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Clark R.H.,University of Oxford | McTaggart J.S.,University of Oxford | Webster R.,Weatherall Institute of Molecular Medicine | Mannikko R.,University of Oxford | And 6 more authors.
Science | Year: 2010

Gain-of-function mutations in Kir6.2 (KCNJ11), the pore-forming subunit of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel, cause neonatal diabetes. Many patients also suffer from hypotonia (weak and flaccid muscles) and balance problems. The diabetes arises from suppressed insulin secretion by overactive KATP channels in pancreatic β-cells, but the source of themotor phenotype is unknown. By using mice carrying a human Kir6.2 mutation (Val59→Met59) targeted to either muscle or nerve, we show that analogous motor impairments originate in the central nervous system rather than in muscle or peripheral nerves. We also identify locomotor hyperactivity as a feature of KATP channel overactivity. These findings suggest that drugs targeted against neuronal, rather than muscle, KATP channels are needed to treat the motor deficits and that such drugs require high blood-brain barrier permeability.

Lundbom J.,University of Helsinki | Hakkarainen A.,University of Helsinki | Fielding B.,Oxford Center for Diabetes Endocrinology and Metabolism | Soderlund S.,University of Helsinki | And 3 more authors.
NMR in Biomedicine | Year: 2010

The aim of this study was to investigate the use of 1H-MRS with various echo times to characterize subcutaneous human adipose tissue (SAT) triglyceride composition and to validate the findings with fatty acid (FA) analysis of SAT biopsies by gas chromatography (GC). 1H-MRS spectra were acquired with a 1.5 Tesla clinical imager from the SATof 17 healthy volunteers, with 10 undergoing SAT biopsy. Spectra were localized with PRESS and a series of echo times; 30,50,80,135,200,300 and 540 ms were acquired with TR=3000 ms. Prior knowledge from phantom measurements was used to construct AMARES fitting models for the lipid spectra. SAT FA composition were compared with serum lipid levels and subject characteristics in 17 subjects. Long TE (135,200 ms) spectra corresponded better with the GC data than short TE (30,50 ms) spectra. TE=135 ms was found optimal for determining diallylic content (R=0.952, p<0.001) and TE=200 ms was optimal for determining olefinic content (R=0.800, p<0.01). The improved performance of long TE spectra is a result of an improved baseline and better peak separation, due to J-modulation and suppression of water. The peak position of the diallylic resonance correlated with the average double bond content of polyunsatured fatty acids with R=0.899 (p<0.005). The apparent T2 of the methylene resonance displayed relatively small inter-individual variation, 88.1±1.1 ms (mean±SD). The outer methyl triplet line of ω-3 PUFA at 1.08ppm could be readily detected and quantitated from spectra obtained at TE=540. The ω-3 resonance correlated with the ω-3 content determined by GC with R=0.737 (p<0.05, n=8). Age correlated significantly with SAT diallylic content (R=0.569, p=0.017, n=17), but serum lipid levels showed no apparent relation to SAT FA composition.We conclude that long TE 1H-MRS provides a robust non-invasive method for characterizing adipose tissue triglycerides in vivo. Copyright © 2010 John Wiley & Sons, Ltd.

Nauck M.,Diabeteszentrum Bad Lauterberg | Frid A.,Skane University Hospital | Hermansen K.,Aarhus University Hospital | Thomsen A.B.,Novo Nordisk AS | And 5 more authors.
Diabetes, Obesity and Metabolism | Year: 2013

