The Novel GLP-1–Gastrin Dual Agonist ZP3022 Improves Glucose Homeostasis and Increases β-Cell Mass without Affecting Islet Number in db/db Mice

Abstract

Antidiabetic treatments aiming to preserve or even to increase b-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, b-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 b-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 b-cell mass after 4 and 8 weeks of treatment, whereas the effect of liraglutide was transient. The expansion in b-cell mass observed in the ZP3022-treated mice appeared to be driven by increased b-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 b-cell mass, increased proliferation, and increased mean islet mass. The results highlight that the GLP-1-gastrin dual agonist increases b-cell mass more than liraglutide and that dual agonists could potentially be developed into a new class of antidiabetic treatments.

Sleeve gastrectomy, but not duodenojejunostomy, preserves total beta-cell mass in Goto-Kakizaki rats evaluated by three-dimensional optical projection tomography

“…If a gastrinmediated improvement in T2DM and expansion of BCM after SG exist, it may very well act in concert with other hormones such as GLP-1. Supportive of this are the promising, preclinical observations of a GLP-1/gastrin dual agonist in terms of glycemic parameters and BCM, even if compared to animals on GLP-1 monotherapy [46,47]. In the present study, the importance of gastrin in terms of BCM or remission of T2DM has not been determined.…”

A Novel CCK-8/GLP-1 Hybrid Peptide Exhibiting Prominent Insulinotropic, Glucose-Lowering, and Satiety Actions With Significant Therapeutic Potential in High-Fat–Fed Mice

“…The bioactive domains of the parent peptides have been fused through use of a (2-[2-aminoethoxy]ethoxy)acetic acid linker molecule (15). We initially assessed enzymatic resistance, in vitro insulin secretion, and in vivo glucoselowering, insulinotropic, and satiety actions of the parent peptides and novel (pGlu-Gln)-CCK-8/exendin-4 hybrid.…”

Liraglutide Exerts Antidiabetic Effect via PTP1B and PI3K/Akt2 Signaling Pathway in Skeletal Muscle of KKAy Mice

“…In recent years, glucagon-like peptide 1 (GLP-1), which was secreted from intestinal L cells, had been reported to decrease blood glucose [4, 5], increase insulin secretion, and improve the damage of β -cell [6]. Liraglutide as a kind of GLP-1 analogue expressed 97% homoousia for amino acid sequences with GLP-1 of human [7].…”