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Lage R.,University of Santiago de Compostela | Lage R.,CIBER ISCIII | Vazquez M.J.,University of Santiago de Compostela | Vazquez M.J.,CIBER ISCIII | And 10 more authors.
FASEB Journal | Year: 2010

The orexigenic effect of ghrelin is mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the hypothalamic arcuate nucleus (ARC). Recent evidence also indicates that ghrelin promotes feeding through a mechanism involving activation of hypothalamic AMP-activated protein kinase (AMPK) and inactivation of acetyl-CoA carboxylase and fatty acid synthase (FAS). This results in decreased hypothalamic levels of malonyl-CoA, increased carnitine palmitoyltransferase 1 (CPT1) activity, and mitochondrial production of reactive oxygen species. We evaluated whether these molecular events are part of a unique signaling cascade or whether they represent alternative pathways mediating the orexigenic effect of ghrelin. Moreover, we examined the gender dependency of these mechanisms, because recent evidence has proposed that ghrelin orexigenic effect is reduced in female rats. We studied in both genders the effect of ghrelin on the expression of AgRP and NPY, as well as their transcription factors: cAMP response-element binding protein (CREB and its phosphorylated form, pCREB), forkhead box O1 (FoxO1 and its phosphorylated form, pFoxO1), and brain-specific homeobox transcription factor (BSX). In addition, to establish a mechanistic link between ghrelin, fatty acid metabolism, and neuropeptides, we evaluated the effect of ghrelin after blockage of hypothalamic fatty acid β oxidation, by using the CPT1 inhibitor etomoxir. Ghrelin-induced changes in the AMPK-CPT1 pathway are associated with increased levels of AgRP and NPY mRNA expression through modulation of BSX, pCREB, and FoxO1, as well as decreased expression of endoplasmic reticulum (ER) stress markers in a gender-independent manner. In addition, blockage of hypothalamic fatty acid β oxidation prevents the ghrelin-promoting action on AgRP and NPY mRNA expression, also in a gender-independent manner. Notably, this effect is associated with decreased BSX expression and reduced food intake. Overall, our data suggest that BSX integrates changes in neuronal metabolic status with ARC-derived neuropeptides in a gender-independent manner. © FASEB.


Black M.,University of Aberdeen | Bhattacharya S.,University of Aberdeen | Philip S.,Diabetes Research Unit | Norman J.E.,University of Edinburgh | McLernon D.J.,University of Aberdeen
PLoS Medicine | Year: 2016

Background: Global cesarean section (CS) rates range from 1% to 52%, with a previous CS being the commonest indication. Labour following a previous CS carries risk of scar rupture, with potential for offspring hypoxic brain injury, leading to high rates of repeat elective CS. However, the effect of delivery by CS on long-term outcomes in children is unclear. Increasing evidence suggests that in avoiding exposure to maternal bowel flora during labour or vaginal birth, offspring delivered by CS may be adversely affected in terms of energy uptake from the gut and immune development, increasing obesity and asthma risks, respectively. This study aimed to address the evidence gap on long-term childhood outcomes following repeat CS by comparing adverse childhood health outcomes after (1) planned repeat CS and (2) unscheduled repeat CS with those that follow vaginal birth after CS (VBAC). Methods and Findings: A data-linkage cohort study was performed. All second-born, term, singleton offspring delivered between 1 January 1993 and 31 December 2007 in Scotland, UK, to women with a history of CS (n = 40,145) were followed up until 31 January 2015. Outcomes assessed included obesity at age 5 y, hospitalisation with asthma, learning disability, cerebral palsy, and death. Cox regression and binary logistic regression were used as appropriate to compare outcomes following planned repeat CS (n = 17,919) and unscheduled repeat CS (n = 8,847) with those following VBAC (n = 13,379). Risk of hospitalisation with asthma was greater following both unscheduled repeat CS (3.7% versus 3.3%, adjusted hazard ratio [HR] 1.18, 95% CI 1.05–1.33) and planned repeat CS (3.6% versus 3.3%, adjusted HR 1.24, 95% CI 1.09–1.42) compared with VBAC. Learning disability and death were more common following unscheduled repeat CS compared with VBAC (3.7% versus 2.3%, adjusted odds ratio 1.64, 95% CI 1.17–2.29, and 0.5% versus 0.4%, adjusted HR 1.50, 95% CI 1.00–2.25, respectively). Risk of obesity at age 5 y and risk of cerebral palsy were similar between planned repeat CS or unscheduled repeat CS and VBAC. Study limitations include the risk that women undergoing an unscheduled CS had intended to have a planned CS, and lack of data on indication for CS, which may confound the findings. Conclusions: Birth by repeat CS, whether planned or unscheduled, was associated with an increased risk of hospitalisation with asthma but no difference in risk of obesity at age 5 y. Greater risk of death and learning disability following unscheduled repeat CS compared to VBAC may reflect complications during labour. Further research, including meta-analyses of studies of rarer outcomes (e.g., cerebral palsy), are needed to confirm whether such risks are similar between delivery groups. © 2016 Black et al.


