Glucocorticoid treatment impairs microvascular function in healthy men in association with its adverse effects on glucose metabolism and blood pressure: a randomised controlled trial.
OBJECTIVE
Glucocorticoids (GCs) are widely used anti-inflammatory agents that frequently induce side effects, including insulin resistance, diabetes and hypertension. Here, we investigated the contribution of microvascular dysfunction to the development of these adverse effects in healthy men.


METHODS
In a randomised, placebo-controlled, dose-response intervention study, 32 healthy normoglycaemic men (age: 21 ± 2 years; BMI: 21.9 ± 1.7 kg/m(2)) were allocated to receive prednisolone 30 mg once daily (n = 12), prednisolone 7.5 mg once daily (n = 12) or placebo (n = 8) for 2 weeks using block randomisation. A central office performed the treatment allocation, and medication was dispersed by the hospital pharmacy that was also blinded. Treatment allocation was kept in concealed envelopes. Participants, study personnel conducting the measures and assessing the outcome were blinded to group assignment. The study was conducted at a university hospital. Primary endpoint was prednisolone-induced changes in microvascular function, which was assessed by capillary microscopy. Insulin sensitivity was determined by hyperinsulinaemic-euglycaemic clamp and postprandial glycaemic excursions by standardised meal tests.


RESULTS
Compared with placebo, prednisolone 7.5 mg and 30 mg decreased insulin-stimulated capillary recruitment by 9 ± 4% and 17 ± 3%, respectively (p < 0.01). In addition, prednisolone 7.5 mg and 30 mg reduced insulin sensitivity (M value) by -11.4 ± 4.5 μmol kg(-1) min(-1) and -25.1 ± 4.1 μmol kg(-1) min(-1) (p < 0.001) and increased postprandial glucose levels by 11 ± 5% and 27 ± 9% (p < 0.001), respectively. Only high-dose prednisolone increased systolic blood pressure (6 ± 1.2 mmHg, p = 0.006). Prednisolone-induced changes in insulin-stimulated capillary recruitment were associated with insulin sensitivity (r = +0.76; p < 0.001), postprandial glucose concentrations (r = -0.52; p < 0.03) and systolic blood pressure (r = -0.62; p < 0.001). Prednisolone increased resistin concentrations, which were negatively related to insulin-stimulated capillary recruitment (r = -0.40; p = 0.03). No effects were noted on adiponectin and leptin concentrations. Prednisolone treatment was well tolerated; none of the participants left the study.


CONCLUSIONS
Prednisolone-induced impairment of insulin-stimulated capillary recruitment was paralleled by insulin resistance, increased postprandial glucose levels, hypertension and increased circulating resistin concentrations in healthy men. We propose that GC-induced impairments of microvascular function may contribute to the adverse effects of GC treatment on glucose metabolism and blood pressure.


BACKGROUND
isrctn.org ISRTCN 78149983.


BACKGROUND
The study was funded by the Dutch Top Institute Pharma T1-106.
Diabetes Center, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands, d.vanraalte@vumc.nl.
Daniël H
DH
van Raalte
Michaela
M
Diamant
D Margriet
DM
Ouwens
Richard G
RG
Ijzerman
Margot M L
MM
Linssen
Bruno
B
Guigas
Etto C
EC
Eringa
Erik H
EH
Serné
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects*; D005938:Glucocorticoids / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D011239:Prednisolone / Q000009:adverse effects / Q000627:therapeutic use; D055815:Young Adult
D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D005938:Glucocorticoids; D011239:Prednisolone