Explore the vast range of titles available.

Background Hypoglycaemia, especially nocturnal, remains the main limiting factor of achieving good glycaemic control in type 1 diabetes. The effect of first generation long-acting insulin analogues in reducing nocturnal hypoglycaemia is well documented in patient with type 1 diabetes. The effect of the newer long-acting insulin degludec on risk of nocturnal hypoglycaemia remains undocumented in patients with type 1 diabetes and recurrent severe nocturnal hypoglycaemia. The HypoDeg trial is designed to investigate whether insulin degludec in comparison with insulin glargine U100 is superior in limiting the occurrence of nocturnal hypoglycaemia in patients with recurrent nocturnal severe hypoglycaemia. This paper reports the study design of the HypoDeg trial. Methods/design A Danish investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, two-year cross-over study investigating the effect of insulin degludec versus insulin glargine U100 on frequency of nocturnal hypoglycaemia in patients with type 1 diabetes and one or more episodes of nocturnal severe hypoglycaemia during the preceding two years as the major inclusion criteria. Patients are randomised (1:1) to basal therapy with insulin degludec or insulin glargine. Insulin aspart is used as bolus therapy in both treatment arms. Discussion In contrast to most other insulin studies the HypoDeg trial includes only patients at high risk of hypoglycaemia. The HypoDeg trial will compare treatment with insulin degludec to insulin glargine U100 in terms of risk of nocturnal hypoglycaemic episodes in patients with type 1 diabetes with the greatest potential to benefit from near-physiological insulin replacement therapy. www.clinicaltrials.gov : NCT02192450.

Glucagon-like peptide-1 (GLP-1) may provide beneficial cardiovascular effects, possibly due to enhanced myocardial energetic efficiency by increasing myocardial glucose uptake (MGU). We assessed the effects of GLP-1 on MGU in healthy subjects during normo- and hypoglycemia. We included eighteen healthy men in two randomized, double-blinded, placebo-controlled cross-over studies. MGU was assessed with GLP-1 or saline infusion during pituitary-pancreatic normo- (plasma glucose (PG): 4.5 mM, n = 10) and hypoglycemic clamps (PG: 3.0 mM, n = 8) by positron emission tomography with (18)fluoro-deoxy-glucose ((18)F-FDG) as tracer. In the normoglycemia study mean (± SD) age was 25±3 years, and BMI was 22.6±0.6 kg/m(2) and in the hypoglycemia study the mean age was 23±2 years with a mean body mass index of 23±2 kg/m(2). GLP-1 did not change MGU during normoglycemia (mean (+/- SD) 0.15+/-0.04 and 0.16+/-0.03 µmol/g/min, P = 0.46) or during hypoglycemia (0.16+/-0.03 and 0.13+/-0.04 µmol/g/min, P = 0.14). However, the effect of GLP-1 on MGU was negatively correlated to baseline MGU both during normo- and hypoglycemia, (P = 0.006, r(2) = 0.64 and P = 0.018, r(2) = 0.64, respectively) and changes in MGU correlated positively with the level of insulin resistance (HOMA 2IR) during hypoglycemia, P = 0.04, r(2) = 0.54. GLP-1 mediated an increase in circulating glucagon levels at PG levels below 3.5 mM and increased glucose infusion rates during the hypoglycemia study. No differences in other circulating hormones or metabolites were found. While GLP-1 does not affect overall MGU, GLP-1 induces changes in MGU dependent on baseline MGU such that GLP-1 increases MGU in subjects with low baseline MGU and decreases MGU in subjects with high baseline MGU. GLP-1 preserves MGU during hypoglycemia in insulin resistant subjects. ClinicalTrials.gov registration numbers: NCT00418288: (hypoglycemia) and NCT00256256: (normoglycemia).