Black M.,University of Aberdeen | Bhattacharya S.,University of Aberdeen | Philip S.,Diabetes Research Unit | Norman J.E.,University of Edinburgh | McLernon D.J.,University of Aberdeen
JAMA - Journal of the American Medical Association | Year: 2015

IMPORTANCE Planned cesarean delivery comprises a significant proportion of births globally, with combined rates of planned and unscheduled cesarean delivery in a number of regions approaching 50%. Observational studies have shown that offspring born by cesarean delivery are at increased risk of ill health in childhood, but these studies have been unable to adjust for some key confounding variables. Additionally, risk of death beyond the neonatal period has not yet been reported for offspring born by planned cesarean delivery. OBJECTIVE To investigate the relationship between planned cesarean delivery and offspring health problems or death in childhood. DESIGN, SETTING, AND PARTICIPANTS Population-based data-linkage study of 321 287 term singleton first-born offspring born in Scotland, United Kingdom, between 1993 and 2007, with follow-up until February 2015. EXPOSURES Offspring born by planned cesarean delivery in a first pregnancy were compared with offspring born by unscheduled cesarean delivery and with offspring delivered vaginally. MAIN OUTCOMES AND MEASURES The primary outcomewas asthma requiring hospital admission; secondary outcomes were salbutamol inhaler prescription at age 5 years, obesity at age 5 years, inflammatory bowel disease, type 1 diabetes, cancer, and death. RESULTS Compared with offspring born by unscheduled cesarean delivery (n = 56 015 [17.4%]), those born by planned cesarean delivery (12 355 [3.8%]) were at no significantly different risk of asthma requiring hospital admission, salbutamol inhaler prescription at age 5 years, obesity at age 5 years, inflammatory bowel disease, cancer, or death but were at increased risk of type 1 diabetes (0.66%vs 0.44%; difference, 0.22%[95%CI, 0.13%-0.31%]; adjusted hazard ratio [HR], 1.35 [95%CI, 1.05-1.75]). In comparison with children born vaginally (n = 252 917 [78.7%]), offspring born by planned cesarean delivery were at increased risk of asthma requiring hospital admission (3.73%vs 3.41%; difference, 0.32% [95%CI, 0.21%-0.42%]; adjusted HR, 1.22 [95%CI, 1.11-1.34]), salbutamol inhaler prescription at age 5 years (10.34%vs 9.62%; difference, 0.72%[95%CI, 0.36%-1.07%]; adjusted HR, 1.13 [95%CI, 1.01-1.26]), and death (0.40% vs 0.32%; difference, 0.08%[95%CI, 0.02%-1.00%]; adjusted HR, 1.41 [95%CI, 1.05-1.90]), whereas there were no significant differences in risk of obesity at age 5 years, inflammatory bowel disease, type 1 diabetes, or cancer. CONCLUSIONS AND RELEVANCE Among offspring of women with first births in Scotland between 1993 and 2007, planned cesarean delivery compared with vaginal delivery (but not compared with unscheduled cesarean delivery) was associated with a small absolute increased risk of asthma requiring hospital admission, salbutamol inhaler prescription at age 5 years, and all-cause death by age 21 years. Further investigation is needed to understand whether the observed associations are causal. Copyright 2015 American Medical Association. All rights reserved.


