Michala Prause - Bone morphogenetic protein induced β-cell dedifferentiation; a possible role of Hes-1 and Hey-1?

Proper function of β-cells is essential for maintaining glucose homeostasis. A significant reduction in both β-cell mass and function is observed in individuals with type 2 diabetes. Recently, it has been questioned whether β-cells actually are lost in type 2 diabetes or rather are dedifferentiating into less mature cells resulting in reduced functional β-cell mass.

We have recently demonstrated that Bone Morphogenetic Proteins (BMPs) 2 and -4 are expressed in islets of Langerhans and the expression is regulated by cytokines and fatty acids that are involved in the development of β-cell dysfunction and diabetes. We find BMP-2 and -4 to be potent inhibitors of β-cell function and proliferation of mature rodent and human β-cells in vitro. Of special interest, BMP-2 and 4 significantly increase expression of a bHLH family of transcriptional repressors Hes-1 and Hey-1, known to affect the differentiated state of the β-cell. Hes-1 and Hey-1 are downstream targets of the NOTCH signaling pathway and Hes-1 expression in β-cells is associated with dedifferentiation and poor β-cell function.

Our newest data indicate that long-term exposure of rat islets to BMP-2 significantly reduce insulin content and inhibits expression of markers for mature beta-cells, such as MafA, while expression of Hes-1/Hey-1 is significantly increased. We hypothesize that metabolic stress resulting from insulin resistance and obesity induce expression of BMP-2 and 4 in islets of Langerhans and that through induction of Hes-1 and Hey-1 BMP mediates dedifferentiation and thereby dysfunction of β-cells. Inhibition of BMP activity prevents β-cell dedifferentiation, normalizes β-cell function and restores glucose homeostasis.