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Metabolic fingerprints in testicular biopsies from type 1 diabetic patients

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Abstract

Diabetes mellitus (DM) is a metabolic disease that has grown to pandemic proportions. Recent reports have highlighted the effect of DM on male reproductive function. Here, we hypothesize that testicular metabolism is altered in type 1 diabetic (T1D) men seeking fertility treatment. We propose to determine some metabolic fingerprints in testicular biopsies of diabetic patients. For that, testicular tissue from five normal and five type 1 diabetic men was analyzed by high-resolution magic-angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy. mRNA and protein expression of glucose transporters and glycolysis-related enzymes were also evaluated. Our results show that testes from diabetic men presented decreased levels of lactate, alanine, citrate and creatine. The mRNA levels of glucose transporter 1 (GLUT1) and phosphofructokinase 1 (PFK1) were decreased in testes from diabetic men but only GLUT3 presented decreased mRNA and protein levels. Lactate dehydrogenase (LDH) and glutamate pyruvate transaminase (GPT) protein levels were also found to be decreased in testes from diabetic men. Overall, our results show that T1D alters glycolysis-related transporters and enzymes, compromising lactate content in the testes. Moreover, testicular creatine content was severely depressed in T1D men. Since lactate and creatine are essential for germ cells development and support, the data discussed here open new insights into the molecular mechanism by which DM promotes subfertility/infertility in human males.

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References

  • Agbaje IM, Rogers DA, McVicar CM, McClure N, Atkinson AB, Mallidis C, Lewis SE (2007) Insulin dependant diabetes mellitus: implications for male reproductive function. Hum Reprod 22:1871–1877

    Article  CAS  PubMed  Google Scholar 

  • Alves MG, Socorro S, Silva J, Barros A, Sousa M, Cavaco JE, Oliveira PF (2012) In vitro cultured human Sertoli cells secrete high amounts of acetate that is stimulated by 17beta-estradiol and suppressed by insulin deprivation. Biochim Biophys Acta 1823:1389–1394

    Article  CAS  PubMed  Google Scholar 

  • Alves MG, Martins AD, Rato L, Moreira PI, Socorro S, Oliveira PF (2013a) Molecular mechanisms beyond glucose transport in diabetes-related male infertility. Biochim Biophys Acta 1832:626–635

    Article  CAS  PubMed  Google Scholar 

  • Alves MG, Neuhaus-Oliveira A, Moreira PI, Socorro S, Oliveira PF (2013b) Exposure to 2,4-dichlorophenoxyacetic acid alters glucose metabolism in immature rat Sertoli cells. Reprod Toxicol 38C:81–88

    Article  Google Scholar 

  • Alves MG, Rato L, Carvalho RA, Moreira PI, Socorro S, Oliveira PF (2013c) Hormonal control of Sertoli cell metabolism regulates spermatogenesis. Cell Mol Life Sci 70:777–793

    Article  CAS  PubMed  Google Scholar 

  • Alves MG, Martins AD, Vaz CV, Correia S, Moreira PI, Oliveira PF, Socorro S (2014) Metformin and male reproduction: effects on Sertoli cell metabolism. Br J Pharmacol 171:1033–1042

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bartak V (1979) Sperm quality in adult diabetic men. Int J Fertil 24:226–232

    CAS  PubMed  Google Scholar 

  • Bartak V, Josifko M, Horackova M (1975) Juvenile diabetes and human sperm quality. Int J Fertil 20:30–32

    CAS  PubMed  Google Scholar 

  • Bernardino RL, Jesus TT, Martins AD, Sousa M, Barros A, Cavaco JE, Socorro S, Alves MG, Oliveira PF (2013) Molecular basis of bicarbonate membrane transport in the male reproductive tract. Curr Med Chem 20:4037–4049

    Article  CAS  PubMed  Google Scholar 

  • Bourne RB, Kretzschmar WA, Esser JH (1971) Successful artificial insemination in a diabetic with retrograde ejaculation. Fertil Steril 22:275–277

    CAS  PubMed  Google Scholar 

  • Boussouar F, Benahmed M (1999) Epidermal growth factor regulates glucose metabolism through lactate dehydrogenase A messenger ribonucleic acid expression in cultured porcine Sertoli cells. Biol Reprod 61:1139–1145

    Article  CAS  PubMed  Google Scholar 

  • Boussouar F, Benahmed M (2004) Lactate and energy metabolism in male germ cells. Trends Endocrinol Metab 15:345–350

    Article  CAS  PubMed  Google Scholar 

  • Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    Article  CAS  PubMed  Google Scholar 

