Lawrence C. B. Chan, M.D.

Endocrinology

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.