The effects of the glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 (EX4) and antagonist EX4(9-39) EX4-A on entero-insular axis have been investigated in normoglycemic and streptozotocin (STZ)-induced diabetic rats. Rats were administered daily subcutaneous injections of 1 nmol/kg EX4 and/or EX4-A for 7 days, and were decapitated 3 h after the last injection. In STZ-untreated rats, EX4 reduced body-weight (BW) gain and raised glycemia, and the effects were prevented by EX4-A; conversely, EX4 did not alter plasma concentrations of insulin, glucagon and leptin. STZ-treated rats displayed body and hematochemical alterations typical of experimental diabetes: decrease in BW and insulin blood level, coupled with normal glucagon plasma concentration and marked hyperglycemia. In diabetic rats, both EX4 and EX4-A decreased BW gain, thereby suggesting a mechanism at least in part independent of GLP-1 receptors. EX4 did not alter glucagon blood level, but decreased glycemia and raised insulin and leptin plasma levels. These effects were annulled by EX4-A, which indicates that they occur through the activation of GLP-1 receptors. Collectively, our findings add support to the view that EX4 can be considered an important therapeutical tool to improve glucose metabolism in diabetes.

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