and appetite reduction. Methods: The glycopeptide containing two additional non‐proteinogenic amino acids was synthesized by standard solid‐phase methods. Normal mice were fed with peanuts until their blood laboratory data and liver histology showed typical signs of obesity but not diabetes. The mice were treated with the peptidomimetic at 0.02, 0.1 or 0.5 mg/kg/day intraperitoneally side‐by‐side with 0.1 mg/kg/day leptin for 11 days. After termination of the assay, the blood cholesterol and glucose amounts were measured, the liver fat content was visualized and quantified and the remaining mice returned to normal diet and were allowed to mate. In parallel experiments normal rats were treated intranasally with the glycopeptide at 0.1 mg/kg/day for 10 days. Results: The 12‐residue glycosylated leptin‐based peptidomimetic E1/6‐amino‐hexanoic acid (Aca) was designed to target a principal leptin/ObR‐binding interface. E1/Aca induced leptin effects in ObR‐positive cell lines at picomolar concentrations and readily crossed the blood‐brain barrier (BBB) following intraperitoneal administration. The peptide initiated typical leptin‐dependent signal transduction pathways both in the presence and absence of leptin protein. The peptide also reduced weight gain in mice fed with high‐fat peanut diet in a dose‐dependent manner. Obese mice receiving peptide E1/Aca at a 0.5 mg/kg/day dose lost weight, corresponding to a net 6.5% total body weight loss, while similar mice treated with leptin protein did not. Upon cessation of the weight loss treatment, several obesity‐related pathologies (i.e. abnormal metabolic profile and liver histology as well as infertility) normalized in peptide‐, but not leptin‐treated, mice. Peptide E1/Aca added intranasally to growing normal rats decelerated normal weight gain corresponding to a net 6.8% net total body weight loss with statistical significance. Conclusions: No resistance induction to peptide E1/Aca or toxicity in either obese or healthy rodents was observed, indicating the potential for widespread utility of the peptidomimetic in the treatment of leptin‐deficiency disorders. We provide additional proof for the hypothesis that difficulties in current leptin therapies reside at the BBB penetration stage, and we document that by either glycosylation or intranasal peptide administration we can overcome this limitation.
Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes
Authors: Vilsbøll T. , Rosenstock J. , Yki‐Järvinen H. , Cefalu W. T. , Chen Y. , Luo E. , Musser B. , Andryuk P. J. , Ling Y. , Kaufman K. D. , Amatruda J. M. , Engel S. S. , Katz L. 
Published: November 2009

Objective: To evaluate the efficacy and tolerability of sitagliptin when added to insulin therapy alone or in combination with metformin in patients with type 2 diabetes. Methods: After a 2 week placebo run‐in period, eligible patients inadequately controlled on long‐acting, intermediate‐acting or premixed insulin (HbA1c ≥ 7.5% and ≤ 11%), were randomised 1:1 to the addition of once‐daily sitagliptin 100 mg or matching placebo over a 24‐week study period. The study capped the proportion of randomised patients on insulin plus metformin at 75%. Further, the study capped the proportion of randomised patients on premixed insulin at 25%. The metformin dose and the insulin dose were to remain stable throughout the study. The primary endpoint was HbA1c change from baseline at week 24. Results: Mean baseline characteristics were similar between the sitagliptin (n = 322) and placebo (n = 319) groups, including HbA1c (8.7 vs. 8.6%), diabetes duration (13 vs. 12 years), body mass index (31.4 vs. 31.4 kg/m2), and total daily insulin dose (51 vs. 52 IU), respectively. At 24 weeks, the addition of sitagliptin significantly (p < 0.001) reduced HbA1c by 0.6% compared with placebo (0.0%). A greater proportion of patients achieved an HbA1c level < 7% while randomised to sitagliptin as compared with placebo (13 vs. 5% respectively; p < 0.001). Similar HbA1c reductions were observed in the patient strata defined by insulin type (long‐acting and intermediate‐acting insulins or premixed insulins) and by baseline metformin treatment. The addition of sitagliptin significantly (p < 0.001) reduced fasting plasma glucose by 15.0 mg/dl (0.8 mmol/l) and 2‐h postmeal glucose by 36.1 mg/dl (2.0 mmol/l) relative to placebo. A higher incidence of adverse experiences was reported with sitagliptin (52%) compared with placebo (43%), due mainly to the increased incidence of hypoglycaemia (sitagliptin, 16% vs. placebo, 8%). The number of hypoglycaemic events meeting the protocol‐specified criteria for severity was low with sitagliptin (n = 2) and placebo (n = 1). No significant change from baseline in body weight was observed in either group. Conclusion: In this 24‐week study, the addition of sitagliptin to ongoing, stable‐dose insulin therapy with or without concomitant metformin improved glycaemic control and was generally well tolerated in patients with type 2 diabetes.
Moderate caloric restriction during gestation results in lower arcuate nucleus NPY‐ andαMSH‐neurons and impairs hypothalamic response to fed/fasting conditions in weaned rats
Authors: García A. P. , Palou M. , Priego T. , Sánchez J. , Palou A. , Picó C. 
Published: November 2009

