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INVITED REVIEW
-cell growth and survival in the onset of type 2 diabetes: a role for protein kinase B in the Akt?
The Pacific Northwest Research Institute and Department of Pharmacology, University of Washington, Seattle, Washington 98122
The control of pancreatic 
-cell growth and survival in the adult plays a pivotal role in the pathogenesis of type 2 diabetes. In certain insulin-resistant states, such as obesity, the increased insulin-secretory demand can often be compensated for by an increase in -cell mass, so that the onset of type 2 diabetes is avoided. This is why approximately two-thirds of obese individuals do not progress to type 2 diabetes. However, the remaining one-third of obese subjects that do acquire type 2 diabetes do so because they have inadequate compensatory -cell mass and function. As such, type 2 diabetes is a disease of insulin insufficiency. Indeed, it is now realized that, in the vast majority of type 2 diabetes cases, there is a decreased -cell mass caused by a marked increase in -cell apoptosis that outweighs rates of -cell mitogenesis and neogenesis. Thus a means of promoting -cell survival has potential therapeutic implications for treating type 2 diabetes. However, understanding the control of -cell growth and survival at the molecular level is a relatively new subject area of research and still in its infancy. Notwithstanding, recent advances have implicated signal transduction via insulin receptor substrate-2 (IRS-2) and downstream via protein kinase B (PKB, also known as Akt) as critical to the control of -cell survival. In this review, we highlight the mechanism of IRS-2, PKB, and anti-apoptotic PKB substrate control of -cell growth and survival, and we discuss whether these may be targeted therapeutically to delay the onset of type 2 diabetes.
apoptosis; obesity; insulin receptor substrate-2; protein kinase B substrates
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