2 - TI Pharma

Chapter 9 Glucocorticoids, mitochondrial function & glycosphingolipid metabolism
Intracellular lipid accumulation and peripheral insulin resistance have also been associated
with decreased mitochondrial function [32]. Interestingly, chronic GC treatment in patients
causes myopathy, characterized by increased proteolysis, oxidative stress and mitochondrial
dysfunction [33]. Whether decreased mitochondrial function plays a role in GC-induced
insulin resistance has not been elucidated.
In the present study we investigated whether GC-induced peripheral insulin resistance
could be explained by either accumulation of intramyocellular ceramide and GM3 levels or
mitochondrial dysfunction in healthy men.
METHoDS
Participants: Thirty-two healthy normoglycemic Caucasian men were recruited via local
advertisements. All participants were in good health as confirmed by medical history,
physical examination, screening blood tests and a 75-g 2-hr oral glucose tolerance test
(OGTT), performed at screening visit. Inclusion criteria were: age between 18-35 years and
body mass index (BMI) ≤ 25 kg/m2 . Exclusion criteria were any previous or current illness,
use of any medication, first-degree relative with T2DM, smoking, shift work and a history of
GC use. In addition, participants who exercised more than two times per week were excluded.
Participants were instructed not to change their physical activity or diet during the study. To
achieve homogeneity of the study group, a physical fitness test was performed as described
previously [34]. Participants with a maximal oxygen uptake (VO2 max) between 45 and
60 ml/kg.min were included. The study was approved by an independent ethics committee
and the study was conducted in accordance with the Declaration of Helsinki. All participants
provided written informed consent before participation.
Study design: Details on study design were reported previously [5]. Briefly, in a randomized,
placebo-controlled, double-blind, dose-response intervention trial, 32 healthy volunteers
were allocated to a treatment with prednisolone 7.5 mg once daily (n=12), prednisolone 30
mg once daily (n=12) or placebo (n=8) for a period of two weeks using block randomization
as carried out by the department of Experimental Pharmacology of the VU University Medical
Center. Before and at day 14 of treatment, peripheral insulin sensitivity was measured
during a hyperinsulinemic-euglycemic clamp using a stable glucose isotope. At the end
of the clamp, biopsies from the vastus lateralis muscle were collected for measurement of
glycosphingolipids and mitochondrial function. During all visits, including a follow-up visit at
day 7 of treatment, safety and tolerability were assessed.
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