Patrick E. MacDonald
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View article: Supervised machine learning identifies impaired mitochondrial quality control in β cells with development of type 2 diabetes
Supervised machine learning identifies impaired mitochondrial quality control in β cells with development of type 2 diabetes Open
In type 2 diabetes (T2D), molecular pathways driving β cell failure are difficult to resolve with standard single cell analysis. Here we developed an interpretable, supervised machine learning framework that couples sparse rule-based class…
View article: Altered immune and metabolic molecular pathways drive islet cell dysfunction in human type 1 diabetes
Altered immune and metabolic molecular pathways drive islet cell dysfunction in human type 1 diabetes Open
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of most insulin-producing β cells, along with dysregulated glucagon secretion from pancreatic α cells. We conducted an integrated analysis that combines electrophysiologi…
View article: Heparan sulfate fine-tuned interleukin-1 (IL-1) signaling inhibits insulin secretion of grafted pancreatic islets
Heparan sulfate fine-tuned interleukin-1 (IL-1) signaling inhibits insulin secretion of grafted pancreatic islets Open
Islet-resident macrophages contribute to hypoxia-induced islet cell death during pancreatic islet transplantation. However, their specific role during this process remains elusive. Here, we report that interleukin-1α (IL-1α) and IL-1β are …
View article: Spatially bound functional heterogeneity drives modular organization in β-cell networks
Spatially bound functional heterogeneity drives modular organization in β-cell networks Open
Coordinated responses of pancreatic β-cell networks to changes in extracellular nutrient concentrations are a well-established phenomenon with significant implications for insulin secretion. This study investigates the organization and spa…
View article: CK2 regulates somatostatin expression in pancreatic delta cells
CK2 regulates somatostatin expression in pancreatic delta cells Open
Pancreatic and duodenal homeobox protein (PDX)1 is a major transcription factor for the regulation of insulin, glucagon and somatostatin (SST) expression. PDX1 is phosphorylated by CK2 and inhibition of this kinase results in an increased …
View article: The Gut Microbial Metabolite Butyrate Alleviates IL‐1β‐Induced Mitochondrial Dysfunction and Oxidative Stress in Pancreatic Islets
The Gut Microbial Metabolite Butyrate Alleviates IL‐1β‐Induced Mitochondrial Dysfunction and Oxidative Stress in Pancreatic Islets Open
Butyrate, a gut microbiota‐derived metabolite, supports cellular health. In pancreatic beta cells, inflammation and oxidative stress disrupt mitochondrial function, contributing to dysfunction. This study explores how butyrate influences m…
View article: Persistent organic pollutant concentrations in human pancreas and peripancreatic adipose tissues correlate with markers of beta cell dysfunction
Persistent organic pollutant concentrations in human pancreas and peripancreatic adipose tissues correlate with markers of beta cell dysfunction Open
Epidemiological studies consistently report associations between circulating concentrations of persistent organic pollutants (POPs) and increased type 2 diabetes risk. Measures of POP concentrations in pancreas are limited; given the role …
View article: Multiplexed Deep Visual Proteomics Unveils Spatial Heterogeneity and Rare Endocrine States in Human Adult Pancreatic Islets
Multiplexed Deep Visual Proteomics Unveils Spatial Heterogeneity and Rare Endocrine States in Human Adult Pancreatic Islets Open
Pancreatic islets are highly specialized tissue compartments that regulate metabolism, and their dysfunction contributes to diseases such as prediabetes and diabetes. Characterizing islet morphology and cell plasticity is essential for und…
View article: TMEM55A-mediated PI5P signalling regulates alpha cell actin depolymerisation and glucagon secretion
TMEM55A-mediated PI5P signalling regulates alpha cell actin depolymerisation and glucagon secretion Open
We reveal a novel pathway by which TMEM55A regulates alpha cell exocytosis by controlling intracellular PI5P and the F-actin network.
