The role of GIP in the pathogenesis of spontaneous syndromes of obesity-diabetes wasexamined in ob/ob mice of the Aston stock and db/db mice of the C57BL/KsJ background. Compared with lean controls, fed adult ob/ob and db/db mice, respectively, exhibited 1.8- fold and 2.1-fold increases in body weight, 1.8-fold and 2.8-fold elevations of plasma glucose, and 15.4-fold and 5.6-fold elevations of plasma insulin. As indicatedby the relative magnitude of the hyperglycemia and hyperinsulinemia, db/db mice displayed a particularly severe form of diabetes. Plasma GIP concentrations of ob/ob and db/db mice were elevated 15.1-fold and 6.2- fold, respectively; the increments closely corresponded with the degrees of hyperinsulinemia. Small intestinal weight was increased 1.4-fold and 1.8-fold in ob/ob and db/db mice, respectively, but the intestinal GIP content expressed as μg/g intestine or μg/intestine was raised only in ob/ob mice (1.9-fold and 2.8- fold, respectively). Since glucose stimulation of insulin release is defective in both mutant strains, the results strongly implicate pathologically raised GIP concentrations in the hyperinsulinemia and related metabolic abnormalities of the obesity-diabetes syndromes. It is suggested that hypersecretion of GIP results in part from loss of normal feedback inhibition by endogenous insulin.

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