Dogfish glucagon analogues counter hyperglycaemia and enhance both insulin secretion and action in diet-induced obese diabetic mice

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

AIMS: We investigated the antidiabetic actions of three dogfish glucagon peptide analogues (known GLP-1 and glucagon receptor co-agonists) following chronic administration to diet-induced high fat fed (HFD) diabetic mice.MATERIALS AND METHODS: NIH Swiss mice were pre-conditioned to a HFD (45% fat) for 100 days, or control mice were fed a normal diet (10% fat). Normal diet control and HFD control mice received twice daily i.p. saline and HFD groups (n = 8) received twice daily injections of or exendin-4(1-39), [S2a]dogfish glucagon, [S2a]dogfish glucagon exendin-4(31-39) or [S2a]dogfish glucagon-Lys30 -γ-glutamyl-PAL (25 nmol/kg body weight) for 51 days.RESULTS: Following dogfish glucagon analogue treatment, there was a rapid and sustained decrease in non-fasting blood glucose and associated insulinotropic effect (ANOVA, p <0.05-p <0.001) compared to saline-treated HFD controls. All peptide treatments significantly improved i.p. and oral glucose tolerance with concomitant increased insulin secretion compared to saline-treated HFD controls (p <0.05-p <0.001). Following chronic treatment, no receptor desensitisation was observed but insulin sensitivity was enhanced for all peptide treated groups (p <0.01-p <0.001) except [S2a]dogfish glucagon. Both exendin-4 and [S2a]dogfish glucagon exendin-4(31-39) significantly reduced plasma triglycerides concentrations compared to lean controls (p = 0.0105 and p = 0.0048, respectively). Pancreatic insulin content was not affected by peptide treatments but [S2a]dogfish glucagon and [S2a]dogfish glucagon exendin-4(31-39) decreased pancreatic glucagon by 28-34% (p = 0.0221 and p = 0.0075, respectively). The percentage β-cell area within islets was increased by exendin-4 and peptide analogue treatment groups compared with HFD controls and the α-cell area decreased (p <0.05-p <0.01) CONCLUSIONS: Overall, dogfish glucagon co-agonist analogues demonstrated several beneficial metabolic effects showing therapeutic potential for T2DM.
LanguageEnglish
Pages1013-1024
JournalDiabetes Obesity and Metabolism
Volume18
Issue number10
Early online date15 Aug 2016
DOIs
Publication statusE-pub ahead of print - 15 Aug 2016

Fingerprint

Dogfish
Obese Mice
Glucagon
Hyperglycemia
Insulin
Diet
Fats
Peptides
High Fat Diet
Glucagon Receptors
Therapeutics
Therapeutic Uses
Glucose Tolerance Test
Hypoglycemic Agents
Insulin Resistance
Blood Glucose
exenatide
Analysis of Variance
Triglycerides

Keywords

  • Dogfish glucagon
  • chronic study
  • co-agonist
  • diabetic mice
  • glucagon like peptide-1
  • peptide analogues
  • therapy

Cite this

@article{9d3c28d06ef74ddf90d65da6bc90b11f,
title = "Dogfish glucagon analogues counter hyperglycaemia and enhance both insulin secretion and action in diet-induced obese diabetic mice",
abstract = "AIMS: We investigated the antidiabetic actions of three dogfish glucagon peptide analogues (known GLP-1 and glucagon receptor co-agonists) following chronic administration to diet-induced high fat fed (HFD) diabetic mice.MATERIALS AND METHODS: NIH Swiss mice were pre-conditioned to a HFD (45{\%} fat) for 100 days, or control mice were fed a normal diet (10{\%} fat). Normal diet control and HFD control mice received twice daily i.p. saline and HFD groups (n = 8) received twice daily injections of or exendin-4(1-39), [S2a]dogfish glucagon, [S2a]dogfish glucagon exendin-4(31-39) or [S2a]dogfish glucagon-Lys30 -γ-glutamyl-PAL (25 nmol/kg body weight) for 51 days.RESULTS: Following dogfish glucagon analogue treatment, there was a rapid and sustained decrease in non-fasting blood glucose and associated insulinotropic effect (ANOVA, p <0.05-p <0.001) compared to saline-treated HFD controls. All peptide treatments significantly improved i.p. and oral glucose tolerance with concomitant increased insulin secretion compared to saline-treated HFD controls (p <0.05-p <0.001). Following chronic treatment, no receptor desensitisation was observed but insulin sensitivity was enhanced for all peptide treated groups (p <0.01-p <0.001) except [S2a]dogfish glucagon. Both exendin-4 and [S2a]dogfish glucagon exendin-4(31-39) significantly reduced plasma triglycerides concentrations compared to lean controls (p = 0.0105 and p = 0.0048, respectively). Pancreatic insulin content was not affected by peptide treatments but [S2a]dogfish glucagon and [S2a]dogfish glucagon exendin-4(31-39) decreased pancreatic glucagon by 28-34{\%} (p = 0.0221 and p = 0.0075, respectively). The percentage β-cell area within islets was increased by exendin-4 and peptide analogue treatment groups compared with HFD controls and the α-cell area decreased (p <0.05-p <0.01) CONCLUSIONS: Overall, dogfish glucagon co-agonist analogues demonstrated several beneficial metabolic effects showing therapeutic potential for T2DM.",
keywords = "Dogfish glucagon, chronic study, co-agonist, diabetic mice, glucagon like peptide-1, peptide analogues, therapy",
author = "Finbarr O'Harte and Tony Ng and AM Lynch and Conlon, {J. Michael} and Peter Flatt",
note = "Compliant in UIR; evidence uploaded to 'Other files'",
year = "2016",
month = "8",
day = "15",
doi = "10.1111/dom.12713",
language = "English",
volume = "18",
pages = "1013--1024",
journal = "Diabetes, Obesity and Metabolism",
issn = "1463-1326",
number = "10",

