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Horm Metab Res 2014; 46(04): 269-273
DOI: 10.1055/s-0033-1363223
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Characterization of a Standardized Glucagon Challenge Test as a Pharmacodynamic Tool in Pharmacological Research

M.G. J. van Dongen
1   Centre for Human Drug Research, Leiden, The Netherlands
,
B. F. Geerts
2   Leiden University Medical Center, Leiden, The Netherlands
,
S. Bhanot
3   Isis Pharmaceuticals Inc, Carlsbad, CA, USA
,
E. S. Morgan
3   Isis Pharmaceuticals Inc, Carlsbad, CA, USA
,
M. L. de Kam
1   Centre for Human Drug Research, Leiden, The Netherlands
,
M. Moerland
1   Centre for Human Drug Research, Leiden, The Netherlands
,
J. A. Romijn
4   Academic Medical Center, Amsterdam, The Netherlands
,
A. F. Cohen
1   Centre for Human Drug Research, Leiden, The Netherlands
,
J. Burggraaf
1   Centre for Human Drug Research, Leiden, The Netherlands
› Author Affiliations
Further Information

Publication History

received 18 August 2013

accepted 18 November 2013

Publication Date:
08 January 2014 (online)

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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.

Key words

glucagon - diabetes mellitus type 2 - hepatic glucose production - autonomic nervous system
 

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