Dysregulation of beta-Cell Proliferation in Diabetes: Possibilities of Combination Therapy in the Development of a Comprehensive Treatment

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia as a result of insufficient insulin levels and/or impaired function as a result of autoimmune destruction or insulin resistance. While Type 1 DM (T1DM) and Type 2 DM (T2DM) occur through different pathological processes, both result in beta-cell destruction and/or dysfunction, which ultimately lead to insufficient beta-cell mass to maintain normoglycemia. Therefore, therapeutic agents capable of inducing beta-cell proliferation is crucial in treating and reversing diabetes; unfortunately, adult human beta-cell proliferation has been shown to be very limited (similar to 0.2% of beta-cells/24 h) and poorly responsive to many mitogens. Furthermore, diabetogenic insults result in damage to beta cells, making it ever more difficult to induce proliferation. In this review, we discuss beta-cell mass/proliferation pathways dysregulated in diabetes and current therapeutic agents studied to induce beta-cell proliferation. Furthermore, we discuss possible combination therapies of proliferation agents with immunosuppressants and antioxidative therapy to improve overall long-term outcomes of diabetes.