ArticleThe Journal of clinical investigation2022
α Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody-positive individuals.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 64 citations in OpenAlex.
- Article
- Heterogeneous endocrine cell composition defines human islet functional phenotypes.Nature communications · 2026Article
- Altered Glucagon Response to Oral Glucose in Individuals at Different Stages of Type 1 Diabetes Development.The Journal of clinical endocrinology and metabolism · 2026Article
- β-Cell Obligation in α-Cell Glucagon Response to Low Glucose.Research square · 2026Article
- Biological sex affects human islet gene expression and mitochondrial function in type 2 diabetes.Endocrinology · 2026Article
- Spatial transcriptomics from pancreas and local draining lymph node tissue reveals a lymphotoxin-β signature in human type 1 diabetes.Cell reports · 2026Article
- PTPN2 deficiency amplifies inflammatory signalling and impairs functional maturation of human stem cell-derived islets.Stem cell research & therapy · 2026Article
- Article
- Biological sex affects human islet gene expression and mitochondrial function in type 2 diabetes.bioRxiv : the preprint server for biology · 2025Article
- Single-cell mRNA-regulation analysis reveals cell type-specific mechanisms of type 2 diabetes.Nature communications · 2025Article
- The protein deacetylase SIRT2 exerts metabolic control over adaptive β cell proliferation.The Journal of clinical investigation · 2025Article
- Beta cell dysfunction occurs independently of insulitis in type 1 diabetes pathogenesis.Cell reports · 2025Article
- Single-cell multiome and spatial profiling reveals pancreas cell type-specific gene regulatory programs of type 1 diabetes progression.Science advances · 2025Article
- Heterogeneous endocrine cell composition defines human islet functional phenotypes.bioRxiv : the preprint server for biology · 2025Article
- The pathophysiology, presentation and classification of Type 1 diabetes.Diabetes, obesity & metabolism · 2025Review
- Article
- Proinflammatory cytokine-induced alpha cell impairment in human islet microtissues is partially restored by dual incretin receptor agonism.Diabetologia · 2025Article
- Modeling diabetic alpha cell dysfunction using stem cell-derived alpha cells.Stem cell reports · 2025Article
- Distribution of glutathione peroxidase-1 immunoreactive cells in pancreatic islets from type 1 diabetic donors and non-diabetic donors with and without islet cell autoantibodies is variable and independent of disease.Cell and tissue research · 2025Article
- Acute Inhibition of Adipose Triglyceride Lipase by NG497 Dysregulates Insulin and Glucagon Secretion From Human Islets.Endocrinology · 2025Article
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Authors and funding
19 authors at 5 institutions in 4 countries.
Funding
Abstract
BACKGROUNDMultiple 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.METHODSHere, we functionally, histologically, and molecularly phenotyped human islets from nondiabetic GADA+ and T1D donors.RESULTSSimilar 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.CONCLUSIONWe 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.FUNDINGThis 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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