Abstract

Antidiabetic treatments aiming to preserve or even to increase β-cell mass are currently gaining increased interest. Here we investigated the effect of chronic treatment with the novel glucagon-like peptide-1 (GLP-1)–gastrin dual agonist ZP3022 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2) on glycemic control, β-cell mass and proliferation, and islet number. Male db/db mice were treated with ZP3022, liraglutide, or vehicle for 2, 4, or 8 weeks, with terminal assessment of hemoglobin A1c, basal blood glucose, and plasma insulin concentrations. Pancreata were removed for immunohistochemical staining and stereological quantification of β-cell mass, islet numbers, proliferation, and apoptosis. Treatment with ZP3022 or liraglutide led to a significant improvement in glycemic control. ZP3022 treatment resulted in a sustained increase in β-cell mass after 4 and 8 weeks of treatment, whereas the effect of liraglutide was transient. The expansion in β-cell mass observed in the ZP3022-treated mice appeared to be driven by increased β-cell proliferation in existing islets rather than by formation of new islets, as mean islet mass increased but the number of islets remained constant. Our data demonstrate that the GLP-1–gastrin dual agonist ZP3022 causes a sustained improvement in glycemic control accompanied by an increase in β-cell mass, increased proliferation, and increased mean islet mass. The results highlight that the GLP-1–gastrin dual agonist increases β-cell mass more than liraglutide and that dual agonists could potentially be developed into a new class of antidiabetic treatments.