title: Characterization of a standardized glucagon challenge test as a pharmacodynamic tool in pharmacological research.
abstract: The aim of this study was to characterize a glucagon challenge test as a tool in diabetes research by assessing the inter- and intra-individual variability, and investigating the activity of the autonomic nervous system (ANS) during the challenge, as this might have an indirect impact on glucose homeostasis. The study was performed in 24 healthy volunteers separated in 2 groups. The first group of 12 volunteers underwent a 5-h glucagon challenge during a pancreatic clamp procedure with infusion of [6,6-2H2]-glucose infusion in combination with heart rate variability measurements. In the second group, 12 other healthy volunteers underwent two 6-h glucagon challenges separated by 6 weeks, and fat biopsies were taken for analysis of glucagon receptor expression. Serum glucose rose rapidly after glucagon infusion, and reached a plateau at 90 min. The time profiles suggested rapid development of tolerance for glucagon-induced hyperglycemia. During the glucagon challenge intra- and inter-individual variabilities for hepatic glucose production, the rate of disappearance of glucose, and plasma glucose were approximately 10-15% for all variables. Hyperglucagonemia did not affect heart rate variability. Human adipose tissue had a low, but variable, expression of glucagon receptor mRNA. This standardized glucagon challenge test has a good reproducibility with only limited variability over 6 weeks. It is a robust tool to explore in detail the contribution of glucagon in normal and altered glucose homeostasis and can also be used to evaluate the effects of drugs antagonizing glucagon action in humans without confounding changes in ANS tone.
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: M G J
authors.initials: MG
authors.lastname: van Dongen
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: B F
authors.initials: BF
authors.lastname: Geerts
authors.affiliation: Isis Pharmaceuticals Inc, Carlsbad, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bhanot
authors.affiliation: Isis Pharmaceuticals Inc, Carlsbad, CA, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Morgan
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: de Kam
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Moerland
authors.affiliation: Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: J A
authors.initials: JA
authors.lastname: Romijn
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: A F
authors.initials: AF
authors.lastname: Cohen
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Burggraaf
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005934:Glucagon / Q000097:blood / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010601:Pharmacology, Clinical / Q000379:methods* / Q000592:standards*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D012015:Reference Standards; D012106:Research; D013997:Time Factors; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D005934:Glucagon