title: Effect of danazol-induced chronic hyperglucagonaemia on glucose tolerance and turnover.
abstract: It has been shown that danazol (14-ethinyltestosterone) induces hyperglucagonaemia. To investigate the effect of chronic glucagon excess on carbohydrate metabolism, we studied six patients before and after treatment with danazol for immunothrombopenia. Glucose tolerance and insulin, C-peptide and glucagon secretion during an oral glucose tolerance test (oGTT) as well as peripheral and hepatic insulin sensitivity were determined by means of euglycaemic clamp technique (40 mU m-2 min-1) before and after 3 months of danazol therapy. Overall glucose turnover (Rd) was assessed radioisotopically. (1) Plasma glucagon levels rose significantly from 88 +/- 16 pg mL-1 before to 683 +/- 148 pg mL-1 after therapy (P < 0.01). (2) Glucose levels during an oGTT were not significantly different before and after therapy. Glucose-stimulated insulin secretion at 60 and 120 min and the area under the curve (AUC) for insulin during the oGTT, were significantly increased after danazol treatment compared with pre-treatment values (P < 0.05), whereas glucagon secretion showed a similar decrease at both time points of investigation (NS). (3) Rd during steady state showed a significant decrease during the entire period of euglycaemic clamp following therapy (after 240 min, 3.8 +/- 0.6 vs. 5.3 +/- 0.7 mg kg-1 min-1, P < 0.05). The decline in glucagon during the clamp was similar during steady state before and after therapy. (4) Basal hepatic glucose output did not differ significantly before and after therapy (1.74 +/- 0.41 vs. 1.45 +/- 0.22 mg kg-1, NS), whereas hepatic glucose output during the clamp was significantly less suppressed after danazol therapy. The authors conclude that chronic glucagon excess leads to a decrease in peripheral and hepatic insulin action which is accompanied by an increase in insulin secretion.
authors.affiliation: Department of Medicine III, University of Vienna, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Kotzmann
authors.forename: M
authors.initials: M
authors.lastname: Linkesch
authors.forename: B
authors.initials: B
authors.lastname: Ludvik
authors.forename: M
authors.initials: M
authors.lastname: Clodi
authors.forename: A
authors.initials: A
authors.lastname: Luger
authors.forename: G
authors.initials: G
authors.lastname: Schernthaner
authors.forename: R
authors.initials: R
authors.lastname: Prager
authors.forename: R
authors.initials: R
authors.lastname: Klauser
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D003613:Danazol / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005934:Glucagon / Q000097:blood*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D013921:Thrombocytopenia / Q000188:drug therapy
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D005934:Glucagon; D005947:Glucose; D003613:Danazol