title: DHEA-induced modulation of renal gluconeogenesis, insulin sensitivity and plasma lipid profile in the control- and dexamethasone-treated rabbits. Metabolic studies.
abstract: In view of antidiabetic and antiglucocorticoid effects of dehydroepiandrosterone (DHEA) both in vitro and in vivo studies were undertaken: (i) to elucidate the mechanism of action of both dexamethasone phosphate (dexP) and DHEA on glucose synthesis in primary cultured rabbit kidney-cortex tubules and (ii) to investigate the influence of DHEA on glucose synthesis, insulin sensitivity and plasma lipid profile in the control- and dexP-treated rabbits. Data show, that in cultured kidney-cortex tubules dexP significantly stimulated gluconeogenesis by increasing flux through fructose-1,6-bisphosphatase (FBPase). DexP-induced effects were dependent only upon glucocorticoid receptor. DHEA decreased glucose synthesis via inhibition of glucose-6-phosphatase (G6Pase) and suppressed the dexP-induced stimulation of renal gluconeogenesis. Studies with the use of inhibitors of DHEA metabolism in cultured renal tubules showed for the first time that DHEA directly affects renal gluconeogenesis. However, in view of analysis of glucocorticoids and DHEA metabolites levels in urine, it seems likely, that testosterone may also contribute to DHEA-evoked effects. In dexP-treated rabbits, plasma glucose level was not altered despite increased renal and hepatic FBPase and G6Pase activities, while a significant elevation of both plasma insulin and HOMA-IR was accompanied by a decline of ISI index. It thus appears that increased insulin levels were required to maintain normoglycaemia and to compensate the insulin resistance. DHEA alone affected neither plasma glucose nor lipid levels, while it increased insulin sensitivity and diminished both renal and hepatic G6Pase activities. Surprisingly, DHEA co-administrated with dexP did not alter insulin sensitivity, while it partially suppressed the dexP-induced elevation of renal G6Pase activity and plasma cholesterol and triglyceride contents. As (i) gluconeogenic pathway in rabbit is similar to that in human, and (ii) DHEA counteracts several dexP-evoked effects, it seems likely, that its supplementation might be beneficial to patients treated with glucocorticoids.
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, I. Miecznikowa 1, 02-096 Warsaw, Poland. Electronic address: akiersztan@biol.uw.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Kiersztan
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, I. Miecznikowa 1, 02-096 Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Nagalski
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, I. Miecznikowa 1, 02-096 Warsaw, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Nalepa
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, I. Miecznikowa 1, 02-096 Warsaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Tempes
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, I. Miecznikowa 1, 02-096 Warsaw, Poland.
authors.forename: Nina
authors.initials: N
authors.lastname: Trojan
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, I. Miecznikowa 1, 02-096 Warsaw, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Usarek
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, I. Miecznikowa 1, 02-096 Warsaw, Poland.
authors.forename: Adam K
authors.initials: AK
authors.lastname: Jagielski
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000235:genetics / Q000502:physiology*; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011817:Rabbits; D053719:Tandem Mass Spectrometry
chemical_list: D000276:Adjuvants, Immunologic; D003687:Dehydroepiandrosterone
keywords: Cortisol; Dehydroepiandrosterone (DHEA); Dexamethasone phosphate (dexP); FBPase; G6Pase; Glucocorticoids (GCs); Renal gluconeogenesis