Biology subjects

Skovso, S.

Publications and source records attributed to Skovso, S..

2 recordsLinked to original sources

bioRxiv2019

Ins2 gene bursting activity defines a mature beta-cell state

Transcriptional and functional cellular specialization has been described for insulin-secreting {beta}-cells of the endocrine pancreas. However, it is not clear whether {beta}-cell heterogeneity is stable or reflects dynamic cellular states. We investigated the temporal kinetics of endogenous insulin gene activity using live cell imaging, with complementary experiments employing FACS and single cell RNA sequencing, in {beta}-cells from Ins2GFP knock-in mice. In vivo staining and FACS analysis of islets from Ins2GFP mice confirmed that at a given moment, ~25% of {beta}-cells exhibited significantly higher activity at the conserved insulin gene Ins2. Live cell imaging captured Ins2 gene activity dynamics in single {beta}-cells over days. Autocorrelation analysis revealed a subset of cells with oscillating behavior, with mean oscillation periods of 17 hours. Increased glucose concentrations stimulated more cells to oscillate and resulted in higher average Ins2 gene activity per cell. Single cell RNA sequencing showed that Ins2(GFP)HIGH {beta}-cells were enriched for markers of {beta}-cell maturity. Ins2(GFP)HIGH {beta}-cells were also significantly less viable at all glucose concentrations and in the context of ER stress. Collectively, our results demonstrate that the heterogeneity of insulin production, observed in mouse and human {beta}-cells, can be accounted for by dynamic states of insulin gene activity. BlurbPreviously reported pancreatic {beta}-cell heterogeneity reflects {beta}-cell state transitions.

cell biology↗

bioRxiv2019

Endogenous insulin contributes to pancreatic cancer development

Obesity and early-stage type 2 diabetes (T2D) increase the risk for many cancers, including pancreatic ductal adenocarcinoma (PDAC). The mechanisms linking obesity and T2D to cancer have not been established, preventing targeted interventions. Arguments have been made that hyperinsulinemia, hyperglycemia, or inflammation could drive cancer initiation and/or progression1. Hyperinsulinemia is a cardinal feature of obesity and T2D, and is independently associated with PDAC incidence and mortality2-4, even in non-obese people5. Despite ample human epidemiological evidence linking hyperinsulinemia to PDAC, there is no direct in vivo evidence of a causal role for endogenous insulin in cancer in any system. Using mice with reduced insulin gene dosage6, 7, we show here that a modest reduction in endogenous insulin production leads to a ~50% reduction in pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in high fat diet-fed mice expressing the KrasG12D oncogene8. The significant reduction in PanIN lesions occurred in the absence of changes in fasting glucose. Reduced insulin also led to a ~50% reduction in pancreatic fibrosis, suggesting that endogenous insulin drives PanIN development, in part, via its pro-fibrotic effects on the stroma surrounding acinar cells and PanIN. Collectively, our data indicate that endogenous insulin hypersecretion contributes causally to pancreatic cancer development. This suggests a modest reduction in fasting insulin via lifestyle interventions or therapeutics may be useful in cancer prevention.

cancer biology↗