Effects of M16209, a new antihyperglycemic agent, on insulin sensitivity in vivo: euglycemic clamp studies in rats

The effects of M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) on the in vivo insulin sensitivity of rats were studied by euglycemic clamp methods after 1 week of administration (10 or 100 mg/kg/d). M16209 increased both the glucose infusion rate (GIR) and metabolic clearance rate (MCR) of 3-[3H]-glucose, but did not suppress hepatic glucose output. M16209 also increased the [3H]-2-deoxyglucose utilization rate, rate of incorporation of [14C]-glucose into glycogen, and glycolytic flux in the soleus and red gastrocnemius muscles, but not in the extensor digitorum lungus and white gastrocnemius muscles. M16209 affected neither the [3H]-2-deoxyglucose utilization rate nor the rate of incorporation of [14C]-glucose into lipids in epididymal adipose tissue. In the soleus muscle, M16209 decreased glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P) content, but did not affect fructose-1,6-bisphosphate (F-1,6-BP) content. Moreover, M16209 increased glycogen synthase-I activity and fructose-2,6-bisphosphate (F-2,6-BP) content in the soleus muscle. These results suggest that M16209 increases insulin-stimulated glucose uptake in peripheral tissues, particularly oxidative muscles, through potentiation of insulin action on glycogen synthesis and glycolysis. Glycogen synthase and phosphofructokinase (PFK) appear to be major targets of the action of M16209.