A5021853876- Pancreatic function and diabetes
- Diabetes Treatment and Management
- Liver Disease Diagnosis and Treatment
- Endoplasmic Reticulum Stress and Disease
- Receptor Mechanisms and Signaling
- Pancreatitis Pathology and Treatment
- Diabetes and associated disorders
- Metabolism, Diabetes, and Cancer
- Liver physiology and pathology
- Lipid metabolism and biosynthesis
- Metabolomics and Mass Spectrometry Studies
- Synthesis of Tetrazole Derivatives
- Inflammatory mediators and NSAID effects
- Enzyme function and inhibition
- Diabetes Management and Research
- Muscle metabolism and nutrition
- Polysaccharides Composition and Applications
- Neuropeptides and Animal Physiology
- Computational Drug Discovery Methods
- Genetics and Neurodevelopmental Disorders
- Phosphodiesterase function and regulation
- Hormonal Regulation and Hypertension
- Eicosanoids and Hypertension Pharmacology
- Biochemical Analysis and Sensing Techniques
- Phenothiazines and Benzothiazines Synthesis and Activities
Janssen (United States)
2016-2025
Springhouse
2016-2023
Janssen (Belgium)
2020
University of Illinois Chicago
2013
NHS Blood and Transplant
2013
Pancreatic β cell failure is key to type 2 diabetes (T2D) onset and progression. Here, we assess whether human dysfunction induced by metabolic stress reversible, evaluate the molecular pathways underlying persistent or transient damage, explore relationships with T2D islet traits. Twenty-six preparations are exposed several lipotoxic/glucotoxic conditions, some of which impair insulin release, depending on stressor type, concentration, combination. The reversal occurs after washout for...
Metabolic labeling with heavy water (D2O) followed by LC-MS has become a powerful tool for studying protein turnover in vivo. Developing quantitative method to measure partially labeled low-abundance proteins poses many challenges because isotopomers of peptides, especially their changes through deuterium labeling, are difficult detect. A workflow that coupled immunocapture and LC-high-resolution MS determine the synthesis rate HSD17β13 mouse liver was presented. Deuterium tryptic peptides...
The mechanisms that control proliferation, or lack thereof, in adult human β cells are poorly understood. Controlled induction of proliferation could dramatically expand the clinical application islet cell transplantation and represents an important component regenerative approaches to a functional cure diabetes. Adult particularly resistant common proliferative targets often dedifferentiate during proliferation. Here we show expression transcription factor E2F3 has role regulating β-cell...
GPR40 is a clinically validated molecular target for the treatment of diabetes. Many agonists have been identified to date, with partial agonist fasiglifam (TAK-875) reaching phase III clinical trials before its development was terminated due off-target liver toxicity. Since then, attention has shifted toward full that exhibit superior efficacy in preclinical models. Full bind distinct binding site, suggesting conformational plasticity and potential biased agonism. Indeed, it suggested...
GPR40 is a G-protein-coupled receptor which mediates fatty acid-induced glucose-stimulated insulin secretion from pancreatic beta cells and incretion release enteroendocrine of the small intestine. full agonists exhibit superior glucose lowering compared to partial in preclinical species due increased GLP-1 secretion, with added benefit promoting weight loss. In our search for potent agonists, we discovered superagonist displayed excellent vitro potency efficacy Gαs-mediated signaling...
The free fatty acid receptor 1 (FFAR1/GPR40) mediates acid-induced insulin secretion from pancreatic β-cells. At least 3 distinct binding sites exist on the FFAR1 and numerous synthetic ligands have been investigated for their anti-diabetic actions. Fasiglifam, binds to site-1 stimulates intra-cellular calcium release improves glycemic control in diabetic patients. Recently, small molecule agonists were discovered which bind site-3, stimulating both cAMP, resulting glucagon-like peptide-1...
Non-alcoholic steatohepatitis (NASH) results, in part, from the interaction of metabolic derangements with predisposing genetic variants, leading to liver-related complications and mortality. The strongest determinant is a highly prevalent missense variant patatin-like phospholipase domain-containing protein 3 (PNPLA3 p.I148M). In human liver hepatocytes PNPLA3 localizes surface lipid droplets where mutant form believed enhance accumulation release pro-inflammatory cytokines. Less known...
Abstract JNJ‐75220795 or ARO‐PNPLA3 is an investigational small interfering ribonucleic acid agent conjugated with N‐acetyl‐ d ‐galactosamine that targets the PNPLA3 gene, currently being developed for metabolic dysfunction‐associated steatohepatitis (MASH). This study evaluated pharmacokinetics (PK) profile of single subcutaneous doses in preclinical species as well human subjects homozygous heterozygous I148M mutation two phase 1 studies—a first‐in‐human United States and a...
This review outlines the current status of microfluidic devices used to study physiology and pathophysiology pancreatic islets Langerhans, mainly focusing on design features specialized applications existing devices, as well their advantages limitations. then briefly concludes by describing future perspectives ways improve implement technology for islet study. Keywords: β-cells, Insulin Secretion, Islet Microencapsulation, Microfluidics, Oxygen, Transplantation.
The EP3 receptor (EP3r) is a member of the EP subfamily, which facilitate broad range physiological and pathological prostaglandin E2 (PGE2) actions. Multiple reports have demonstrated that infusion PGE2 blunts glucose-stimulated insulin secretion (GSIS) in healthy subjects inhibition production noninsulin dependent diabetes mellitus (NIDDM) patients can partially restore impaired GSIS. suppression GSIS by has been attributed to EP3r, resulting suggestion EP3r antagonism may be an attractive...
The free fatty acid receptor 1 (FFAR1) mediates acid-induced insulin secretion from pancreatic β-cells. Numerous ligands have been investigated for their antidiabetic actions. most advanced, fasiglifam (TAK-875), is a site binding agonist that stimulates IPone and improves glycemic control in diabetic patients via glucose-dependent (GSIS). Recently, FFAR1 agonists were discovered bind to 3, stimulate cAMP result both glucagon-like peptide-1 (GLP-1) secretion. We hypothesized this novel...
Nonalcoholic fatty liver disease (NAFLD) is a leading cause of failure that prevalent in 70% people with diabetes. Human genetic studies (i.e. GWAS) have identified dozens potentially causal genes/loci increasing NAFLD susceptibility but translation into actionable drug targets has been impeded by lack cellular and molecular mechanistic studies. To address this knowledge gap, we developed platform for high-throughput perturbation assessment acid-triggered lipid accumulation hepatic...
Pancreatic β-cell failure is key to type 2 diabetes (T2D) onset and progression. We assessed whether human dysfunction induced by metabolic stress reversible, evaluated the molecular pathways underlying persistent or transient damage, explored relationships with T2D islet traits. Twenty-six preparations were exposed several lipo- and/or glucotoxicity conditions, some of which impaired insulin release depending on stressor type, concentration combination. Interestingly, reversal occurred...