A5089848866- Pancreatic function and diabetes
- Diabetes Treatment and Management
- Diabetes Management and Research
- Metabolism, Diabetes, and Cancer
- Ion channel regulation and function
- Diabetes and associated disorders
- Cellular transport and secretion
- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Calcium signaling and nucleotide metabolism
- Adenosine and Purinergic Signaling
- Lipid Membrane Structure and Behavior
- Diet, Metabolism, and Disease
- Neuroscience and Neural Engineering
- Erythrocyte Function and Pathophysiology
- Photoreceptor and optogenetics research
- Ion Transport and Channel Regulation
- Adipose Tissue and Metabolism
- Neuropeptides and Animal Physiology
- Cardiac Ischemia and Reperfusion
- Cannabis and Cannabinoid Research
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Pancreatitis Pathology and Treatment
- Regulation of Appetite and Obesity
- Diet and metabolism studies
University of Oxford
2016-2025
University of Gothenburg
2016-2025
Oxford Centre for Diabetes, Endocrinology and Metabolism
2015-2024
Churchill Hospital
2015-2024
National Institute for Health Research
2012-2024
University of Ulster
2024
Science Oxford
2007-2018
Oxford BioMedica (United Kingdom)
2010-2018
Centre for Human Genetics
2017
University of Alberta
2011-2012
Variants in the FTO (fat mass and obesity associated) gene are associated with increased body index humans. Here, we show by bioinformatics analysis that shares sequence motifs Fe(II)- 2-oxoglutarate–dependent oxygenases. We find recombinant murine Fto catalyzes 2OG-dependent demethylation of 3-methylthymine single-stranded DNA, concomitant production succinate, formaldehyde, carbon dioxide. Consistent a potential role nucleic acid demethylation, localizes to nucleus transfected cells....
Altered growth and development of the endocrine pancreas is a frequent cause hyperglycemia associated with diabetes. Here we show that microRNA-375 (miR-375), which highly expressed in pancreatic islets, required for normal glucose homeostasis. Mice lacking miR-375 (375KO) are hyperglycemic, exhibit increased total alpha-cell numbers, fasting fed plasma glucagon levels, gluconeogenesis hepatic output. Furthermore, beta-cell mass decreased 375KO mice as result impaired proliferation. In...
OBJECTIVE— To characterize the voltage-gated ion channels in human β-cells from nondiabetic donors and their role glucose-stimulated insulin release. RESEARCH DESIGN AND METHODS— Insulin release was measured intact islets. Whole-cell patch-clamp experiments measurements of cell capacitance were performed on isolated β-cells. The channel complement determined by quantitative PCR. RESULTS— Human express two types K+ currents that flow through delayed rectifying (KV2.1/2.2) large-conductance...
The transcriptional machinery in individual cells is controlled by a relatively small number of molecules, which may result stochastic behavior gene activity. Because technical limitations current collection and recording methods, most expression measurements are carried out on populations therefore reflect average mRNA levels. variability the transcript levels between different remains undefined, although it have profound effects cellular activities. Here we measured five genes ActB, Ins1,...
In vitro studies suggest that the G protein-coupled receptor (GPR) 30 is a functional estrogen receptor. However, physiological role of GPR30 in vivo unknown, and it remains to be determined whether an also vivo. To this end, we studied effects disrupting gene female male mice. Female GPR30((-/-)) mice had hyperglycemia impaired glucose tolerance, reduced body growth, increased blood pressure, serum IGF-I levels. The growth correlated with proportional decrease skeletal development. elevated...
Pancreatic islets of NMRI mice were dissociated into single cells which kept in tissue culture for 1-3 days. The whole-cell configuration the patch-clamp technique was used to study inward and delayed outward currents beta-cells under voltage-clamp conditions at 20-22 degrees C. Outward suppressed by substituting impermeant cation N-methyl-D-glucamine intracellular K+. remaining current had a V-shaped current-voltage relation reaching peak value 39 +/- 4 pA (mean S.E. mean) around -15 mV. It...
Several common genetic variations have been associated with type 2 diabetes, but the exact disease mechanisms are still poorly elucidated. Using congenic strains from diabetic Goto-Kakizaki rat, we identified a 1.4-megabase genomic locus that was linked to impaired insulin granule docking at plasma membrane and reduced beta cell exocytosis. In this locus, Adra2a, encoding alpha2A-adrenergic receptor [alpha(2A)AR], significantly overexpressed. Alpha(2A)AR mediates adrenergic suppression of...
Dysfunctional microRNA (miRNA) networks contribute to inappropriate responses following pathological stress and are the underlying cause of several disease conditions. In pancreatic β cells, miRNAs have been largely unstudied little is known about how specific regulate glucose-stimulated insulin secretion (GSIS) or impact adaptation cell function metabolic stress. this study, we determined that miR-7 a negative regulator GSIS in cells. Using Mir7a2 deficient mice, revealed miR-7a2 regulates...
Abstract Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels insulin. The molecular mechanisms underlying progressive failure respond glucose in type-2 diabetes remain unresolved. Using combination transcriptomics and proteomics, we find significant dysregulation major metabolic pathways islets diabetic βV59M mice, non-obese, eulipidaemic model. Multiple genes/proteins involved glycolysis/gluconeogenesis are upregulated,...
Abstract Diabetes is characterized by hyperglycaemia due to impaired insulin secretion and aberrant glucagon resulting from changes in pancreatic islet cell function and/or mass. The extent which per se underlies these alterations remains poorly understood. Here we show that β-cell-specific expression of a human activating K ATP channel mutation adult mice leads rapid diabetes marked morphology, ultrastructure gene expression. Chronic associated with dramatic reduction insulin-positive cells...
The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features in relation profiles diabetic nondiabetic donors. Islets from donors with T2D exhibited impaired was more pronounced lean than obese assessed impact 14 disease susceptibility on measures glucose...
Glucose-stimulated insulin secretion consists of a transient first phase followed by sustained second phase. Diabetes (type II) is associated with abnormalities in this release pattern. Here we review the evidence that biphasic reflects exocytosis two functional subsets secretory granules and implications for diabetes.