Lopez M.,University of Santiago de Compostela | Lopez M.,Research Center Biomedica En Red Of La Fisiopatologia Of La Obesidad tricion | Lopez M.,University of Cambridge | Varela L.,University of Santiago de Compostela | And 28 more authors.
Nature Medicine | Year: 2010

Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone-induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis. © 2010 Nature America, Inc. All rights reserved.


Liu Q.,Whitehead Institute For Biomedical Research | Gauthier M.-S.,Diabetes Research Unit | Sun L.,Whitehead Institute For Biomedical Research | Ruderman N.,Diabetes Research Unit | And 2 more authors.
FASEB Journal | Year: 2010

Adiponectin activates AMP-activated protein kinase (AMPK) in adipocytes, but the underlying mechanism remains unclear. Here we tested the hypothesis that AMP, generated in activating fatty acids to their CoA derivatives, catalyzed by acyl-CoA synthetases, is involved in AMPK activation by adiponectin. Moreover, in adipocytes, insulin affects the subcellular localization of acyl-CoA synthetase FATP1. Thus, we also tested whether insulin activates AMPK in these cells and, if so, whether it activates through a similar mechanism. We examined these hypotheses by measuring the AMP/ ATP ratio and AMPK activation on adiponectin and insulin stimulation and after knocking down acyl-CoA synthetases in adipocytes. We show that adiponectin activation of AMPK is accompanied by an ∼2-fold increase in the cellular AMP/ATP ratio. Moreover, FATP1 and Acsl1, the 2 major acyl-CoA synthetase isoforms in adipocytes, are essential for AMPK activation by adiponectin. We also show that after 40 min. insulin activated AMPK in adipocytes, which was coupled with a 5-fold increase in the cellular AMP/ATP ratio. Knockdown studies show that FATP1 and Acsl1 are required for these processes, as well as for stimulation of long-chain fatty acid uptake by adiponection and insulin. These studies demonstrate that a change in cellular energy state is associated with AMPK activation by both adiponectin and insulin, which requires the activity of FATP1 and Acsl1. © FASEB.


Tremblay A.J.,Laval University | Tremblay A.J.,Lipid Research Center | Lamarche B.,Laval University | Deacon C.F.,Copenhagen University | And 3 more authors.
Metabolism: Clinical and Experimental | Year: 2014

Inflammation and endothelial dysfunction are increasingly being recognized as key etiological factors in the development of atherosclerosis and subsequent cardiovascular disease. These pro-atherogenic factors are strongly correlated and are often found to co-segregate in patients with type 2 diabetes. The impact of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4, on inflammation and markers of endothelial function remains to be fully characterized. Objective The objective of the present study was to examine the effects of treatment with sitagliptin on the plasma levels of various markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. Methods and results Thirty-six subjects with type 2 diabetes (30 men/6 postmenopausal women with a mean age of 58.1 ± 6.4 years and a body mass index of 30.7 ± 4.9 kg/m2) were recruited into this double-blind, cross-over study using sitagliptin (100 mg/d) or placebo, each for a 6-week period, including a 4-week washout period between the two phases. Blood samples were taken at the end of each phase of treatment. Compared with placebo, treatment with sitagliptin significantly reduced the plasma levels of C-reactive protein (CRP) (44.9%, P = 0.006), interleukin (IL)-6 (24.7%, P = 0.04), IL-18 (7.3%, P = 0.004), secreted phospholipase-A2 (sPLA 2) (12.9%, P = 0.04), soluble intercellular adhesion molecule-1 (5.3%, P = 0.002), and E-selectin (5.9%, P = 0.005). A significant inverse correlation was found between changes in glucagon-like peptide-1 (GLP-1) and changes in CRP levels (r = 0.41, P = 0.01) following sitagliptin therapy. Sitagliptin therapy had more pronounced effects in subjects with higher levels of inflammatory markers and cell adhesion molecules compared with subjects with lower levels. Conclusions Treatment with sitagliptin for 6 weeks reduced plasma markers of low-grade inflammation and cell adhesion molecules, most likely by increasing plasma GLP-1 levels and improving glucose-insulin homeostasis. These beneficial effects of sitagliptin might represent a further advantage in the management of diabetes and its proatherogenic comorbidities. © 2014 Elsevier Inc.


