Metabolic effects of sustained activation of the GLP-1 receptor alone and in combination with background GIP receptor antagonism in high fat–fed mice

Aim: Enzyme‐resistant glucagon‐like peptide‐1 (GLP‐1) receptor agonists and GIP receptor antagonists have been proposed to have therapeutic potential for the treatment of type 2 diabetes. Such benefits are based on actions mediated primarily through stimulation of insulin secretion or alleviation of insulin resistance respectively. This study examined the long‐term actions of the stable GLP‐1 receptor agonist (d ‐Ala⁸)GLP‐1 and the GIP receptor antagonist (Pro³)GIP alone and in combination in high fat–fed mice. Methods: Mice on high‐fat diet for 155 days were injected once daily with (d ‐Ala⁸)GLP‐1 or (Pro³)GIP (25 nmol/kg body weight) for 24 days. In the following 24‐day period, half of the (Pro³)GIP‐treated mice were administered an additional dose of (d ‐Ala⁸)GLP‐1 (25 nmol/kg body weight), while the remaining mice continued their original treatment regimes. Results: Daily intraperitoneal injections of (d ‐Ala⁸)GLP‐1 or (Pro³)GIP restored glycaemic control to normal levels and significantly (p < 0.05) improved glucose tolerance compared with high‐fat controls by day 24. Food intake and body weights were not affected. On day 48, all treatment groups displayed significantly improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001) compared with high‐fat controls on day 48. HDL cholesterol levels were significantly increased in mice treated with (d ‐Ala⁸)GLP‐1 alone (p < 0.05) or in combination with (Pro³)GIP (p < 0.01) compared with normal chow‐fed controls. Conclusions: These results illustrate efficacy of (Pro³)GIP and (d ‐Ala⁸)GLP‐1 for treatment of glucose intolerance and insulin resistance caused by high‐fat feeding. Combination therapy appeared to have little benefit over either treatment alone.