b-Cell death during progression to diabetes

792 NATURE | VOL 414 | 13 DECEMBER 2001 | www.nature.com Type 1 diabetes is an autoimmune disease resulting from specific destruction of the insulin-producing b-cells of the islets of Langerhans of the pancreas. It has two distinct phases: insulitis, when a mixed population of leukocytes invades the islets; and diabetes, when most b-cells have been killed off, and there is no longer sufficient insulin production to regulate blood glucose levels, resulting in hyperglycaemia. Individuals can have covert insulitis for a long time (years in humans, months in rodent models) before it finally progresses to overt diabetes, and sometimes it never does. Type 1 diabetes is an old disorder — descriptions of it appear in ancient Egyptian and Greek writings. It is also a common disease, currently affecting about 0.5% of the population in developed countries and increasing in incidence. In addition, there is mounting evidence that a fraction (variously estimated at 5–15%) of people originally diagnosed as type 2 diabetic may actually have a slowly progressing and less severe form of type 1 termed ‘latent autoimmune diabetes of adults’. It is surprising, then, that we remain so ignorant about the aetiology and pathogenesis of autoimmune diabetes. We do not know what triggers it, have little understanding of the genetic and environmental factors regulating its progression, and have a confused view of the final effector mechanism(s). Consequently, we still do not know how to prevent or reverse type 1 diabetes in a sufficiently innocuous manner to be therapeutically useful. Faced with the difficulties of addressing these issues in humans, many investigators have turned to small-animal models of diabetes, in particular the non-obese diabetic (NOD) mouse and transgenic derivatives of it (Box 1). Here we focus on the crux of autoimmune diabetes — b-cell death. We explore the possibility that physiological destruction of b-cells is a crucial event at disease outset, initiating autoimmunity. We also evaluate what is known about the mechanism(s) of b-cell death in the terminal phases of the autoimmune attack, and weigh the contention that destruction of b-cells can convert type 2 into type 1 diabetes.