DubI M.-C.,Diabetes Research Unit | Lavoie C.,University of Quebec at Trois - Rivieres | Galibois I.,Laval University | John Weisnagel S.,Diabetes Research Unit | John Weisnagel S.,Laval University
Medicine and Science in Sports and Exercise | Year: 2012

Studies on nutritional strategies to prevent exercise-induced hypoglycemia in adolescents with type 1 diabetes are scarce. OBJECTIVE: This study aimed to compare the effect of two food strategies on blood glucose (BG) during and after 60 min of moderate-intensity exercise. Methods: Subjects performed exercise 120 min after breakfast in three conditions: 1) standardized breakfast + preexercise placebo beverage (PL), 2) standardized breakfast + preexercise CHO beverage (8 mg of CHO•kg of body weight•min of exercise; CHO), or 3) protein-supplemented breakfast (8 mg of protein•kg of body weight•min of exercise added to the standardized breakfast) + preexercise placebo beverage (PROT). As soon as BG falls <4 mmol•L or symptomatic hypoglycemia occurred during exercise, the session was stopped and CHO tablets were provided to correct hypoglycemia. Results: Ten subjects (age = 14.0 ± 1.5 yr) participated in all conditions. BG decreased by 6.0 ± 1.9, 1.0 ± 3.1, and 4.6 ± 1.9 mmol•L in PL, CHO, and PROT conditions, respectively (P < 0.05). The proportion of subjects reaching hypoglycemic values or sensations of hypoglycemia was significantly different between conditions with 4/10, 1/10, and 0/10 in the PL, CHO, and PROT conditions (P < 0.05). Conclusions: The preexercise CHO beverage induced the least dramatic BG decrease during exercise. The PROT breakfast induced an overall similar BG drop compared to PL, a larger BG drop compared to CHO, but a similar rate of hypoglycemia compared to CHO. Our results suggest that taking CHO supplement before unplanned exercise is still the best strategy to prevent exercise-induced hypoglycemia in an adolescent population. However, a protein supplement strategy may also have some benefits in limiting the rate of hypoglycemia during and immediately after exercise. © 2012 by the American College of Sports Medicine.


Dube M.-C.,Diabetes Research Unit | Dube M.-C.,Laval University | Prud'homme D.,University of Ottawa | Lemieux S.,Laval University | And 3 more authors.
Journal of Science and Medicine in Sport | Year: 2014

Objectives: To examine the relationships between daily energy expenditure, energy intake and glycemic control in young adults with type 1 diabetes. Design: Cross-sectional study. Methods: Energy expenditure (kcalkg-1d-1) and duration of participation in physical activity were measured from a 3-d activity diary and categorized according to their intensity on a 1-9 scale. Energy intake was measured by a 3-d food record. Glycemic control was measured using the HbA1c. Results: Energy expenditure and intake were assessed in 35 young adults with type 1 diabetes (age: 28±7 years). Participants with higher energy expenditure from moderate to intense physical activity (categories 6-9) presented higher proportion of energy intake derived from carbohydrate and lower proportion of lipids in the diet with significantly higher HbA1c values (7.3±1.0% vs 6.7±0.6%). Conclusions: These results suggest that highly physically active individuals with type 1 diabetes consume more carbohydrates than lipids, a strategy that may affect their glycemic control. Further studies are needed to develop interventions to improve glycemic control in highly active individuals with type 1 diabetes. © 2013 Sports Medicine Australia.


