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.

AM Lynch, N Pathak, V Pathak, Finbarr O'Harte, Peter Flatt, Nigel Irwin, Victor Gault

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Abstract

AIMS/HYPOTHESIS: Modification of the structure of glucagon could provide useful compounds for the potential treatment of obesity-related diabetes.METHODS: This study evaluated N-acetyl-glucagon, (D-Ser(2))glucagon and an analogue of (D-Ser(2))glucagon with the addition of nine amino acids from the C-terminal of exendin(1-39), namely (D-Ser(2))glucagon-exe.RESULTS: All analogues were resistant to dipeptidyl peptidase IV degradation. N-Acetyl-glucagon lacked acute insulinotropic effects in BRIN BD11 cells, whereas (D-Ser(2))glucagon and (D-Ser(2))glucagon-exe evoked significant (p <0.001) insulin release. (D-Ser(2))glucagon-exe stimulated cAMP production (p <0.001) in glucagon- and GLP-1-receptor (GLP-1R)-transfected cells but not in glucose-dependent insulinotropic polypeptide-receptor-transfected cells. In normal mice, N-acetyl-glucagon and (D-Ser(2))glucagon retained glucagon-like effects of increasing (p <0.001) plasma glucose and insulin levels. (D-Ser(2))glucagon-exe was devoid of hyperglycaemic actions but substantially (p <0.001) increased plasma insulin levels. (D-Ser(2))glucagon-exe reduced the glycaemic excursion (p <0.01) and increased the insulin secretory (p <0.01) response following a glucose challenge 12 h after administration. Studies in GLP-1R knockout mice confirmed involvement of the GLP-1R pathway in the biological actions of (D-Ser(2))glucagon-exe. Twice-daily administration of (D-Ser(2))glucagon-exe to high-fat-fed mice for 28 days significantly (p <0.05 to p <0.001) reduced body weight, energy intake and non-fasting glucose levels, as well as increasing insulin concentrations. Glucose tolerance and insulin sensitivity were significantly (p <0.01) improved and energy expenditure, O2 consumption and locomotor activity were (p <0.05 to p <0.001) augmented. The metabolic benefits were accompanied by increases in pancreatic islet number (p <0.001) and area (p <0.05), as well as beta cell area (p <0.05). Beneficial effects were largely retained for 14 days following cessation of treatment.
LanguageEnglish
Pages1927-1936
JournalDiabetologia
Volume57
Issue number9
DOIs
Publication statusPublished - 25 Jun 2014

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Glucagon
Fats
Weights and Measures
Insulin
Glucose
Glucagon-Like Peptide-1 Receptor
Dipeptidyl Peptidase 4
Withholding Treatment
Locomotion
Energy Intake
Islets of Langerhans
Knockout Mice
Energy Metabolism
Insulin Resistance

Cite this

@article{2e88e20da3894d798f8523d102bde5e0,
title = "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.",
abstract = "AIMS/HYPOTHESIS: Modification of the structure of glucagon could provide useful compounds for the potential treatment of obesity-related diabetes.METHODS: This study evaluated N-acetyl-glucagon, (D-Ser(2))glucagon and an analogue of (D-Ser(2))glucagon with the addition of nine amino acids from the C-terminal of exendin(1-39), namely (D-Ser(2))glucagon-exe.RESULTS: All analogues were resistant to dipeptidyl peptidase IV degradation. N-Acetyl-glucagon lacked acute insulinotropic effects in BRIN BD11 cells, whereas (D-Ser(2))glucagon and (D-Ser(2))glucagon-exe evoked significant (p <0.001) insulin release. (D-Ser(2))glucagon-exe stimulated cAMP production (p <0.001) in glucagon- and GLP-1-receptor (GLP-1R)-transfected cells but not in glucose-dependent insulinotropic polypeptide-receptor-transfected cells. In normal mice, N-acetyl-glucagon and (D-Ser(2))glucagon retained glucagon-like effects of increasing (p <0.001) plasma glucose and insulin levels. (D-Ser(2))glucagon-exe was devoid of hyperglycaemic actions but substantially (p <0.001) increased plasma insulin levels. (D-Ser(2))glucagon-exe reduced the glycaemic excursion (p <0.01) and increased the insulin secretory (p <0.01) response following a glucose challenge 12 h after administration. Studies in GLP-1R knockout mice confirmed involvement of the GLP-1R pathway in the biological actions of (D-Ser(2))glucagon-exe. Twice-daily administration of (D-Ser(2))glucagon-exe to high-fat-fed mice for 28 days significantly (p <0.05 to p <0.001) reduced body weight, energy intake and non-fasting glucose levels, as well as increasing insulin concentrations. Glucose tolerance and insulin sensitivity were significantly (p <0.01) improved and energy expenditure, O2 consumption and locomotor activity were (p <0.05 to p <0.001) augmented. The metabolic benefits were accompanied by increases in pancreatic islet number (p <0.001) and area (p <0.05), as well as beta cell area (p <0.05). Beneficial effects were largely retained for 14 days following cessation of treatment.",
author = "AM Lynch and N Pathak and V Pathak and Finbarr O'Harte and Peter Flatt and Nigel Irwin and Victor Gault",
year = "2014",
month = "6",
day = "25",
doi = "10.1007/s00125-014-3296-7",
language = "English",
volume = "57",
pages = "1927--1936",
journal = "Diabetologia",
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number = "9",

}

TY - JOUR

T1 - 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.

