Endocrine Abstracts

Type 2 diabetes is a disease of insulin secretory dysfunction and insufficiency, that cannot compensate for the acquired insulin resistance. It has now been widely acknowledged that a major contributor to the pathogenesis of type 2 diabetes is a significant decrease in pancreatic ß-cell mass. An optimal pancreatic ß-cell population is normally maintained as a balance between net ß-cell growth (the sum of the extent of ß-cell replication, neogenesis and size) and ß-cell death (mostly apoptosis). But in type 2 diabetes, the degree of apoptosis far outweighs the incidence of ß-cell growth. Thus, promoting ß-cell survival has potential to delay the onset of diabetes. However, the molecular mechanisms as to how this might be achieved are currently unclear.

Here we consider the role of the signalling adapter molecules, insulin receptor substrate-2 (IRS-2) in ß-cell growth and death. Increasing IRS-2 expression promotes ß-cell growth and survival, whereas decreasing ß-cell IRS-2 levels results in ß-cell apoptosis. It will be discussed how IRS-2 expression levels might be decreased relative to decreased ß-cell mass and the pathogenesis of type 2 diabetes. This has some interesting parallels to current thoughts on the molecular mechanisms that give rise to insulin resistance. Moreover, IRS-2 has a rapid turnover in ß-cells and its expression level is highly regulated. Certain mechanisms behind the control of IRS-2 expression levels in ß-cells will be presented and discussed whether these could be manipulated pharmacologically as a potential means of treating type-2 diabetes by maintaining sufficient functional ß-cell mass.