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

Diabetologia. 2001 Nov;44(11):2018-24. doi: 10.1007/s001250100006.

Abstract

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 [6,6-2H]. 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.

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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Biphenyl Compounds / pharmacokinetics
  • Biphenyl Compounds / pharmacology*
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism*
  • Glucagon / pharmacology*
  • Glycated Hemoglobin A / drug effects
  • Glycated Hemoglobin A / metabolism
  • Hormone Antagonists / pharmacokinetics
  • Hormone Antagonists / pharmacology*
  • Humans
  • Insulin / blood
  • Kinetics
  • Male
  • Placebos
  • Receptors, Glucagon / antagonists & inhibitors*
  • Reference Values
  • Somatostatin / pharmacology
  • Time Factors

Substances

  • Bay 27-9955
  • Biphenyl Compounds
  • Blood Glucose
  • Glycated Hemoglobin A
  • Hormone Antagonists
  • Insulin
  • Placebos
  • Receptors, Glucagon
  • Somatostatin
  • Glucagon