Aims: To investigate efficacy and safety of dual therapy with liraglutide and metformin in comparison to glimepiride and metformin, and metformin monotherapy over 2years in patients with type 2 diabetes. Methods: In the 26-week the Liraglutide Effect and Action in Diabetes (LEAD)-2 core trial, patients (n=1091) were randomized (2:2:2:1:2) to liraglutide (0.6, 1.2 or 1.8mg once-daily), placebo or glimepiride; all with metformin. Patients were enrolled if they were 18-80years old with HbA1c 7.0-11.0% (previous monotherapy ≥3months), or 7.0-10.0% (previous combination therapy ≥3months), and body mass index ≤40kg/m2. Patients completing the 26-week double-blinded phase could enter an 18-month open-label extension. Results: HbA1c decreased significantly with liraglutide (0.4% with 0.6mg, 0.6% with 1.2 and 1.8mg) versus 0.3% increase with metformin monotherapy (p<0.0001). HbA1c decrease with liraglutide was non-inferior versus 0.5% decrease with glimepiride. Liraglutide groups experienced significant weight loss (2.1, 3.0 and 2.9kg with 0.6, 1.2 and 1.8mg, respectively) compared to weight gain (0.7kg) with glimepiride (p<0.0001). Weight loss with liraglutide 1.2 and 1.8mg was significantly greater than with metformin monotherapy (1.8kg; p=0.0185 and p=0.0378 for 1.2 and 1.8mg, respectively). The occurrence of minor hypoglycaemia was <5.0% in all liraglutide groups, significantly less than with glimepiride (24.0%; p<0.0001). Liraglutide was well tolerated overall: gastrointestinal events were more common than with glimepiride or metformin monotherapy, but occurrence decreased with time. Conclusions: Liraglutide provided sustained glycaemic control over 2 years comparable to that provided by glimepiride. Liraglutide was well tolerated, and was associated with weight loss and a low rate of hypoglycaemia. © 2012 Blackwell Publishing Ltd.

Katulanda P.,University of Colombo | Ranasinghe C.,University of Colombo | Rathnapala A.,University of Colombo | Karunaratne N.,University of Colombo | And 2 more authors.
BMC Public Health | Year: 2014

Background: Most studies on alcohol consumption carried out in Sri Lanka are limited to single/few provinces in the island. The objective of this study was to determine the prevalence, patterns and correlates of alcohol consumption among a larger sample of adults in Sri Lanka. Methods. This cross-sectional study was conducted in seven of all nine provinces in Sri Lanka, between 2005 and 2006. A nationally representative sample of 5000 adults aged ≥18 years was selected using multi-stage random cluster sampling. Data of 4532 participants were collected using an interviewer administered questionnaire. Data analysis included chi-squared test, multiple logistic regression analysis and Spearman correlation using Stata/SE 10.0 (StataCorp LP., Texas, USA) software package. Results: Males were 40%; mean age was 46.1 years (±15.1). The overall, urban and rural prevalence (95% CI) of current drinking was 23.7% (21.7 - 25.7), 29.5% (25.7 - 33.3) and 22.2% (19.8 - 24.7) respectively (p = 0.001). Current (M: 48.1%, F: 1.2%, p < 0.0001) and former (M: 21.4%, F: 0.7%, p < 0.0001) drinking was much higher in males. The highest prevalence of drinking in males (58.9%) and females (2.2%) was in the 30 - 39 and <20 year age groups respectively. Lowest prevalence in men (24.6%) and women (0%) was in the >70 years age-group. Hazardous drinking was seen in 5.2% of men and 0.02% of women. Male sex, urban living and current smoking correlated with both current and hazardous drinking. Lower level of education, and age >70 years positively correlated with hazardous drinking. Conclusions: Alcohol is predominantly a problem in Sri Lankan males. In males, both current and hazardous drinking positively correlated with urban living, white collar occupation, Burgher ethnicity and current smoking. Hazardous drinking positively correlated with lower level of education and older age. The data shown here are useful in planning interventions simultaneously targeting alcohol and tobacco. © 2014 Katulanda et al.; licensee BioMed Central Ltd.

Hodson L.,Oxford Center for Diabetes Endocrinology and Metabolism | Karpe F.,Oxford Center for Diabetes Endocrinology and Metabolism | Karpe F.,University of Oxford
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2013

Purpose of Review: The fatty acid, palmitoleate (16:1 n-7), has received a lot of attention in recent years for being 'lipokine' and for the first time, we review the evidence to determine if there is something special about palmitoleate in humans. Recent Findings: Despite dietary intakes being low (<4% of total energy) palmitoleate is the second most abundant monounsaturated fatty acid in most, but not all, blood lipid pools and notably more abundant in adipose tissue. Thus, compared with other fatty acids, the palmitoleate content of lipid pools must be influenced by endogenous synthesis, which appears to be tissue and depot specific. We present a summary of dietary intervention studies of food components enriched in palmitoleate but this gives inconclusive results in regards to an impact on human metabolic regulation. Summary: To date, there is no strong evidence from human studies suggesting that palmitoleate has 'lipokine' effects. However, unlike other fatty acids, there is a clear tendency towards compartmentalization and tissue-specific formation of palmitoleate, which is intriguing and requires further investigation. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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