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

Aisling M Lynch, Nupur Pathak, Varun Pathak, Finbarr P M O'Harte, Peter R Flatt, Nigel Irwin, Victor A Gault

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

CONCLUSIONS/INTERPRETATION: This study emphasises the potential of (D-Ser(2))glucagon-exe for the treatment of obesity-related diabetes.

Original languageEnglish
Pages (from-to)1927-1936
Number of pages10
JournalDiabetologia
Volume57
Issue number9
Early online date25 Jun 2014
DOIs
Publication statusPublished - Sep 2014

Keywords

  • Animals
  • Blood Glucose
  • Body Weight
  • Diabetes Mellitus
  • Dipeptidyl Peptidase 4
  • Glucagon
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Male
  • Mice
  • Mice, Knockout
  • Obesity
  • Receptors, Glucagon
  • Journal Article
  • Research Support, Non-U.S. Gov't

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