Welinder A.C.,Technical University of Denmark | Zhang J.,Technical University of Denmark | Steensgaard D.B.,Diabetes Research Unit | Ulstrup J.,Technical University of Denmark
Physical Chemistry Chemical Physics | Year: 2010

We have explored the adsorption of zinc-free human insulin on the three low-index single-crystalline Au(111)-, Au(100)- and Au(110)-surfaces in aqueous buffer (KH2PO4, pH 5) by a combination of electrochemical scanning tunnelling microscopy (in situ STM) at single-molecule resolution and linear sweep, LSV, cyclic, CV, and square wave (SQWV) voltammetry. Multifarious electrochemical patterns were observed. Most attention was given to reductive desorption caused by insulin binding to the Au-surfaces via up to three disulfide groups per insulin monomer, presumably converted to single Au-S links. SQWV suggested the Au-S bond strength order Au(111) > Au(110) > Au(100) based on the reductive desorption potentials. The voltammetric diversity was paralleled by different in situ STM insulin adsorption modes on the three surfaces. Single-molecule resolution was achieved in all cases. The coverage followed the order Au(110) > Au(100) > Au(111) and differs from the reductive desorption order that records the Au-S bonding element. Evenly distributed single molecules were scattered over large Au(111)-terraces, with intriguing molecular arrays disclosed near the terrace edges. In comparison, high-density molecular scale structures were observed both over the terraces and across terrace edges on Au(100). Larger rectangular structures also appeared (8-12% coverage). These are Au-islands from the lift of the reconstruction. Notably, 10 × 10 nm2 patches of highly ordered much smaller structures, possibly from insulin decomposition emerged sporadically within the dense insulin adlayer. Insulin adsorbed in highest coverage on the Au(110) and followed the directional surface topology with insulin molecules aligned in the Au(110)-surface grooves, occasionally "spilling over" and merging into larger structures. Adsorption, Au-S binding, and insulin unfolding are all parts of insulin surface behaviour and reflected in both voltammetry and in situ STM. In spite of these complications, the data show that molecular scale resolution has been achieved and offer other perspectives of insulin surface science such as single-molecule mapping of the insulin monomer/dimer-hexamer interconversion. © 2010 the Owner Societies.


Zafar A.,Diabetes Research Unit | Stone M.A.,Diabetes Research Unit | Davies M.J.,Diabetes Research Unit | Khunti K.,Diabetes Research Unit
Diabetic Medicine | Year: 2015

Aims: Failure to intensify treatment in patients with Type 2 diabetes with suboptimal blood glucose control has been termed clinical inertia and has been shown to contribute to poorer patient outcomes. We aimed to identify and explore perceptions about clinical inertia from the perspective of primary healthcare providers. Methods: A qualitative study was conducted in Leicestershire and Northamptonshire, UK. Purposive sampling was based on healthcare providers working in primary care settings with 'higher' and 'lower' target achievement based on routine data. Twenty semi-structured interviews were conducted, face-to-face or by telephone. Thematic analysis was informed by the constant comparative approach. Results: An important broad theme that emerged during the analysis was related to attribution and explanation of responsibility for clinical inertia. This included general willingness to accept a degree of responsibility for clinical inertia. In some cases, however, participants had inaccurate perceptions about levels of target achievement in their primary care centres, as indicated by routine data. Participants sought to lessen their own sense of accountability by highlighting patient-level barriers such as comorbidities and human fallibility, and also system-level barriers, particularly time constraints. Perceptions about ways of addressing the problem of clinical inertia were not seen as straightforward, further emphasizing a complex and cumulative pattern of barriers. Conclusions: In order to understand and address the problem of clinical inertia, provider, patient- and system-level barriers should be considered together rather than as separate issues. Acknowledgement of responsibility should be regarded positively as a motivator for change. What's new?: Clinical inertia (failure to intensify treatment) in the management of Type 2 diabetes has been identified quantitatively, but qualitative studies aimed at understanding this problem are lacking. Analysis of our interview data identified ways in which primary healthcare providers sought to explain clinical inertia in terms of responsibility at care provider, patient and system levels. Some interviewees had inaccurate perceptions about levels of clinical inertia in their primary care centres. Perceptions about responsibility for clinical inertia could be explored during training opportunities for healthcare providers, in order to stimulate motivation to change. © 2014 Diabetes UK.

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