Sex-specific regulatory architecture of pancreatic islets from subjects with and without type 2 diabetes.

Patients with type 2 and type 1 diabetes (T2D and T1D) exhibit sex-specific differences in insulin secretion, the mechanisms of which are unknown. We examined sex differences in human pancreatic islets from 52 donors with and without T2D combining single cell RNA-sequencing (scRNA-seq) and single nucleus ATAC-sequencing (snATAC-seq) with assays probing hormone secretion and bioenergetics. In non-diabetic (ND) donors, sex differences in islet cell chromatin accessibility and gene expression predominantly involved sex chromosomes.

Single cell multiome profiling of pancreatic islets reveals physiological changes in cell type-specific regulation associated with diabetes risk.

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-seq) profiling in 28 non-diabetic donors in combination with single cell data from 35 non-diabetic donors in the Human Pancreas Analysis Program. We identified widespread associations with age, sex, BMI, and HbA1c, where gene regulatory responses were highly cell type- and phenotype-specific.

Circulating pancreatic enzyme levels are a causal biomarker of type 1 diabetes.

Novel biomarkers of type 1 diabetes (T1D) are needed for earlier detection of disease and identifying therapeutic targets. We identified biomarkers of T1D by combining plasma and protein QTLs (pQTLs) for 2,922 proteins in the UK Biobank with a T1D genome-wide association study (GWAS) in 157k samples. T1D risk variants at over 20% of known loci colocalized with or pQTLs, and distinct sets of T1D loci colocalized with immune, pancreatic secretion, or gut-related proteins.

Single cell regulatory architecture of human pancreatic islets suggests sex differences in β cell function and the pathogenesis of type 2 diabetes.

Type 2 and type 1 diabetes (T2D, T1D) exhibit sex differences in insulin secretion, the mechanisms of which are unknown. We examined sex differences in human pancreatic islets from 52 donors with and without T2D combining single cell RNA-seq (scRNA-seq), single nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), hormone secretion, and bioenergetics. In nondiabetic (ND) donors, sex differences in islet cells gene accessibility and expression predominantly involved sex chromosomes.

Untangling the genetics of beta cell dysfunction and death in type 1 diabetes.

Background: Type 1 diabetes (T1D) is a complex multi-system disease which arises from both environmental and genetic factors, resulting in the destruction of insulin-producing pancreatic beta cells. Over the past two decades, human genetic studies have provided new insight into the etiology of T1D, including an appreciation for the role of beta cells in their own demise.

Scope Of Review: Here, we outline models supported by human genetic data for the role of beta cell dysfunction and death in T1D.

Single cell regulatory architecture of human pancreatic islets suggests sex differences in β cell function and the pathogenesis of type 2 diabetes.

Biological sex affects the pathogenesis of type 2 and type 1 diabetes (T2D, T1D) including the development of β cell failure observed more often in males. The mechanisms that drive sex differences in β cell failure is unknown. Studying sex differences in islet regulation and function represent a unique avenue to understand the sex-specific heterogeneity in β cell failure in diabetes.

Genetic discovery and risk prediction for type 1 diabetes in individuals without high-risk HLA-DR3/DR4 haplotypes.

Over 10% of type 1 diabetes (T1D) cases do not have high-risk HLA-DR3 or DR4 haplotypes with distinct clinical features such as later onset and reduced insulin dependence. To identify genetic drivers of T1D in the absence of DR3/DR4, we performed association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. Risk variants at the MHC and other loci genome-wide had heterogeneity in effects on T1D dependent on DR3/DR4, and non-DR3/DR4 T1D had evidence for a greater polygenic burden.

Multi-ancestry Polygenic Mechanisms of Type 2 Diabetes Elucidate Disease Processes and Clinical Heterogeneity.

We identified genetic subtypes of type 2 diabetes (T2D) by analyzing genetic data from diverse groups, including non-European populations. We implemented soft clustering with 650 T2D-associated genetic variants, capturing known and novel T2D subtypes with distinct cardiometabolic trait associations. The twelve genetic clusters were distinctively enriched for single-cell regulatory regions.

An Integrated Map of Cell Type-Specific Gene Expression in Pancreatic Islets.

Pancreatic islets consist of multiple cell types that produce hormones required for glucose homeostasis, and islet dysfunction is a major factor in type 1 and type 2 diabetes. Numerous studies have assessed transcription across individual cell types using single-cell assays; however, there is no canonical reference of gene expression in islet cell types that is also easily accessible for researchers to query and use in bioinformatics pipelines. Here we present an integrated map of islet cell type-specific gene expression from 192,203 cells from single-cell RNA sequencing of 65 donors without diabetes, donors who were type 1 diabetes autoantibody positive, donors with type 1 diabetes, and donors with type 2 diabetes from the Human Pancreas Analysis Program.

Leveraging type 1 diabetes human genetic and genomic data in the T1D knowledge portal.

To address the challenge of translating genetic discoveries for type 1 diabetes (T1D) into mechanistic insight, we have developed the T1D Knowledge Portal (T1DKP), an open-access resource for hypothesis development and target discovery in T1D.

Mapping genetic effects on cell type-specific chromatin accessibility and annotating complex immune trait variants using single nucleus ATAC-seq in peripheral blood.

Gene regulation is highly cell type-specific and understanding the function of non-coding genetic variants associated with complex traits requires molecular phenotyping at cell type resolution. In this study we performed single nucleus ATAC-seq (snATAC-seq) and genotyping in peripheral blood mononuclear cells from 13 individuals. Clustering chromatin accessibility profiles of 96,002 total nuclei identified 17 immune cell types and sub-types.

Integrating genetics with single-cell multiomic measurements across disease states identifies mechanisms of beta cell dysfunction in type 2 diabetes.

Dysfunctional pancreatic islet beta cells are a hallmark of type 2 diabetes (T2D), but a comprehensive understanding of the underlying mechanisms, including gene dysregulation, is lacking. Here we integrate information from measurements of chromatin accessibility, gene expression and function in single beta cells with genetic association data to nominate disease-causal gene regulatory changes in T2D. Using machine learning on chromatin accessibility data from 34 nondiabetic, pre-T2D and T2D donors, we identify two transcriptionally and functionally distinct beta cell subtypes that undergo an abundance shift during T2D progression.

Interpreting non-coding disease-associated human variants using single-cell epigenomics.

Genome-wide association studies (GWAS) have linked hundreds of thousands of sequence variants in the human genome to common traits and diseases. However, translating this knowledge into a mechanistic understanding of disease-relevant biology remains challenging, largely because such variants are predominantly in non-protein-coding sequences that still lack functional annotation at cell-type resolution. Recent advances in single-cell epigenomics assays have enabled the generation of cell type-, subtype- and state-resolved maps of the epigenome in heterogeneous human tissues.

Understanding cell fate acquisition in stem-cell-derived pancreatic islets using single-cell multiome-inferred regulomes.

Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem-cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison.

The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits.

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits.