Dual-action lipophilic iminosugar improves glycemic control in obese rodents by reduction of visceral glycosphingolipids and buffering of carbohydrate assimilation.

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Wennekes T, Meijer AJ, Groen AK, Boot RG, Groener JE, van Eijk M, Ottenhoff R, Bijl N, Ghauharali K, Song H, O'Shea TJ, Liu H, Yew N, Copeland D, van den Berg RJ, van der Marel GA, Overkleeft HS, Aerts JM

Dual-action lipophilic iminosugar improves glycemic control in obese rodents by reduction of visceral glycosphingolipids and buffering of carbohydrate assimilation.

J Med Chem. 2010 Jan 28;53(2):689-98. doi: 10.1021/jm901281m.

PubMed ID

20000679 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Miglitol	Maltase-glucoamylase, intestinal	IC 50 (nM)	6000	N/A	N/A	Details
Miglustat	Ceramide glucosyltransferase	IC 50 (nM)	50000	N/A	N/A	Details