A5021150822- Pancreatic function and diabetes
- Diabetes and associated disorders
- Metabolism, Diabetes, and Cancer
- Diabetes Management and Research
- Endoplasmic Reticulum Stress and Disease
- Adipose Tissue and Metabolism
- Immune Cell Function and Interaction
- Regulation of Appetite and Obesity
- Epigenetics and DNA Methylation
- Caveolin-1 and cellular processes
- Pancreatic and Hepatic Oncology Research
- CAR-T cell therapy research
- Protein Kinase Regulation and GTPase Signaling
- Autophagy in Disease and Therapy
- FOXO transcription factor regulation
- CRISPR and Genetic Engineering
- PI3K/AKT/mTOR signaling in cancer
- Genetics, Aging, and Longevity in Model Organisms
- Cancer, Lipids, and Metabolism
- Adipokines, Inflammation, and Metabolic Diseases
- Peroxisome Proliferator-Activated Receptors
- Genetics and Neurodevelopmental Disorders
- RNA regulation and disease
- Adenosine and Purinergic Signaling
- Protein Tyrosine Phosphatases
University of British Columbia
2015-2024
Life Science Institute
2023
University of Copenhagen
2012-2014
University of California, San Diego
2012-2014
Population-level variation and mechanisms behind insulin secretion in response to carbohydrate, protein, fat remain uncharacterized. We defined prototypical responses three macronutrients islets from 140 cadaveric donors, including those with type 2 diabetes. The majority of donors' exhibited the highest glucose, moderate amino acid, minimal fatty acid. However, 9% had acid responses, 8% that were larger than their glucose-stimulated responses. leveraged this heterogeneity used multi-omics...
Pancreatic β cells play a key role in maintaining glucose homeostasis; dysfunction of this critical cell type causes 2 diabetes (T2D). Emerging evidence points to sex differences cells, but few studies have examined male-female stress responses and resilience across multiple contexts, including diabetes. Here, we address the need for high-quality information on islet gene expression function using both human rodent samples.
Insulin receptor (Insr) protein is present at higher levels in pancreatic β-cells than most other tissues, but the consequences of β-cell insulin resistance remain enigmatic. Here, we use an Ins1
The role and mechanisms of insulin receptor internalization remain incompletely understood. Previous trafficking studies receptors involved fluorescent protein tagging at their termini, manipulations that may be expected to result in dysfunctional receptors. Our objective was determine the route molecular functional tagged endogenous pancreatic beta-cells. We generated with pH-resistant proteins between domains. Confocal, TIRF STED imaging revealed a pattern inter-domain detected antibodies....
Pancreatic adenocarcinoma is one of the most lethal cancers, yet it remains understudied and poorly understood. Hyperinsulinemia has been reported to be a risk factor pancreatic cancer, rapid rise hyperinsulinemia associated with obesity type 2 diabetes foreshadows in cancer incidence. However, actions insulin at various stages progression remain defined. Here, we examined effects range doses on signalling, proliferation survival three human cell models meant represent progression: primary...
Antiadiposity effects of caloric restriction (CR) are associated with reduced insulin/IGF-1 signaling, but it is unclear whether the CR would be additive to genetically reducing circulating insulin. To address this question, we examined female Ins1+/−:Ins2−/− mice and Ins1+/+:Ins2−/− littermate controls on either an ad libitum or 60% diet. Although Igf1 levels declined as expected, was unable reduce plasma insulin in genotype below their libitum-fed controls. In fact, 53-week-old exhibited a...
ABSTRACT Population level variation and molecular mechanisms behind insulin secretion in response to carbohydrate, protein, fat remain uncharacterized despite ramifications for personalized nutrition. Here, we define prototypical dynamics the three macronutrients islets from 140 cadaveric donors, including those diagnosed with type 2 diabetes. While majority of donors exhibited expected relative magnitudes, glucose being highest, amino acid moderate, fatty small, 9% stimulated 8% acids had...