Aim:We aimed to characterize the developmental programming effects of moderate caloric restriction during early pregnancy on factors involved in hypothalamic control of energy balance.Methods:Twenty‐five‐days‐old offspring Wistar rats from 20% caloric restricted dams (from 1 to 12 days of pregnancy) (CR) and from control dams were studied under fed and 12 h fasting conditions. Morphometric studies on arcuate nucleus (ARC) and determinations of circulating parameters and hypothalamic levels of neuropeptide Y (NPY), proopiomelanocortin (POMC), long‐form leptin receptor (ObRb), insulin receptor (InsR) and suppressor of cytokine signalling‐3 (SOCS‐3) mRNA were performed.Results:CR animals did not show different body weight with respect to their controls, but presented higher food intake. They exhibited lower neuropeptide Y‐ andα‐melanocyte‐stimulating hormone‐neurons (decreases of 18 and 13% in males, and 10 and 18% in females respectively) and lower total cells (decrease of 3% in males and 18% in females) in ARC. Under fed conditions, CR animals presented lower circulating leptin and ghrelin levels (decreases of 37 and 43% in males, and 15 and 34% in females respectively); furthermore, hypothalamic POMC, NPY (only in females), ObRb and InsR mRNA levels were reduced (39, 16 and 26% in males, and 112, 33, 61 and 56% in females), and those of SOCS‐3 were increased (86% in males and 74% in females). Unlike control animals, under fasting conditions, ObRb, InsR and POMC mRNA levels did not decrease in CR females, and NPY mRNA decreased instead of increase in CR males.Conclusions:Moderate caloric restriction during gestation affects offspring hypothalamic structure and function, impairing its response to fed/fasting conditions, which suggests a predisposition to insulin and leptin resistance.
Better Schools through Health: networking for health promoting schools in Europe
Authors: BUIJS GOOF J. 
Published: November 2009

Education and health have shared interests. Unifying these allows schools to become better places to enjoy learning, teaching and working. Health promoting schools have shown evidence of improving the health and well‐being of the whole school community. At the European level, the Schools for Health in Europe (SHE) network is one of the most sustainable school networks in Europe and worldwide.This article explains how health helps to create better schools. It focuses on the advantages of working as a network at a European level with direct links with schools, policy makers, practitioners and researchers. It describes the impact of networking on schools, what changes take place at the school level, and also at the regional and national level. The SHE strategic plan, which is a roadmap for the future development of the network until 2012, is summarised. Some examples of the results of networking are presented, including the work on developing indicators for health promoting schools within the European context.The article concludes with a report of the 3rd European Conference on health promoting schools held in June 2009 in Lithuania, with the Vilnius Resolution as its important outcome.
656. TWO NEW SPECIES OF SAINTPAULIA FROM THE ULUGURU MOUNTAINS, TANZANIA
Authors: Haston Elspeth M. , Mejissa John , Watkins Colin 
Published: November 2009

Summary.Two new endemic species of Saintpaulia, S. ulugurensis Haston and S. watkinsii Haston (Gesneriaceae) are described from the Uluguru Mountains. Their discovery emphasises the need for additional floristic work to be carried out in this area and supports the calls for strong conservation measures for the fragile forest habitats of Tanzania.