Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans

Aims/hypothesis. To study the effects of a specific glucagon receptor antag onist (Bay 27-9955), on plasma glucose concentrations and rates of glucose production in response to hyperglucagonaemia in humans. Methods. The study was conducted as a two-dose [Low Dose Bay 27-9955 70 mg, (n = 6), High Dose Bay 27-9955 200 mg, (n = 8)], double blind, placebo controlled, crossover study. Basal glucose production was measured after an overnight fast with [ 6,6-(2) H]. At 0 min Bay 27-9955 or placebo was administered and at 120 min an infusion of somatostatin [0.1 mug . (kg . min)(-1)], insulin [24 pmol . (m(2) . min)(-1)] and glucagon [3 ng . (kg . min)(-1)] was initiated. Results. Basal plasma glucose concentrations were about 5 mmol/l and basal rates of glucose production were about 13 mu mol . (kg . min)(-1). During t he hyperglucagonaemic period, plasma glucagon concentrations doubled to 100 pg/ml, plasma glucose concentration increased by 75 % to a peak of about 1 0 mmol/l and glucose production doubled to about 23 mu mol . (kg . min)(-1) (p < 0.0001 vs basal). In the High Dose Group these effects of glucagon we re markedly blunted, plasma glucose concentrations were 7.6 +/- 1.1 mmol/l (p = 0.012 vs placebo) and rates of glucose production increased minimally to 15.3 +/- 1.9 <mu>mol . (kg-min)(-1) (p < 0.0003 vs placebo]. In the Low Dose Group, there was a proportional decrease in the effects of Bay 27-9955 on these parameters. Conclusion/interpretation. Bay 27-9955 is an effective and safe glucagon an tagonist in humans. Given the potentially important role of glucagon in inc reasing glucose production and gluconeogenesis in patients with Type II (no n-insulin-dependent) diabetes mellitus this agent could represent an innova tive class of therapeutic agents for the disease.