A DPP-IV-resistant triple-acting agonist of GIP, GLP-1 and glucagon receptors with potent glucose-lowering and insulinotropic actions in high-fat-fed mice

• Published in: Diabetologia Vol. 56; no. 6; pp. 1417 - 1424
• Main Authors: Bhat, V. K., Kerr, B. D., Vasu, S., Flatt, P. R., Gault, V. A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.06.2013; Springer; Springer Nature B.V
• Subjects: Amino Acid Sequence; Amino acids; Animals; Biological and medical sciences; Blood Glucose - metabolism; Body Weight; Cricetinae; Cricetulus; Diabetes; Diabetes. Impaired glucose tolerance; Diet, High-Fat; Dipeptidyl Peptidase 4 - metabolism; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gastric Inhibitory Polypeptide - metabolism; Glucagon; Glucagon - metabolism; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor; Glucose; HEK293 Cells; Homeostasis; Human Physiology; Humans; Hyperglycemia; Insulin - metabolism; Insulin resistance; Insulin Secretion; Internal Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Molecular Sequence Data; Peptides - chemistry; Plasma; Polypeptides; Receptors, Gastrointestinal Hormone - agonists; Receptors, Glucagon - agonists; United Kingdom > UK; Glucagon-like peptide-1 (GLP-1); Type 2 diabetes; Glucose-lowering; Glucagon; Glucose-dependent insulinotropic polypeptide (GIP); Insulin secretion; Endocrinopathy; Pancreatic hormone; Agonist; Peptide hormone; Glucose; Gastrointestinal hormone; Biological receptor; Secretion; Rodentia; Metabolic diseases; Insulin; Feeding; Glucagon like peptide 1; Vertebrata; Mammalia; Mouse; Polypeptide; Animal; Gastric inhibitory peptide
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-013-2892-2

Aims/hypothesis We designed a chemically modified, enzyme-resistant peptide with triple-acting properties based on human glucagon with amino acid substitutions aligned to strategic positions in the sequence of glucose-dependent insulinotropic polypeptide (GIP). Methods Y 1 -dA 2 -I 12 -N 17 -V 18 -I 27 -G 28,29 -glucagon (termed YAG-glucagon) was incubated with dipeptidylpeptidase IV (DPP-IV) to assess stability, BRIN-BD11 cells to evaluate insulin secretion, and receptor-transfected cells to examine cAMP production. Acute glucose-lowering and insulinotropic properties of YAG-glucagon were assessed in National Institutes of Health (NIH) Swiss mice, while longer-term actions on glucose homeostasis, insulin secretion, food intake and body weight were examined in high-fat-fed mice. Results YAG-glucagon was resistant to DPP-IV, increased in vitro insulin secretion (1.5–3-fold; p  < 0.001) and stimulated cAMP production in GIP receptor-, glucagon-like peptide-1 (GLP-1) receptor- and glucagon receptor-transfected cells. Plasma glucose levels were significantly reduced (by 51%; p  < 0.01) and insulin concentrations increased (1.2-fold; p  < 0.01) after acute injection of YAG-glucagon in NIH Swiss mice. Acute actions were countered by established GIP, GLP-1 and glucagon antagonists. In high-fat-fed mice, twice-daily administration of YAG-glucagon for 14 days reduced plasma glucose (40% reduction; p  < 0.01) and increased plasma insulin concentrations (1.8-fold; p  < 0.05). Glycaemic responses were markedly improved (19–48% reduction; p  < 0.05) and insulin secretion enhanced (1.5-fold; p  < 0.05) after a glucose load, which were independent of changes in insulin sensitivity, food intake and body weight. Conclusions/interpretation YAG-glucagon is a DPP-IV-resistant triple agonist of GIP, GLP-1 and glucagon receptors and exhibits beneficial biological properties suggesting that it may hold promise for treatment of type 2 diabetes.