Mary, Mary, Quite Contrary, How Do Your β-Cells Fail?

The dogma regarding the pathogenesis of type 2 diabetes has evolved over the last decade to view the islet β-cell as the final determinant of whether glucose tolerance is normal or abnormal (1). While obesity and insulin resistance have reached epidemic proportions around the world, the presence of an appropriate compensation of insulin secretion (“healthy β-cells”) allows daylong glycemia to be indistinguishable from metabolically normal individuals (2). In turn, pre-diabetes and type 2 diabetes result from progressive β-cell dysfunction (3). As such, an army of researchers worldwide is searching for the pathogenic basis of this β-cell dysfunction, along with strategies of when, and how, to intervene. What has resulted is a reasonably good mapping of the natural history of the β-cell dysfunction, plus a lengthy list of potential mechanisms. Most are based on animal studies; therefore, homing in on the operative mechanisms in humans remains a challenge. Still, there is high confidence within the β-cell research arena that we are on the right track to identifying the molecular details of β-cell compensation and failure.

Figure 1 shows the proposed stages of β-cell dysfunction. It begins early, perhaps at birth, with β-cells that are programmed to be at risk to fail (“susceptible β-cells”). Indeed, the recent genome-wide scans have identified many susceptibility genes for type 2 diabetes that likely impact the development and ongoing homeostasis of the mass of β-cells, as well as insulin secretion and synthesis (4). Although direct evidence is lacking, many are betting that a lowered mass of normally functional β-cells, from genetics …