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

American Diabetes Association
Publication Date
DOI: 10.2337/db08-0869
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Mary, Mary, Quite Contrary, How Do Your �-Cells Fail? Jack L. Leahy The dogma regarding the pathogenesis of type 2diabetes has evolved over the last decade toview the islet �-cell as the final determinant ofwhether glucose tolerance is normal or abnor- mal (1). While obesity and insulin resistance have reached epidemic proportions around the world, the presence of an appropriate compensation of insulin secretion (“healthy �-cells”) allows daylong glycemia to be indistin- guishable from metabolically normal individuals (2). In turn, pre-diabetes and type 2 diabetes result from progres- sive �-cell dysfunction (3). As such, an army of research- ers worldwide is searching for the pathogenic basis of this �-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 �-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 �-cell research arena that we are on the right track to identifying the molecular details of �-cell compensation and failure. Figure 1 shows the proposed stages of �-cell dysfunc- tion. It begins early, perhaps at birth, with �-cells that are programmed to be at risk to fail (“susceptible �-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 �-cells, as well as insulin secretion and synthesis (4). Although direct evidence is lacking, many are betting that a lowered mass of normally functional �-cells, from genetics or environmentally based imprinting during fetal or early life, will end up being a common cause of susceptible �-cells, based on animal (5,6) and human (Kumar et al. [7]) studies posthemipancreatectomy show- ing a predilection for diabetes. Eventually, �-cell dysfunc- tion (actu

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