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

作者：Bhat V K; Kerr B D; Vasu S; Flatt P R; Gault V A^*

来源：Diabetologia, 2013, 56(6): 1417-1424.

DOI：10.1007/s00125-013-2892-2

• Glucagon
• Glucagon-like peptide-1 (GLP-1)
• Glucose-dependent insulinotropic polypeptide (GIP)
• Glucose-lowering
• Insulin secretion
• Type 2 diabetes

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). %26lt;br%26gt;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. %26lt;br%26gt;YAG-glucagon was resistant to DPP-IV, increased in vitro insulin secretion (1.5-3-fold; p %26lt; 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 %26lt; 0.01) and insulin concentrations increased (1.2-fold; p %26lt; 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 %26lt; 0.01) and increased plasma insulin concentrations (1.8-fold; p %26lt; 0.05). Glycaemic responses were markedly improved (19-48% reduction; p %26lt; 0.05) and insulin secretion enhanced (1.5-fold; p %26lt; 0.05) after a glucose load, which were independent of changes in insulin sensitivity, food intake and body weight. %26lt;br%26gt;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.

• 出版日期2013-6