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 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.
Wennekes
Tom
T
Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
Meijer
Alfred J
AJ
Groen
Albert K
AK
Boot
Rolf G
RG
Groener
Johanna E
JE
van Eijk
Marco
M
Ottenhoff
Roelof
R
Bijl
Nora
N
Ghauharali
Karen
K
Song
Hang
H
O'Shea
Tom J
TJ
Liu
Hanlan
H
Yew
Nelson
N
Copeland
Diane
D
van den Berg
Richard J
RJ
van der Marel
Gijsbert A
GA
Overkleeft
Herman S
HS
Aerts
Johannes M
JM
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
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D006028:Glycosphingolipids; D050111:Imino Sugars; C517652:hemoglobin A1c protein, human