A5049988604- Pancreatic function and diabetes
- Receptor Mechanisms and Signaling
- Diabetes Treatment and Management
- Diabetes and associated disorders
- Diabetes Management and Research
- Metabolism, Diabetes, and Cancer
- Adipose Tissue and Metabolism
- Neuropeptides and Animal Physiology
- Hypothalamic control of reproductive hormones
- Growth Hormone and Insulin-like Growth Factors
- Photoreceptor and optogenetics research
- Regulation of Appetite and Obesity
- Photochromic and Fluorescence Chemistry
- Cancer, Hypoxia, and Metabolism
- Diet and metabolism studies
- Biochemical Analysis and Sensing Techniques
- Diet, Metabolism, and Disease
- Pancreatitis Pathology and Treatment
- Neuroendocrine regulation and behavior
- Monoclonal and Polyclonal Antibodies Research
- Advanced Fluorescence Microscopy Techniques
- Trace Elements in Health
- Stress Responses and Cortisol
- Adenosine and Purinergic Signaling
- Crystallization and Solubility Studies
University of Birmingham
2016-2025
University of Oxford
2022-2025
Oxford Centre for Diabetes, Endocrinology and Metabolism
2018-2025
Churchill Hospital
2022-2024
Oxford Biomedical Research
2024
University of Nottingham
2017-2022
National Institute for Health Research
2022
Imperial College London
2012-2021
Centre National de la Recherche Scientifique
2010-2021
Kyorin University
2021
The arrangement of β cells within islets Langerhans is critical for insulin release through the generation rhythmic activity. A privileged role individual in orchestrating these responses has long been suspected, but not directly demonstrated. We show here that cell population situ operationally heterogeneous. Mapping islet functional architecture revealed presence hub with pacemaker properties, which remain stable over recording periods 2 to 3 hr. Using a dual...
To maintain homeostasis, hypothalamic neurons in the arcuate nucleus must dynamically sense and integrate a multitude of peripheral signals. Blood-borne molecules therefore be able to circumvent tightly sealed vasculature blood-brain barrier rapidly access their target neurons. However, how information encoded by circulating appetite-modifying hormones is conveyed central remains largely unexplored. Using vivo multiphoton microscopy together with fluorescently labeled ligands, we demonstrate...
Pancreatic β cell dysfunction is pathognomonic of type 2 diabetes mellitus (T2DM) and driven by environmental genetic factors. responses to glucose incretins such as glucagon-like peptide-1 (GLP-1) glucose-dependent insulinotropic polypeptide (GIP) are altered in the disease state. While rodent cells act a coordinated syncytium drive insulin release, this property unexplored human islets. In situ imaging approaches were therefore used monitor real time islet dynamics underlying hormone...
Single nucleotide polymorphisms (SNPs) within the ADCY5 gene, encoding adenylate cyclase 5, are associated with elevated fasting glucose and increased type 2 diabetes (T2D) risk. Despite this, mechanisms underlying effects of these polymorphic variants at level pancreatic β-cells remain unclear. Here, we show firstly that mRNA expression in islets is lowered by possession risk alleles rs11708067. Next, demonstrate indispensable for coupling glucose, but not GLP-1, to insulin secretion human...
Increasing evidence suggests that loss of β cell characteristics may cause insulin secretory deficiency in diabetes, but the underlying mechanisms remain unclear. Here, we show Rfx6, whose mutation leads to neonatal diabetes humans, is essential maintain key features functionally mature cells mice. Rfx6 adult glucose intolerance, impaired sensing, and defective secretion. This associated with reduced expression core components secretion pathway, including glucokinase, Abcc8/SUR1 subunit KATP...
Experience-dependent plasticity of cell and tissue function is critical for survival by allowing organisms to dynamically adjust physiological processes in response changing or harsh environmental conditions. Despite the conferred evolutionary advantage, it remains unknown whether emergent experience-dependent properties are present populations organized as networks within endocrine tissues involved regulating body-wide homeostasis. Here we show, using lactation repeatedly activate a...