  • Cameron DF, Murray FT, Drylie DD (1985) Interstitial compartment pathology and spermatogenic disruption in testes from impotent diabetic men. Anat Rec 213:53–62

    Article  CAS  PubMed  Google Scholar 

  • Carosa E, Radico C, Giansante N, Rossi S, D’Adamo F, Di Stasi SM, Lenzi A, Jannini EA (2005) Ontogenetic profile and thyroid hormone regulation of type-1 and type-8 glucose transporters in rat Sertoli cells. Int J Androl 28:99–106

    Article  CAS  PubMed  Google Scholar 

  • Courtens JL, Ploen L (1999) Improvement of spermatogenesis in adult cryptorchid rat testis by intratesticular infusion of lactate. Biol Reprod 61:154–161

    Article  CAS  PubMed  Google Scholar 

  • Dias TR, Rato L, Martins AD, Simões VL, Jesus TT, Alves MG, Oliveira PF (2013) Insulin deprivation decreases caspase-dependent apoptotic signaling in cultured rat Sertoli cells. ISRN Urol 2013:970370

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dias TR, Alves MG, Silva BM, Oliveira PF (2014) Sperm glucose transport and metabolism in diabetic individuals. Mol Cell Endocrinol 396:37–45

    Article  CAS  PubMed  Google Scholar 

  • Donoso P, Tournaye H, Devroey P (2007) Which is the best sperm retrieval technique for non-obstructive azoospermia? A systematic review. Hum Reprod Update 13:539–549

    Article  CAS  PubMed  Google Scholar 

  • Erkkila K, Aito H, Aalto K, Pentikainen V, Dunkel L (2002) Lactate inhibits germ cell apoptosis in the human testis. Mol Hum Reprod 8:109–117

    Article  CAS  PubMed  Google Scholar 

  • Fedele D (2005) Therapy insight: sexual and bladder dysfunction associated with diabetes mellitus. Nat Clin Pract Urol 2:282–290

    Article  PubMed  Google Scholar 

  • Fink RI, Wallace P, Brechtel G, Olefsky JM (1992) Evidence that glucose transport is rate-limiting for in vivo glucose uptake. Metabolism 41:897–902

    Article  CAS  PubMed  Google Scholar 

  • Galardo MN, Riera MF, Pellizzari EH, Chemes HE, Venara MC, Cigorraga SB, Meroni SB (2008) Regulation of expression of Sertoli cell glucose transporters 1 and 3 by FSH, IL1 beta, and bFGF at two different time-points in pubertal development. Cell Tissue Res 334:295–304

    Article  CAS  PubMed  Google Scholar 

  • Griswold MD, Merryweather J (1982) Insulin stimulates the incorporation of 32Pi into ribonucleic acid in cultured sertoli cells. Endocrinology 111:661–667

    Article  CAS  PubMed  Google Scholar 

  • Guma FC, Wagner M, Martini LH, Bernard EA (1997) Effect of FSH and insulin on lipogenesis in cultures of Sertoli cells from immature rats. Braz J Med Biol Res 30:591–597

    Article  CAS  PubMed  Google Scholar 

  • Jutte NH, Jansen R, Grootegoed JA, Rommerts FF, Clausen OP, van der Molen HJ (1982) Regulation of survival of rat pachytene spermatocytes by lactate supply from Sertoli cells. J Reprod Fertil 65:431–438

    Article  CAS  PubMed  Google Scholar 

  • Kaiser GR, Monteiro SC, Gelain DP, Souza LF, Perry ML, Bernard EA (2005) Metabolism of amino acids by cultured rat Sertoli cells. Metabolism 54:515–521

    Article  CAS  PubMed  Google Scholar 

  • Kolodny RC, Kahn CB, Goldstein HH, Barnett DM (1974) Sexual dysfunction in diabetic men. Diabetes 23:306–309

    Article  CAS  PubMed  Google Scholar 

  • Lawler JM, Barnes WS, Wu G, Song W, Demaree S (2002) Direct antioxidant properties of creatine. Biochem Biophys Res Commun 290:47–52

    Article  CAS  PubMed  Google Scholar 

  • Lee H, Kim JH, Chae YJ, Ogawa H, Lee MH, Gerton GL (1998) Creatine synthesis and transport systems in the male rat reproductive tract. Biol Reprod 58:1437–1444

    Article  CAS  PubMed  Google Scholar 

  • Mallidis C, Green BD, Rogers D, Agbaje IM, Hollis J, Migaud M, Amigues E, McClure N, Browne RA (2009) Metabolic profile changes in the testes of mice with streptozotocin-induced type 1 diabetes mellitus. Int J Androl 32:156–165

