Dual-Action Lipophilic Iminosugar Improves Glycemic Control in Obese Rodents by Reduction of Visceral Glycosphingolipids and Buffering of Carbohydrate Assimilation
| Autor: | Rolf G. Boot, Johannes M. F. G. Aerts, Alfred J. Meijer, Tom J O'Shea, Hanlan Liu, Gijsbert A. van der Marel, Tom Wennekes, Nelson S. Yew, Diane Copeland, Nora Bijl, Albert K. Groen, Roelof Ottenhoff, Richard J. B. H. N. van den Berg, Karen Ghauharali, Hang Song, Herman S. Overkleeft, Marco van Eijk, Johanna E. M. Groener |
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| Přispěvatelé: | AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Medical Biochemistry, Vascular Medicine, AII - Amsterdam institute for Infection and Immunity, ACS - Amsterdam Cardiovascular Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Blood Glucose
medicine.medical_specialty medicine.medical_treatment Iminosugar Blood sugar Mice Obese Carbohydrate metabolism Glycosphingolipids Absorption Mice Structure-Activity Relationship Insulin resistance Internal medicine Drug Discovery medicine Glucose homeostasis Animals Obesity Glycated Hemoglobin Chemistry Insulin Carbohydrate medicine.disease Sphingolipid Imino Sugars Rats Rats Zucker Viscera Endocrinology Molecular Medicine Carbohydrate Metabolism |
| Zdroj: | Journal of medicinal chemistry, 53(2), 689-698. American Chemical Society |
| ISSN: | 0022-2623 |
| DOI: | 10.1021/jm901281m |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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