Aim: To present an overview of exendin(9-39)NH 2 usage as a scientific tool in humans and provide recommendations for dosage and infusion regimes. Methods:We systematically searched the literature on exendin(9-39)NH 2 and included for review 44 clinical studies reporting use of exendin(9-39)NH 2 in humans.Results: Exendin(9-39)NH 2 binds to the orthosteric binding site of the glucagon-like peptide-1 (GLP-1) receptor with high affinity. The plasma elimination half-life of exendin(9-39)NH 2 after intravenous administration is $30 minutes, requiring $2.5 hours of constant infusion before steady-state plasma concentrations can be expected. Studies utilizing infusions with exendin(9-39)NH 2 in humans have applied varying regimens (priming with a bolus or constant infusion) and dosages (continuous infusion rate range 30-900 pmol/kg/min) with subsequent differences in effects.Administration of exendin(9-39)NH 2 in healthy individuals, patients with diabetes, obese patients, and patients who have undergone bariatric surgery significantly increases fasting and postprandial levels of glucose and glucagon, but has inconsistent effects on circulating concentrations of insulin and C-peptide, gastric emptying, appetite sensations, and food intake. Importantly, exendin(9-39)NH 2 induces secretion of all L cell products (ie, in addition to GLP-1, also peptide YY, glucagon-like peptide-2, oxyntomodulin, and glicentin) complicating use of exendin(9-39)NH 2 as a tool to study the isolated effect of GLP-1.Conclusions: Exendin(9-39)NH 2 is selective for the GLP-1 receptor, with numerous and complex whole-body effects. To obtain GLP-1 receptor blockade in humans, we recommend an initial high-dose infusion, followed by a continuous infusion rate aiming at a ratio of exendin(9-39)NH 2 to GLP-1 of 2000:1. Highlights• Exendin(9-39)NH 2 is a competitive antagonist of the human GLP-1 receptor.• Exendin(9-39)NH 2 has been used as a tool to delineate human GLP-1 physiology since 1998.• Exendin(9-39)NH 2 induces secretion of GLP-1 and other L cell products.• Reported effects of exendin(9-39)NH 2 on insulin levels and food intake are inconsistent.• Here, we provide recommendations for the use of exendin(9-39)NH 2 in clinical studies.

The glucose‐dependent insulinotropic polypeptide (GIP) fragment GIP(3‐30)NH2 is a selective, competitive GIP receptor antagonist, and doses of 800 to 1200 pmol/kg/min inhibit GIP‐induced potentiation of glucose‐stimulated insulin secretion by >80% in humans. We evaluated the effects of GIP(3‐30)NH2 across a wider dose range in eight healthy men undergoing six separate and randomized 10‐mmol/L hyperglycaemic clamps (A–F) with concomitant intravenous infusion of GIP (1.5 pmol/kg/min; A–E) or saline (F). Clamps A to E involved double‐blinded, infusions of saline (A) and GIP(3‐30)NH2 at four rates: 2 (B), 20 (C), 200 (D) and 2000 pmol/kg/min (E), respectively. Mean plasma concentrations of glucose (A–F) and GIP (A–E) were similar. GIP‐induced potentiation of glucose‐stimulated insulin secretion was reduced by 44 ± 10% and 84 ± 10% during clamps D and E, respectively. Correspondingly, the amounts of glucose required to maintain the clamp during D and E were not different from F. GIP‐induced suppression of bone resorption and increase in heart rate were lowered by clamps D and E. In conclusion, GIP(3‐30)NH2 provides extensive, dose‐dependent inhibition of the GIP receptor in humans, with most pronounced effects of the doses 200 to 2000 pmol/kg/min within the tested range.

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