A Novel Glucagon-like Peptide-1 (GLP-1)/Glucagon Hybrid Peptide with Triple-acting Agonist Activity at Glucose-dependent Insulinotropic Polypeptide, GLP-1, and Glucagon Receptors and Therapeutic Potential in High Fat-fed Mice

Abstract

Background: Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon have important gluco-regulatory actions. Results: Fusion of amino acid sequences of GLP-1, GIP, and glucagon produces hybrid peptides with triple-acting agonist activity. Conclusion: Hybrid peptides possess beneficial biological actions equivalent, or superior to, activation of single receptors. Significance: Multitargeting peptides offer a new class of therapeutics for obesity and diabetes.

A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation

“…This is a positive effect, given that locomotor activity of mice is already increased during the dark phase [19]. Energy expenditure and O 2 consumption were also increased by (D-Ser 2 )glucagon-exe, which may be due in part to increased activity [18]. Such effects, combined with significant reductions in food intake are clearly responsible for the substantial body weight loss [12].…”

“…In vitro cAMP production Chinese hamster lung (CHL) cells transfected with either the human glucose-dependent insulinotropic polypeptide (GIP) receptor (GIP-R) or human GLP-1R, as well as human embryonic kidney (HEK293) cells transfected with the human glucagon-R, were used to assess effects on cAMP production [18]. Cells were seeded (200,000 cells per well) into 96-well plates (Nunc, Fisher Scientific, Loughborough, UK) and washed with Hanks' balanced salt solution buffer before incubation with test peptides (10 −12 and 10 −6 μmol/l) in the presence of 200 μmol/l 3-isobutyl-1-methylxanthine for 20 min at 37°C.…”

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

“…Successful generation of hybrid peptides has been achieved through fusion of the key bioactive amino acid sequences of the parent peptides [19][20][21][22]. This increases the therapeutic applicability of gut-hormone-based drugs by facilitating formulation and dosing with a single molecule, rather than coinjection of separate parent peptide forms.…”

“…As such, therapeutic interventions that combine the biological actions of xenin and GIP, and potentially restore GIP action in type 2 diabetes, would have particularly exciting potential. There has been a recent upsurge in interest focused on generating designer hybrid peptides that can modulate multiple regulatory peptide hormone receptor pathways [19][20][21][22].…”

Sequential induction of beta cell rest and stimulation using stable GIP inhibitor and GLP-1 mimetic peptides improves metabolic control in C57BL/KsJ db/db mice

“…Importantly, benefits where chiefly apparent when GIP(6-30)Cex-K 40 [Pal] was administered during the light cycle, coupled with liraglutide injection during the dark cycle. Thus, although the current trend is to develop dual or triple agonist for diabetes [29][30][31][32], treatment modalities that incorporate sustained periods of beta cell rest combined with suitable intervals of beta cell stimulation appear to have significant therapeutic potential for diabetes. As such, appropriate combined, but non-simultaneous, administration of a GIP receptor inhibitor and GLP-1 receptor mimetic should be further investigated for therapeutic efficacy in other animal models of diabetes and type 2 diabetes in humans.…”