In previous studies on the enteroinsular axis in Zucker rats, it was found that glucose-dependent insulinotropic polypeptide (GIP) levels were normal in obese animals, but the glucose threshold for the insulinotropic action of GIP in the perfused rat pancreas was reduced. Glucagonlike peptide I (GLP-I)(7–36) is also an important incretin, and in the current study, glucose, insulin, and immunoreactive (IR)–COOH-terminal GLP-I responses to oral glucose were compared in lean (Fa/?) and obese (fa/fa) rats. In addition, the concentration thresholds for stimulation and glucose dependence of perfused pancreases to GLP-I(7–36) were examined. Glucose responses to oral glucose were similar in fa/fa and Fa/? rats. Obese animals were hyperinsulinemic when fasting and after oral glucose. Significant increases in IR–GLP-I levels in response to glucose were only observed in fa/fa rats. Perfused pancreases from fa/fa rats hypersecreted insulin at all glucose concentrations. In the presence of 4.4 mmol/l glucose, GLP-I(7–36) increased insulin secretion in fa/fa pancreases ∼25-fold, whereas there was only a 5-fold increase in Fa/? Pancreases. Pancreases from fa/fa rats, perfused with a glucose gradient (2.8–11 mmol/l) in the presence of GLP-I(7–36), responded with an immediate increase in insulin secretion, i.e., at a glucose concentration of 2.8 mmol/l, whereas Fa/? pancreases required a minimum of 4.22 mmol/l glucose for stimulation. With high glucose (16.7 mmol/l), both fa/fa and Fa/? rat pancreases exhibited similar responsiveness to GLP-I(7–36), having thresholds of <50 pmol/l. In conclusion, in adult obese Zucker rats, GLP-I(7–36) may contribute to the fasting hyperinsulinemia seen in vivo, and there appears to be a general reduction in the glucose dependence of responses to incretins.

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