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Methylglyoxal treatment in lactating mothers leads to type 2 diabetes phenotype in male rat offspring at adulthood

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Abstract

Purpose

Environmental and nutritional disorders during perinatal period cause metabolic dysfunction in the progeny and impair human health. Advanced glycation end products (AGEs) are primarily produced during metabolism of excess blood glucose, which is observed in diabetes. Methylglyoxal (MG) is a precursor for the generation of endogenous AGEs, which disturbs the metabolism. This work aimed to investigate whether the maternal MG treatment during lactation programs the progeny to metabolic dysfunction later in life.

Methods

Female Wistar rats were divided into two groups: control group (C) treated with saline and MG group treated with MG (60 mg/kg/day) by gavage throughout the lactation period. Both mothers and offspring were fed a standard chow. At weaning, breast milk composition was analyzed and mothers euthanized for blood and tissue sample collections. At 90 days of age, offspring were submitted to glucose tolerance test (ivGTT) and euthanized for blood and tissue samples collection.

Results

MG mothers showed increase in glucose and fructosamine levels; however, they showed low insulin levels and failure in β-cell function (p < 0.05). MG mothers also showed dyslipidemia (p < 0.05). Moreover, breast milk had elevated levels of glucose, triglycerides, cholesterol and fructosamine and low insulin (p < 0.05). Interestingly, MG offspring had increased body weight and adipose tissue at adulthood, and they also showed glucose intolerance and failure in β-cell function (p < 0.05). Besides, MG offspring showed dyslipidemia (p < 0.05) increasing cardiovascular diseases risk.

Conclusions

Maternal MG treatment negatively affects the male rat offspring, leading to type 2 diabetes and dyslipidemia in later life, possibly by changes in breast milk composition.

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References

  1. Hales CN, Barker DJ (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35(7):595–601

    Article  CAS  Google Scholar 

  2. Barker CJ, Berggren PO (1999) Inositol hexakisphosphate and beta-cell stimulus-secretion coupling. Anticancer Res 19(5A):3737–3741

    CAS  Google Scholar 

  3. Lesage J, Sebaai N, Leonhardt M, Dutriez-Casteloot I, Breton C, Deloof S, Vieau D (2006) Perinatal maternal undernutrition programs the offspring hypothalamo-pituitary-adrenal (HPA) axis. Stress 9(4):183–198. doi:10.1080/10253890601056192

    Article  CAS  Google Scholar 

  4. Martins PA, Sawaya AL (2006) Evidence for impaired insulin production and higher sensitivity in stunted children living in slums. Br J Nutr 95(5):996–1001

    Article  CAS  Google Scholar 

  5. Vieau D, Sebaai N, Leonhardt M, Dutriez-Casteloot I, Molendi-Coste O, Laborie C, Breton C, Deloof S, Lesage J (2007) HPA axis programming by maternal undernutrition in the male rat offspring. Psychoneuroendocrinology 32(Suppl 1):S16–S20

    Article  CAS  Google Scholar 

  6. Moura AS, Carpinelli AR, Barbosa FB, Gravena C, Mathias PC (1996) Undernutrition during early lactation as an alternative model to study the onset of diabetes mellitus type II. Res Commun Mol Pathol Pharmacol 92(1):73–84

    CAS  Google Scholar 

  7. de Oliveira JC, Scomparin DX, Andreazzi AE, Branco RC, Martins AG, Gravena C, Grassiolli S, Rinaldi W, Barbosa FB, Mathias PC (2011) Metabolic imprinting by maternal protein malnourishment impairs vagal activity in adult rats. J Neuroendocrinol 23(2):148–157. doi:10.1111/j.1365-2826.2010.02095.x

    Article  Google Scholar 

  8. Li M, Sloboda DM, Vickers MH (2011) Maternal obesity and developmental programming of metabolic disorders in offspring: evidence from animal models. Exp Diabetes Res 2011:592408. doi:10.1155/2011/592408

