Dual-Action Lipophilic Iminosugar Improves Glycemic Control in Obese Rodents by Reduction of Visceral Glycosphingolipids and Buffering of Carbohydrate Assimilation

The lipophilic iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1-deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded...

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Published in:	Journal of medicinal chemistry Vol. 53; no. 2; pp. 689 - 698
Main Authors:	Wennekes, Tom, Meijer, Alfred J, Groen, Albert K, Boot, Rolf G, Groener, Johanna E, van Eijk, Marco, Ottenhoff, Roelof, Bijl, Nora, Ghauharali, Karen, Song, Hang, O’Shea, Tom J, Liu, Hanlan, Yew, Nelson, Copeland, Diane, van den Berg, Richard J, van der Marel, Gijsbert A, Overkleeft, Herman S, Aerts, Johannes M
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 28-01-2010
Subjects:	Absorption - drug effects Animals Blood Glucose - drug effects Carbohydrate Metabolism - drug effects Glycated Hemoglobin A - drug effects Glycosphingolipids - metabolism Imino Sugars - chemistry Imino Sugars - pharmacology Imino Sugars - therapeutic use Mice Mice, Obese Obesity - drug therapy Rats Rats, Zucker Structure-Activity Relationship Viscera - metabolism
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Summary:	The lipophilic iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1-deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded that concomitant inhibition of intestinal glycosidases and associated buffering of carbohydrate assimilation add to this. To firmly establish the mode of action of 2, we developed a panel of lipophilic iminosugars varying in configuration at C-4/C-5 and N-substitution of the iminosugar. From these we identified the l-ido derivative of 2, l-ido-AMP-DNM (4), as a selective inhibitor of glycosphingolipid synthesis. Compound 4 lowered visceral glycosphingolipids in ob/ob mice and ZDF rats on a par with 2. In contrast to 2, 4 did not inhibit sucrase activity or sucrose assimilation. Treatment with 4 was significantly less effective in reducing blood glucose and HbA1c. We conclude that the combination of reduction of glycosphingolipids in tissue and buffering of carbohydrate assimilation by 2 produces a superior glucose homeostasis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm901281m