Glucagon-Like Peptide-1 Inhibits Blood-Brain Glucose Transfer in Humans Susanne Lerche 1 , Birgitte Brock 1 , Jørgen Rungby 1 , Hans E. Bøtker 2 , Niels Møller 3 , Anders Rodell 4 , Bo Martin Bibby 5 , Jens J. Holst 6 , Ole Schmitz 1 and Albert Gjedde 4 1 Institute of Pharmacology, University of Aarhus, Aarhus, Denmark 2 Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark 3 Department of Endocrinology M, Aarhus University Hospital, Aarhus, Denmark 4 PET-Center, Aarhus University Hospital, Aarhus, Denmark 5 Department of Biostatistics, University of Aarhus, Aarhus, Denmark 6 Department of Medical Physiology, University of Copenhagen, Panum Institute, Copenhagen, Denmark Address correspondence and reprint requests to Susanne Lerche, MD, Institute of Pharmacology, University of Aarhus, The Bartholin Building, University Park 1240, 8000 Aarhus C, Denmark. E-mail: lerche{at}ki.au.dk Abstract OBJECTIVE— Glucagon-like peptide-1 (GLP-1) has many effects on glucose homeostasis, and GLP-1 receptors are broadly represented in many tissues including the brain. Recent research in rodents suggests a protective effect of GLP-1 on brain tissue. The mechanism is unknown. We therefore tested whether these neuroprotective effects could relate to changes of glucose transport and consumption. RESEARCH DESIGN AND METHODS— We studied 10 healthy men in a randomized, double-blinded, placebo-controlled cross-over experiment. We used positron emission tomography to determine the acute insulin-independent effect of GLP-1 on unidirectional glucose transport into the brain during a pituitary-pancreatic normoglycemic (plasma glucose ∼4.5 mmol/l) clamp with 18-fluoro-deoxy-glucose as tracer. RESULTS— On average, GLP-1 reduced cerebral glucose transport by 27% in total cerebral gray matter ( P = 0.05) and by 25–30% in individual gray matter regions ( P = 0.02–0.06). The same regions revealed a uniform trend toward similarly reduced cerebral glucose metabolism. Consequently, the intracerebral glucose concentration remained constant in all regions, with and without GLP-1. CONCLUSIONS— We have demonstrated that a hormone involved in postprandial glucose regulation also limits glucose delivery to brain tissue and hence provides a possible regulatory mechanism for the link between plasma glucose and brain glucose. Because GLP-1 reduces glucose uptake across the intact blood-brain barrier at normal glycemia, GLP-1 may also protect the brain by limiting intracerebral glucose fluctuation when plasma glucose is increased. BBB, blood-brain barrier FDG, 18-fluoro-deoxy-glucose GLP-1, glucagon-like peptide 1 GLP-1R, GLP-1 receptor PET, positron emission tomography rGLP-1, recombinant GLP-1 Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 8 November 2007. DOI: 10.2337/db07-1162. Clinical trial reg. no. NCT00256256, clinicaltrials.gov. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted November 3, 2007. Received August 16, 2007. DIABETES

Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and metabolism during a hyperglycemic clamp with 18fluoro-deoxy-glucose as tracer. Glucagon-like peptide-1 lowered brain glucose (P = 0.023) in all regions. The cerebral metabolic rate for glucose was increased everywhere (P = 0.039) but not to the same extent in all regions (P = 0.022). The unidirectional glucose transfer across the blood-brain barrier remained unchanged (P = 0.099) in all regions, while the unidirectional clearance and the phosphorylation rate increased (P = 0.013 and 0.017), leading to increased net clearance of the glucose tracer (P = 0.006). We show that GLP-1 plays a role in a regulatory mechanism involved in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia.

Paroxysmal dyskinesias are episodic movement disorders that can be inherited or are sporadic in nature. The pathophysiology underlying these disorders remains largely unknown but may involve disrupted ion homeostasis due to defects in cell-surface channels or nutrient transporters. In this study, we describe a family with paroxysmal exertion-induced dyskinesia (PED) over 3 generations. Their PED was accompanied by epilepsy, mild developmental delay, reduced CSF glucose levels, hemolytic anemia with echinocytosis, and altered erythrocyte ion concentrations. Using a candidate gene approach, we identified a causative deletion of 4 highly conserved amino acids (Q282_S285del) in the pore region of the glucose transporter 1 (GLUT1). Functional studies in Xenopus oocytes and human erythrocytes revealed that this mutation decreased glucose transport and caused a cation leak that alters intracellular concentrations of sodium, potassium, and calcium. We screened 4 additional families, in which PED is combined with epilepsy, developmental delay, or migraine, but not with hemolysis or echinocytosis, and identified 2 additional GLUT1 mutations (A275T, G314S) that decreased glucose transport but did not affect cation permeability. Combining these data with brain imaging studies, we propose that the dyskinesias result from an exertion-induced energy deficit that may cause episodic dysfunction of the basal ganglia, and that the hemolysis with echinocytosis may result from alterations in intracellular electrolytes caused by a cation leak through mutant GLUT1.

Background While underlying mechanisms and pathways of social inequalities in cancer survival have been extensively examined in adults, this is less so for children with cancer. Hypothesized mechanisms include prediagnostic utilization of and navigation through the health care system, which may differ by socioeconomic resources of the families. In this nationwide register-based study we investigated the association between measures of family socioeconomic position in relation to prediagnostic health care contacts and stage of disease at diagnosis in children with cancer in Denmark. Methods We identified all children diagnosed with a cancer at ages 0–15 years in 1998–2016 ( N  = 3043) from the Danish Childhood Cancer Registry. We obtained comprehensive information on measures of socioeconomic position, parental health and prediagnostic contacts to both general practitioners and hospitals 24 months prior to diagnosis from various national registries. We fitted multivariable conditional logistic regression models for the association of family socioeconomic and health-related variables with firstly, frequent health care contacts and secondly, advanced stage. Results We found higher odds ratios (OR) of frequent both overall and emergency health care contacts in the last 3 months before diagnosis in children from households with short parental education and mixed affiliation to work market, when compared to children with high family socioeconomic position. Further, children of parents with depression or of non-Western origin, respectively, had higher OR for frequent overall and emergency contacts. We found no association between socioeconomic position, parental health and stage of disease. Conclusion Families with socioeconomic disadvantage, non-Western origin or depression more frequently utilize prediagnostic health care services, both generally and in the acute setting, indicating that some disadvantaged families may struggle to navigate the health care system when their child is sick. Reassuringly, this was not reflected in disparities in stage at diagnosis. In order to improve the diagnostic process and potentially reduce health care contacts, attention and support should be given to families with a high number of health care contacts over a short period of time.

