The loss of the number and function of pancreatic beta cells in both type-1 and type-2 diabetes results in a reduction in the amount of insulin secreted by the pancreas, and thus a chronic hyperglycemia that ultimately claims the lives of diabetic patients. This state leads to the various complications that ultimately claim the lives of diabetic patients. A chemical compound that could increase human beta-cell proliferation would have a tremendous clinical impact on both type-1 and type-2 diabetes. For example, such a compound could be developed for in vivo delivery. This type of discovery would transform the treatment of diabetes. We are focused on the discovery of chemicals and genes that amplify the number of functional beta cells by increasing beta-cell proliferation. We have developed methods for high-throughput cell culture of primary human pancreatic islet cells, and use this system to screen for small-molecule inducers of human beta-cell proliferation. In an ideal therapeutic setting, chemical compounds derived from these agents would accomplish their actions on beta-cell function and number in vivo, without the need for transplantation and its accompanying immunosuppressive therapy. Our approach aims to stimulate beta-cell proliferation with small-molecule drugs in a way that increases overall beta-cell mass.