A major focus of my lab is to identify genes that are involved in the
pathogenesis of type 2 diabetes and related metabolic traits and to understand
their function. We have used whole genome high-throughput methodology and have
identified multiple loci harboring genetic variants affecting risk for
diabetes. We are now applying induced pluripotent stem (iPS) cell technology to
explore their biological function in human cells derived from patients and
subjects of a local diabetes cohort.
One application currently underway in my lab is the study of the role of the
T2D-associated gene TCF7L2 in hypothalamic control of glucose metabolism. We
have developed and mastered protocols to reproducibly differentiate human iPSC
into CNS forebrain glutamatergic neurons with a genomic profile similar to
mouse neurons isolated from the hypothalamus. Since human CNS neurons and
many other tissues that regulate glucose homeostasis are inaccessible in
vivo, the use of iPSC technology is a powerful tool to circumvent this
roadblock and generate ample supply of human cells for study.
My research program also includes studies examining the mechanisms of
effects and interactions of diabetic and lipid lowering medications as well as
finasteride on risk and progression of prostate cancer among diabetic men. We
were the first to report a synergistic, beneficial effect of combination
therapy with metformin and statins on prostate cancer incidence.
Yao L, Ayala I, Liu Y, Chen Y, Curran J, Kumar S, Lehman D. Human induced
pluripotent stem cell-derived models to investigate neuronal signaling involved
in control of metabolism. Presented at Neuronal Control of Appetite,
Metabolism, and Weight, Keystone Symposia. Alberta, Canada, 2013.
Blackburn A, Göring HH, Dean A, Carless MA, Dyer T, Kumar S, Fowler S,
Curran JE, Almasy L, Mahaney M, Comuzzie A, Duggirala R, Blangero J,
Lehman DM. Utilizing extended pedigree information for discovery and confirmation of copy number variable regions among Mexican Americans. Eur J Hum Genet. 2013 Apr;21(4):404-9.
Lehman DM, Lorenzo C, Hernandez J, Wang CP. Statin use as a moderator of metformin effect on risk for prostate cancer among type 2 diabetic patients. Diabetes Care. 2012 May;35(5):1002-7.
Lehman DM, Hunt KJ, Leach RJ, Hamlington J, Arya R, Abboud HE, Duggirala R, Blangero J, Göring HH, Stern MP. Haplotypes of transcription factor 7-like 2 (TCF7L2) gene and its upstream region are associated with type 2 diabetes and age of onset in Mexican Americans. Diabetes. 2007 Feb;56(2):389-93.
Williams AL, et al., The SIGMA Type 2
Diabetes Consortium et al. Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature. 2014 Feb 6;506(7486):97-101.