Lawrence C. B. Chan, M.D., D.Sc.
Department of Medicine-Endocrinology
Department of Molecular and Cellular Biology
Betty Rutherford Chair for Diabetes Research
Chief, Division of Diabetes, Endocrinology and Metabolism
Director, Diabetes and Endocrinology Research Center
Dr. Chan is interested in the molecular pathology of hyperglycemia and diabetic complications. Dr. Chan and his colleagues first described the appearance of insulin-producing cells in multiple extrapancreatic tissues in diabetes. The laboratory showed that the insulin-producing cells are derived from bone marrow cells that migrate from the bone marrow to multiple tissues, including the liver and adipose tissues. They may retain their bone marrow cell characteristics or they may fuse with the local cells in various tissues and organs. His laboratory further showed that the fusion of these abnormal bone marrow-derived cells with nerve cells is an important factor in diabetic neuropathy.
Dr. Chan developed a novel therapy for a type 1 diabetes model in mice. He showed that gene therapy-mediated delivery of a transcription factor, Neurog3 (together with an islet growth factor, betacelluln) to the liver of diabetic mice leads to the development of new islets in the liver. These islets produce insulin and other islet hormones, leading to complete correction of the diabetes. The gene therapy-induced islet neogenesis strategy that "cures" type 1 diabetes in mice is significant, not only for its potential as a new treatment, but also because it is the first time a single transcription factor has been shown to lead to the biogenesis of a complete organ (endocrine pancreas) in an adult animal. His laboratory showed that the newly formed β cells were derived from adult stem cells in the liver by a process consistent with transdetermination.
Glis3 is a krüppel-like zinc finger transcription factor that is expressed in essentially all cells in the body. The factor is expressed at high levels in pancreatic β cells. Genome wide association studies among adult populations have found a strong association of Glis3 polymorphisms in type 1 and type 2 diabetes. Intriguingly, mutations in Glis3 have been reported to cause a syndrome of neonatal diabetes. The Chan laboratory is interested in the developmental biology of the endocrine pancreas, particularly in the molecular pathology of the neonatal diabetes syndrome. They found that Glis3 regulates pancreatic islet growth and differentiation during fetal development in mice. Moreover, they showed that Glis3 is required for normal insulin gene expression; importantly, it is indispensable for normal β cell function and β cell mass maintenance in adult animals. His group is pursuing the molecular characterization of the action of Glis3 in pancreatic β cell biology and function.
In the area of metabolic syndrome and type 2 diabetes, the Chan laboratory is investigating the role of different fat cell proteins in carbohydrate and lipid homeostasis. They produced mutant mice, including those with inactivated perilipin and adipocyte differentiation related protein (ADRP), as well as the gene for multiple other lipid droplet proteins, to dissect the biochemical pathways that regulate lipolysis and energy metabolism in vivo. He is interested in the role of the lipid droplet proteins in the molecular pathogenesis of lipodystrophy and type 2 diabetes. In collaboration with investigators at MD Anderson Cancer Center, the Chan laboratory used a fat vasculature homing peptide to deliver a pro-apoptotic gene, leading to targeted ablation of adipose tissue and reversal of obesity and diabetes in mice. The laboratory is investigating the use of this "molecular liposuction" as a possible approach to the treatment of obesity in nonhuman primates.
- Chen W, Chang B, Li L, Chan L (2010) Patatin-like phopholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease. Hepatology 52: 1134-42.
- Saha PK, Reddy VT, Konopleva M, Andreeff M, Chan L (2010) The triterpernoid CDDO-Me has potent antidiabetic effects in diet-induced diabetic mice and Leprdb/db mice. J Biol Chem 285: 40581-92.
- Yang Y, Chang B H-J, Yechoor V, Chen W, Li L, Tsai M-J, Chan L (2011) The Krüppel-like zinc finger protein Glis3 transactivates Neurog3 for proper fetal pancreatic islet differentiation. Diabetologia 54: 2595-2605.
- Barnhart KF, Christianson DR, Hanley PW, Driessen WH, Bernacky BJ, Baze WB, Wen S, Tian M, Ma J, Kolonin MG, Saha PK, Do KA, Hulvat JF, Gelovani JG, Chan L, Arap W, Pasqualini R. (2011) A peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys. Sci Transl Med 3 (108):108ra112.
- Chan L, Terashima T, Urabe H, Fan L, Kojima H (2011) Pathogenesis of diabetic neuropathy: Bad to the bone. Ann N Y Acad Sci. 1240(1):70-6.
- Tschop MH, Speakman JR, Arch JRS, Auwerx J, Bruning JC, Chan L, Eckel R, Farese RVJr, Galgani JE, Hambly C, Herman MA, Horvath TL, Kahn BB, Kozma S, Maratos-Flier E, Muller TD, Muenzberg H, Pfluger PT, Plum L, Reitman M, Rahmouni K, Shulman GI, Thomas G,Kahn CR, Ravussion E (2011) A guide to analysis of mouse energy metabolism. Nature Methods 9: 57-63.
- Terashima T, Kojima H, Chan L (2012) Bone marrow expression of poly(ADP-ribose) polymerase underlies diabetic neuropathy via hematopoietic-neuronal cell fusion. FASEB J 26: 295-308.
- Poungvarin N, Lee JK, Yechoor VJ, Li MV, Assavapokee T, Suksaranjit P, Thepsongwajja JJ, Saha PK, Oka K, Chan L (2012) Carbohydrate response element binding protein (ChREBP) plays a pviotal role in β cell glucotoxicity. Diabetologia 55: 1783-96.
- Chen W, Chang B, Saha P, Hartig SM, Li L, Reddy VT, Yang Y, Yechoor Y, Chan L (2012) Berardinelli-Seip congenital lipodystrophy-2 (BSCL2)/Seipin is a cell autonomous regulator of lipolysis essential for adipocyte differentiation. Mol Cell Biology 32: 1099-111.
- Lacaria M, Saha P, Potocki L, Bi W, Yan J, Girirajan S, Burns B, Elsea S, Walz K, Chan L, Lupski JR, Gu W (2012) A duplication CNV that conveys traits reciprocal to metabolic syndrome and protects against diet induced obesity in mice and men. PLoS Genetics 8(5): e1002713.