    Article  CAS  Google Scholar 

  9. Lisboa PC, de Oliveira E, Manhaes AC, Santos-Silva AP, Pinheiro CR, Younes-Rapozo V, Faustino LC, Ortiga-Carvalho TM, Moura EG (2015) Effects of maternal nicotine exposure on thyroid hormone metabolism and function in adult rat progeny. J Endocrinol 224(3):315–325. doi:10.1530/JOE-14-0473

    Article  CAS  Google Scholar 

  10. Habener JF, Kemp DM, Thomas MK (2005) Minireview: transcriptional regulation in pancreatic development. Endocrinology 146(3):1025–1034. doi:10.1210/en.2004-1576

    Article  CAS  Google Scholar 

  11. Oben JA, Patel T, Mouralidarane A, Samuelsson AM, Matthews P, Pombo J, Morgan M, McKee C, Soeda J, Novelli M, Poston L, Taylor P (2010) Maternal obesity programmes offspring development of non-alcoholic fatty pancreas disease. Biochem Biophys Res Commun 394(1):24–28. doi:10.1016/j.bbrc.2010.02.057

    Article  CAS  Google Scholar 

  12. Melo AM, Benatti RO, Ignacio-Souza LM, Okino C, Torsoni AS, Milanski M, Velloso LA, Torsoni MA (2014) Hypothalamic endoplasmic reticulum stress and insulin resistance in offspring of mice dams fed high-fat diet during pregnancy and lactation. Metabolism 63(5):682–692. doi:10.1016/j.metabol.2014.02.002

    Article  CAS  Google Scholar 

  13. Chen H, Simar D, Lambert K, Mercier J, Morris MJ (2008) Maternal and postnatal overnutrition differentially impact appetite regulators and fuel metabolism. Endocrinology 149(11):5348–5356. doi:10.1210/en.2008-0582

    Article  CAS  Google Scholar 

  14. Goldberg T, Cai W, Peppa M, Dardaine V, Baliga BS, Uribarri J, Vlassara H (2004) Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc 104(8):1287–1291. doi:10.1016/j.jada.2004.05.214

    Article  CAS  Google Scholar 

  15. Vlassara H (2005) Advanced glycation in health and disease: role of the modern environment. Ann N Y Acad Sci 1043:452–460. doi:10.1196/annals.1333.051

    Article  CAS  Google Scholar 

  16. Clarke RE, Dordevic AL, Tan SM, Ryan L, Coughlan MT (2016) Dietary advanced glycation end products and risk factors for chronic disease: a systematic review of randomised controlled trials. Nutrients. doi:10.3390/nu8030125

    Google Scholar 

  17. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414(6865):813–820. doi:10.1038/414813a

    Article  CAS  Google Scholar 

  18. de Courten B, de Courten MP, Soldatos G, Dougherty SL, Straznicky N, Schlaich M, Sourris KC, Chand V, Scheijen JL, Kingwell BA, Cooper ME, Schalkwijk CG, Walker KZ, Forbes JM (2016) Diet low in advanced glycation end products increases insulin sensitivity in healthy overweight individuals: a double-blind, randomized, crossover trial. Am J Clin Nutr. doi:10.3945/ajcn.115.125427

    Google Scholar 

  19. Wells-Knecht KJ, Zyzak DV, Litchfield JE, Thorpe SR, Baynes JW (1995) Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose. Biochemistry 34(11):3702–3709

    Article  CAS  Google Scholar 

  20. Thornalley PJ (1990) The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life. Biochem J 269(1):1–11

    Article  CAS  Google Scholar 

  21. Degen J, Vogel M, Richter D, Hellwig M, Henle T (2013) Metabolic transit of dietary methylglyoxal. J Agric Food Chem 61(43):10253–10260. doi:10.1021/jf304946p

    Article  CAS  Google Scholar 

  22. Berlanga J, Cibrian D, Guillen I, Freyre F, Alba JS, Lopez-Saura P, Merino N, Aldama A, Quintela AM, Triana ME, Montequin JF, Ajamieh H, Urquiza D, Ahmed N, Thornalley PJ (2005) Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds. Clin Sci (Lond) 109(1):83–95. doi:10.1042/CS20050026

