Single-cell multi-omics analysis of human pancreatic islets reveals novel cellular states in type 1 diabetes

Fasolino, Maria; Schwartz, Gregory W.; Patil, Abhijeet R.; Mongia, Aanchal; Golson, Maria L.; Wang, Yue J.; Morgan, Ashleigh; Liu, Chengyang; Schug, Jonathan; Liu, Jinping; Wu, Minghui; Traum, Daniel; Kondo, Ayano; May, Catherine Lee; Goldman, Naomi; Wang, Wenliang; Feldman, Michael D.; Moore, Jason H.; Japp, Alberto Sada; Betts, Michael R.; Faryabi, Robert B.; Naji, Ali; Kaestner, Klaus H.; Vahedi, Golnaz

doi:10.1038/s42255-022-00531-x

Cited by 80 publications

(103 citation statements)

References 67 publications

(89 reference statements)

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“…Cell Ranger (10x Genomics, version 3.0.1) was used for bcl2fastq conversion, alignment (using the hg38 reference genome), filtering, counting, cell calling, and aggregation (--normalize=none). scRNA-Seq data were preprocessed as described previously ( 48 ). The resulting Seurat ( 49 , 50 ) object was downloaded from the cellxgene resource ( https://cellxgene.cziscience.com/collections/51544e44-293b-4c2b-8c26-560678423380 ).…”

Section: Methodsmentioning

confidence: 99%

α Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody–positive individuals

Doliba¹,

Rozo²,

Roman³

et al. 2022

Journal of Clinical Investigation

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BACKGROUND Multiple islet autoantibodies (AAbs) predict the development of type 1 diabetes (T1D) and hyperglycemia within 10 years. By contrast, T1D develops in only approximately 15% of individuals who are positive for single AAbs (generally against glutamic acid decarboxylase [GADA]); hence, the single GADA + state may represent an early stage of T1D. METHODS Here, we functionally, histologically, and molecularly phenotyped human islets from nondiabetic GADA + and T1D donors. RESULTS Similar to the few remaining β cells in the T1D islets, GADA + donor islets demonstrated a preserved insulin secretory response. By contrast, α cell glucagon secretion was dysregulated in both GADA + and T1D islets, with impaired glucose suppression of glucagon secretion. Single-cell RNA-Seq of GADA + α cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of cAMP-dependent protein kinase inhibitor β ( PKIB ), providing a molecular basis for the loss of glucose suppression and the increased effect of 3-isobutyl-1-methylxanthine (IBMX) observed in GADA + donor islets. CONCLUSION We found that α cell dysfunction was present during the early stages of islet autoimmunity at a time when β cell mass was still normal, raising important questions about the role of early α cell dysfunction in the progression of T1D. FUNDING This work was supported by grants from the NIH (3UC4DK112217-01S1, U01DK123594-02, UC4DK112217, UC4DK112232, U01DK123716, and P30 DK019525) and the Vanderbilt Diabetes Research and Training Center (DK20593).

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Section: Methodsmentioning

confidence: 99%

α Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody–positive individuals

Doliba¹,

Rozo²,

Roman³

et al. 2022

Journal of Clinical Investigation

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“…In the future, the increasing availability of genetic information, combined with the proven ability of autoantibody screening to identify early-stage type 1 diabetes, may lead to an era of precision prediction in which we are able to predict type 1 diabetes and intercept before and prevent or delay disease onset. Many groups are working to improve the precision prediction of type 1 diabetes using novel biomarker and 'omics' approaches [27], including advanced omic, single cell and advanced imaging analysis of pancreatic tissue from organ donors with autoantibody positivity and established type 1 diabetes [28][29][30][31]. We are now able to study the complex environmental, metabolomic, virome, molecular and microbiome associations in type 1 diabetes progression.…”

Section: Predictionmentioning

confidence: 99%

Precision medicine in type 1 diabetes

Evans‐Molina

Oram

2022

Diabetologia

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First envisioned by early diabetes clinicians, a person-centred approach to care was an aspirational goal that aimed to match insulin therapy to each individual’s unique requirements. In the 100 years since the discovery of insulin, this goal has evolved to include personalised approaches to type 1 diabetes diagnosis, treatment, prevention and prediction. These advances have been facilitated by the recognition of type 1 diabetes as an autoimmune disease and by advances in our understanding of diabetes pathophysiology, genetics and natural history, which have occurred in parallel with advancements in insulin delivery, glucose monitoring and tools for self-management. In this review, we discuss how these personalised approaches have improved diabetes care and how improved understanding of pathogenesis and human biology might inform precision medicine in the future. Graphical abstract

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“…Notably, the patch-seq approach is feasible for cryopreserved human islet samples, opening a possible route for studies in archive material. In a recent study [63] (using islets from five donors with type 1 diabetes, eight donors with type 1 diabetesassociated autoantibodies [AAB + ], and 11 control donors), type 1 diabetes donors were found to have a lower proportion of beta cells and a higher proportion of duct and acinar cells. Furthermore, beta cellspecific downregulation of pathways related to immune/stress response, apoptosis and TNF signalling was observed in cells from donors with type 1 diabetes.…”

Section: Studies Of Type 1 Diabetes Isletsmentioning

confidence: 99%

Lessons from single-cell RNA sequencing of human islets

Ngara

Wierup

2022

Diabetologia

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Islet dysfunction is central in type 2 diabetes and full-blown type 2 diabetes develops first when the beta cells lose their ability to secrete adequate amounts of insulin in response to raised plasma glucose. Several mechanisms behind beta cell dysfunction have been put forward but many important questions still remain. Furthermore, our understanding of the contribution of each islet cell type in type 2 diabetes pathophysiology has been limited by technical boundaries. Closing this knowledge gap will lead to a leap forward in our understanding of the islet as an organ and potentially lead to improved treatments. The development of single-cell RNA sequencing (scRNAseq) has led to a breakthrough for characterising the transcriptome of each islet cell type and several important observations on the regulation of cell-type-specific gene expression have been made. When it comes to identifying type 2 diabetes disease mechanisms, the outcome is still limited. Several studies have identified differentially expressed genes, although there is very limited consensus between the studies. As with all new techniques, scRNAseq has limitations; in addition to being extremely expensive, genes expressed at low levels may not be detected, noise may not be appropriately filtered and selection biases for certain cell types are at hand. Furthermore, recent advances suggest that commonly used computational tools may be suboptimal for analysis of scRNAseq data in small-scale studies. Fortunately, development of new computational tools holds promise for harnessing the full potential of scRNAseq data. Here we summarise how scRNAseq has contributed to increasing the understanding of various aspects of islet biology as well as type 2 diabetes disease mechanisms. We also focus on challenges that remain and propose steps to promote the utilisation of the full potential of scRNAseq in this area. Graphical abstract

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Single-cell multi-omics analysis of human pancreatic islets reveals novel cellular states in type 1 diabetes

Cited by 80 publications

References 67 publications

α Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody–positive individuals

α Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody–positive individuals

Precision medicine in type 1 diabetes

Lessons from single-cell RNA sequencing of human islets

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