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J. Biol. Chem., Vol. 279, Issue 44, 45708-45712, October 29, 2004

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Modulation of Methyl Group Metabolism by Streptozotocin-induced Diabetes and All-trans-retinoic Acid^*

Kristin M. Nieman, Matthew J. Rowling, Timothy A. Garrow¶, and Kevin L. Schalinske||

From the Department of Food Science and Human Nutrition, Iowa State University, Ames, Iowa 50011 and the ^¶Department of Food Science and Human Nutrition and the Division of Nutritional Sciences, University of Illinois, Urbana, Illinois 61801

The hepatic enzyme glycine N-methyltransferase (GNMT) plays a major role in the control of methyl group and homocysteine metabolism. Because disruption of these vital pathways is associated with numerous pathologies, understanding GNMT control is important for evaluating methyl group regulation. Recently, gluconeogenic conditions have been shown to modulate homocysteine metabolism and treatment with glucocorticoids and/or all-trans-retinoic acid (RA)-induced active GNMT protein, thereby leading to methyl group loss. This study was conducted to determine the effect of diabetes, alone and in combination with RA, on GNMT regulation. Diabetes and RA increased GNMT activity 87 and 148%, respectively. Moreover, the induction of GNMT activity by diabetes and RA was reflected in its abundance. Cell culture studies demonstrated that pretreatment with insulin prevented GNMT induction by both RA and dexamethasone. There was a significant decline in homocysteine concentrations in diabetic rats, owing in part to a 38% increase in the abundance of the transsulfuration enzyme cystathionine -synthase; treatment of diabetic rats with RA prevented cystathionine -synthase induction. A diabetic state also increased the activity of the folate-independent homocysteine remethylation enzyme betaine-homocysteine S-methyltransferase, whereas the activity of the folate-dependent enzyme methionine synthase was diminished 52%. In contrast, RA treatment attenuated the streptozotocin-mediated increase in betaine-homocysteine S-methyltransferase, whereas methionine synthase activity remained diminished. These results indicate that both a diabetic condition and RA treatment have marked effects on the metabolism of methyl groups and homocysteine, a finding that may have significant implications for diabetics and their potential sensitivity to retinoids.

Received for publication, July 30, 2004 , and in revised form, August 23, 2004.

^* This work was supported in part by the Iowa Agriculture and Home Economics Experiment Station, the Iowa State University Office of Biotechnology, United States Department of Agriculture Grant NRI 01-35200-9854 (to K. L. S.), American Institute for Cancer Research Grant 00B078REV (to K. L. S.), the American Diabetes Association (to K. L. S.), and National Institutes of Health Grant DK52501 (to T. A. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Dept. of Food Science and Human Nutrition, Iowa State University, 220 MacKay Hall, Ames, IA 50011. Tel.: 515-294-9230; Fax: 515-294-6193; E-mail: kschalin{at}iastate.edu.

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