Induction of β-cell replication by a synthetic HNF4α antagonist.

Increasing the number of β cells is critical to a definitive therapy for diabetes. Previously, we discovered potent synthetic small molecule antagonists of the nuclear receptor transcription factor HNF4α. The natural ligands of HNF4α are thought to be fatty acids. Because obesity, in which there are high circulating levels of free fatty acids, is one of the few conditions leading to β-cell hyperplasia, we tested the hypothesis that a potent HNF4α antagonist might stimulate β-cell replication. A bioavailable HNF4α antagonist was injected into normal mice and rabbits and β-cell ablated mice and the effect on β-cell replication was measured. In normal mice and rabbits, the compound induced β-cell replication and repressed the expression of multiple cyclin-dependent kinase inhibitors, including p16 that plays a critical role in suppressing β-cell replication. Interestingly, in β-cell ablated mice, the compound induced α- and δ-cell, in addition to β-cell replication, and β-cell number was substantially increased. Overall, the data presented here are consistent with a model in which the well-known effects of obesity and high fat diet on β-cell replication occur by inhibition of HNF4α. The availability of a potent synthetic HNF4α antagonist raises the possibility that this effect might be a viable route to promote significant increases in β-cell replication in diseases with reduced β-cell mass, including type I and type II diabetes.