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.