Biology subjects

Harrington, A. R.

Publications and source records attributed to Harrington, A. R..

5 recordsLinked to original sources

bioRxiv2026

Workload-induced changes to cell state contribute to β-cell failure in diabetes

Insufficient insulin secretion relative to insulin demand is a key feature of type 2 diabetes (T2D). While the defects of insulin-producing {beta}-cells in T2D are well defined, little is known about how {beta}-cells progress from the functionally normal state to the decompensated state during the natural history of this disease. Here, we provide evidence that workload-induced {beta}-cell overstimulation precipitates {beta}-cell failure in T2D. We employ scRNA-seq to define workload-induced changes to {beta}-cell transcriptional states, identifying a novel compensating state that is distinct from the stressed state of decompensated {beta}-cells. We demonstrate a key role for the chromatin-modifying enzyme Lysine-specific demethylase 1 (Lsd1) in restraining workload-induced {beta}-cell state transitions, indicating epigenomic control of {beta}-cell state. Experimental manipulations that promote the compensating state accelerate {beta}-cell failure in mouse models of diabetes. Altogether, these findings show that the compensatory response of the {beta}-cell to increased workload becomes maladaptive over time and contributes to the pathogenesis of T2D.

physiology↗

bioRxiv2024

Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2

Selective and controlled expansion of endogenous {beta}-cells has been pursued as a potential therapy for diabetes. Ideally, such therapies would preserve feedback control of {beta}-cell proliferation to avoid excessive {beta}-cell expansion and an increased risk of hypoglycemia. Here, we identified a regulator of {beta}-cell proliferation whose inactivation results in controlled {beta}-cell expansion: the protein deacetylase Sirtuin 2 (SIRT2). Sirt2 deletion in {beta}-cells of mice increased {beta}-cell proliferation during hyperglycemia with little effect in homeostatic conditions, indicating preservation of feedback control of {beta}-cell mass. SIRT2 restrains proliferation of human islet {beta}-cells cultured in glucose concentrations above the glycemic set point, demonstrating conserved SIRT2 function. Analysis of acetylated proteins in islets treated with a SIRT2 inhibitor revealed that SIRT2 deacetylates enzymes involved in oxidative phosphorylation, dampening the adaptive increase in oxygen consumption during hyperglycemia. At the transcriptomic level, Sirt2 inactivation has context-dependent effects on {beta}-cells, with Sirt2 controlling how {beta}-cells interpret hyperglycemia as a stress. Finally, we provide proof-of-principle that systemic administration of a GLP1-coupled Sirt2-targeting antisense oligonucleotide achieves {beta}-cell selective Sirt2 inactivation and stimulates {beta}-cell proliferation under hyperglycemic conditions. Overall, these studies identify a therapeutic strategy for increasing {beta}-cell mass in diabetes without circumventing feedback control of {beta}-cell proliferation.

physiology↗

bioRxiv2022

Improving 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. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, CDX2+ pre-{beta}-cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro {beta}-cell maturation and identify sex hormones as drivers of {beta}-cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem cell-derived islets and a framework for manipulating cell identities and maturity.

cell biology↗

bioRxiv2021

Systemic LSD1 inhibition prevents aberrant remodeling of metabolism in obesity

The transition from lean to obese states involves systemic metabolic remodeling that impacts insulin sensitivity, lipid partitioning, inflammation, and glycemic control. Here, we have taken a pharmacological approach to test the role of a nutrient-regulated chromatin modifier, lysine-specific demethylase (LSD1), in obesity-associated metabolic reprogramming. We show that systemic administration of an LSD1 inhibitor (GSK-LSD1) reduces food intake and body weight, ameliorates non-alcoholic fatty liver disease (NAFLD), and improves insulin sensitivity and glycemic control in mouse models of obesity. GSK-LSD1 has little effect on systemic metabolism of lean mice, suggesting LSD1 has a context-dependent role in promoting maladaptive changes in obesity. Analysis of insulin target tissues identified white adipose tissue as the major site of insulin sensitization by GSK-LSD1, where it reduces adipocyte inflammation and lipolysis. We demonstrate that GSK-LSD1 reverses NAFLD in a non-hepatocyte-autonomous manner, suggesting an indirect mechanism via inhibition of adipocyte lipolysis and subsequent effects on lipid partitioning. Pair-feeding experiments further revealed that effects of GSK-LSD1 on hyperglycemia and NAFLD are not a consequence of reduced food intake and weight loss. These findings suggest that targeting LSD1 could be a strategy for treatment of obesity and its associated complications including type 2 diabetes and NAFLD. O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/469928v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@17232dcorg.highwire.dtl.DTLVardef@6940a0org.highwire.dtl.DTLVardef@11d3deorg.highwire.dtl.DTLVardef@6cc0fd_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2019

Nutrient regulation of the islet epigenome controls adaptive insulin secretion

Adaptation of the islet {beta}-cell insulin secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we show that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in {beta}-cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurs at sites occupied by the chromatin-modifying enzyme Lsd1 in islets. We demonstrate that {beta}-cell-specific deletion of Lsd1 leads to insulin hypersecretion, aberrant expression of nutrient response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited similar epigenetic and transcriptional changes. Moreover, genetic variants associated with fasting glucose and type 2 diabetes are enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined. Our findings reveal that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome.

physiology↗