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Glucagon-like peptide 1 (GLP-1) exhibits considerable potential for the treatment of type 2 diabetes because of its effects on stimulation of insulin secretion and the inhibition of gastric emptying, appetite, and glucagon secretion. However, native GLP-1 undergoes rapid enzymatic inactivation, prompting development of long-acting degradation-resistant GLP-1 receptor agonists such as exendin-4 (Ex-4). To study the consequences of sustained exposure to Ex-4, we generated metallothionein promoter-exendin-4 (MT-Exendin) mice that continuously express a proexendin-4 transgene in multiple murine tissues. We now report that MT-Exendin mice develop extensive tissue lymphocytic infiltration with increased numbers of CD[4.sup.+] and CD[8a.sup.+] cells in the liver and/or kidney and increased numbers of B[220.sup.+] cells present in the pancreas and liver. MT-Exendin mice generate antibodies directed against Ex-4, exendin N[H.sub.2]-terminal peptide (ENTP), and proexendin-4 as well as antibodies that cross-react with native GLP-1. Furthermore, lymphocytes isolated from MT-Exendin mice proliferate in response to proexendin-4 but not after exposure to Ex-4 or ENTP. These findings demonstrate that expression of a proexendin-4 transgene may be associated with activation of humoral and cellular immune responses in mice., Glucagon-like peptide 1 (GLP-1) lowers blood glucose through several distinct mechanisms that include amplification of glucose-stimulated insulin secretion and inhibition of both glucagon secretion and gastric emptying. In diabetic rodents, [...]