Xian-Man Zhang, PhD

Associate Research Scientist in Medicine (Endocrinology)

Departments & Organizations

Internal Medicine: Endocrinology

Biography

BIOGRAPHY

Dr. Zhang has worked as a physical organic chemist/professor for near twenty years in various academia, industrial and national research laboratories. He has authored/co-authored over 70 scientific publications before joined Yale University in 2004. During the past decade, he mainly employed his broad chemistry knowledge and hands-on research experience to develop various practical analytical methods to characterize and quantitate any interesting metabolites in the related plasma/tissue biological samples using different analytical techniques. In the past few years, he and his analytical team has worked on many projects.

1. Can we develop well-tolerated therapeutic agents to reverse hypertriglyceridemia, insulin resistance, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease?

A series of 2,4-dinitrophenol derivatives have been synthesized and characterized. Animal studies show that these novel chemicals are non-toxic and safe for in-vivo injections and are efficient mitochondrial protonophore to reverse diabetes and steatohepatitis in rats.

2. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase.

Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia.

3. Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis.

The antidiabetic effect of leptin has been postulated to occur through suppression of glucagon production, suppression of glucagon responsiveness.

4. How does inflammation contribute to insulin resistance and fasting hyperglycemia in diet-induced obesity in rodents and humans?

Using a novel in vivo metabolomics approach, we show that the major insulin suppresses HGP mechanism is through reductions in hepatic acetyl CoA by suppression of lipolysis.

Selected publications (from over 100 publications):

  1. R. J. Perry, D. Zhang, X.-M. Zhang, J. L. Boyer, and G. I. Shulman, “Controlled-release mitochondrial protonophore reverses diabetes and protonophore reverses diabetes and steatohepatitis in rats”, Science, 2015, 347(6227), pp1253-1256.
  2. Perry, R.J., Camporez, J.-P.G., Kursawe, R., Titchenell, P.M., Zhang, D., Perry, C.J., Jurczak, M.J., Abudukadier, A., Han, M.S., Zhang, X.-M., Ruan, H.-B., Yang, X., Caprio, S., Kaech, S.M., Sul, H.S., Birnbaum, M.J., Davis, R.J., Cline, G.W., Petersen, K.F., Shulman, G.I., “Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes”, Cell, 2015, 160(4), 745-758.
  3. Perry RJ, Borders CB, Cline GW, Zhang XM, Alves TC, Petersen KF, Rothman DL, Kibbey RG, Shulman GI., “Propionate Increases Hepatic Pyruvate Cycling and Anaplerosis and Alters Mitochondrial Metabolism”, J Biol Chem. 2016, 291(23):12161-70.
  4. A. Madiraju, D. M. Erion, Y. Rahimi, X.-M. Zhang, D. Braddock, R. A. Albright, B. J. Prigaro, J. L. Wood, S. Bhanot, G. W. Cline, V. T. Samuel, R. G. Kibbey, G. I. Shulman, “Metformin suppresses hepatic gluconeogenesis via inhibition of mitochondrial glycerophosphate dehydrogenase and modulation of the hepatocellular redox state”, Nature, 2014, 510(7506), pp542-546.
  5. R. J. Perry, X. M. Zhang, D. Zhang, N. Kumashiro, J. P. Camporez, G. Cline, D. L. Rothman, G. I. Shulman, Mechanism for the anti-diabetic effect of leptin. Nature Medicine, 2014, 20, 759-763.
  6. Mehra, V.C., Jackson, E., Zhang, X.M., Jiang, X.-C., Dobrucki, L.W., Yu, J., Bernatchez, P.,Sinusas, A.J., Shulman, G.I., Sessa, W.C., Yarovinsky, T.O., Bender, J.R. “Ceramide-activated phosphatase mediates fatty acid-induced endothelial VEGF resistance and impaired angiogenesis, American Journal of Pathology, 2014, 184, 1562-1576.
  7. M. P. Gillum, D. Zhang, X.-M. Zhang,D. M. Erion,R. A. Jamison,C. Choi, J. Dong,M. Shanabrough,H. R. Duenas,D. W. Frederick,J. J. Hsiao, T. L. Horvath, C. M. Lo, P. Tso,G. W. Cline,and G. I. Shulman, Cell, 2008, 135, 813-824.
  8. Zhang, X.-M.; Patel, A.B.; de Graaf, R.A.; Behar, K.L., Determination of liposomal encapsulation efficiency using proton NMR spectroscopy,. Chem. Phys. Lipid, 2004, 127, 113-120.
  9. Zhang, X.-M. "Radical Substituent Effects of Fluorine and Trifluoromethyl Groups", J. Org. Chem. 1998, 63, 3590.
  10. Zhang, X.-M.; Zhu, Q. “Olefinic Ozonation Electron Transfer Mechanisms”, J. Org. Chem. 1997, 62, 5934-5938.
  11. X.-M. Zhang, F.G. Bordwell, "Bond Dissociation Energies of the Acidic H-A Bonds in HA+. Radical Cations and in HA-. Radical Anions in DMSO Solution", J. Am. Chem. Soc. 1994, 116(3), 904-908.
  12. X.-M. Zhang, F.G. Bordwell,"Equilibrium Acidities and Homolytic Bond Dissociation Energies of the Acidic C-H Bonds in P-Substituted Triphenylphosphonium Cations", J. Am. Chem. Soc. 1994, 116(3), 968-972.
  13. X.-M. Zhang, D.-L. Yang, Y.-C. Liu, " Effects of Electron Acceptors and Radical Scavengers on Non-chain Radical Nucleophilic Substitution Reactions", J. Org. Chem. 1993, 58, 224-227.
  14. F.G. Bordwell, X.-M. Zhang," From Equilibrium Acidities to Radical Stabilization Energies", Acc. Chem. Res. 1993, 26(9), 510-517.

Education & Training

PhD Lanzhou University (1989)
MSc Lanzhou University (1987)

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