Adult pancreatic regeneration holds the key to future treatments for several diseases such as diabetes and chronic pancreatitis. Beta-cell deficit is the major pathological feature in type 1 and type 2 diabetes and plays a key role in disease progression. In principle, beta-cell regeneration can occur by replication of pre-existing beta-cells, or by beta-cell neogenesis from stem/progenitors. Unfortunately, beta cell regeneration through beta-cell replication is limited by the almost complete absence of beta-cells in type 1 diabetes and the increasing recognition that the beta-cell replicative capacity declines severely with age. Therefore, beta-cell neogenesis has received increasing interest. Many different cell types within the pancreas have been suggested as potential beta-cell stem/progenitor cells, but the data have been conflicting. Our study revealed that alpha-cells can function as a novel beta-cell stem/ progenitor. To further understand the mechanism governing alpha to beta cell conversion, we evaluated the role of maternal embryonic leucine zipper kinase (MELK) in this process. The loss of MELK kinase function did not significantly affect beta-cell neogenesis from alpha-cells. Instead, adult m ice with a functional deficiency of MELK had smaller ducts with higher ductal density in the regenerating pancreas. Of note, beta-cell neogenesis from alpha-cells and MELK regulating pancreatic ductal regeneration appear to be unique events in the adults, as the embryonic pathway of beta-cell neogenesis does not proceed through a glucagon positive intermediate nor does MELK govern pancreatic ductal formation during development. In conclusion, these findings might provide new insights into adult pancreatic regeneration and demonstrated that adult regeneration doesn’t have to recapitulate embryonic pathway.