Objective Cannabidiol (CBD) is approved for treatment of Dravet syndrome (DS), Lennox‐Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC). Several studies suggest antiseizure effects also beyond these three epilepsy syndromes. Methods In a retrospective multicenter study, we analyzed the efficacy and tolerability of CBD in patients with epilepsy at 16 epilepsy centers. Results The study cohort comprised 311 patients with epilepsy with a median age of 11.3 (0‐72) years (235 children and adolescents, 76 adults). Therapy with CBD was off‐label in 91.3% of cases due to age, epilepsy subtype, lack of adjunct therapy with clobazam, and/or higher dose applied. CBD titration regimens were slower than recommended, with good tolerability of higher doses particularly in children. Of all patients, 36.9% experienced a reduction in seizure frequency of >50%, independent of their epilepsy subtype or clobazam co‐medication. The median observation period was 15.8 months. About one third of all patients discontinued therapy within the observation period due to adverse effects or lack of efficacy. Adverse effects were reported frequently (46.9%). Significance Our study highlights that CBD has an antiseizure effect comparable to other antiseizure medications with a positive safety profile independent of the epilepsy subtype. Comedication with clobazam was not associated with a better outcome. Higher doses to achieve seizure frequency reduction were safe, particularly in children. These findings call for further trials for an extended approval of CBD for other epilepsy subtypes and for children <2 years of age.

Purpose Large-scale population-based registry studies investigating the risk of breast cancer after removal of both ovaries at hysterectomy for benign conditions in women with no known genetic predisposition to cancer are needed. We aimed to perform such a study taking into account the age at surgery status and use of hormone replacement therapy (HRT). Methods Within the female population of Denmark born 1937–1996, we evaluated breast cancer incidence after unilateral or bilateral oophorectomy concomitant with or after benign hysterectomy in comparison with no surgery and with hysterectomy alone using health registry data during 1978–2016. In a subpopulation followed from 1996, the analyses were stratified according to use of HRT. Results We found a reduced risk of breast cancer among women aged < 45 years at bilateral oophorectomy compared with women with hysterectomy alone (HR = 0.78; 95% CI 0.66, 0.92), whereas slightly increased risks were seen in women above 50 years. In the subpopulation, non-users of HRT aged ≥ 50 years at oophorectomy had a HR of 0.74 (95% CI 0.56, 0.98) for breast cancer after bilateral oophorectomy compared with hysterectomy alone. Conclusions Our large-scale study covering four decades provides evidence that bilateral oophorectomy performed at young age in women with benign indications for hysterectomy is associated with a reduction in breast cancer risk. The finding of a negative association at older ages in women not using HRT deserves further attention.

ObjectiveThe term ‘precision medicine’ describes a rational treatment strategy tailored to one person that reverses or modifies the disease pathophysiology. In epilepsy, single case and small cohort reports document nascent precision medicine strategies in specific genetic epilepsies. The aim of this multicentre observational study was to investigate the deeper complexity of precision medicine in epilepsy.MethodsA systematic survey of patients with epilepsy with a molecular genetic diagnosis was conducted in six tertiary epilepsy centres including children and adults. A standardised questionnaire was used for data collection, including genetic findings and impact on clinical and therapeutic management.ResultsWe included 293 patients with genetic epilepsies, 137 children and 156 adults, 162 females and 131 males. Treatment changes were undertaken because of the genetic findings in 94 patients (32%), including rational precision medicine treatment and/or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms. There was a rational precision medicine treatment for 56 patients (19%), and this was tried in 33/56 (59%) and was successful (ie, >50% seizure reduction) in 10/33 (30%) patients. In 73/293 (25%) patients there was a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms, and this was successful in 24/73 (33%).SignificanceOur survey of clinical practice in specialised epilepsy centres shows high variability of clinical outcomes following the identification of a genetic cause for an epilepsy. Meaningful change in the treatment paradigm after genetic testing is not yet possible for many people with epilepsy. This systematic survey provides an overview of the current application of precision medicine in the epilepsies, and suggests the adoption of a more considered approach.