Transcriptional signature of islet neogenesis-associated protein peptide-treated rat pancreatic islets reveals induction of novel long non-coding RNAs

Diabetes mellitus is characterized by chronic hyperglycemia with loss of β-cell function and mass. An attractive therapeutic approach to treat patients with diabetes in a non-invasive way is to harness the innate regenerative potential of the pancreas. The Islet Neogenesis-Associated Protein pentadecapeptide (INGAP-PP) has been shown to induce β-cell regeneration and improve their function in rodents. To investigate its possible mechanism of action, we report here the global transcriptional effects induced by the short-term INGAP-PP in vitro treatment of adult rat pancreatic islets. We identify 1,669 differentially expressed genes by INGAP-PP treatment, including dozens of previously unannotated rat transcripts. In-depth analysis suggests that INGAP-PP engages the transcriptional program regulated by vitamin D receptor activation, among other pathways relevant for β-cell function, ultimately leading to enhanced glucose-stimulated insulin release. Supported by epigenomic and single-cell RNA-seq data, we identify 9 previously unannotated long noncoding RNAs upregulated by INGAP-PP, some of which are also differentially regulated by IL1β and vitamin D in β-cells. These include Ri-lnc1, which is enriched in mature β-cells. Taken together, the results presented here reveal novel potential mechanisms that could underlie the positive physiological effects of INGAP on β-cell function and mass. We purified rat pancreatic islets and treated them in vitro with/without INGAP (50 μg/mL) for 4 days. Afterwards we purified RNA and processed it for RNA-seq.