NIHR Exeter Clinical Research Facility

Exeter, United Kingdom

NIHR Exeter Clinical Research Facility

Exeter, United Kingdom
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Shields B.M.,University of Exeter | Shields B.M.,NIHR Exeter Clinical Research Facility | Shepherd M.,University of Exeter | Shepherd M.,NIHR Exeter Clinical Research Facility | And 13 more authors.
Diabetes Care | Year: 2017

OBJECTIVE Monogenic diabetes, a young-onset formof diabetes, is often misdiagnosed as type 1 diabetes, resulting in unnecessary treatment with insulin. A screening approach for monogenic diabetes is needed to accurately select suitable patients for expensive diagnostic genetic testing. We used C-peptide and islet autoantibodies, highly sensitive and specific biomarkers for discriminating type 1 fromnon-type 1 diabetes, in a biomarker screening pathway for monogenic diabetes. RESEARCH DESIGN AND METHODS We studied patients diagnosed at age 30 years or younger, currently younger than 50 years, in two U.K. regionswith existing high detection ofmonogenic diabetes. The biomarker screening pathway comprised three stages: 1) assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR); 2) if UCPCR was 0.2 nmol/mmol, measurement of GAD and IA2 islet autoantibodies; and 3) if negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes. RESULTS A total of 1,407 patients participated (1,365 with no known genetic cause, 34 with monogenic diabetes, and 8with cystic fibrosis-related diabetes).A total of 386 out of 1,365 (28%) patients had a UCPCR 0.2 nmol/mmol, and 216 out of 386 (56%) were negative for GAD and IA2 and underwent molecular genetic testing. Seventeen new cases ofmonogenic diabeteswere diagnosed (8 commonMaturityOnset Diabetes of the Young [Sanger sequencing] and 9 rarer causes [next-generation sequencing]) in addition to the 34 known cases (estimated prevalence of 3.6% [51/1,407] [95% CI 2.7-4.7%]). The positive predictive value was 20%, suggesting a 1-in-5 detection rate for the pathway. The negative predictive value was 99.9%. CONCLUSIONS The biomarker screening pathway formonogenic diabetes is an effective, cheap, and easily implemented approach to systematically screening all young-onset patients. Theminimumprevalence ofmonogenic diabetes is 3.6%of patients diagnosed at age 30 years or younger.


Munkley J.,Northumbria University | Oltean S.,University of Bristol | Vodak D.,University of Oslo | Wilson B.T.,Northumbria University | And 20 more authors.
Oncotarget | Year: 2015

Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castrationresistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, being significantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression.


PubMed | RD&E NHS Foundation Trust, Exeter Surgical Health Services Research Unit, University of Oslo, Cancer Research UK Research Institute and 5 more.
Type: | Journal: EBioMedicine | Year: 2016

Steroid androgen hormones play a key role in the progression and treatment of prostate cancer, with androgen deprivation therapy being the first-line treatment used to control cancer growth. Here we apply a novel search strategy to identify androgen-regulated cellular pathways that may be clinically important in prostate cancer. Using RNASeq data, we searched for genes that showed reciprocal changes in expression in response to acute androgen stimulation in culture, and androgen deprivation in patients with prostate cancer. Amongst 700 genes displaying reciprocal expression patterns we observed a significant enrichment in the cellular process glycosylation. Of 31 reciprocally-regulated glycosylation enzymes, a set of 8 (GALNT7, ST6GalNAc1, GCNT1, UAP1, PGM3, CSGALNACT1, ST6GAL1 and EDEM3) were significantly up-regulated in clinical prostate carcinoma. Androgen exposure stimulated synthesis of glycan structures downstream of this core set of regulated enzymes including sialyl-Tn (sTn), sialyl Lewis(X) (SLe(X)), O-GlcNAc and chondroitin sulphate, suggesting androgen regulation of the core set of enzymes controls key steps in glycan synthesis. Expression of each of these enzymes also contributed to prostate cancer cell viability. This study identifies glycosylation as a global target for androgen control, and suggests loss of specific glycosylation enzymes might contribute to tumour regression following androgen depletion therapy.


PubMed | Exeter Surgical Health Services Research Unit, University of Oslo, University of Bristol, University of Exeter and 4 more.
Type: Journal Article | Journal: Oncotarget | Year: 2015

Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, beingsignificantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression.


