Decreased insulin binding to pancreatic islets of genetically obese (fa/fa) rats

Summary Binding of insulin and insulin secretion were studied in isolated pancreatic islets of homozygous obese fa/fa rats, their lean littermates ( Fa/? ) and Wistar rats. Despite normoglycemia fa/fa rats exhibit hyperinsulinemia. Glucose-induced insulin secretion from pancreatic islets in vitro was increased by more than 50% in fa/fa rats compared with islets of lean littermates and normal Wistar rats when calculated per μ g islet protein. Exogenous insulin inhibited glucose (16.7 mM)-induced insulin secretion in islets of either of these rats, and maximum inhibition was rather the same (secretion was reduced by 62.3–65.6%). However, the EC 50 (half-maximal effective concentration) for inhibition was increased in fa/fa rats being 1.4 ± 0.1 nM compared with 0.6 ± 0.2 and 0.5 ± 0.2 nM in lean littermates and Wistar rats, respectively ( P fa/fa rats). Islets of fa/fa rats found 24% less [ 125 I]insulin ( P 125 I]insulin binding by native insulin showed 2 binding sites; a decrease in the number of high affinity insulin binding sites ( B max ) from 4.2 ± 1.3 and 4.7 ± 1.6 fmol/mg protein to 2.6 ± 0.7 fmol/mg protein was calculated when islets of lean littermates and normal Wistar rats were compared to islets of fa/fa rats. The K d of the high affinity binding site was not changed (0.77 ± 0.06, 0.78 ± 0.11 and 0.61 ± 0.14 nM, respectively). In conclusion, the present in vitro data suggest a decreased insulin binding to islets of fa/fa rats and a decreased inhibition of glucose-mediated insulin secretion due to a decreased feedback of insulin indicated by the elevated EC 50 for insulin on its own secretion. These in vitro data in obese rats may also hold for hyperinsulinemia in obese patients in which it was already suggested that hyperinsulinemia partly reflects decreased negative feedback.