title: 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 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.
authors.affiliation: Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.).
authors.forename: Louise S
authors.initials: LS
authors.lastname: Dalbøge
authors.affiliation: Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.).
authors.forename: Dorthe L C
authors.initials: DL
authors.lastname: Almholt
authors.affiliation: Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.).
authors.forename: Trine S R
authors.initials: TS
authors.lastname: Neerup
authors.affiliation: Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.).
authors.forename: Niels
authors.initials: N
authors.lastname: Vrang
authors.affiliation: Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.).
authors.forename: Jacob
authors.initials: J
authors.lastname: Jelsing
authors.affiliation: Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.) kfo@zealandpharma.com.
authors.forename: Keld
authors.initials: K
authors.lastname: Fosgerau
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005755:Gastrins / Q000819:agonists*; D052216:Glucagon-Like Peptide 1 / Q000819:agonists*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*
chemical_list: D005755:Gastrins; D007004:Hypoglycemic Agents; D010455:Peptides; C581977:ZP3022; D052216:Glucagon-Like Peptide 1; D005947:Glucose