INVESTIGADORES
ASTORT Francisco
congresos y reuniones científicas
Título:
Sucrose-induced insulin resistance is accompanied by morphologic and functional changes in the adrenal cortex of the rat
Autor/es:
MARTINEZ CALEJMAN C; ASTORT F; REPETTO EM; SANCHEZ R; DI GRUCCIO JM; CB CYMERYNG; ARIAS P
Lugar:
Estocolmo, Suecia
Reunión:
Congreso; 46th Meeting of the European Association for the Study of Diabetes (EASD); 2010
Institución organizadora:
European Association for the Study of Diabetes (EASD)
Resumen:
Background and aims: Hyperactivation of the
hypothalamic-pituitary-adrenal (HPA) axis has been widely described in both
human and animals showing insulin resistance (IR). However, a direct effect of
the biochemical abnormalities that characterize this syndrome (e.g. elevated
plasma glucose, serum insulin and free fatty acid levels, hypertriglicerydemia
and oxidative stress) on adrenal function has not been elucidated yet. In this
study we assesed the effect of a sucrose-enriched diet (SED) on adrenocortical
structure and function (corticosterone secretion) in rats. Materials and
methods: Male Wistar rats were fed a sucrose-enriched diet (SED, drinking water
contaning 30% w/v sucrose) up to 12 weeks. Rosiglitazone (4mg/kg, orally and
daily) was administered throughout the duration of the sucrose treatment to a
group of animals. Protein levels of different isoforms of nitric oxide synthase
(NOS), phosphorylated Akt and cyclooxygenase 2 (COX-2) were analyzed by
immunoblot while mRNA levels of steroidogenic acute regulatory protein (StAR)
and the macrophage marker F4/80 were assesed by semiquantitative RT-PCR. Steroid
levels were determined by RIA. Sudan III staining was performed on
adrenocortical slices previously fixed in 4% formaldehyde. Results: As compared
to controls, rats under SED for 7 weeks showed higher fasting plasma glucose
(74 ± 5 and 130 ± 6 mg/dl; p<0,001, Mann-Whitney test) and serum
triacylglyceride (104 ± 52 vs.604 ± 60 mg/dl; p<0,001) and insulin
concentrations (0.99 ± 0.14 vs. 1.97 ± 0.4 ng/ml; p<0,005). An impairment in
the insulin signalling pathway was detected at adrenal level as decreased p-Akt
protein levels were measured by immunoblot analysis. The adrenal glands were
lighter and showed a significant lipidic infiltration, as demonstrated by
histochemistry. NOS activity and the expression levels of eNOS, iNOS and COX-2
were increased in the SED group. StAR and F4/80 mRNAs were also elevated. These
animals showed significantly elevated basal serum corticosterone levels (6,63 ±
1,14 vs. 9,62 ± 0,84 ng/ml p<0,001) but a lower response to an acute
stimulation with 4 UI/kg ACTH i.v., (115,68 ± 34, 03 vs 40,59 ± 25,39 percentage
stimulation, p<0,05). On another set of experiments, rosiglitazone, a
selective PPARgamma agonist, reverted the nutritionally-induced changes in NOS
activity and corticosterone levels and decreased lipid infiltration in the
adrenal tissue. Conclusions: A sucrose enriched diet seems to induce IR at
adrenal level after 7 weeks of treatment, generating morphological and
functional disturbances that finally could lead to the dysregulation of adrenal
steroidogenesis. In this sense, the increase in NOS activity could trigger
posttranscriptional modifications of several proteins (nitration,
S-nitrosilation etc). Among them, those involved in steroid biosynthesis and its
regulation. Both COX-2 and F4/80 could also be related to the chronic
inflammatory state linked to IR in several tissues. Finally, some of these
effects were prevented by rosiglitazone treatment, suggesting a signal
transduction pathway that could be a target for pharmacological interventions
designed to ameliorate this adrenal disfunction.