Oram R.A.,NIHR Exeter Clinical Research Facility | Brooks A.M.,Newcastle University | Forbes S.,Royal Infirmary | Eckoldt S.,Southmead Hospital | And 11 more authors.
Diabetes Care | Year: 2014

OBJECTIVE Islet graft function is defined by serum C-peptide in a standardized challenge test. We assessed whether urine C-peptide creatinine ratio (UCPCR) sent from home could provide a viable alternative. RESEARCH DESIGN AND METHODS Seventeen islet recipients provided 90-min serum C-peptide (sCP90) and 120-min UCPCR (UCPCR120) samples during 68 interval posttransplant mixed-meal tolerance tests, also posting from home a 120-min postbreakfast UCPCR sample every 2 weeks. UCPCR was compared with a clinical score of islet function, derived from HbA1c and insulin dose. RESULTS UCPCR120 and mean home postmeal UCPCR were strongly correlated with sCP90 (rs = 0.73, P > 0.001; and rs = 0.73, P > 0.01, respectively). Mean home UCPCR increased with clinical score (rs = 0.75; P > 0.001) and with graft function defined both by sCP90 <200 pmol/L and insulin independence. UCPCR cutoffs to detect insulin independence and poor graft function were sensitive and specific. CONCLUSIONS Home UCPCR provides a valid measure of C-peptide production in islet transplant recipients. © 2014 by the American Diabetes Association.


Morel K.,University of Sussex | Colclough K.,Royal Devon and Exeter NHS Healthcare Trust | Vaughan N.,University of Sussex | Shepherd M.,Royal Devon and Exeter NHS Healthcare Trust | Shepherd M.,NIHR Exeter Clinical Research Facility
Journal of Diabetes Nursing | Year: 2013

Monogenic diabetes is poorly recognised but identification is important as many people may be successfully managed with sulphonylureas rather than insulin (Pearson et al, 2000; Stride and Hattersley, 2002; Pearson et al, 2003; Shepherd et al, 2003; Hattersley, 2005). Ensuring the correct diagnosis also allows appropriate follow up and counselling of family members (Shepherd et al, 2010). The Genetic Diabetes Nurse (GDN) project was set up in 2002 to increase awareness of monogenic diabetes (Dudding et al, 2005; Shepherd et al, 2005) and prior to the appointment of a GDN for Sussex in 2005, only one person had a confirmed diagnosis of monogenic diabetes in the Brighton and Hove area. This paper describes how training a GDN improved care through the identification of 54 people with monogenic diabetes and the establishment of a specialist clinic.


Shepherd M.,University of Exeter | Shepherd M.,NIHR Exeter Clinical Research Facility | Cropper J.,Leeds Teaching Hospitals NHS Trust
Journal of Diabetes Nursing | Year: 2013

Although type 1 diabetes accounts for most cases of diabetes presenting in childhood, skills and knowledge enabling paediatric teams to confidently identify other forms of diabetes are clearly required. Ensuring correct diagnosis by recognising cases of "non-type 1" diabetes in children and young people is crucial as it has implications for treatment and follow up. This article highlights three cases of diabetes presenting in children with features suggesting potential monogenic causes of diabetes. The cases include hepatocyte nuclear factor 1-alpha maturity onset diabetes of the young (MODY), glucokinase MODY and KCNJ11 neonatal diabetes. The implications of the correct diagnosis are also discussed.


PubMed | Exeter Surgical Health Services Research Unit, University of Exeter, Northumbria University, Cancer Research UK Research Institute and 2 more.
Type: Journal Article | Journal: Oncoscience | Year: 2015

Androgen receptor (AR) signalling and the PI3K pathway mediate survival signals in prostate cancer, and have been shown to regulate each other by reciprocal negative feedback, such that inhibition of one activates the other. Understanding the reciprocal regulation of these pathways is important for disease management as tumour cells can adapt and survive when either single pathway is inhibited pharmacologically. We recently carried out genome-wide exon-specific profiling of prostate cancer cells to identify novel androgen-regulated transcriptional events. Here we interrogated this dataset for novel androgen-regulated genes associated with the PI3K pathway. We find that the PI3K regulatory subunits PIK3R1 (p85) and PIK3R3 (p55) are direct targets of the AR which are rapidly repressed by androgens in LNCaP cells. Further characterisation revealed that the PIK3CA p110 catalytic subunit is also indirectly regulated by androgens at the protein level. We show that PIK3R1 mRNA is significantly under-expressed in prostate cancer (PCa) tissue, and provide data to suggest a context-dependent regulatory mechanism whereby repression of the p85 protein by the AR results in destabilisation of the PI3K p110 catalytic subunit and downstream PI3K pathway inhibition that functionally affects the properties of prostate cancer cells.