}

TY - JOUR

T1 - Dogfish glucagon analogues counter hyperglycaemia and enhance both insulin secretion and action in diet-induced obese diabetic mice

AU - O'Harte, Finbarr

AU - Ng, Tony

AU - Lynch, AM

AU - Conlon, J. Michael

AU - Flatt, Peter

N1 - Compliant in UIR; evidence uploaded to 'Other files'

PY - 2016/8/15

Y1 - 2016/8/15

N2 - AIMS: We investigated the antidiabetic actions of three dogfish glucagon peptide analogues (known GLP-1 and glucagon receptor co-agonists) following chronic administration to diet-induced high fat fed (HFD) diabetic mice.MATERIALS AND METHODS: NIH Swiss mice were pre-conditioned to a HFD (45% fat) for 100 days, or control mice were fed a normal diet (10% fat). Normal diet control and HFD control mice received twice daily i.p. saline and HFD groups (n = 8) received twice daily injections of or exendin-4(1-39), [S2a]dogfish glucagon, [S2a]dogfish glucagon exendin-4(31-39) or [S2a]dogfish glucagon-Lys30 -γ-glutamyl-PAL (25 nmol/kg body weight) for 51 days.RESULTS: Following dogfish glucagon analogue treatment, there was a rapid and sustained decrease in non-fasting blood glucose and associated insulinotropic effect (ANOVA, p <0.05-p <0.001) compared to saline-treated HFD controls. All peptide treatments significantly improved i.p. and oral glucose tolerance with concomitant increased insulin secretion compared to saline-treated HFD controls (p <0.05-p <0.001). Following chronic treatment, no receptor desensitisation was observed but insulin sensitivity was enhanced for all peptide treated groups (p <0.01-p <0.001) except [S2a]dogfish glucagon. Both exendin-4 and [S2a]dogfish glucagon exendin-4(31-39) significantly reduced plasma triglycerides concentrations compared to lean controls (p = 0.0105 and p = 0.0048, respectively). Pancreatic insulin content was not affected by peptide treatments but [S2a]dogfish glucagon and [S2a]dogfish glucagon exendin-4(31-39) decreased pancreatic glucagon by 28-34% (p = 0.0221 and p = 0.0075, respectively). The percentage β-cell area within islets was increased by exendin-4 and peptide analogue treatment groups compared with HFD controls and the α-cell area decreased (p <0.05-p <0.01) CONCLUSIONS: Overall, dogfish glucagon co-agonist analogues demonstrated several beneficial metabolic effects showing therapeutic potential for T2DM.

AB - AIMS: We investigated the antidiabetic actions of three dogfish glucagon peptide analogues (known GLP-1 and glucagon receptor co-agonists) following chronic administration to diet-induced high fat fed (HFD) diabetic mice.MATERIALS AND METHODS: NIH Swiss mice were pre-conditioned to a HFD (45% fat) for 100 days, or control mice were fed a normal diet (10% fat). Normal diet control and HFD control mice received twice daily i.p. saline and HFD groups (n = 8) received twice daily injections of or exendin-4(1-39), [S2a]dogfish glucagon, [S2a]dogfish glucagon exendin-4(31-39) or [S2a]dogfish glucagon-Lys30 -γ-glutamyl-PAL (25 nmol/kg body weight) for 51 days.RESULTS: Following dogfish glucagon analogue treatment, there was a rapid and sustained decrease in non-fasting blood glucose and associated insulinotropic effect (ANOVA, p <0.05-p <0.001) compared to saline-treated HFD controls. All peptide treatments significantly improved i.p. and oral glucose tolerance with concomitant increased insulin secretion compared to saline-treated HFD controls (p <0.05-p <0.001). Following chronic treatment, no receptor desensitisation was observed but insulin sensitivity was enhanced for all peptide treated groups (p <0.01-p <0.001) except [S2a]dogfish glucagon. Both exendin-4 and [S2a]dogfish glucagon exendin-4(31-39) significantly reduced plasma triglycerides concentrations compared to lean controls (p = 0.0105 and p = 0.0048, respectively). Pancreatic insulin content was not affected by peptide treatments but [S2a]dogfish glucagon and [S2a]dogfish glucagon exendin-4(31-39) decreased pancreatic glucagon by 28-34% (p = 0.0221 and p = 0.0075, respectively). The percentage β-cell area within islets was increased by exendin-4 and peptide analogue treatment groups compared with HFD controls and the α-cell area decreased (p <0.05-p <0.01) CONCLUSIONS: Overall, dogfish glucagon co-agonist analogues demonstrated several beneficial metabolic effects showing therapeutic potential for T2DM.

KW - Dogfish glucagon

KW - chronic study

KW - co-agonist

KW - diabetic mice

KW - glucagon like peptide-1

KW - peptide analogues

KW - therapy

U2 - 10.1111/dom.12713

DO - 10.1111/dom.12713

M3 - Article

VL - 18

SP - 1013

EP - 1024

JO - Diabetes, Obesity and Metabolism

T2 - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1463-1326

IS - 10

ER -