A5003348334- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Diabetes Treatment and Management
- Diabetes and associated disorders
- Diet and metabolism studies
- Genetics and Neurodevelopmental Disorders
- Diabetes Management and Research
- Adipose Tissue and Metabolism
- Cellular transport and secretion
- Epigenetics and DNA Methylation
- Biochemical Analysis and Sensing Techniques
- Ubiquitin and proteasome pathways
- Adenosine and Purinergic Signaling
- Scientific Computing and Data Management
- Mitochondrial Function and Pathology
- Bioinformatics and Genomic Networks
- Nutrition, Genetics, and Disease
- Bipolar Disorder and Treatment
- Gene expression and cancer classification
- Cell death mechanisms and regulation
- Renal Transplantation Outcomes and Treatments
- Metabolomics and Mass Spectrometry Studies
- Health, Environment, Cognitive Aging
- Single-cell and spatial transcriptomics
University of British Columbia
2016-2024
Life Science Institute
2023
University of Alberta
2009-2016
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...
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 covalent attachment of small ubiquitin-like modifier (SUMO) proteins regulates protein localization and function. SUMOylation has recently been shown to modulate ion-channel function; however, the extent which this affects native currents cellular excitability remains be determined. voltage-dependent K+ (Kv) channel Kv2.1 pancreatic β-cell insulin secretion. We found that YFP-tagged SUMO1 (SUMO1-YFP) can immunoprecipitated with when these two are coexpressed in HEK 293 cells....
OBJECTIVE Phosphatidylinositol 3-OH kinase (PI3K) has a long-recognized role in β-cell mass regulation and gene transcription is implicated the modulation of insulin secretion. The nontyrosine receptor–activated PI3K isoforms largely unexplored. We therefore investigated G-protein–coupled PI3Kγ its catalytic subunit p110γ granule recruitment exocytosis. RESEARCH DESIGN AND METHODS expression was knocked down by small-interfering RNA, activity selectively inhibited with AS605240 (40 nmol/l)....
Epidemiological studies consistently report associations between circulating concentrations of persistent organic pollutants (POPs) and increased type 2 diabetes risk. Measures POP in pancreas are limited; given the role endocrine pathogenesis, this is an important gap literature. Additionally, no have correlated with direct measures beta cell function humans. We hypothesized that lipophilic POPs accumulate human correlate markers To test hypothesis, we measured concentration from 3 chemical...
Comprehensive molecular and cellular phenotyping of human islets can enable deep mechanistic insights for diabetes research. We established the Human Islet Data Analysis Sharing (HI-DAS) consortium to advance goals in accessibility, usability, integration data from isolated donors with without at Alberta Diabetes Institute (ADI) IsletCore. Here we introduce HumanIslets.com, an open resource research community. This platform, which presently includes on 547 islet donors, allows users access...
The incidence of new onset diabetes after transplant (NODAT) has increased over the past decade, likely due to calcineurin inhibitor-based immunosuppressants, including tacrolimus (TAC) and cyclosporin. Voclosporin (VCS), a next-generation inhibitor, is reported cause fewer incidences NODAT but reason unclear. While signaling plays important roles in pancreatic β-cell survival, proliferation, function, its effects on human β-cells remain understudied. In particular, we do not understand why...
PI3Kγ, a G-protein-coupled type 1B phosphoinositol 3-kinase, exhibits basal glucose-independent activity in β-cells and can be activated by the glucose-dependent insulinotropic polypeptide (GIP). We therefore investigated role of PI3Kγ catalytic subunit (p110γ) insulin secretion β-cell exocytosis stimulated GIP. inhibited p110γ with AS604850 (1 μmol/liter) or knocked it down using an shRNA adenovirus siRNA duplex mouse human islets β-cells. Inhibition blunted exocytotic response to GIP...
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...
Abstract Our understanding of adult human β-cells is advancing, but we know little about the function and plasticity from infants. We therefore characterized islets single islet cells infants after isolation culture. Although morphology in pancreas biopsies was similar to that adults, infant 24–48 hours culture had less insulin staining, content, secretion. The cultured expressed pancreatic duodenal homeobox 1 several (Glut1, Cav1.3, Kir6.2) not all (syntaxin 1A synaptosomal-associated...
Phosphatidylinositol-3-OH kinase (PI3K) signalling in the endocrine pancreas contributes to glycaemic control. However, mechanism by which PI3K modulates insulin secretion from pancreatic beta cell is poorly understood. Thus, our objective was two-fold; determine pathway acute inhibition enhances glucose-stimulated (GSIS) and examine role of this islets type-2 diabetic (T2D) donors. Isolated mice non-diabetic or T2D human donors, INS 832/13 cells, were treated with inhibitors and/or...
Dietary carbohydrates raise blood glucose levels, and limiting carbohydrate intake improves glycemia in patients with type 2 diabetes. Low (< 25 g) allows the body to utilize fat as its primary fuel. As a consequence of increased fatty acid oxidation, liver produces ketones serve an alternative energy source. β-Hydroxybutyrate (βHB) is most abundant ketone. While βHB has wide range functions outside pancreas, direct effects on islet cell function remain understudied. We examined human...
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 Dietary carbohydrates raise blood glucose and limiting carbohydrate intake improves glycemia in patients with type 2 diabetes. Low (< 25 g) allows the body to utilize fat as its primary fuel. As a consequence of increased fatty acid oxidation, liver produces ketones serve an alternative energy source. β-Hydroxybutyrate (βHB) is most abundant ketone. While βHB has wide range functions outside pancreas, direct effects on islet cell function remain understudied. We examined human...
Introduction & Objective: High-risk single-nucleotide polymorphisms (SNPs) account for only ~20% of type 2 diabetes heritability, implying islet genes greatly influence one another to alter risk. Correlative analysis does not reveal conditional dependencies between key players regulating function whereas machine learning (ML) may do so. Methods: Using data from 374 genetically diverse mice, we derived models predicting protein abundance with gradient-boosted decision tree algorithms....
Abstract Insulin receptor (Insr) protein can be found at higher levels in pancreatic β-cells than most other tissues, but the consequences of β-cell insulin resistance remain enigmatic. Ins1 cre allele was used to delete Insr specifically both female and male mice. Experimental mice were compared -containing littermate controls multiple ages on diets. RNA-seq purified recombined revealed transcriptomic loss, which differed between Action potential calcium oscillation frequencies increased...