Gastric inhibitory polypeptide and hyperinsulinemia in the Zucker (fa/fa) rat: a developmental study

The role of the gut hormone GIP (gastric inhibitory polypeptide; glucose-dependent insulinotropic polypeptide) in the development of hyperinsulinemia of pre-obese (fa/fa) Zucker rats was investigated. Plasma GIP levels were compared in lean and fa/fa pups from 21 to 35 days of age. The onset of both basal and glucose-stimulated hyperinsulinemia was studied. Possible causal roles for glucose, GIP and acetylcholine in hyperinsulinemia were investigated in the isolated perfused pancreas preparation. Immunocytochemical studies of pancreatic islets were also carried out. Glucose-stimulated hyperinsulinemia was present in fa/fa rats at 21 days of age but fasting hyperinsulinemia did not become apparent until 35 days of age. At no time did plasma GIP levels differ between lean and fa/fa rats. Immunocytochemical analysis of the pancreas revealed enlarged islets in fa/fa rats from 7 days of age onward. In the in vitro perfused pancreas of 21 day old fa/fa pups the insulin response was not different from that of lean controls in the presence of glucose (300 mg/dl) plus GIP or acetylcholine. An increased pancreatic insulin response to glucose (300 mg/dl or 80 mg/dl) plus GIP in fa/fa compared to lean animals was observed at 35 days of age. These data suggest that defects in the beta-cell response to GIP become apparent at 35 days of age in fa/fa rats resulting in a loss of the glucose threshold for the insulinotropic action of GIP and onset of fasting hyperinsulinemia in vivo. Causal factors for glucose-stimulated hyperinsulinemia at 21 days of age appear to be complex and not easily replicated in in vitro experiments.