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Aim: Analogues of several gastrointestinal peptide hormones have been developed into effective medicines for treatment of diseases such as type 2 diabetes mellitus (T2DM), obesity and short bowel syndrome (SBS). In this study, we aimed to explore whether the combination of glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) into a potent co-agonist could provide additional benefits compared to existing monotherapies., Methods: A short-acting (GUB09-123) and a half-life extended (GUB09-145) GLP-1/GLP-2 co-agonist were generated using solid-phase peptide synthesis and tested for effects on food intake, body weight, glucose homeostasis, and gut proliferation in lean mice and in diabetic db/db mice., Results: Sub-chronic administration of GUB09-123 to lean mice significantly reduced food intake, improved glucose tolerance, and increased gut volume, superior to monotherapy with the GLP-2 analogue teduglutide. Chronic administration of GUB09-123 to diabetic mice significantly improved glycemic control and showed persistent effects on gastric emptying, superior to monotherapy with the GLP-1 analogue liraglutide. Due to the short-acting nature of the molecule, no effects on body weight were observed, whereas a marked and robust intestinotrophic effect on mainly the small intestine volume and surface area was obtained. In contrast to GUB09-123, sub-chronic administration of a half-life extended GUB09-145 to lean mice caused marked dose-dependent effects on body weight while maintaining its potent intestinotrophic effect., Conclusion: Our data demonstrate that the GLP-1/GLP-2 co-agonists have effects on gut morphometry, showing a marked increase in intestinal volume and mucosal surface area. Furthermore, effects on glucose tolerance and long-term glycemic control are evident. Effects on body weight and gastric emptying are also observed depending on the pharmacokinetic properties of the molecule. We suggest that this novel co-agonistic approach could exemplify a novel concept for treatment of T2DM or SBS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

GLP-1-gastrin dual agonist ZP3022 has been shown to increase β-cell mass with a concomitant improvement of glycemic control in diabetic mice and rats. Here we tested the in-vitro effects of ZP3022 on β-cell proliferation, islet apoptosis and glucose-stimulated insulin secretion (GSIS) in rat islets of Langerhans. Moreover, gene expression profiling in whole pancreas from Zucker Diabetic Fatty (ZDF) rats was performed to characterize genes differently regulated by short-term treatment with ZP3022. Treatments with exendin-4, gastrin-17 alone or in combination were included in the studies. ZP3022 promoted β-cell proliferation, protected from palmitate-, but not from cytokine-induced apoptosis, and induced an increase in GSIS, demonstrating a glucose dependent insulinotropic action of ZP3022 on β-cells. The combination treatment with exendin-4 and gastrin-17 showed comparable effects on proliferation, apoptosis, and GSIS as did ZP3022. Microarray analysis revealed that ZP3022 exerted specific effects on pancreatic gene expression not observed when treating ZDF rats with either exendin-4 alone or in combination with gastrin-17. In particular MAPK signaling pathway was observed among the highest affected pathways; while also pathways related to insulin signaling and secretion were regulated by ZP3022. Moreover, rats treated with ZP3022 had a higher expression of genes encoding for the specific β-cell/endocrine cell markers, such as islet amyloid polypeptide (IAPP), protein convertase 1/3 and -2 (PC 1/3 and-2), as well as transmembrane protein 27(TMEM27) compared to vehicle treated rats. We conclude that ZP3022 may have therapeutic potential in the prevention/delay of β cell dysfunction., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims/hypothesis: Combination treatment with exendin-4 and gastrin has proven beneficial in treatment of diabetes and preservation of beta cell mass in diabetic mice. Here, we examined the chronic effects of a GLP-1-gastrin dual agonist ZP3022 on glycemic control and beta cell dysfunction in overtly diabetic Zucker Diabetic Fatty (ZDF) rats., Methods: ZDF rats aged 11 weeks were dosed s.c., b.i.d. for 8 weeks with vehicle, ZP3022, liraglutide, exendin-4, or gastrin-17 with or without exendin-4. Glycemic control was assessed by measurements of HbA1c and blood glucose levels, as well as glucose tolerance during an oral glucose tolerance test (OGTT). Beta cell dynamics were examined by morphometric analyses of beta and alpha cell fractions., Results: ZP3022 improved glycemic control as measured by terminal HbA1c levels (6.2±0.12 (high dose) vs. 7.9±0.07% (vehicle), P<0.001), as did all treatments, except gastrin-17 monotherapy. In contrast, only ZP3022, exendin-4 and combination treatment with exendin-4 and gastrin-17 significantly improved glucose tolerance and increased insulin levels during an OGTT. Moreover, only ZP3022 significantly enhanced the beta cell fraction in ZDF rats, a difference of 41%, when compared to the vehicle group (0.31±0.03 vs. 0.22±0.02%, respectively, P<0.05)., Conclusion: These data suggest that ZP3022 may have therapeutic potential in the prevention/delay of beta cell dysfunction in type 2 diabetes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Peptides are recognized for being highly selective and efficacious and, at the same time, relatively safe and well tolerated. Consequently, there is an increased interest in peptides in pharmaceutical research and development (R&D), and approximately 140 peptide therapeutics are currently being evaluated in clinical trials. Given that the low-hanging fruits in the form of obvious peptide targets have already been picked, it has now become necessary to explore new routes beyond traditional peptide design. Examples of such approaches are multifunctional and cell penetrating peptides, as well as peptide drug conjugates. Here, we discuss the current status, strengths, and weaknesses of peptides as medicines and the emerging new opportunities in peptide drug design and development., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)