Functional pancreatic beta-cell mass: Involvement in type 2 diabetes and therapeutic intervention

Abstract

In the adult, the pancreatic β-cell mass adapts insulin secretion to meet long-term changes in insulin demand and, in particular, in the presence of insulinresistance that is either physiological, such as pregnancy, or pathophysiological, such as obesity. The failure of β cells to compensate for insulinresistance is a major component of impaired glucose homeostasis and overt diabetes. This defect is clearly the consequence of a decline of insulin response to glucose due to functional β-cell deficiency. It is also the consequence of an inability of the endocrine pancreas to adapt the β-cell mass to insulin demand (pancreas plasticity), which eventually leads to a decrease in functional β-cell mass. This idea has resulted in considerable attention being paid to the development of new therapeutic strategies aiming to preserve and/or regenerate functional β-cell mass. The latter is governed by a constant balance between β-cell growth (replication from pre-existing β cells and neogenesis from precursor cells) and β-cell death (mainly apoptosis). Disruption of this balance may lead to rapid and marked changes in β-cell mass. Glucagon-like peptide-1 (GLP-1), an incretin, enhances β-cell survival (by activating β-cell proliferation and differentiation, and inhibiting β-cell apoptosis), thus contributing to the long-term regulation of insulin secretion by maintaining a functional β-cell mass. The development of drugs regulating this parameter will be the major challenge of the next few years in the management of type 2 diabetes.