Glucagon from the phylogenetically ancient paddlefish provides a template for the design of a long-acting peptide with effective anti-diabetic and anti-obesity activities

Abstract

Highlights• [D-Ser 2 ]palmitoyl-paddlefish glucagon is resistant to degradation by plasma peptidases and DPP-IV• The peptide enhanced in vitro insulin secretion from BRIN-BD11 clonal β-cells and mouse islets• The peptide augmented β-cell proliferation and reduced cytokine-mediated apoptosis• The peptide improved glucose tolerance in lean mice when injected up to 4 h before a glucose load.• Twice daily administration to high-fat fed mice over 21 days reduced food intake and body weight• The peptide improved glucose tolerance, insulin sensitivity and functional islet gene expression.

Antimicrobial Peptides: Classification, Design, Application and Research Progress in Multiple Fields

“…Simply put, anti-inflammatory peptides decrease the release of inflammatory mediators and inflammatory cytokines (nitric oxide, interleukin-6, and interleukin-1β) and some of them also inhibit inflammatory signals like NF-κB, MAPK, and JAK-STAT pathways ( Meram and Wu, 2017 ; Gao et al, 2020 ). Anti-diabetic peptides play their function by modulating the G protein-coupled receptor kinase (GRK 2/3) or activating glucagon-like peptide-1 (GLP-1), glucagon receptors ( Marya et al, 2018 ; Graham et al, 2020 ). However, it is not accurate to classify these types of peptides as AMPs and bioactive peptides may be more convincing.…”

Effects of long‐acting analogues of lamprey GLP‐1 and paddlefish glucagon on alpha‐ to beta‐cell transdifferentiation in an insulin‐deficient transgenic mouse model

“…Prompted by encouraging effects on glucose homeostasis observed in high fat-fed mice, 5,6 peptidase-resistant analogues of lamprey GLP-1 and paddlefish glucagon were selected for this study using insulindeficient Glu CreERT2 ;ROSA26-eYFP mice. This animal model was *P < 0.05, **P < 0.01 and *** P < 0.001 compared with untreated control; Δ P < 0.05 and ΔΔΔ P < 0.001 compared with STZ-treated control developed in order to establish a method for direct identification of viable α-cells.…”

“…[1][2][3] However, the value of such peptides is limited by their rapid clearance from the circulation so that long-acting analogues were developed with resistance to degradation by dipeptidyl peptidase-4 (DPP-4) and containing an albumin-binding C-16 fatty acid moiety. [4][5][6] Twice-daily administration of [D-Ser 2 ]palmitoyl-paddlefish glucagon (25 nmol/kg body weight) over 21 days to mice with diet-induced insulin resistance and glucose intolerance reduced food intake, bodyweight, nonfasting blood glucose concentrations and significantly improving glucose tolerance, insulin secretion and insulin sensitivity. 5 Treatment with the same dose of [D-Ala 2 ]palmitoyl-lamprey GLP-1 produced similar beneficial effects.…”

“…[4][5][6] Twice-daily administration of [D-Ser 2 ]palmitoyl-paddlefish glucagon (25 nmol/kg body weight) over 21 days to mice with diet-induced insulin resistance and glucose intolerance reduced food intake, bodyweight, nonfasting blood glucose concentrations and significantly improving glucose tolerance, insulin secretion and insulin sensitivity. 5 Treatment with the same dose of [D-Ala 2 ]palmitoyl-lamprey GLP-1 produced similar beneficial effects. 6 Mechanistic studies demonstrated that both analogues, like the native peptides, were acting as dual agonists at the GLP-1 receptor (Glp1r) and the glucagon receptor (Gcgr).…”

“…6 Mechanistic studies demonstrated that both analogues, like the native peptides, were acting as dual agonists at the GLP-1 receptor (Glp1r) and the glucagon receptor (Gcgr). 5,6 Loss of functional β-cell mass is associated with long standing T2DM as well as with Type 1 diabetes. 7,8 Absolute or relative deficiency of functional β-cells leads to impaired control of blood glucose resulting in the diabetic state.…”