Peninsula NIHR Clinical Research Facility

Exeter, United Kingdom

Peninsula NIHR Clinical Research Facility

Exeter, United Kingdom
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Fulford J.,Peninsula NIHR Clinical Research Facility | Winyard P.G.,University of Exeter
Journal of Physiology | Year: 2011

Exercise in hypoxia is associated with reduced muscle oxidative function and impaired exercise tolerance. We hypothesised that dietary nitrate supplementation (which increases plasma [nitrite] and thus NO bioavailability) would ameliorate the adverse effects of hypoxia on muscle metabolism and oxidative function. In a double-blind, randomised crossover study, nine healthy subjects completed knee-extension exercise to the limit of tolerance (T lim), once in normoxia (20.9% O 2; CON) and twice in hypoxia (14.5% O 2). During 24 h prior to the hypoxia trials, subjects consumed 0.75 L of nitrate-rich beetroot juice (9.3 mmol nitrate; H-BR) or 0.75 L of nitrate-depleted beetroot juice as a placebo (0.006 mmol nitrate; H-PL). Muscle metabolism was assessed using calibrated 31P-MRS. Plasma [nitrite] was elevated (P < 0.01) following BR (194 ± 51 nm) compared to PL (129 ± 23 nm) and CON (142 ± 37 nM). T lim was reduced in H-PL compared to CON (393 ± 169 vs. 471 ± 200 s; P < 0.05) but was not different between CON and H-BR (477 ± 200 s). The muscle [PCr], [P i] and pH changed at a faster rate in H-PL compared to CON and H-BR. The [PCr] recovery time constant was greater (P < 0.01) in H-PL (29 ± 5 s) compared to CON (23 ± 5 s) and H-BR (24 ± 5 s). Nitrate supplementation reduced muscle metabolic perturbation during exercise in hypoxia and restored exercise tolerance and oxidative function to values observed in normoxia. The results suggest that augmenting the nitrate-nitrite-NO pathway may have important therapeutic applications for improving muscle energetics and functional capacity in hypoxia. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.


Freathy R.M.,University of Bristol | Freathy R.M.,University of Exeter | Kazeem G.R.,Glaxosmithkline | Morris R.W.,University College London | And 25 more authors.
International Journal of Epidemiology | Year: 2011

Background Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers. Methods We stratified nine European study samples by smoking status and, in each stratum, analysed the association between genotype of the 15q25 SNP, rs1051730, and BMI. We meta-analysed the results (n = 24 198) and then tested for a genotype × smoking status interaction.Results There was no evidence of association between BMI and genotype in the never smokers {difference per T-allele: 0.05 kg/m 2 [95% confidence interval (95% CI): -0.05 to 0.18]; P = 0.25}. However, in ever smokers, each additional smoking-related T-allele was associated with a 0.23 kg/m 2 (95% CI: 0.13-0.31) lower BMI (P = 8 × 10 -6). The effect size was larger in current [0.33 kg/m 2 lower BMI per T-allele (95% CI: 0.18-0.48); P = 6 × 10 -5], than in former smokers [0.16 kg/m 2 (95% CI: 0.03-0.29); P = 0.01]. There was strong evidence of genotype × smoking interaction (P = 0.0001).Conclusions Smoking status modifies the association between the 15q25 variant and BMI, which strengthens evidence that smoking exposure is causally associated with reduced BMI. Smoking cessation initiatives might be more successful if they include support to maintain a healthy BMI. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2011; all rights reserved.


Brooks A.M.,Newcastle University | Oram R.,Peninsula NIHR Clinical Research Facility | Home P.,Newcastle University | Steen N.,Newcastle University | Shaw J.A.M.,Newcastle University
Diabetes Care | Year: 2015

OBJECTIVE: Maintenance of endogenous pancreatic β-cell function could be an important goal in the management of type 1 diabetes. However, the impact of stimulated C-peptide level on overall glycemic control is unknown. The relationship between C-peptide and parameters of glucose control was therefore characterized in a cohort with rapidly changing β-cell function following islet transplantation.RESEARCH DESIGN AND METHODS: Standardized mixed-meal tolerance test was undertaken in 12 consecutive islet recipients at 1-6-month intervals, with graft function determined by 90-min stimulated C-peptide. Continuous glucose monitoring was undertaken in the week preceding each assessment and the relationship between C-peptide and glucose control evaluated by mixed Poisson regression.RESULTS: Recipients completed 5 (1-14) [median (range)] clinical assessments over 18 (1-51)months posttransplant encompassing a wide range of stimulated C-peptide levels (7-2,622 pmol/L). Increasing β-cell function across predefined C-peptide groups was associated with reduced insulin dose, HbA1c,mean glucose (low [<200 pmol/L] 10.7 vs. excellent [>1,000 pmol/L] 7.5 mmol/L), and glucose SD (low, 4.4 vs. excellent, 1.4 mmol/L). Highly statistically significant continuous associations between stimulated C-peptide and mean interstitial glucose (lower by 2.5% [95% CI 1.5-3.5%] per 100 pmol/L higher C-peptide), glucose SD, time outside glucose target range, and measures of hyper-/hypoglycemia risk were confirmed.CONCLUSIONS: Repeated assessment of islet transplant recipients has enabled modeling of the relationship between endogenous β-cell function and measures of glycemic control providing quantitative estimates of likely impact of an acute change in β-cell function in individuals with type 1 diabetes. © 2015 by the American Diabetes Association.


