title: Testosterone deficiency induced by progressive stages of diabetes mellitus impairs glucose metabolism and favors glycogenesis in mature rat Sertoli cells.
abstract: The incidence of type 2 diabetes mellitus and its prodromal stage, pre-diabetes, is rapidly increasing among young men, leading to disturbances in testosterone synthesis. However, the impact of testosterone deficiency induced by these progressive stages of diabetes on the metabolic behavior of Sertoli cells remains unknown. We evaluated the effects of testosterone deficiency associated with pre-diabetes and type 2 diabetes on Sertoli cells metabolism, by measuring (1) the expression and/or activities of glycolysis and glycogen metabolism-related proteins and (2) the metabolite secretion/consumption in Sertoli cells obtained from rat models of different development stages of the disease, to unveil the mechanisms by which testosterone deregulation may affect spermatogenesis. Glucose and pyruvate uptake were decreased in cells exposed to the testosterone concentration found in pre-diabetic rats (600nM), whereas the decreased testosterone concentrations found in type 2 diabetic rats (7nM) reversed this profile. Lactate production was not altered, although the expression and/or activity of lactate dehydrogenase and monocarboxylate transporter 4 were affected by progressive testosterone-deficiency. Sertoli cells exposed to type 2 diabetic conditions exhibited intracellular glycogen accumulation. These results illustrate that gradually reduced levels of testosterone, induced by progressive stages of diabetes mellitus, favor a metabolic reprogramming toward glycogen synthesis. Our data highlights a pivotal role for testosterone in the regulation of spermatogenesis metabolic support by Sertoli cells, particularly in individuals suffering from metabolic diseases. Such alterations may be in the basis of male subfertility/infertility associated with the progression of diabetes mellitus.
authors.affiliation: CICS - UBI - Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Rato
authors.affiliation: CICS - UBI - Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Portugal.
authors.forename: Marco G
authors.initials: MG
authors.lastname: Alves
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Portugal.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Duarte
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Life Sciences Department, Faculty of Sciences and Technology, University of Coimbra, Portugal.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Santos
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Laboratory of Physiology, Faculty of Medicine, University of Coimbra, Portugal.
authors.forename: Paula I
authors.initials: PI
authors.lastname: Moreira
authors.affiliation: CICS - UBI - Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Portugal.
authors.forename: José E
authors.initials: JE
authors.lastname: Cavaco
authors.affiliation: CICS - UBI - Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Portugal; Department of Microscopy, Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS) and Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Portugal. Electronic address: pfobox@gmail.com.
authors.forename: Pedro F
authors.initials: PF
authors.lastname: Oliveira
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000097:blood / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis*; D007265:Inhibins / Q000235:genetics / Q000378:metabolism; D008297:Male; D011236:Prediabetic State / Q000097:blood / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012708:Sertoli Cells / Q000378:metabolism*; D013737:Testis / Q000378:metabolism; D013739:Testosterone / Q000097:blood / Q000172:deficiency / Q000378:metabolism*
chemical_list: D011944:Receptors, Androgen; C422364:inhibin B; D013739:Testosterone; D004958:Estradiol; D007265:Inhibins; D006003:Glycogen; D005947:Glucose
keywords: Glucose metabolism; Glycogen; Pre-diabetes; Sertoli cell; Testosterone deficiency; Type 2 diabetes mellitus