    Article  CAS  PubMed  Google Scholar 

  • Martins AD, Alves MG, Simoes VL, Dias TR, Rato L, Moreira PI, Socorro S, Cavaco JE, Oliveira PF (2013) Control of Sertoli cell metabolism by sex steroid hormones is mediated through modulation in glycolysis-related transporters and enzymes. Cell Tissue Res 354:861–868

    Article  CAS  PubMed  Google Scholar 

  • Martins AD, Alves MG, Bernardino RL, Dias TR, Silva BM, Oliveira PF (2014) Effect of white tea (Camellia sinensis (L.)) extract in the glycolytic profile of Sertoli cell. Eur J Nutr 53:1383–1391

    Article  CAS  PubMed  Google Scholar 

  • Meroni SB, Riera MF, Pellizzari EH, Cigorraga SB (2002) Regulation of rat Sertoli cell function by FSH: possible role of phosphatidylinositol 3-kinase/protein kinase B pathway. J Endocrinol 174:195–204

    Article  CAS  PubMed  Google Scholar 

  • Mita M, Borland K, Price JM, Hall PF (1985) The influence of insulin and insulin-like growth factor-I on hexose transport by Sertoli cells. Endocrinology 116:987–992

    Article  CAS  PubMed  Google Scholar 

  • Nakamura M, Hino A, Yasumasu I, Kato J (1981) Stimulation of protein synthesis in round spermatids from rat testes by lactate. J Biochem 89:1309–1315

    CAS  PubMed  Google Scholar 

  • Oliveira PF, Alves MG, Rato L, Laurentino S, Silva J, Sa R, Barros A, Sousa M, Carvalho RA, Cavaco JE, Socorro S (2012) Effect of insulin deprivation on metabolism and metabolism-associated gene transcript levels of in vitro cultured human Sertoli cells. Biochim Biophys Acta Protein Struct Mol Enzymol 1820:84–89

    CAS  Google Scholar 

  • Oliveira PF, Martins AD, Moreira AC, Cheng CY, Alves MG (2015) The Warburg effect revisited-lesson from the sertoli cell. Med Res Rev 35:126–151

    Article  PubMed  Google Scholar 

  • Oonk RB, Grootegoed JA, van der Molen HJ (1985) Comparison of the effects of insulin and follitropin on glucose metabolism by Sertoli cells from immature rats. Mol Cell Endocrinol 42:39–48

    Article  CAS  PubMed  Google Scholar 

  • Padron RS, Dambay A, Suarez R, Mas J (1984) Semen analyses in adolescent diabetic patients. Acta Diabetol Lat 21:115–121

    Article  CAS  PubMed  Google Scholar 

  • Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rato L, Socorro S, Cavaco JE, Oliveira PF (2010) Tubular fluid secretion in the seminiferous epithelium: ion transporters and aquaporins in Sertoli cells. J Membr Biol 236:215–224

    Article  CAS  PubMed  Google Scholar 

  • Rato L, Alves MG, Socorro S, Carvalho RA, Cavaco JE, Oliveira PF (2012) Metabolic modulation induced by oestradiol and DHT in immature rat Sertoli cells cultured in vitro. Biosci Rep 32:61–69

    Article  CAS  PubMed  Google Scholar 

  • Rato L, Alves MG, Dias TR, Lopes G, Cavaco JE, Socorro S, Oliveira PF (2013) High-energy diets may induce a pre-diabetic state altering testicular glycolytic metabolic profile and male reproductive parameters. Andrology 1:495–504

    Article  CAS  PubMed  Google Scholar 

  • Rato L, Alves MG, Cavaco JE, Oliveira PF (2014a) High-energy diets: a threat for male fertility? Obes Rev 15:996–1007

    Article  CAS  PubMed  Google Scholar 

  • Rato L, Duarte AI, Tomas GD, Santos MS, Moreira PI, Socorro S, Cavaco JE, Alves MG, Oliveira PF (2014b) Pre-diabetes alters testicular PGC1-alpha/SIRT3 axis modulating mitochondrial bioenergetics and oxidative stress. Biochim Biophys Acta 1837:335–344

    Article  CAS  PubMed  Google Scholar 

  • Riera MF, Meroni SB, Gomez GE, Schteingart HF, Pellizzari EH, Cigorraga SB (2001) Regulation of lactate production by FSH, iL1beta, and TNFalpha in rat Sertoli cells. Gen Comp Endocrinol 122:88–97

    Article  CAS  PubMed  Google Scholar 

  • Robinson R, Fritz IB (1981) Metabolism of glucose by Sertoli cells in culture. Biol Reprod 24:1032–1041

