Metabolism of [1,3-C-13]glycerol-1,2,3-tris(methylsuccinate) and glycerol-1,2,3-tris(methyl[2,3-C-13]succinate) in hepatocytes from Goto-Kakizaki rats

The metabolism of [1,3-C-13]glycerol-1,2,3-tris (methylsuccinate) and glyce rol-l,2,3-tris(methy1[2,3- C-13] succinate) was examined in hepatocytes pre pared from hereditarily diabetic Goto-Kakizaki rats. Over 120 min incubatio n in the presence of one of the two C-13-labelled esters (2.5 mM), the outp ut of C-13-enriched glucose averaged 57.1+/-18.5 and 54.1+/-22.7 nmol per 1 0(6) cells, when expressed as [1,3-C-13]glycerol and [2,3-C-13]succinate eq uivalent, respectively. In the case of [1,3-C-13]glycerol-l,2,3-tris(methyl succinate), the molecules of glucose were symmetrically labelled. In the ca se of glycerol-1,2,3:tris(methy1[2,3- C-13] succinate), however, both the s ingle-labelled and double-labelled isotopomers of glucose contained more C- 13 atoms in their C-6-C-5-C-4 than C-1-C-2-C-3 moiety. These findings indic ate that glycerol-l,2,3-tris(methylsuccinate), recently proposed as a novel insulinotropic tool for the treatment of non-insulin-dependent diabetes me llitus, is efficiently metabolized in hepatocytes from diabetic rats, the h igh rate of gluconeogenesis coinciding with channelling of D-glyceraldehyde -3-phosphate between glyceraldehyde-3-phosphate dehydrogenase and phosphofr uctoaldolase.