AU - Lynch, AM

AU - Pathak, N

AU - Pathak, V

AU - O'Harte, Finbarr

AU - Flatt, Peter

AU - Irwin, Nigel

AU - Gault, Victor

PY - 2014/6/25

Y1 - 2014/6/25

N2 - AIMS/HYPOTHESIS: Modification of the structure of glucagon could provide useful compounds for the potential treatment of obesity-related diabetes.METHODS: This study evaluated N-acetyl-glucagon, (D-Ser(2))glucagon and an analogue of (D-Ser(2))glucagon with the addition of nine amino acids from the C-terminal of exendin(1-39), namely (D-Ser(2))glucagon-exe.RESULTS: All analogues were resistant to dipeptidyl peptidase IV degradation. N-Acetyl-glucagon lacked acute insulinotropic effects in BRIN BD11 cells, whereas (D-Ser(2))glucagon and (D-Ser(2))glucagon-exe evoked significant (p <0.001) insulin release. (D-Ser(2))glucagon-exe stimulated cAMP production (p <0.001) in glucagon- and GLP-1-receptor (GLP-1R)-transfected cells but not in glucose-dependent insulinotropic polypeptide-receptor-transfected cells. In normal mice, N-acetyl-glucagon and (D-Ser(2))glucagon retained glucagon-like effects of increasing (p <0.001) plasma glucose and insulin levels. (D-Ser(2))glucagon-exe was devoid of hyperglycaemic actions but substantially (p <0.001) increased plasma insulin levels. (D-Ser(2))glucagon-exe reduced the glycaemic excursion (p <0.01) and increased the insulin secretory (p <0.01) response following a glucose challenge 12 h after administration. Studies in GLP-1R knockout mice confirmed involvement of the GLP-1R pathway in the biological actions of (D-Ser(2))glucagon-exe. Twice-daily administration of (D-Ser(2))glucagon-exe to high-fat-fed mice for 28 days significantly (p <0.05 to p <0.001) reduced body weight, energy intake and non-fasting glucose levels, as well as increasing insulin concentrations. Glucose tolerance and insulin sensitivity were significantly (p <0.01) improved and energy expenditure, O2 consumption and locomotor activity were (p <0.05 to p <0.001) augmented. The metabolic benefits were accompanied by increases in pancreatic islet number (p <0.001) and area (p <0.05), as well as beta cell area (p <0.05). Beneficial effects were largely retained for 14 days following cessation of treatment.

AB - AIMS/HYPOTHESIS: Modification of the structure of glucagon could provide useful compounds for the potential treatment of obesity-related diabetes.METHODS: This study evaluated N-acetyl-glucagon, (D-Ser(2))glucagon and an analogue of (D-Ser(2))glucagon with the addition of nine amino acids from the C-terminal of exendin(1-39), namely (D-Ser(2))glucagon-exe.RESULTS: All analogues were resistant to dipeptidyl peptidase IV degradation. N-Acetyl-glucagon lacked acute insulinotropic effects in BRIN BD11 cells, whereas (D-Ser(2))glucagon and (D-Ser(2))glucagon-exe evoked significant (p <0.001) insulin release. (D-Ser(2))glucagon-exe stimulated cAMP production (p <0.001) in glucagon- and GLP-1-receptor (GLP-1R)-transfected cells but not in glucose-dependent insulinotropic polypeptide-receptor-transfected cells. In normal mice, N-acetyl-glucagon and (D-Ser(2))glucagon retained glucagon-like effects of increasing (p <0.001) plasma glucose and insulin levels. (D-Ser(2))glucagon-exe was devoid of hyperglycaemic actions but substantially (p <0.001) increased plasma insulin levels. (D-Ser(2))glucagon-exe reduced the glycaemic excursion (p <0.01) and increased the insulin secretory (p <0.01) response following a glucose challenge 12 h after administration. Studies in GLP-1R knockout mice confirmed involvement of the GLP-1R pathway in the biological actions of (D-Ser(2))glucagon-exe. Twice-daily administration of (D-Ser(2))glucagon-exe to high-fat-fed mice for 28 days significantly (p <0.05 to p <0.001) reduced body weight, energy intake and non-fasting glucose levels, as well as increasing insulin concentrations. Glucose tolerance and insulin sensitivity were significantly (p <0.01) improved and energy expenditure, O2 consumption and locomotor activity were (p <0.05 to p <0.001) augmented. The metabolic benefits were accompanied by increases in pancreatic islet number (p <0.001) and area (p <0.05), as well as beta cell area (p <0.05). Beneficial effects were largely retained for 14 days following cessation of treatment.

U2 - 10.1007/s00125-014-3296-7

DO - 10.1007/s00125-014-3296-7

M3 - Article

VL - 57

SP - 1927

EP - 1936

JO - Diabetologia

T2 - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 9

ER -