Pancreatic β-cell mitogenic regeneration in type 1 diabetes: A preclinical review

Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing pancreatic β-cells, resulting in hyperglycaemia. The first-line treatment for symptomatic T1D is exogenous insulin replacement to maintain glycaemic control. Islet transplant therapy is available to a small number of individuals, and stem cell-derived islet transplant therapies are in clinical development. Recent advances in immunotherapy for T1D enable β-cells to be protected from autoimmune destruction, delaying disease progression. Set against this therapeutic landscape, innate pancreatic β-cell regeneration strategies have the potential to reverse β-cell loss in T1D, restoring regulated, endogenous insulin secretion and stable glycaemic control. In this review, we evaluate the preclinical literature investigating β-cell regeneration strategies via proliferation of residual β-cells. We cover therapeutic goals for a potential regenerative therapy, drawing on lessons from studies of residual β-cell function, immunotherapy and islet transplantation in T1D. We review the role of 14 distinct targets/mechanisms with in vitro and/or in vivo data supporting their role in β-cell proliferation and potential for therapeutic regeneration. In particular, we focus on the role of DYRK1A in β-cell proliferation, evaluating the range of small molecule inhibitors and in vivo studies underpinning this well-validated target. We provide perspectives on how future clinical translation could be optimised, including improved drug development, considerations for clinical trial metrics, patient stratification and the potential for combinatorial regenerative and immunotherapy approaches to shield nascent regenerating β-cells.