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A new specific peroxisome proliferator-activated receptor (PPAR) modulator has demonstrated promise in a new study reported in November issue of Diabetes.
The researchers, led by Dr. Luc Penicaud of the National Institute of Health and Medical Research, Toulouse, note that the thiazolidinedione (TZD) class of drugs, although effective and widely used to treat type 2 diabetes, tends to cause weight gain. This study was undertaken to evaluate S26948, a novel ligand for PPAR-gamma.
The study found that S26948 is a specific high-affinity agonist for PPAR-gamma, binding it with the same affinity as the TZD rosiglitazone does. Further, the results suggest that S26948 promoted a PPAR-gamma conformation distinct from that elicited by rosiglitazone.
In addition, S26948 decreased blood glucose levels and plasma insulin levels in male ob/ob mice, indicating that the drug increased insulin sensitivity, paralleling the effects of rosiglitazone treatment.
Results showed that the agent did not promote body-weight gain in the diabetic mice. Instead, the S26948-treated mice gained less weight than the controls, indicating "a profoundly decreased food efficiency," the authors write.
The researchers concluded that S26948’s pattern of coactivator recruitment, which differs from that of rosiglitazone, decreases its adipogenic capacity compared with rosiglitazone.
In a cohort of homozygous human apolipoprotein E2 knock-in mice, S26948 reduced atherosclerotic lesion surfaces by 46% compared with controls (P < 0.01). Rosiglitazone had no effect on atherosclerotic lesion size.
Dr. Penicaud stated that, this line of research is ongoing with related compounds that are considered even more promising, not specifically with S26948. This research is in close collaboration with the French pharmaceutical company Servier.
Diabetes 2007;56:2797-2808.
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