Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans.
OBJECTIVE
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 [6,6-2H]. At 0 min Bay 27-9955 or placebo was administered and at 120 min an infusion of somatostatin [0.1 microg x (kg x min)(-1)], insulin [24 pmol x (m2 x min)(-1)] and glucagon [3 ng x (kg x min)(-1)] was initiated.


RESULTS
Basal plasma glucose concentrations were about 5 mmol/l and basal rates of glucose production were about 13 micromol x (kg x 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 micromol x (kg x 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 micromol x (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.


CONCLUSIONS
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.
Petersen
K F
KF
Yale University School of Medicine, Department of Internal Medicine, New Haven, Connecticut 06520-8020, USA. kitt.petersen@yale.edu
Sullivan
J T
JT
D000328:Adult; D001713:Biphenyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D005934:Glucagon / Q000494:pharmacology*; D006442:Glycated Hemoglobin / Q000187:drug effects / Q000378:metabolism; D006727:Hormone Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000097:blood; D007700:Kinetics; D008297:Male; D010919:Placebos; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D012016:Reference Values; D013004:Somatostatin / Q000494:pharmacology; D013997:Time Factors
D001713:Biphenyl Compounds; D001786:Blood Glucose; D005934:Glucagon; D006442:Glycated Hemoglobin; D006727:Hormone Antagonists; D007328:Insulin; D010919:Placebos; D018027:Receptors, Glucagon; D013004:Somatostatin; C449721:Bay 27-9955