Introduction and Objective: Type 1 diabetes (T1D) is characterized by pancreatic β-cell loss, impaired insulin secretion and hyperglycaemia. Insulin replacement normalises blood glucose, but may cause potentially lethal hypoglycaemia. Islet transplantation and stem cell therapy are limited by donor scarcity, and require life-long immunosuppression. This highlights the importance of preserving existing β-cells and/or regenerating new β-cells in T1D. C-II-a is a mimetic peptide that regenerates insulin-containing, glucose-responsive cells and reduces hyperglycaemia in C57BL/6J mice with diabetes. The study identifies C-II-a target genes in these mice and evaluates their relevance to T1D. Methods: C57BL/6J mice were rendered diabetic with streptozotocin, then treated with C-II-a or PBS twice weekly for four weeks. Differentially expressed pancreatic genes were identified and localized by spatial transcriptomics. Changes in expression of key genes were validated by incubating INS-1E and AR42J cells with C-II-a, followed by RT-PCR and Western blotting. The functional impact of these changes were evaluated by glucose-stimulated insulin secretion. Results: Fasting blood glucose was 8.8±1.5 mM in C-II-a-treated mice, and 11.9±1.4 mM in control mice (p 0.05). C-II-a treatment down regulated pancreatic Reg3 α, Reg3 β , Reg3 γ and Mt1, and up regulated PRSS1 (p0.0001 for all). Incubation of INS-1E and AR42J cells with C-II-a decreased Reg3α, Reg3γ, and Mt1 mRNA and protein levels (p0.05 for all) and increased PRSS1 expression (p0.05). Mt1 knockdown in INS-1E cells increased GSIS (p0.01). Conclusion: This study identifies C-II-a target genes associated with reduced fasting blood glucose in C57BL/6J mice with diabetes and potential therapeutic approaches for improving glycaemic control in T1D. Disclosure I. Haleem: None. T. King: None. K. Chemello: None. B. Cochran: None. S. Thomas: None. K. Rye: None. Funding National Health and Medical Research Council of Australia (APPP2004064)
Haleem et al. (Fri,) studied this question.