Cell Cycle Regulation in Human Pancreatic Beta Cells

For decades, it had been assumed that pancreatic β cells were terminally differentiated and thus unable to replicate, and that β-cell replication did not exist in any quantitatively meaningful way. This view has changed dramatically in the past decade, with abundant data demonstrating that fetal, neonatal, and adult rodent β cells replicate at physiologically important rates. These new data have resulted in a plethora of new reports exploring the nutrient, growth factor, and signaling cascades that lie upstream and regulate the cell cycle machinery that controls rodent β-cell replication. Moreover, myriad reports of murine genetic models of cell cycle molecule knockout or overexpression have appeared and have documented unequivocally the importance and therapeutic relevance of cell cycle regulatory mechanisms in murine β cells. These events contrast with the pace of development of new knowledge regarding human β-cell replication. It seems clear that unlike in rodents, spontaneous replication of adult human β cells is uncommon. Further, standard manipulations, nutrients, and growth factors that induce rodent β-cell replication fail to do so in human β cells. In this chapter we focus on the molecular control of cell cycle progression in human β cells, illustrate the differences between human and rodent β-cell cycle regulatory control, and provide examples of approaches to inducing human β-cell replication.