A5088435331- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Trace Elements in Health
- Mitochondrial Function and Pathology
- Genetics and Neurodevelopmental Disorders
- Adipose Tissue and Metabolism
- Diabetes and associated disorders
- Diabetes Treatment and Management
- Genetic Syndromes and Imprinting
- MicroRNA in disease regulation
- Diet, Metabolism, and Disease
- Epigenetics and DNA Methylation
- Endoplasmic Reticulum Stress and Disease
- RNA and protein synthesis mechanisms
- Molecular Sensors and Ion Detection
- Genetic Associations and Epidemiology
- DNA Repair Mechanisms
- Viral Infections and Immunology Research
- Genetic and Kidney Cyst Diseases
- Advanced biosensing and bioanalysis techniques
- Pancreatitis Pathology and Treatment
- Hemoglobinopathies and Related Disorders
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- RNA modifications and cancer
- CRISPR and Genetic Engineering
Université de Montréal
2022-2025
Imperial College London
2015-2024
Hammersmith Hospital
2015-2021
Genomics (United Kingdom)
2016-2021
Transnational Press London
2018
Genomics England
2017
Medical Research Council
2015
Institut Curie
2010-2011
Inserm
2010
Centre National de la Recherche Scientifique
2010
Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but functional therapeutic consequences of modulating endocytic trafficking have not been clearly defined. Here, we investigate a series biased agonists with variable propensities for internalization...
Zinc (Zn2+) ions are increasingly recognized as playing an important role in cellular physiology. Whereas the free Zn2+ concentration cytosol has been established to be 0.1-1 nM, subcellular organelles is not well-established. Here, we extend eCALWY family of genetically encoded Förster Resonance Energy Transfer (FRET) probes permit measurements endo(sarco)plasmic reticulum (ER) and mitochondrial matrix. Deployed a variety mammalian cell types, these reveal resting [Zn2+] values ∼300 pM,...
Zn(2+) plays essential and diverse roles in numerous cellular processes. To get a better understanding of intracellular homeostasis the putative signaling role Zn(2+), various fluorescent sensors have been developed that allow monitoring concentrations single living cells real time. Thus far, two families genetically encoded FRET-based most widely applied, eCALWY by our group ZapCY Palmer co-workers. Both successfully used to measure cytosolic free but distinctly different reported when...
A novel autosomal recessive cerebro-renal syndrome was identified in consanguineous Bedouin kindred: neurological deterioration evident as of early age, progressing into severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia. Brain MRI normal. Four the six affected individuals also had early-onset nephropathy with features tubulo-interstitial nephritis, hypertension tendency for hyperkalemia, though none rapid renal function. Genome wide linkage analysis an ∼18...
Zinc is an important micronutrient, essential in the diet to avoid a variety of conditions associated with malnutrition such as diarrhoea and alopecia. Lowered circulating levels zinc are also found diabetes mellitus, condition which affects one twelve adult population whose treatments consume approximately 10 % healthcare budgets. Zn2+ ions for huge range cellular functions and, specialised pancreatic β-cell, storage insulin within secretory granule. Correspondingly, genetic variants...
Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of causal nor gene(s) through which is conferred have been firmly established. Whereas encodes a GTPase activating protein, member steroidogenic acute regulatory protein (StAR)-related...
Spatially-organized increases in cytosolic Ca2+ within pancreatic beta cells the islet underlie stimulation of insulin secretion by high glucose. Recent data have revealed existence subpopulations including "leaders" which initiate waves. Whether leader possess unique molecular features, or localisation, is unknown.High speed confocal imaging was used to identify and connectivity analysis, running under MATLAB Python, highly connected "hub" cells. To explore transcriptomic differences...
Zinc transporter 8 (ZnT8), encoded by SLC30A8, is chiefly expressed within pancreatic islet cells, where it mediates zinc (Zn(2+)) uptake into secretory granules. Although a common nonsynonymous polymorphism (R325W), which lowers activity, associated with increased type 2 diabetes (T2D) risk, rare inactivating mutations in SLC30A8 have been reported to protect against T2D. Here, we generate and characterize new mouse models explore the impact on glucose homeostasis of graded changes ZnT8...
Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed neuroendocrine metabolic tissues a hormone- nutrient-sensitive manner. However, its molecular cellular functions precise role organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient excess. In contrast, report no...
Significance The zinc transporter SLC30A8 is primarily expressed in islets of the endocrine pancreas. Human loss-of-function mutations protect against type 2 diabetes. However, Slc30a8 knockout mice do not show this protection. We have generated a mouse model mimicking common protective human allele. This shows beneficial effect loss function on β-cell biology. In particular, carrying R138X allele an increased capacity to secrete insulin high-glucose conditions. Understanding signaling...
Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic β-cells. Whether mitofusin gene expression, and hence, mitochondrial network integrity, important or incretin signaling has not previously been explored. Here, we generated mice with β-cell-selective, adult-restricted deletion knock-out (dKO) of the genes Mfn1 Mfn2 (βMfn1/2 dKO). βMfn1/2-dKO displayed elevated fed fasted glycemia a more than fivefold decrease in plasma insulin. length,...
Abstract The tightly‐regulated spatial and temporal distribution of zinc ion concentrations within cellular compartments is controlled by two groups Zn 2+ transporters: the 14‐member ZIP/SLC39 family, facilitating influx into cytoplasm from extracellular space or intracellular organelles; 10‐member ZnT/SLC30 mobilizing in opposite direction. Genetic aberrations most transporters cause human syndromes. Notably, previous studies demonstrated osteopenia male‐specific cardiac death mice lacking...
The glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) is a key target for type 2 diabetes (T2D) treatment. Because endocytic trafficking of agonist-bound receptors one the most important routes regulation signaling, better understanding this process may facilitate development new T2D therapeutic strategies. Here, we screened 29 proteins with known functions in G protein-coupled their role GLP-1R potentiation insulin secretion pancreatic β-cells. We identify five (clathrin, dynamin1, AP2,...
Impaired pancreatic β-cell function and insulin secretion are hallmarks of type 2 diabetes. miRNAs short, noncoding RNAs that silence gene expression vital for the development β cells. We have previously shown cell–specific deletion important energy sensor AMP-activated protein kinase (AMPK) results in increased miR-125b-5p levels. Nevertheless, this miRNA cells is unclear. hypothesized regulated by glucose mediates some deleterious effects hyperglycemia Here, we show islet upregulated an...
Aims Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors improve glucose tolerance by still incompletely understood mechanisms. Each class of antihyperglycemic drugs has also been proposed to increase pancreatitis risk. Here, we compare systematically the effects two widely-used GLP-1 analogues, liraglutide exendin-4, DPP4 inhibitor, sitagliptin, in mouse. Methods C57BL6 mice were maintained for 131 days on a normal diet (ND) or comprising 60% fat...
Abstract Bariatric surgery improves both insulin sensitivity and secretion can induce diabetes remission. However, the mechanisms time courses of these changes, particularly impact on β cell function, are difficult to monitor directly. In this study, we investigated effect Vertical Sleeve Gastrectomy (VSG) function in vivo by imaging Ca 2+ dynamics islets engrafted into anterior eye chamber. Mirroring its clinical utility, VSG mice results significantly improved glucose tolerance, enhanced...