Partial beta cell loss induces transient compensatory proliferation II

Loss of functional ß-cells is a pivotal event in the dysregulation of glucose homeostasis observed in diabetes. While the plasticity of ß-cells in response to increased metabolic demand has been extensively studied, the common drivers of ß-cell proliferation and the molecular mechanisms governing regeneration in humans remain elusive. Here, we investigated the proliferative response following targeted chemical ablation of ß-cells using diphtheria toxin (DT) and streptozotocin (STZ) in mice. Hemizygous expression of the RIP-DTR transgene enabled efficient partial ablation of ß-cells, leading to close to 50% ß-cell loss five days post ablation, stabilizing at this level up to 10 weeks post ablation. Transcriptomic analysis revealed a dynamic molecular landscape following ablation, with early activation of tissue remodeling and clearance of dead cells, followed by transient activation of regenerative signaling pathways. Furthermore, we observed a distinct proliferative boost in the immediate aftermath of ablation, characterized by upregulation of cell cycle progression markers. Interestingly, long-term follow-up revealed compound stress from partial ß-cell loss and high-fat diet feeding induced a robust proliferative response, albeit with a negative impact on ß-cell signature. Additionally, single low-dose STZ injections induced partial ß-cell loss and compensatory proliferation, with the regulatory landscape deregulated by STZ injection in the long term. The compound stress of high-fat diet and STZ ablation further altered the islet transcriptional landscape, particularly affecting metabolic pathways. Overall, our study provides insights into the dynamic response of ß-cells to partial ablation and highlights the impact of compound stressors on islet function and metabolism, shedding light on potential strategies for promoting ß-cell regeneration in diabetes. Loss of functional ß-cells is a pivotal event in the dysregulation of glucose homeostasis observed in diabetes. While the plasticity of ß-cells in response to increased metabolic demand has been extensively studied, the common drivers of ß-cell proliferation and the molecular mechanisms governing regeneration in humans remain elusive. Here, we investigated the proliferative response following targeted chemical ablation of ß-cells using diphtheria toxin (DT) and streptozotocin (STZ) in mice. Hemizygous expression of the RIP-DTR transgene enabled efficient partial ablation of ß-cells, leading to close to 50% ß-cell loss five days post ablation, stabilizing at this level up to 10 weeks post ablation. Transcriptomic analysis revealed a dynamic molecular landscape following ablation, with early activation of tissue remodeling and clearance of dead cells, followed by transient activation of regenerative signaling pathways. Furthermore, we observed a distinct proliferative boost in the immediate aftermath of ablation, characterized by upregulation of cell cycle progression markers. Interestingly, long-term follow-up revealed compound stress from partial ß-cell loss and high-fat diet feeding induced a robust proliferative response, albeit with a negative impact on ß-cell signature. Additionally, single low-dose STZ injections induced partial ß-cell loss and compensatory proliferation, with the regulatory landscape deregulated by STZ injection in the long term. The compound stress of high-fat diet and STZ ablation further altered the islet transcriptional landscape, particularly affecting metabolic pathways. Overall, our study provides insights into the dynamic response of ß-cells to partial ablation and highlights the impact of compound stressors on islet function and metabolism, shedding light on potential strategies for promoting ß-cell regeneration in diabetes. Loss of functional ß-cells is a pivotal event in the dysregulation of glucose homeostasis observed in diabetes. While the plasticity of ß-cells in response to increased metabolic demand has been extensively studied, the common drivers of ß-cell proliferation and the molecular mechanisms governing regeneration in humans remain elusive. Here, we investigated the proliferative response following targeted chemical ablation of ß-cells using diphtheria toxin (DT) and streptozotocin (STZ) in mice. Hemizygous expression of the RIP-DTR transgene enabled efficient partial ablation of ß-cells, leading to close to 50% ß-cell loss five days post ablation, stabilizing at this level up to 10 weeks post ablation. Transcriptomic analysis revealed a dynamic molecular landscape following ablation, with early activation of tissue remodeling and clearance of dead cells, followed by transient activation of regenerative signaling pathways. Furthermore, we observed a distinct proliferative boost in the immediate aftermath of ablation, characterized by upregulation of cell cycle progression markers. Interestingly, long-term follow-up revealed compound stress from partial ß-cell loss and high-fat diet feeding induced a robust proliferative response, albeit with a negative impact on ß-cell signature. Additionally, single low-dose STZ injections induced partial ß-cell loss and compensatory proliferation, with the regulatory landscape deregulated by STZ injection in the long term. The compound stress of high-fat diet and STZ ablation further altered the islet transcriptional landscape, particularly affecting metabolic pathways. Overall, our study provides insights into the dynamic response of ß-cells to partial ablation and highlights the impact of compound stressors on islet function and metabolism, shedding light on potential strategies for promoting ß-cell regeneration in diabetes. Overall design: Mice were followed up at different timepoints following partial ablation using either a RIP-DTR system or STZ mediated ablation. Islets were isolated and analyzed with bulk transcriptomics to identify the molecular response to partial beta-cell loss.