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 antagonist (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 the hyperglucagonaemic period, plasma glucagon concentrations doubled to 100 pg/ml, plasma glucose concentration increased by 75 % to a peak of about 10 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 were 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 antagonist in humans. Given the potentially important role of glucagon in increasing glucose production and gluconeogenesis in patients with Type II (non-insulin-dependent) diabetes mellitus this agent could represent an innovative class of therapeutic agents for the disease.