Besser R.E.J.,Peninsula NIHR Clinical Research Facility | Jones J.,Peninsula Community Health | McDonald T.J.,Peninsula NIHR Clinical Research Facility | Smith R.,Derriford Hospital | And 2 more authors.
BMJ Case Reports | Year: 2012

The authors report an adolescent who was found to have diabetes on routine blood testing. The initial diagnosis was type 2 diabetes because she was obese, did not have type 1 diabetes antibodies and both parents had diabetes. Highly sensitive C-reactive protein (hsCRP) was low in the proband and her father (≤0.1 mg/l) indicating that type 2 diabetes was unlikely, and that hepatocyte nuclear factor 1-α-iquest;-maturity onset diabetes of the young (HNF1A-MODY) was the most likely diagnosis. Following a genetic diagnosis of HNF1A-MODY in the proband and her father, both patients were treated with gliclazide, with improvement in HbA1c. This case highlights the challenges of making a correct diagnosis of MODY in young onset diabetes. The authors report the first case where hsCRP, an easily available biomarker, has been used on an individual level to determine appropriate genetic testing of MODY in a family whose main differential diagnosis was familial type 2 diabetes.


Veeramootoo D.,Royal Devon and Exeter Foundation Hospital | Veeramootoo D.,Peninsula NIHR Clinical Research Facility | Shore A.C.,Peninsula NIHR Clinical Research Facility | Shields B.,Peninsula NIHR Clinical Research Facility | And 4 more authors.
Surgical Endoscopy and Other Interventional Techniques | Year: 2010

Background Minimally invasive esophagectomy (MIO) is now established as a valid alternative to open surgery for the management of esophagogastric cancers. However, a high incidence of ischemia-related gastric conduit failure (ICF) is observed, which is detrimental to any potential benefits of this approach. Methods Since April 2004, MIO has been the procedure of choice for esophagogastric resection in the authors' unit. Data relating to the surgical technique were collected, with a focus on ischemic conditioning by laparoscopic ligation of the left gastric artery (LIC) 2 weeks or 5 days before resection. Results A total of 97 patients underwent a planned MIO. Four in-patient deaths (4.1%) occurred, none of which were conduit related, and overall, 20 patients experienced ICF (20.6%). In four patients, ICF was recognized and dealt with at the initial surgery. The remaining 16 patients experienced this complication postoperatively, with 9 (9.3%) of them requiring further surgery. Of the 97 patients, 55 did not undergo ischemic conditioning, and conduit failure was observed in 11 (20%). Thirty-five patients had LIC at 2 weeks, and 2 (5.7%) experienced ICF. All seven patients (100%) who had LIC at 5 days experienced ICF. Timing of ischemic conditioning (p<0.0001) had a definite impact on the conduit failure rate, and the benefit of ischemic conditioning at 2 weeks compared with no conditioning neared significance (p = 0.07). Conclusions Ischemic failure of the gastric conduit significantly impairs recovery after MIO. Ischemic conditioning 2 weeks before surgery may reduce this complication and allow the benefits of this approach to be realized. © Springer Science+Business Media, LLC 2009.


Steele A.M.,Peninsula NIHR Clinical Research Facility | Shields B.M.,Peninsula NIHR Clinical Research Facility | Shepherd M.,Peninsula NIHR Clinical Research Facility | Ellard S.,Peninsula NIHR Clinical Research Facility | And 3 more authors.
Diabetic Medicine | Year: 2010

Aims To investigate all-cause and cardiovascular mortality in subjects with diabetes caused by a mutation in the hepatocyte nuclear factor 1α gene (HNF1A). Methods We identified 39 British families with HNF1A mutations. Consenting individuals were asked details of age and cause of death of parents and siblings. Copies of death certificates were requested from the family or were obtained via the Offices for National Statistics. Results Data were collated on 241 control subjects and 153 mutation carriers. Of those who died, 66% of mutation carriers died from a cardiovascular-related illness compared with 43% of control subjects (P = 0.02). Family members with HNF1A mutations died at a younger age than familial control subjects [all-cause hazard ratio, adjusting for sex and smoking status: 1.9 (95% confidence interval 1.2, 2.9, P = 0.006; cardiovascular hazard ratio: 2.3, confidence interval 1.3, 4.2, P = 0.006)]. Conclusions We have shown that individuals known to have diabetes caused by a mutation in the HNF1A gene have an increased risk of cardiovascular mortality compared with their unaffected family members. As with other forms of diabetes, consideration should be given to early statin therapy despite a seemingly protective lipid profile. © 2010 Diabetes UK.


Besser R.E.,Peninsula NIHR Clinical Research Facility
BMJ case reports | Year: 2012

The authors report an adolescent who was found to have diabetes on routine blood testing. The initial diagnosis was type 2 diabetes because she was obese, did not have type 1 diabetes antibodies and both parents had diabetes. Highly sensitive C-reactive protein (hsCRP) was low in the proband and her father (≤0.1 mg/l) indicating that type 2 diabetes was unlikely, and that hepatocyte nuclear factor 1-α-maturity onset diabetes of the young (HNF1A-MODY) was the most likely diagnosis. Following a genetic diagnosis of HNF1A-MODY in the proband and her father, both patients were treated with gliclazide, with improvement in HbA1c. This case highlights the challenges of making a correct diagnosis of MODY in young onset diabetes. The authors report the first case where hsCRP, an easily available biomarker, has been used on an individual level to determine appropriate genetic testing of MODY in a family whose main differential diagnosis was familial type 2 diabetes.

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