Biology subjects

Carapeto, P.

Publications and source records attributed to Carapeto, P..

2 recordsLinked to original sources

bioRxiv2025

A human and mouse subpopulation of senescent β-cells induces pathologic dysfunction through targetable paracrine signaling

Cellular senescence is a stress response mechanism marked by irreversible growth arrest, upregulation of antiapoptotic pathways, loss of cellular function, and remodelling of the cellular secretory profile. In both humans and mice, pancreatic {beta}-cells undergo senescence with age and insulin resistance. Targeted removal of senescent cells in mouse models of diabetes improves glucose homeostasis, demonstrating the role {beta}-cell senescence in diabetes progression. In contrast, {beta}-cell senescence also promotes immune surveillance, promoting {beta}-cell survival and function. Thus, a better understanding of senescent cells phenotypic and functional heterogeneity is needed to develop effective therapeutic strategies. Herein, we show that subpopulations of senescent {beta}-cells in mice and humans, which were identified through the expression of Cdkn1a (encoding p21Cip1) and Cdkn2a (encoding p16Ink4a) by single-cell RNA sequencing (scRNA-seq), flow cytometry, spatial transcriptomics, and spatial proteomics, exhibit distinct transcriptional and functional identities. The predominant senescent {beta}-cell subpopulation expressed Cdkn1a and was characterized by a lack of glucose responsiveness, high basal insulin secretion, and transcription of canonical SASP factors. The SASP of Cdkn1a-expressing {beta}-cells had non-cell autonomous effects on neighbouring cells. A subset of four SASP factors from Cdkn1a+ cells was sufficient to induce secondary senescence and {beta}-cell dysfunction in vitro. JAK inhibitors (JAK1/2 and JAK1/3) counteracted secondary senescence induction and restored {beta}-cell function in high-fat diet-fed mice and human islets from donors with or without type 2 diabetes. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/648438v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@9b8addorg.highwire.dtl.DTLVardef@1b9c4eborg.highwire.dtl.DTLVardef@12f2964org.highwire.dtl.DTLVardef@1468297_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2024

Sex-dependent additive effects of dorzagliatin and incretin on insulin secretion in a novel mouse model of GCK-MODY

Glucokinase (GK) catalyses the key regulatory step in glucose-stimulated insulin secretion. Correspondingly, hetero- and homozygous mutations in human GCK cause maturity-onset diabetes of the young (GCK-MODY) and permanent neonatal diabetes (PNDM), respectively. To explore the possible utility of glucokinase activators (GKA) and of glucagon-like receptor-1 (GLP-1) agonists in these diseases, we have developed a novel hypomorphic Gck allele in mice encoding an aberrantly spliced mRNA deleted for exons 2 and 3. In islets from homozygous knock-in (GckKI/KI) mice, GK immunoreactivity was reduced by >85%, and glucose-stimulated insulin secretion eliminated. Homozygous GckKI/KI mice were smaller than wildtype littermates and displayed frank diabetes (fasting blood glucose >18 mmol/L; HbA1c [~]12%), ketosis and nephropathy. Heterozygous GckKI/+ mice were glucose intolerant (HbA1c [~]5.5%). Abnormal glucose-stimulated Ca2+ dynamics and beta cell-beta cell connectivity in GckKI/+ islets were completely reversed by the recently-developed GKA, dorzagliatin, which was largely inactive in homozygous GckKI/KI mouse islets. The GLP-1 receptor agonist exendin-4 improved glucose tolerance in male GckKI/+ mice, an action potentiated by dorzagliatin, in male but not female mice. Sex-dependent additive effects of these agents were also observed on insulin secretion in vitro. Combined treatment with GKA and incretin may thus be useful in GCK-MODY or GCK-PNDM. Article Highlightsa. Glucokinase deficiency can drive maturity-onset diabetes of the young (GCK-MODY; heterozygotes) and permanent neonatal diabetes (GCK-PNDM; homozygotes) b. We describe a hypomorphic Gck allele where aberrant splicing in islets lowers GK activity to by [~]85%. We use these mice to explore the effects of the glucokinase activator, dorzagliatin, and incretin on insulin secretion c. Whereas heterozygous mutant mice are mildly hyperglycemic, homozygotes have frank diabetes but survive to adulthood. Dorzagliatin potentiates the effects of GLP-1 receptor activation sex-dependently in heterozygotes d. Combined use of these drugs may be useful in some forms of GCK diabetes

physiology↗