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Hovorka R.,Wellcome Trust MRC Institute of Metabolic Science | Hovorka R.,University of Cambridge
Diabetic Medicine | Year: 2015

The development and clinical testing of closed-loop systems (the artificial pancreas) is underpinned by advances in continuous glucose monitoring and benefits from concerted academic and industry collaborative efforts. This review describes the progress of the Artificial Pancreas Project at the University of Cambridge from 2006 to 2014. Initial studies under controlled laboratory conditions, designed to collect representative safety and performance data, were followed by short to medium free-living unsupervised outpatient studies demonstrating the safety and efficacy of closed-loop insulin delivery using a model predictive control algorithm. Accompanying investigations included assessment of the psychosocial impact and key factors affecting glucose control such as insulin kinetics and glucose absorption. Translation to other disease conditions such as critical illness and Type 2 diabetes took place. It is concluded that innovation of iteratively enhanced closed-loop systems will provide tangible means to improve outcomes and quality of life in people with Type 1 diabetes and their families in the next decade. © 2015 Diabetes UK. Source


Stears A.,Wellcome Trust MRC Institute of Metabolic Science | Hames C.,Wellcome Trust MRC Institute of Metabolic Science
Clinical Lipidology | Year: 2014

Lipodystrophy is a group of rare conditions characterized by partial or complete loss of subcutaneous adipose tissue. Lipodystrophy is associated with metabolic derangements including severe insulin resistance, diabetes, hypertriglyceridemia, pancreatitis, nonalcoholic fatty liver disease and, in females, hyperandrogenism, polycystic ovarian syndrome and subfertility. The underlying cause may be genetic or acquired. Patients may present in childhood or adulthood. The diagnosis is frequently delayed, especially in partial lipodystrophy. Avoidance of excess dietary energy intake, despite the often lean appearance of the patient, is the current mainstay of treatment, aiming to avoid short- and long-term complications, while allowing normal growth in children. Early involvement of a specialized multidisciplinary team in the diagnosis and management of patients with lipodystrophy may enable evidence-based management guidelines to be developed. The timely diagnosis of lipodystrophy is becoming more important as novel treatment options such as recombinant methionyl human leptin therapy has recently been approved for use in some patients. © 2014 Future Medicine Ltd. Source


Volmer R.,University of Cambridge | Volmer R.,Wellcome Trust MRC Institute of Metabolic Science | Volmer R.,Cambridge Biomedical Research Center | Volmer R.,National Polytechnic Institute of Toulouse | And 3 more authors.
Current Opinion in Cell Biology | Year: 2015

Protein folding homeostasis in the lumen of the endoplasmic reticulum is defended by signal transduction pathways that are activated by an imbalance between unfolded proteins and chaperones (so called ER stress). Collectively referred to as the unfolded protein response (UPR) this homeostatic response is initiated by three known ER stress transducers: IRE1, PERK and ATF6. These ER-localised transmembrane (TM) proteins posses lumenal stress sensing domains and cytosolic effector domains that collectively activate a gene expression programme regulating the production of proteins involved in the processing and maturation of secreted proteins that enter the ER. However, beyond limiting unfolded protein stress in the ER the UPR has important connections to lipid metabolism that are the subject of this review. © 2014 The Authors. Source


Challis B.G.,Metabolic Research Laboratories | Kandasamy N.,Metabolic Research Laboratories | Powlson A.S.,Metabolic Research Laboratories | Koulouri O.,Metabolic Research Laboratories | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2016

Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Although the majority of childhood ACC arises in the context of inherited cancer susceptibility syndromes, it remains less clear whether a hereditary tumor predisposition exists for the development of ACC in adults. Here, we report the first occurrence of familial ACC in a kindred with Lynch syndrome resulting from a pathogenic germline MSH2 mutation. Case: A 54-year-old female with a history of ovarian and colorectal malignancy was found to have an ACC.Adetailed family history revealed her mother had died ofACCand her sister had previously been diagnosed with endometrial and colorectal cancers. A unifying diagnosis of Lynch syndrome was considered, and immunohistochemical analyses demonstrated loss of MSH2 and MSH6 expression in both AACs (proband and her mother) and in the endometrial carcinoma of her sister. Subsequent genetic screening confirmed the presence of a germline MSH2 mutation (resulting in deletions of exons 1-3) in the proband and her sister. Conclusion: Our findings provide strong support for the recent proposal that ACC should be considered a Lynch syndrome-associated tumor and included in the Amsterdam II clinical diagnostic criteria. We also suggest that screening for ACC should be considered in cancer surveillance strategies directed at individuals with germline mutations in DNA mismatch repair genes. © 2016 by the Endocrine Society. Source


Elleri D.,University of Cambridge | Elleri D.,Wellcome Trust MRC Institute of Metabolic Science | Allen J.M.,University of Cambridge | Allen J.M.,Wellcome Trust MRC Institute of Metabolic Science | And 13 more authors.
Diabetes, Obesity and Metabolism | Year: 2014

We evaluated the safety and efficacy of closed-loop therapy with meal announcement during reduction and omission of meal insulin boluses in adolescents with type 1 diabetes (T1D). Twelve adolescents with T1D [six male; mean (s.d.) age 15.9 (1.8) years; mean (s.d.) glycated haemoglobin (HbA1c) 77 (27) mmol/mol] were studied in a randomized crossover study comparing closed-loop therapy with meal announcement with conventional pump therapy over two 24-h stays at a clinical research facility. Identical meals were given on both occasions. The evening meal insulin bolus was calculated to cover half of the carbohydrate content of the meal and no bolus was delivered for lunch. Plasma glucose levels were in the target range of 3.9-10mmol/l for a median [interquartile range (IQR)] of 74 (55,86)% of the time during closed-loop therapy with meal announcement and for 62 (49,75)% of the time during conventional therapy (p=0.26). Median (IQR) time spent with plasma glucose levels>10mmol/l [23 (13,39) vs. 27 (10,50)%; p=0.88] or<3.9mmol/l [1(0,4) vs. 5 (1,10)%; p=0.24] and mean [standard deviation (SD)] glucose levels [8.0 (7.6,9.3) vs. 7.7 (6.6,10.1) mmol/l, p=0.79] were also similar. In conclusion, these results assist home testing of closed-loop delivery with meal announcement in adolescents with poorly controlled T1D who miscalculate or miss meal insulin boluses. © 2014 John Wiley & Sons Ltd. Source

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