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Lymphocytic Infiltration and Immune Activation in Metallothionein Promoter–Exendin-4 (MT-Exendin) Transgenic Mice

Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

Address correspondence and reprint requests to Dr. Daniel J. Drucker, Toronto General Hospital, 200 Elizabeth St., MBRW4R-402, Toronto, Ontario, Canada M5G2C4. E-mail: d.drucker{at}utoronto.ca

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 CD4⁺ and CD8a⁺ cells in the liver and/or kidney and increased numbers of B220⁺ cells present in the pancreas and liver. MT-Exendin mice generate antibodies directed against Ex-4, exendin NH₂-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.

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