View article: Peptidylglycine alpha-amidating monooxygenase is important in mice for beta-cell cilia formation and insulin secretion but promotes diabetes risk through beta-cell independent mechanisms
Peptidylglycine alpha-amidating monooxygenase is important in mice for beta-cell cilia formation and insulin secretion but promotes diabetes risk through beta-cell independent mechanisms Open
Eliminating Pam expression only in beta cells leads to morphological changes in insulin granules, reduced insulin secretion, reduced hIAPP amyloid burden and altered ciliogenesis. However, in mice beta-cell Pam deficiency has no impact on …
View article: Linking molecular pathways and islet cell dysfunction in human type 1 diabetes
Linking molecular pathways and islet cell dysfunction in human type 1 diabetes Open
Summary Type 1 diabetes (T1D) is characterized by the autoimmune destruction of most insulin-producing β-cells, along with dysregulated glucagon secretion from pancreatic α-cells. We conducted an integrated analysis that combines electroph…
View article: Cisplatin Exposure Dysregulates Insulin Secretion in Male and Female Mice
Cisplatin Exposure Dysregulates Insulin Secretion in Male and Female Mice Open
Cancer survivors have an increased risk of developing type 2 diabetes compared with the general population. Patients treated with cisplatin, a common chemotherapeutic agent, are more likely to develop metabolic syndrome and type 2 diabetes…
View article: Cisplatin exposure dysregulates insulin secretion in male and female mice
Cisplatin exposure dysregulates insulin secretion in male and female mice Open
Cancer survivors have an increased risk of developing Type 2 diabetes compared to the general population. Patients treated with cisplatin, a common chemotherapeutic agent, are more likely to develop metabolic syndrome and Type 2 diabetes t…
View article: Cisplatin exposure dysregulates insulin secretion in male and female mice
Cisplatin exposure dysregulates insulin secretion in male and female mice Open
Cancer survivors have an increased risk of developing Type 2 diabetes compared to the general population. Patients treated with cisplatin, a common chemotherapeutic agent, are more likely to develop metabolic syndrome and Type 2 diabetes t…
View article: TMEM55A-mediated PI5P signaling regulates α-cell actin depolymerization and glucagon secretion
TMEM55A-mediated PI5P signaling regulates α-cell actin depolymerization and glucagon secretion Open
Diabetes is associated with the dysfunction of glucagon-producing pancreatic islet α-cells, although the underlying mechanisms regulating glucagon secretion and α-cell dysfunction remain unclear. While insulin secretion from pancreatic β-c…
View article: Molecular Correlates of Glycine Receptor Activity in Human β Cells
Molecular Correlates of Glycine Receptor Activity in Human β Cells Open
Objectives Glycine acts in an autocrine positive feedback loop in human β cells through its ionotropic receptors (GlyRs). In type 2 diabetes (T2D), islet GlyR activity is impaired by unknown mechanisms. We sought to investigate if the GlyR…
View article: An INSULIN and IAPP dual reporter enables tracking of functional maturation of stem cell-derived insulin producing cells
An INSULIN and IAPP dual reporter enables tracking of functional maturation of stem cell-derived insulin producing cells Open
The INS2A-EGFP/+;IAPP2A-mScarlet/+ hESC line provides a useful tool for tracking populations of maturing hESC-derived β cells in vitro. This tool has already been shared with 3 groups and is freely available to all.
View article: Single cell multiome profiling of pancreatic islets reveals physiological changes in cell type-specific regulation associated with diabetes risk
Single cell multiome profiling of pancreatic islets reveals physiological changes in cell type-specific regulation associated with diabetes risk Open
Physiological variability in pancreatic cell type gene regulation and the impact on diabetes risk is poorly understood. In this study we mapped gene regulation in pancreatic cell types using single cell multiomic (joint RNA-seq and ATAC-se…
View article: Human research islet cell culture outcomes at the Alberta Diabetes Institute IsletCore
Human research islet cell culture outcomes at the Alberta Diabetes Institute IsletCore Open
Human islets from deceased organ donors have made important contributions to our understanding of pancreatic endocrine function and continue to be an important resource for research studies aimed at understanding, treating, and preventing …
View article: HumanIslets: An integrated platform for human islet data access and analysis
HumanIslets: An integrated platform for human islet data access and analysis Open
SUMMARY Comprehensive molecular and cellular phenotyping of human islets can enable deep mechanistic insights for diabetes research. We established the Human Islet Data Analysis and Sharing (HI-DAS) consortium to advance goals in accessibi…
View article: Human research islet cell culture outcomes at the Alberta Diabetes Institute IsletCore
Human research islet cell culture outcomes at the Alberta Diabetes Institute IsletCore Open
Human islets from deceased organ donors have made important contributions to our understanding of pancreatic endocrine function and continue to be an important resource for research studies aimed at understanding, treating, and preventing …
View article: Evaluating Islet Cell Isolation and Transplantation From Donors Following Medical Assistance in Dying
Evaluating Islet Cell Isolation and Transplantation From Donors Following Medical Assistance in Dying Open
Background. Limited information is available regarding outcomes of islet cell isolation (ICI) and transplantation (ITx) using medical assistance in dying (MAiD) donors. We aimed to assess the feasibility and outcomes of ICI and ITx in MAiD…
View article: MetaboAnalyst 6.0: towards a unified platform for metabolomics data processing, analysis and interpretation
MetaboAnalyst 6.0: towards a unified platform for metabolomics data processing, analysis and interpretation Open
We introduce MetaboAnalyst version 6.0 as a unified platform for processing, analyzing, and interpreting data from targeted as well as untargeted metabolomics studies using liquid chromatography - mass spectrometry (LC–MS). The two main ob…
View article: <b>RFX6 </b><b>maintains </b><b>gene expression and function of adult human islet </b><b>a</b><b> cells</b>
<b>RFX6 </b><b>maintains </b><b>gene expression and function of adult human islet </b><b>a</b><b> cells</b> Open
ABSTRACTMutations in the gene encoding the transcription factor RFX6 are associated with human diabetes mellitus. Within pancreatic islets, RFX6 expression is most abundant in islet a cells, and a cell RFX6 expression is altered in diabete…