Thursday, February 14, 2013

[50] New Beta-Cell Paradigm?

mp111212 [Dor,NEJM,13,beta-cell dedifferentiation, Foxo1,alpha-cell mass]

Type 2 diabetes results from a combination of insulin resistance and dysfunction of insulin-producing pancreatic beta cells. Insulin deficiency is thought to be caused by both beta-cell dysfunction and decreased beta-cell mass. Reduced beta-cell mass has been attributed to enhanced beta-cell apoptosis and perhaps failure of beta-cell proliferation. Consequently, many research efforts are aimed toward the restoration of functional beta-cell mass by preventing beta-cell death and inducing replication.
Increased glucagon secretion from islet alpha cells has also been observed in type 2 diabetes, and its central role in metabolic dysregulation has recently been emphasized.1 Hyperglucagonemia is thought to result from decreased paracrine inhibition of alpha cells by locally secreted insulin, although a relative increase in alpha-cell mass has also been postulated.
Talchai and colleagues2 recently offered a provocative explanation for both beta-cell failure and alpha-cell hyperfunction in type 2 diabetes. They examined the role of the key transcription factor Foxo1 in beta cells. Beta-cell expression of Foxo1 is markedly decreased in severe hyperglycemia. To study this phenomenon, Talchai et al. genetically modified mice so that their beta cells could not express Foxo1. These mice were generally healthy; however, aging or multiple pregnancies (conditions that presumably increase metabolic pressure on beta cells) caused hyperglycemia, an apparent dramatic reduction of beta-cell mass, and increased numbers of alpha cells. In addition, expression of the proinsulin processing enzyme Pcsk1 (proprotein convertase subtilisin/kexin type 1) was reduced in beta cells of the engineered mice after stress; this led to an increase in the secretion of biologically inactive proinsulin, which has also been observed in uncontrolled type 2 diabetes. Thus, Foxo1 deletion in beta cells provides a new model for stress-induced diabetes.

No comments:

Post a Comment

Note: Only a member of this blog may post a comment.