Diacylglycerol Production and Protein Kinase C Activity Are Increased in a Mouse Model of Diabetic Embryopathy

  1. Yuji Hiramatsu124,
  2. Naotaka Sekiguchi23,
  3. Michio Hayashi23,
  4. Keiji Isshiki23,
  5. Tamotsu Yokota23,
  6. George L. King23 and
  7. Mary R. Loeken13
  1. 1Section on Cellular and Molecular Physiology, Joslin Diabetes Center, Boston, Massachusetts
  2. 2Section on Vascular Cell Biology, Joslin Diabetes Center, Boston, Massachusetts
  3. 3Department of Medicine, Harvard Medical School, Boston, Massachusetts
  4. 4Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

    Abstract

    Activation of the diacylglycerol-protein kinase C (DAG-PKC) cascade by excess glucose has been implicated in vascular complications of diabetes. Its involvement in diabetic embryopathy has not been established. We examined DAG production and PKC activities in embryos and decidua of streptozotocin (STZ)-diabetic or transiently hyperglycemic mice during neural tube formation. STZ diabetes significantly increased DAG and total PKC activity in decidua (1.5- and 1.4-fold, respectively) and embryos (1.7- and 1.3-fold, respectively) on day 9.5. Membrane-associated PKC α, βII, δ, and ζ were increased in decidua by 1.25- to 2.8-fold. Maternal hyperglycemia induced by glucose injection on day 7.5, the day before the onset of neural tube formation, also increased DAG, PKC activity, and PKC isoforms (1.1-, 1.6-, and 1.5-fold, respectively) in the embryo on day 9.5. Notably, membrane-associated PKC activity was increased 24-fold in embryos of diabetic mice with structural defects. These data indicate that hyperglycemia just before organogenesis activates the DAG-PKC cascade and is correlated with congenital defects.

    Footnotes

    • Address correspondence and reprint requests to Mary R. Loeken, Section on Cellular and Molecular Physiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: mary.loeken{at}joslin.harvard.edu.

      Received for publication 28 September 2001 and accepted in revised form 22 May 2002.

      DAG, diacylglycerol; NTD, neural tube defect; PKC, protein kinase C; STZ, streptozotocin.

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