Dataset Information

CGAS Suppresses β-cell Proliferation by a STING-independent but CEBPβ-dependent Mechanism

ABSTRACT: Aims/hypothesis cGAS (cyclic GMP-AMP synthase) has been implicated in various cellular processes, but its role in β-cell proliferation and diabetes is not fully understood. This study investigates the impact of cGAS on β-cell proliferation, particularly in the context of diabetes. Methods Utilizing mouse models, including cGAS and STING (stimulator of interferon genes) knockout mice, we explored the role of cGAS in β-cell function. This involved β-cell-specific cGAS knockout (cGASβKO) mice, created by breeding cGAS floxed mice with transgenic mice expressing Cre recombinase under the insulin II promoter. We analyzed cGAS expression in diabetic mouse models, evaluated the effects of cGAS deficiency on glucose tolerance, and investigated the molecular mechanisms underlying these effects through RNA sequencing. Results Our study found that cGAS expression is upregulated in the islets of diabetic mice and in response to high glucose conditions in MIN6 cells. Global cGAS deficiency enhanced glucose tolerance, while β-cell-specific cGAS knockout improved glucose intolerance under high-fat diet conditions. Interestingly, STING knockout did not affect pancreatic β-cell mass, suggesting a STING-independent mechanism for cGAS's role in β-cells. Further analyses revealed that cGAS deficiency leads to increased β-cell proliferation and reduced expression of CEBPβ, a known suppressor of β-cell proliferation. This effect appears to be mediated by a STING-independent pathway and is specific to pancreatic tissue. Conclusions/interpretation Our findings indicate that cGAS plays a pivotal role in modulating β-cell proliferation and glucose homeostasis, potentially through regulating CEBPβ expression in a STING-independent manner. This study highlights the importance of cGAS in diabetes pathology and suggests it as a potential therapeutic target for enhancing β-cell proliferation in diabetes treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE264386 | GEO | 2025/04/18

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Relative beta cell deficit and increased beta cell apoptosis are hallmarks of type 2 diabetes (T2D). The Insulin/Insulin Growth Factor (Igf) signaling pathway is an established regulator of beta cell survival and is found downregulated in human T2D islets. The Insulin Receptor Substrate 2 (Irs2) plays a central role in the coordination of this pathway in beta cells. Thus, Irs2 knockout mice (Irs2 -/-) exhibit increased beta cell apoptosis that leads to a progressive decline of beta cell mass and hyperglycaemia. In this study, we sought to determine whether the anti-diabetic compound sodium tungstate could prevent the onset of diabetes in Irs2 -/- mice. Oral administration of tungstate resulted in an overall improvement in whole-body glucose tolerance in Irs2 -/- mice which correlated with increased beta cell mass. Enhanced beta cell mass was due to a dramatic reduction of beta cell apoptosis without changes in proliferation. Whole genome gene profiling analysis of islets isolated from treated Irs2 -/- mice confirmed a broad impact of tungstate on cell death pathways. Mechanistically, tungstate induced Erk1/2 phosphorylation in islets in vitro and, in agreement, treated Irs2 -/- islets exhibited increased basal Erk1/2 phosphorylation. Tungstate also downregulated expression of apoptosis-related genes in Irs2-/- islets in vitro, uncovering a direct effect of this compound in islets. All together, our data demonstrate that tungstate can restore beta cell mass and glucose homeostasis in a context of deficient Insulin/Igf signaling. This study underscores the importance of developing strategies specifically designed to arrest beta cell apoptosis as a means to prevent progressive beta cell failure in diabetes. 10-week old WT and Irs2 -/- mice were randomly divided into two treatment group, in a total of 4 experimental groups. For 21 days one group received distilled water as drinking water (untreated group) whilst the other received ad libitum a solution of 2mg/ml of sodium tungstate in distilled water (treated group). For each experimental group 2 independent samples were analysed, in a total of 8 samples.

Dataset Information

CGAS Suppresses β-cell Proliferation by a STING-independent but CEBPβ-dependent Mechanism

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets