Recent advances of GIP and future horizons.

Recently GIP-GLP-1 co-agonists with powerful effects on glycemic control and body weight in patients with type 2 diabetes have been described. While such effects are the expected ones from a glucagonlike peptide-1 receptor agonist, similar contributions from the GIP component of the co-agonist would be surprising and contrast to the existing literature. Conventionally, GIP is thought of as an important incretin hormone regulating postprandial insulin secretion in glucose tolerant individuals, but such effects are weak or absent in patients with type 2 diabetes, and GIP has been proposed to an obesity-promoting hormone, rather than the opposite. Recent studies with a GIP receptor antagonist suitable for human studies have confirmed these concepts regarding the actions of endogenous GIP and point to potential beneficial metabolic effects of GIP receptor antagonists rather than agonist in the treatment of obesity and type 2 diabetes. So how is it possible that apparently similar results can be obtained with GIP receptor agonists and antagonists? Maybe the explanation should be sought in GIP receptor dynamics, where the agonists clearly elicit beta-arrestin mediated receptor internalization, rendering the target tissues unresponsive, whereas antagonists block the internalization and increase receptor expression on the cell surfaces. This may explain that both antagonists and agonists show efficacy in obesity and type 2 diabetes.