Diabetes Anti-diabetogenic and Slimming, Too

Thiazolidinedione ligands of the peroxisome proliferator-activated receptor (PPAR) are used in the clinic to treat type 2 diabetes; however, these agents are not without unwanted side effects. A new ligand N-(9-fluorenylmethyloxycarbonyl)-L-leucine (FMOC-L-Leu) appears to overcome some of these side effects. FMOC-L-Leu activated PPAR trascriptional activity. Analysis of the ligand and receptor interaction showed that two FMOC-L-Leu molecules bind to a single receptor and that the conformation of the receptor is altered when bound. FMOC-L-Leu promoted the interaction of PPAR with the cofactors p300 and SRC-1, but not with TIF2. Its interaction with TIF2 is preferentially stimulated by a thiazolidinedione compound, rosiglitazone. In terms of stimulating adipocyte differentiation, FMOC-L-Leu was less potent than rosiglitazone both in cultured cells and in mice. However, in two different in vivo insulin sensitivity tests, FMOC-L-Leu enhanced glucose clearance in normal mice, whereas rosiglitazone did not. In mouse models of type 2 diabetes, the diet-induced insulin-resistant mouse and db/db mice, FMOC-L-Leu improved glucose homeostasis without promoting the weight gain seen in the rosiglitazone-treated animals. Thus, FMOC-L-Leu and drugs with similar chemical structure may be new pharmacological tools in the arsenal against type 2 diabetes.

S. Rocchi, F. Picard, J. Vamecq, L. Gelman, N. Potier, D. Zeyer, L. Dubuquoy, P. Bac, M.-F. Champy, K. D. Plunket, L. M. Leesnitzer, S. G. Blanchard, P. Desreumaux, D. Moras, J.-P. Renaud, J. Auwerx, A unique PPAR ligand with potent insulin-sensitizing yet weak adipogenic activity. Mol. Cell 8, 737-747 (2001). [Online Journal]