title: Dual-action lipophilic iminosugar improves glycemic control in obese rodents by reduction of visceral glycosphingolipids and buffering of carbohydrate assimilation.
abstract: 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.
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Wennekes
authors.forename: Alfred J
authors.initials: AJ
authors.lastname: Meijer
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.forename: Rolf G
authors.initials: RG
authors.lastname: Boot
authors.forename: Johanna E
authors.initials: JE
authors.lastname: Groener
authors.forename: Marco
authors.initials: M
authors.lastname: van Eijk
authors.forename: Roelof
authors.initials: R
authors.lastname: Ottenhoff
authors.forename: Nora
authors.initials: N
authors.lastname: Bijl
authors.forename: Karen
authors.initials: K
authors.lastname: Ghauharali
authors.forename: Hang
authors.initials: H
authors.lastname: Song
authors.forename: Tom J
authors.initials: TJ
authors.lastname: O'Shea
authors.forename: Hanlan
authors.initials: H
authors.lastname: Liu
authors.forename: Nelson
authors.initials: N
authors.lastname: Yew
authors.forename: Diane
authors.initials: D
authors.lastname: Copeland
authors.forename: Richard J
authors.initials: RJ
authors.lastname: van den Berg
authors.forename: Gijsbert A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Aerts
mesh_terms: D000042:Absorption / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D050260:Carbohydrate Metabolism / Q000187:drug effects*; D006442:Glycated Hemoglobin / Q000187:drug effects; D006028:Glycosphingolipids / Q000378:metabolism*; D050111:Imino Sugars / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D011924:Rats, Zucker; D013329:Structure-Activity Relationship; D014781:Viscera / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D006028:Glycosphingolipids; D050111:Imino Sugars; C517652:hemoglobin A1c protein, human