David Kuo,

"Nothing in Biology Makes Sense Except in the Light of Evolution" - Dobzhansky (1973)

Alumni

E-Mail
dkuo@get-your-addresses-elsewhere.inf.ethz.ch
Phone
+1 646 331 8884
Address
MSKCC – Computational Biology Center
1275 York Avenue, Box # 357
New York, NY 10065
Room
MSKCC: Z-677, HSS: 8th Floor
twitter
@dkuo

I studied Biology at Stanford University and worked as a Developer at McMaster-Carr Supply

Company before beginning my PhD studies in Systems Biology at Weill Cornell Medicine in New York City.

I began biomedical research in the laboratory of alternative splicing expert Jane Wu in the summers from 2001-2005. I earned my BS in Biological Sciences at Stanford University in 2008. While at Stanford, I performed research in the laboratory of cancer biologist Calvin Kuo (no relation), where we studied the effects of VEGF blockade on liver vasculature. After college, I worked as an Information Systems Developer for McMaster-Carr Supply Company before matriculating at the Weill Cornell Graduate School of Medical Sciences in the Physiology, Biophysics & Systems Biology Department. I joined the Rätsch Lab in 2012 with primary interests in genomics and biological data analysis. I collaborate actively with the laboratories of Lionel Ivashkiv at Hospital for Special Surgery and the Hans-Guido Wendel at MSKCC.

Abstract Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis. The liver possesses a rich sinusoidal capillary network with a higher degree of hypoxia and lower gluconeogenesis in the perivenous zone as compared to the rest of the organ. Here, we show that diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in nondiabetic C57BL/6 and diabetic db/db mice, potentiating hepatic insulin signaling with lower gluconeogenic gene expression, higher glycogen storage and suppressed hepatic glucose production. VEGF inhibition induced hepatic hypoxia through sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia-inducible factor-2α (Hif-2α, encoded by Epas1) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling through direct and indirect induction of insulin receptor substrate-2 (Irs2), an essential insulin receptor adaptor protein. Further, liver Irs2 was both necessary and sufficient to mediate Hif-2α and Vegf inhibition effects on glucose tolerance and hepatic insulin signaling. These results demonstrate an unsuspected intersection between Hif-2α-mediated hypoxic signaling and hepatic insulin action through Irs2 induction, which can be co-opted by Vegf inhibitors to modulate glucose metabolism. These studies also indicate distinct roles in hepatic metabolism for Hif-1α, which promotes glycolysis, and Hif-2α, which suppresses gluconeogenesis, and suggest new treatment approaches for type 2 diabetes mellitus.

Authors K Wei, SM Piecewicz, LM McGinnis, CM Taniguchi, SJ Wiegand, K Anderson, CW M Chan, KX Mulligan, David Kuo, J Yuan, M Vallon, LC Morton, E Lefai, MC Simon, JJ Maher, G Mithieux, F Rajas, JP Annes, OP McGuinness, G Thurston, AJ Giaccia, CJ Kuo

Submitted Nat Med

Link DOI