A long-acting, dual-agonist analogue of lamprey GLP-1 shows potent insulinotropic, β-cell protective, and anorexic activities and improves glucose homeostasis in high fat-fed mice

Graham, Galyna V.; McCloskey, Andrew; Abdel-Wahab, Yasser; Conlon, J. Michael; Flatt, Peter

doi:10.1016/j.mce.2019.110584

Cited by 8 publications

(11 citation statements)

References 48 publications

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“…Given the high expression of GLP-1R in four-hormonal cells, these results raise the possibility that monohormonal cells in neogenic pancreas may be derived directly from four-hormonal cells and Ngn3 + endocrine progenitors. In addition, given the high proliferation rate of immature alpha- and beta-cells in the primitive bud and data showing that liraglutide promotes cell proliferation in vivo 8 , 9 , monohormonal cells in neogenic pancreas may also be derived from the proliferation of pre-existing immature alpha- and beta-cells in the primitive bud.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in mice and humans have shown anti-inflammatory effects, improved lipid metabolism and hepatic steatosis, and weight loss with GLP-1 receptor (GLP-1R) agonists 5 – 7 . In addition, GLP-1 increases pancreatic beta-cell gene expression, promotes beta-cell proliferation, and inhibits apoptosis 8 , 9 . In recent years, GLP-1 has attracted considerable attention for its effects on beta-cell growth and differentiation 10 , 11 .…”

Section: Introductionmentioning

confidence: 99%

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Long-Term Liraglutide Administration Induces Pancreas Neogenesis in Adult T2DM Mice

Deng

Yang

et al. 2020

Cell Transplant

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In vivo beta-cell neogenesis may be one way to treat diabetes. We aimed to investigate the effect of glucagon-like peptide-1 (GLP-1) on beta-cell neogenesis in type 2 diabetes mellitus (T2DM). Male C57BL/6J mice, 6 wk old, were randomly divided into three groups: Control, T2DM, and T2DM + Lira. T2DM was induced using high-fat diet and intraperitoneal injection of streptozotocin (40 mg/kg/d for 3 d). At 8 wk after streptozotocin injection, T2DM + Lira group was injected intraperitoneally with GLP-1 analog liraglutide (0.8 mg/kg/d) for 4 wk. Apparently for the first time, we report the appearance of a primitive bud connected to pancreas in all adult mice from each group. The primitive bud was characterized by scattered single monohormonal cells expressing insulin, GLP-1, somatostatin, or pancreatic polypeptide, and four-hormonal cells, but no acinar cells and ductal epithelial cells. Monohormonal cells in it were small, newborn, immature cells that rapidly proliferated and expressed cell markers indicative of immaturity. In parallel, Ngn3+ endocrine progenitors and Nestin+ cells existed in the primitive bud. Liraglutide facilitated neogenesis and rapid growth of acinar cells, pancreatic ducts, and blood vessels in the primitive bud. Meanwhile, scattered hormonal cells aggregated into cell clusters and grew into larger islets; polyhormonal cells differentiated into monohormonal cells. Extensive growth of exocrine and endocrine glands resulted in the neogenesis of immature pancreatic lobes in adult mice of T2DM + Lira group. Contrary to predominant acinar cells in mature pancreatic lobes, there were still a substantial number of mesenchymal cells around acinar cells in immature pancreatic lobes, which resulted in the loose appearance. Our results suggest that adult mice preserve the capacity of pancreatic neogenesis from the primitive bud, which liraglutide facilitates in adult T2DM mice. To our knowledge, this is the first time such a phenomenon has been reported.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long-Term Liraglutide Administration Induces Pancreas Neogenesis in Adult T2DM Mice

Deng

Yang

et al. 2020

Cell Transplant

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“…[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.…”

Section: Introductionmentioning

confidence: 99%

“…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). 5,6 Loss of functional β-cell mass is associated with long standing T2DM as well as with Type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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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

Graham

Conlon

Moffett

et al. 2021

Journal of Peptide Science

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The abilities of the long-acting, dual-agonist anti-diabetic peptides [D-Ala 2 ]palmitoyllamprey GLP-1 and [D-Ser 2 ]palmitoyl-paddlefish glucagon to induce α-cell to β-cell transdifferentiation were investigated in Glu CreERT2 ;ROSA26-eYFP mice. These animals have been genetically engineered so that yellow fluorescent protein is specifically expressed in glucagon-producing α-cells, thereby allowing cell lineage tracing.Insulin deficiency was produced by treatment of the mice with multiple low doses of streptozotocin. Administration of the peptides (twice daily intraperitoneal injections of 25 nmol/kg body weight over 10 days) to streptozotocin-treated mice produced significant (P < 0.05) increases in pancreatic insulin content and plasma insulin concentrations compared with control mice. Immunohistochemical studies demonstrated a significant (P < 0.05) increase in the % of cells staining for both insulin and fluorescent protein in islets located in the head region of the pancreas (from 10.0 ± 1.3% of total cells in untreated mice to 20.0 ± 3.85% in mice treated with D-Ala 2 ]palmitoyllamprey GLP-1 and to 17.3 ± 1.1% in mice treated with [D-Ser 2 ]palmitoyl-paddlefish glucagon). Corresponding effects upon islets in the tail region were not significant.The data indicate an improvement in β-cell mass and positive effects on transdifferentiation of glucagon-producing to insulin-producing cells. The study provides further evidence that proglucagon-derived peptides from phylogenetical ancient fish show therapeutic potential for treatment of diabetes.

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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

Graham

Conlon

Abdel-Wahab

et al. 2020

European Journal of Pharmacology

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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.

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A long-acting, dual-agonist analogue of lamprey GLP-1 shows potent insulinotropic, β-cell protective, and anorexic activities and improves glucose homeostasis in high fat-fed mice

Cited by 8 publications

References 48 publications

Long-Term Liraglutide Administration Induces Pancreas Neogenesis in Adult T2DM Mice

Long-Term Liraglutide Administration Induces Pancreas Neogenesis in Adult T2DM Mice

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

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

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