LDB1-mediated transcriptional complexes are sensitive to islet stress.

ABSTRACT

Excess nutrients and proinflammatory cytokines impart stresses on pancreatic islet ß-cells that, if unchecked, can lead to cellular dysfunction and/or death. Among these stress-induced effects is loss of key ß-cell transcriptional regulator mRNA and protein levels required for ß-cell function. Previously, our lab and others reported that LIM-domain complexes comprised the LDB1 transcriptional co-regulator and Islet-1 (ISL1) transcription factor are required for islet ß-cell development, maturation, and function. The LDB1ISL1 complex directly occupies and regulates key ß-cell genes, including MafA, Pdx1, and Slc2a2, to maintain ß-cell identity and function. Given the importance of LDB1ISL1 complexes, we hypothesized that LDB1 and/or ISL1 levels, like other transcriptional regulators, are sensitive to ß-cell nutrient and cytokine stresses, likely contributing to ß-cell (dys)function under various stimuli. We tested this by treating ß-cell lines or primary mouse islets with elevating glucose concentrations, palmitate, or a cytokine cocktail of IL-1ß, TNFα, and IFNγ. We indeed observed that LDB1 mRNA and/or protein levels were reduced upon palmitate and cytokine (cocktail or singly) incubation. Conversely, acute high glucose treatment of ß-cells did not impair LDB1 or ISL1 levels, but increased LDB1ISL1 interactions. These observations suggest that LDB1ISL1 complex formation is sensitive to ß-cell stresses and that targeting and/or stabilizing this complex may rescue lost ß-cell gene expression to preserve cellular function.