Understanding and controlling human beta cell replication and regeneration are major goals of the JDRF specifically, and of the diabetes community in general. Whereas the field of beta cell replication is a relatively new one, and much new data has recently accumulated regarding the molecular control of rodent beta cells, very little is known regarding the molecular mechanisms that govern human beta cell replication. We have received support from the JDRF and the NIDDK to specifically define the presence and subcellular location of all human cell cycle control molecules in the human beta cell. The major cell cycle control point in all cells is the “G1/S checkpoint”, or the “pRb pathway”, which contains the cell cycle proteins pRb, p107, p130, p15, p16, p18, p19, p21, p27, p57, p53, cyclins A,D,E, and cdks 1,2,4,6. Until recently, very little has been done to elucidate the presence, absence or role of these molecules in physiologic human beta cell regeneration, nor in attempts at therapeutic human beta cell replication. We are therefore trying to develop a “Human G1/S Proteome” Atlas, a task we have largely completed using human cadaveric islets provided by the JDRF and by the IIDP. We have demonstrated that when we overexpress these cell cycle molecules using adenovirus, we can induce both robust human beta cell replication, as well as nuclear translocation of these molecules. Thus, this is an observation of great significance to beta cell regeneration investigators: it suggests that the proximate reason that human adult beta cells do not replicate and cannot be induced to replicate as that the requisite nuclear machinery does not, and apparently cannot, access the nucleus where it would drive beta cell replication. These are paradigm-changing observations, with major implications for therapeutic human beta cell replication and regeneration.\

ADDENDUM: Type 1 Diabetes results from the loss of the insulin producing beta cells. It is now clear that beta cell replacement can reverse diabetes in humans. One way to replace beta cells is to induce the regeneration of the endogenous beta cells or to expend beta cells from human donors for transplant. However, we know little about human beta cell replication. Therefore, information on human beta cell replication is critical for the development of new therapies for diabetes. Adult human beta cells proliferate at an extremely slow pace and are mysteriously resistant to the induction of replication. Rare examples of physiological replication of human cells are during the first years after birth and during pregnancy. Recently, we have made the novel and unexpected observation that many key cell cycle accelerator proteins are excluded from the nucleus in adult human pancreatic beta cells. It is possible to induce some replication of adult human beta cells by manipulating the cell cycle. However, this induction of replication is dramatically reduced during diabetes, such as Type 2 Diabetes. We propose to define the expression of cell cycle molecules in neonatal human beta cells, or human beta cells from pregnant donors or Type 2 diabetic donors. The overall goal of our research is to identify therapeutic targets to promote human pancreatic beta cell proliferation.