Type 1 diabetes is an autoimmune disease characterized by T-cell-mediated destruction of pancreatic beta-cells. Islet transplantation effective therapy, but its success limited islet quality and availability along with the need for immunosuppression. New approaches include use stem cell-derived insulin-producing cells immunomodulatory therapies, a limitation paucity reproducible animal models in which interactions between human immune can be studied without complication xenogeneic...
Transcriptional and functional cellular specialization has been described for insulin-secreting β-cells of the endocrine pancreas. However, it is not clear whether β-cell heterogeneity stable or reflects dynamic states. We investigated temporal kinetics endogenous insulin gene activity using live cell imaging, with complementary experiments FACS single-cell RNA sequencing, in from Ins2GFP knockin mice. In vivo staining analysis islets mice confirmed that at a given moment, ∼25% exhibited...
Abstract Pancreatic β-cells are critical for systemic glucose homeostasis, and most of them undergo cell death during the pathogenesis type 1 diabetes. We previously showed that a Na + channel inhibitor, carbamazepine, could protect in vitro vivo . Here, we confirmed effects carbamazepine other inhibitors on human islets focused specific role gene, Scn9a (Nav1.7), β-cell function survival. Because can be found multiple mouse islet types, generated knockout non-obese diabetic (NOD)...
Abstract Transcriptional and functional cellular specialization has been described for insulin-secreting β-cells of the endocrine pancreas. However, it is not clear whether β-cell heterogeneity stable or reflects dynamic states. We investigated temporal kinetics endogenous insulin gene activity using live cell imaging, with complementary experiments employing FACS single RNA sequencing, in from Ins2 GFP knock-in mice. In vivo staining analysis islets mice confirmed that at a given moment,...
Abstract A central goal of physiological research is the understanding cell-specific roles disease-associated genes. Cre-mediated recombineering tool choice for cell type–specific analysis gene function in preclinical models. In type 1 diabetes (T1D) field, multiple lines nonobese diabetic (NOD) mice have been engineered to express Cre recombinase pancreatic β cells using insulin promoter fragments, but tissue promiscuity remains a concern. Constitutive Ins1tm1.1(cre)Thor (Ins1Cre) on...
The endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) helps decide β cell survival in diabetes. alternative eukaryotic initiation factor 2A (EIF2A) has been proposed to mediate EIF2S1-independent translation during cellular stress and viral infection, but its role cells is unknown. EIF2A abundance high human mouse islets relative other tissues, both thapsigargin palmitate significantly increased EIF2AmRNA levels MIN6 cells, islets. Knockdowns ofEIF2A, the related...
Type 1 diabetes (T1D) is an autoimmune disease characterised by T cell mediated destruction of pancreatic beta-cells. Islet transplantation effective therapy, but its success limited islet quality and availability along with the need for immunosuppression. New approaches include use stem cell-derived insulin-producing cells immunomodulatory therapies, a limitation paucity reproducible animal models in which interactions between human immune can be studied without complication xenogeneic graft-
ABSTRACT The endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) helps decide β cell survival in diabetes. alternative eukaryotic initiation factor 2A (EIF2A) has been proposed to mediate EIF2S1-independent translation during cellular stress and viral infection, but its role cells is unknown. EIF2A abundance high human mouse islets relative other tissues, both thapsigargin palmitate significantly increased mRNA levels MIN6 cells, islets. Knockdowns of EIF2A, the related...
ABSTRACT Objective Pancreatic β cells play a key role in glucose homeostasis; dysfunction of this critical cell type causes 2 diabetes (T2D). Emerging evidence points to sex differences cells, but few studies have examined male-female stress responses and resilience across multiple contexts, including diabetes. Here, we address the need for high-quality information on cell/islet gene expression function using both human rodent samples. Methods We compared insulin secretion donors living with...
Obesity and early-stage type 2 diabetes (T2D) increase the risk for many cancers, including pancreatic ductal adenocarcinoma (PDAC). The mechanisms linking obesity T2D to cancer have not been established, preventing targeted interventions. Arguments made that hyperinsulinemia, hyperglycemia, or inflammation could drive initiation and/or progression 1 . Hyperinsulinemia is a cardinal feature of T2D, independently associated with PDAC incidence mortality 2–4 , even in non-obese people 5...