    Article  CAS  PubMed  Google Scholar 

  • Rocha CS, Martins AD, Rato L, Silva BM, Oliveira PF, Alves MG (2014) Melatonin alters the glycolytic profile of Sertoli cells: implications for male fertility. Mol Hum Reprod 20:1067–1076

    Article  PubMed  Google Scholar 

  • Salvaterra T, Alves MG, Domingues I, Pereira R, Rasteiro MG, Carvalho RA, Soares AM, Lopes I (2013) Biochemical and metabolic effects of a short-term exposure to nanoparticles of titanium silicate in tadpoles of Pelophylax perezi (Seoane). Aquat Toxicol 128–129:190–192

    Article  PubMed  Google Scholar 

  • Sexton WJ, Jarow JP (1997) Effect of diabetes mellitus upon male reproductive function. Urology 49:508–513

    Article  CAS  PubMed  Google Scholar 

  • Skinner MK, Griswold MD (1982) Secretion of testicular transferrin by cultured Sertoli cells is regulated by hormones and retinoids. Biol Reprod 27:211–221

    Article  CAS  PubMed  Google Scholar 

  • Tabak O, Gelisgen R, Erman H, Erdenen F, Muderrisoglu C, Aral H, Uzun H (2011) Oxidative lipid, protein, and DNA damage as oxidative stress markers in vascular complications of diabetes mellitus. Clin Invest Med 34:E163–E171

    CAS  PubMed  Google Scholar 

  • Ulisse S, Jannini EA, Pepe M, De Matteis S, D’Armiento M (1992) Thyroid hormone stimulates glucose transport and GLUT1 mRNA in rat Sertoli cells. Mol Cell Endocrinol 87:131–137

    Article  CAS  PubMed  Google Scholar 

  • Vaz CV, Alves MG, Marques R, Moreira PI, Oliveira PF, Maia CJ, Socorro S (2012) Androgen-responsive and nonresponsive prostate cancer cells present a distinct glycolytic metabolism profile. Int J Biochem Cell Biol 44:2077–2084

    Article  CAS  PubMed  Google Scholar 

  • Zysk JR, Bushway AA, Whistler RL, Carlton WW (1975) Temporary sterility produced in male mice by 5-thio-D-glucose. J Reprod Fertil 45:69–72

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the ‘Fundação para a Ciência e a Tecnologia’ – FCT (PTDC/QUI-BIQ/121446/2010 and PEst-C/SAU/UI0709/2011) co-funded by Fundo Europeu de Desenvolvimento Regional – FEDER via Programa Operacional Factores de Competitividade – COMPETE/QREN. M.G. Alves and P.F. Oliveira were funded by FCT through SFRH/BPD/80451/2011 and FSE and POPH funds (Programa Ciência 2008), respectively. The funding agency had no role in study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the article for publication.

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Authors and Affiliations

  1. CICS – UBI – Health Sciences Research Centre, University of Beira Interior, 6201-506, Covilhã, Portugal

    Marco G. Alves, Ana D. Martins & Pedro Fontes Oliveira

  2. Laboratory of Physiology, Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal

    Paula I. Moreira

  3. CNC – Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517, Coimbra, Portugal

    Paula I. Moreira & Rui A. Carvalho

  4. Department of Life Sciences, Faculty of Science and Technology (FCTUC), University of Coimbra, 3004-517, Coimbra, Portugal

    Rui A. Carvalho

  5. Department of Microscopy, Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS) and Multidisciplinary Unit for Biomedical Research (UMIB), University of Porto, 4050-313, Porto, Portugal

    Ana D. Martins, Mário Sousa & Pedro Fontes Oliveira

  6. Centre for Reproductive Genetics Prof. Alberto Barros, 4100-009, Porto, Portugal

    Mário Sousa, Alberto Barros & Joaquina Silva

  7. Department of Genetics, Faculty of Medicine, University of Porto, 4200 - 319, Porto, Portugal

    Alberto Barros

  8. Center of Reproductive Medicine, Maternity Dr. Alfredo da Costa, Centro Hospitalar de Lisboa Central (CHLC), 1069-089, Lisboa, Portugal

    Soraia Pinto & Teresinha Simões

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  1. Marco G. Alves
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  2. Ana D. Martins
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  3. Paula I. Moreira
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  5. Mário Sousa
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  9. Teresinha Simões
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  10. Pedro Fontes Oliveira
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Correspondence to Marco G. Alves or Pedro Fontes Oliveira.

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Alves, M.G., Martins, A.D., Moreira, P.I. et al. Metabolic fingerprints in testicular biopsies from type 1 diabetic patients. Cell Tissue Res 362, 431–440 (2015). https://doi.org/10.1007/s00441-015-2217-5

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