Induction of Insulin Resistance (IR) by a sucrose-rich diet in rats is accompanied by increased corticosterone secretion and lipid infiltration of the adrenal cortex

MARTINEZ CALEJMAN C; REPETTO EM; ASTORT F; SANCHEZ R; MERCAU M; DI GRUCCIO JM; CYMERYNG CB; ARIAS P

Montreal, Canada

Congreso; 20TH World Diabetes Congress; 2009

World Diabetes Congress

body { background: #FFFFFF; margin: 0px; padding: 0px; } Hyperactivation of the hypothalamic-pituitary-adrenal axis has been described in humans and in animals with insulin resistance (IR). However, biochemical and cellular abnormalities associated to IR (e.g. elevated plasma glucose [GLU], serum insulin [INS], free fatty acids [FA] and triglyceride [TG] levels, changes in nitric oxide synthase [NOS] activity, oxidative stress) could directly affect adrenal steroid synthesis and release. Aims: We studied the effects of the development of IR in adult male Wistar rats fed a sucrose-enriched diet (SED, 30% w/v of sucrose added to drinking water) for 12 weeks on serum corticosterone levels, as well as on histological changes and NOS activity in adrenocortical cells. Furthermore, the effect of high GLU, INS and palmitate concentrations (10 mM, 50 mIU/l and 80 µM respectively) on steroid production by cultured murine adrenocortical Y1 cells was evaluated. Results: Fasting hyperinsulinemia was observed in SED-treated rats from week 3 (1.97±0.24 vs. 0.99±0.14 ng/ml; p<0.005 vs. control animals; mean±SD) onwards. After 7 weeks of SED, rats showed higher fasting plasma GLU (130±6 vs. 74±5 mg/dl; p<0.001) and serum TG (605 ± 60 vs. 105±52 mg/dl; p<0.001) levels. SED-treated animals also showed increased body weight and fat depots. Interestingly, after 12 weeks of SED administration, their adrenal glands showed a marked lipid infiltration as demonstrated by light microscopy. Simultaneously, an impairment in the insulin signalling pathway was detected in adrenocortical homogenates: lower p-Akt levels were detected by immunoblot analysis. Adrenocortical NOS activity was increased in treated animals between weeks 3 and 9. Moreover, significantly elevated serum corticosterone levels were detected in these rats between weeks 5 and 9. Only a three-day long incubation of Y1 cells with elevated palmitate concentrations induced a clear increase in steroid (progesterone) release. Conclusions: IR induced by a sucrose-rich diet in rats is accompanied by histological and functional changes in the adrenal cortex. In particular, IR seems to develop also in adrenocortical cells, probably related to lipid infiltration of these glands. Lipid metabolites and/or locally produced adipokines could also increase adrenal steroidogenesis. In addition, an increase in NO generation could trigger post-transcriptional modifications of proteins involved in steroid biosynthesis and its modulation, and/or adversely affect insulin sensitivity in adrenocortical cells. Other factors (hypothalamic/pituitary activation, decreased corticosterone clearance) could be also responsible for the observed hypercorticosteronemia. Elevated glucocorticoid levels could contribute to the somatic and metabolic changes observed in subjects with IR.