Aizawa K.,University of Exeter | Aizawa K.,NIHR Exeter Clinical Research Facility | Elyas S.,University of Exeter | Elyas S.,NIHR Exeter Clinical Research Facility | And 14 more authors.
Ultrasound in Medicine and Biology | Year: 2016

The grey-scale median of the common carotid artery intima-media complex (IM-GSM) characterizes arterial wall composition, and a low IM-GSM is associated with increased cardiovascular mortality in the elderly. We aimed to determine differences in the IM-GSM between a cohort with cerebrovascular disease and a healthy cohort. Eighty-two healthy individuals (control group: 63.2 ± 8.7 y) and 96 patients with either stroke or transient ischemic attacks (CRVD group: 68.6 ± 9.8 y) were studied. Common carotid artery intima-media thickness and IM-GSM obtained by ultrasound were analyzed using semi-automated edge-detection software. The IM-GSM was significantly lower in the CRVD group than in the control group (106 ± 24 vs. 124 ± 27 au, p < 0.001). The IM-GSM was similar for the infarct and non-infarct sides in CRVD. In the pooled cohort of all participants, the lower the quartile of IM-GSM, the greater were the carotid artery intima-media thickness and carotid artery remodeling. These results suggest the presence of an altered atherosclerotic phenotype in the intima-media complex of CRVD patients that can be detected by ultrasound. © 2016 World Federation for Ultrasound in Medicine & Biology.


Hope S.V.,Royal Devon and Exeter NHS Foundation Trust | Hope S.V.,NIHR Exeter Clinical Research Facility | Jones A.G.,NIHR Exeter Clinical Research Facility | Goodchild E.,NIHR Exeter Clinical Research Facility | And 7 more authors.
Diabetic Medicine | Year: 2013

Aims: To determine the prevalence and clinical characteristics of absolute insulin deficiency in long-standing Type 2 diabetes, using a strategy based on home urinary C-peptide creatinine ratio measurement. Methods: We assessed the urinary C-peptide creatinine ratios, from urine samples taken at home 2 h after the largest meal of the day, in 191 insulin-treated subjects with Type 2 diabetes (diagnosis age ≥45 years, no insulin in the first year). If the initial urinary C-peptide creatinine ratio was ≤0.2 nmol/mmol (representing absolute insulin deficiency), the assessment was repeated. A standardized mixed-meal tolerance test with 90-min stimulated serum C-peptide measurement was performed in nine subjects with a urinary C-peptide creatinine ratio ≤ 0.2 nmol/mmol (and in nine controls with a urinary C-peptide creatinine ratio >0.2 nmol/mmol) to confirm absolute insulin deficiency. Results: A total of 2.7% of participants had absolute insulin deficiency confirmed by a mixed-meal tolerance test. They were identified initially using urinary C-peptide creatinine ratio: 11/191 subjects (5.8%) had two consistent urinary C-peptide creatinine ratios ≤ 0.2 nmol/mmol; 9 of these 11 subjects completed a mixed-meal tolerance test and had a median stimulated serum C-peptide of 0.18 nmol/l. Five of these 9 had stimulated serum C-peptide <0.2 nmol/l and 9/9 subjects with urinary C-peptide creatinine ratio >0.2 had endogenous insulin secretion confirmed by the mixed-meal tolerance test. Compared with subjects with a urinary C-peptide creatinine ratio >0.2 nmol/mmol, those with confirmed absolute insulin deficiency had a shorter time to insulin treatment (median 2.5 vs. 6 years, P=0.005) and lower BMI (25.1 vs. 29.1 kg/m2, P=0.04). Two out of the five patients with absolute insulin deficiency were glutamic acid decarboxylase autoantibody-positive. Conclusions: Absolute insulin deficiency may occur in long-standing Type 2 diabetes, and cannot be reliably predicted by clinical features or autoantibodies. Absolute insulin deficiency in Type 2 diabetes may increase the risk of hypoglycaemia and ketoacidosis, as in Type 1 diabetes. Its recognition should help guide treatment, education and management. The urinary C-peptide creatinine ratio is a practical non-invasive method to aid detection of absolute insulin deficiency, with a urinary C-peptide creatinine ratio > 0.2 nmol/mmol being a reliable indicator of retained endogenous insulin secretion. © 2013 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

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