Therapeutic approaches based on beta-cell mass preservation and/or regeneration

Abstract

Beta-cell deficiency is a pathophysiologic component of diabetes mellitus and a primary cause of islet dysfunction. Islet dysfunction is a prerequisite for the development of diabetes mellitus since individuals with insulin resistance (e.g. obesity, pregnancy) do not develop hyperglycemia unless beta-cell compensation fails. Therefore, understanding of the biology and mechanisms involved in normal beta-cell adaptation may provide novel therapeutic targets for preservation and/or regeneration of beta-cell mass in diabetes mellitus. Normal adaptation of beta-cell mass occurs by beta-cell replication and/or neogenesis from precursor cells inside the pancreas. However, the relative importance of both processes for successful adaptation is unknown. In type-2 diabetes, the primary defect is increased beta-cell apoptosis. Since replicating beta-cells are more vulnerable to apoptosis, the proapoptotic diabetic milieu limits the regenerative capacity of the islet and directly causes accelerated islet loss. Therapeutic approaches need to address both processes of islet turnover (regeneration and cell loss) in order to be successful. It may be anticipated that such an intervention is also effective early in the course of diabetes or in prediabetic conditions.