GIP and GLP-1: Stepsiblings Rather Than Monozygotic Twins Within the Incretin Family

The importance of the incretin effect for the postprandial augmentation of insulin released has long been recognized (1). However, there has been a long-standing controversy as to the relative importance of the various gastrointestinal hormones in mediating this effect. While earlier studies suggested a contribution of gastrin, secretin, and cholecystokinin (2), it later became obvious that in humans, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are the predominant incretin hormones (1). Which of the two incretins is the most relevant one is still a matter of debate. Gasbjerg et al. (3) performed studies in healthy human subjects receiving oral glucose loads of 75 g in the fasting state on four different days. The known incretin hormones, GIP and GLP-1, which are secreted in response to glucose administration/absorption, were antagonized with the established peptide receptor antagonist exendin(9-39), blocking the stimulation of GLP-1 receptors, or with the novel GIP receptor antagonist, GIP(3-30)amide, a naturally occurring fragment of intact GIP (full sequence 1–42), which has recently been characterized as a specific GIP receptor antagonist for use in human studies (4). A similar GIP receptor antagonist, GIP(7-30)amide, had previously been used in animal studies but had not been validated for human experiments (5). These incretin receptor antagonists were compared with placebo and used alone and in combination. The result was a slight rise in postload glucose concentrations and a minor reduction in insulin secretory responses, when the GLP-1 receptor was blocked, and a substantial rise in glycemic excursions after the glucose load and a more pronounced reduction in insulin secretory responses, when the recently validated GIP antagonist GIP(3-30)amide was administered at an approximately 1,000-fold excess (∼60 nmol/L) over endogenous peak GIP concentrations (∼60 pmol/L). The combination of exendin(9-39) and GIP(3-30)amide further raised plasma glucose and reduced insulin secretory responses over and above …