Mitophagy is a key process regulating mitochondrial quality control. Several mechanisms have been proposed to regulate mitophagy, but these mostly studied using stably expressed non-native proteins in immortalized cell lines. In skeletal muscle, mitophagy and its molecular require more thorough investigation. To measure directly, we generated stable muscle C2C12 line, expressing reporter construct (mCherry-green fluorescence protein-mtFIS1101-152). Here, report that both carbonyl cyanide...
Insulin-secreting β-cells are heterogeneous in their regulation of hormone release. While long known, recent technological advances and new markers have allowed the identification novel subpopulations, improving our understanding molecular basis for heterogeneity. This includes specific subpopulations with distinct functional characteristics, developmental programs, abilities to proliferate response metabolic or cues, resistance immune-mediated damage. Importantly, these change disease...
Abstract The glucagon-like peptide-1 receptor (GLP1R) is a class B G protein-coupled (GPCR) involved in metabolism. Presently, its visualization limited to genetic manipulation, antibody detection or the use of probes that stimulate activation. Herein, we present LUXendin645 , far-red fluorescent GLP1R antagonistic peptide label. produces intense and specific membrane labeling throughout live fixed tissue. signaling can additionally be evoked when allosterically modulated presence . Using...
Abstract Sulfonylureas are widely prescribed for the treatment of type 2 diabetes mellitus (T2DM). Through their actions on ATP-sensitive potassium (K ATP ) channels, sulfonylureas boost insulin release from pancreatic beta cell mass to restore glucose homeostasis. A limitation these compounds is elevated risk developing hypoglycemia and cardiovascular disease, both potentially fatal complications. Here, we describe design development a photoswitchable sulfonylurea, JB253, which reversibly...
GLP-1R agonists show promise as a therapeutic agent to lower intracranial pressure in rodents.
Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women reproductive age. In this study, we comprehensively examined the systemic cerebrospinal fluid (CSF) androgen metabolome in comparison sex-, BMI-, age-matched control groups either simple obesity or PCOS (i.e., excess). Women showed...
Abstract Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion induce weight loss preserve normoglycemia. Despite this, incretin therapy has been associated with off‐target effects, including nausea gastrointestinal disturbance. A novel photoswitchable mimetic based upon specific glucagon‐like peptide‐1 receptor (GLP‐1R) agonist liraglutide was designed, synthesized, tested. This peptidic compound,...
Type 2 diabetes (T2D) is characterized by β cell dysfunction and loss. Single nucleotide polymorphisms in the T-cell factor 7-like (TCF7L2) gene, associated with T2D genome-wide association studies, lead to impaired function. While deletion of homologous murine Tcf7l2 gene throughout developing pancreas leads glucose tolerance, adult mice reportedly has more modest effects. To inactivate highly selectively cells from earliest expression Ins1 (∼E11.5) we have therefore used a Cre recombinase...
Abstract Transcriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 MAFA expression, contribute islet operation. Functional mapping of rodent human islets containing proportionally more HIGH reveals defects metabolism, ionic fluxes secretion. At transcriptomic level, presence increased numbers leads dysregulation gene...
Background: Aberrant sympathetic nerve activity exacerbates cardiovascular risk in hypertension and diabetes, which are common comorbidities, yet clinically remains poorly controlled. The hypertensive diabetic state is associated with increased reflex sensitivity tonic drive from the peripheral chemoreceptors, cause of unknown. We have previously shown to be critically dependent on carotid body (CB) input spontaneously rat, a model that also exhibits number traits. CB overstimulation by...
Insulin-secreting β-cells are functionally heterogeneous. Whether there exist cells driving the first-phase calcium response in individual islets, has not been examined. We examine "first responder" cells, defined by earliest [Ca2+] during elevation, distinct from previously identified "hub" and "leader" cells. used islets isolated Mip-CreER; Rosa-Stop-Lox-Stop-GCamP6s mice (β-GCamP6s) that show β-cell-specific GCamP6s expression following tamoxifen-induced CreER-mediated recombination....