Islets in the liver: induced islet neogenesis as a novel approach to diabetes therapy
Lawrence Chan, M.D., received the award for his work on the role of lipid breakdown on body fat and energy homeostasis as well as on induced islet neogenesis as a novel experimental therapy for diabetes, demonstrating that a single transcription factor can turn on a complete differentiation program for a miniorgan. His laboratory showed that perilipin, a fat cell lipid droplet protein, controls lipolysis, or fat breakdown, in vivo. Mice born without perilipin were found to be lean and resistant to diet-induced and genetic obesity. The Chan laboratory worked out some of the pathways that were turned on by the unbridled lipolysis resulting from the absence of the protein. Recent developments in drug and insulin therapy and in islet transplantation have greatly improved the management of diabetes, but they fall far short of a cure. Dr. Chan developed induced islet neogenesis as a novel therapy for diabetes. His laboratory found that delivery of the Beta2/NeuroD transcription factor to diabetic mice led to the formation of pancreatic islets in the liver and complete reversal of the diabetes of these animals. The newly formed insulin-producing cells in the liver possessed glucose sensing mechanisms, proinsulin processing enzymes and secretory pathways normally found in pancreatic beta cells. In addition to insulin, they also produced the other islet hormones glucagon, somatostatin and pancreatic polypeptide. This experiment provides proof of concept for induced islet neogenesis by a single transcription factor, and could serve as the basis for a novel form of therapy for diabetes. Drs. Javier Martinez-Botas and Hideto Kojima, former postdoctoral fellows in the Chan laboratory, were responsible for the two projects. Dr. Ming-Jer Tsai provided the Beta2/NeuroD cDNA clone used for the gene transfer.
Dr. Chan’s nomination was based on the following publications:
Martinez-Botas J, Anderson JB, Tessier D, Lapillonne A, Chang BH, Quast MJ, Gorenstein D, Chen KH, Chan L. Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice. Nat Genet. 2000 Dec;26(4):474-9.
Kojima H, Fujimiya M, Matsumura K, Younan P, Imaeda H, Maeda M, Chan L. NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat Med. 2003 May;9(5):596-603.
Drs. Chan and Vijay Yechoor received the award for their joint contributions to the understanding of cell fate determination and the molecular therapy of diabetes.
In a publication in Developmental Cell in 2009, Yechoor et al. found that following the introduction of a single gene, Neurogenin3, cells in the liver can take on the structure and function of the endocrine pancreas and go on to completely reverse diabetes in mice. Yechoor and Chan also uncovered a novel mechanism for the induced beta cell neogenesis. They found that transfer of a single transcription factor into an endoderm-derived lineage is sufficient to cause cell lineage switching and induce formation of neo-islets. The newly formed islets display a complete islet-specific transcription program and produce insulin in a glucose-responsive manner, stably reversing diabetes.
Yechoor and Chan further found that the newly formed periportal beta cells possess are structured similarly to pancreatic beta cells. These findings shed light on the fundamental processes of cell fate determination and reprogramming and provide a blueprint for a potential curative therapy for insulin-deficient diabetes.
Drs. Chan and Yechoor's nomination was based on the following publications:
Yechoor V, Liu V, Espiritu C, Paul A, Oka K, Kijima H, Chan L. Neurogenin3 Is Sufficient for Transdetermination of Hepatic Progenitor Cells into Neo-Islets In Vivo but Not Transdifferentiation of Hepatocytes. Developmental Cell 2009 Mar 16: 358-73.
Yechoor V, Liu V, Paul A, Lee J, Buras E, Ozer K, Samson S, Chan L. Gene Therapy with Neurogenin 3 and Betacellulin Reverses Major Metabolic Problems in Insulin-Deficient Diabetic Mice. Endocrinology 2009 150(11); 4863-73.