Endocrine Abstracts

Background: The differential diagnosis between central diabetes insipidus and primary polydipsia is challenging. To date, the most reliable approaches are copeptin measurement after hypertonic saline infusion or arginine, which is a known growth hormone secretagogue but has recently been shown also to stimulate the neurohypophysis. Similar to arginine, glucagon is also known to stimulate growth hormone release, but its effect on the neurohypophysis and in the differential diagnosis of diabetes insipidus is unknown.

Methods: In this double-blind, randomized, placebo-controlled trial, we enrolled 22 healthy participants, 10 patients with central diabetes insipidus, and 10 patients with primary polydipsia at the University Hospital Basel. Each participant underwent the glucagon test, i.e., subcutaneous injection of 1 mg glucagon, and placebo test, i.e., subcutaneous injection of 1 ml 0.9% sodium. Plasma copeptin levels were measured at baseline and 30, 60, 90, 120, 150, 180 minutes after injection. The primary objective was to determine whether glucagon stimulates copeptin and to explore whether the copeptin response differentiates between central diabetes insipidus and primary polydipsia.

Results: All 42 participants underwent both tests. The median (IQR) age of all participants was 27 years (23; 32), 59% were female. In healthy participants, glucagon injection stimulated copeptin with a median (IQR) increase of 7.56 (2.38; 28.03) pmol/l, while placebo had no effect (0.10 pmol/l (-0.70; 0.68); treatment difference: 7.67 (1.98, 27.09) pmol/l, P< 0.001). In patients with central diabetes insipidus, copeptin showed no relevant increase after glucagon injection, with an increase of 0.55 pmol/l (0.21; 1.65), whereas copeptin was stimulated in patients with primary polydipsia with an increase of 15.70 (5.99; 24.39) pmol/l. Using a copeptin cutoff level of > 4.6 pmol/l had a 100% sensitivity (95%CI 100-100) and 90% specificity (95%CI 70-100) to discriminate between diabetes insipidus and primary polydipsia. The test was safe and well tolerated with a median (IQR) test burden according to VAS of 1.5 (1; 4) in healthy participants, 3 (1.5; 4.5) in central diabetes insipidus, and 3 (2; 4.5) in primary polydipsia.

Conclusion: In conclusion, glucagon stimulates the neurohypophysis, and glucagon-stimulated plasma copeptin has the potential to be used for a safe, novel, and precise test in the differential diagnosis of polyuria-polydipsia syndrome.