    Article  CAS  Google Scholar 

  23. Guarda DS, Lisboa PC, de Oliveira E, Nogueira-Neto JF, de Moura EG, Figueiredo MS (2014) Flaxseed oil during lactation changes milk and body composition in male and female suckling pups rats. Food Chem Toxicol 69C:69–75. doi:10.1016/j.fct.2014.04.003

    Article  Google Scholar 

  24. Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18(6):499–502

    CAS  Google Scholar 

  25. Fagundes AT, Moura EG, Passos MC, Santos-Silva AP, de Oliveira E, Trevenzoli IH, Casimiro-Lopes G, Nogueira-Neto JF, Lisboa PC (2009) Temporal evaluation of body composition, glucose homeostasis and lipid profile of male rats programmed by maternal protein restriction during lactation. Horm Metab Res 41(12):866–873. doi:10.1055/s-0029-1233457

    Article  CAS  Google Scholar 

  26. Nogales F, Ojeda ML, Del Valle PM, Serrano A, Murillo ML, Carreras Sanchez O (2015) Metabolic syndrome and selenium during gestation and lactation. Eur J Nutr. doi:10.1007/s00394-015-1129-1

    Google Scholar 

  27. Miranda RA, Agostinho AR, Trevenzoli IH, Barella LF, Franco CC, Trombini AB, Malta A, Gravena C, Torrezan R, Mathias PC, de Oliveira JC (2014) Insulin oversecretion in MSG-obese rats is related to alterations in cholinergic muscarinic receptor subtypes in pancreatic Islets. Cell Physiol Biochem 33(4):1075–1086. doi:10.1159/000358677

    Article  CAS  Google Scholar 

  28. Franco JG, Fernandes TP, Rocha CP, Calvino C, Pazos-Moura CC, Lisboa PC, Moura EG, Trevenzoli IH (2012) Maternal high-fat diet induces obesity and adrenal and thyroid dysfunction in male rat offspring at weaning. J Physiol 590(21):5503–5518. doi:10.1113/jphysiol.2012.240655

    Article  CAS  Google Scholar 

  29. Lima NS, de Moura EG, Passos MC, Nogueira Neto FJ, Reis AM, de Oliveira E, Lisboa PC (2011) Early weaning causes undernutrition for a short period and programmes some metabolic syndrome components and leptin resistance in adult rat offspring. Br J Nutr 105(9):1405–1413. doi:10.1017/S0007114510005064

    Article  CAS  Google Scholar 

  30. Meerwaldt R, Links T, Zeebregts C, Tio R, Hillebrands JL, Smit A (2008) The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes. Cardiovasc Diabetol 7:29. doi:10.1186/1475-2840-7-29

    Article  Google Scholar 

  31. DePerno CS, Chitwood MC, Kennedy-Stoskopf S, Jenks JA (2015) Fructosamine: an Alternative to Serum Glucose Measurement in White-tailed Deer (Odocoileus virginianus). J Wildl Dis 51(4):876–879. doi:10.7589/2014-07-182

    Article  CAS  Google Scholar 

  32. Vetter SW (2015) Glycated serum albumin and AGE receptors. Adv Clin Chem 72:205–275. doi:10.1016/bs.acc.2015.07.005

    Article  Google Scholar 

  33. Howie GJ, Sloboda DM, Kamal T, Vickers MH (2009) Maternal nutritional history predicts obesity in adult offspring independent of postnatal diet. J Physiol 587(4):905–915. doi:10.1113/jphysiol.2008.163477

    Article  CAS  Google Scholar 

  34. Younes-Rapozo V, de Moura EG, Lima ND, Barradas PC, Manhaes AC, de Oliveira E, Lisboa PC (2012) Early weaning is associated with higher neuropeptide Y (NPY) and lower cocaine- and amphetamine-regulated transcript (CART) expressions in the paraventricular nucleus (PVN) in adulthood. Br J Nutr 108(12):2286–2295. doi:10.1017/S0007114512000487

    Article  CAS  Google Scholar 

  35. Ikeda N, Shoji H, Murano Y, Mori M, Matsunaga N, Suganuma H, Ikeno M, Hisata K, Hirayama S, Ueno T, Miida T, Shimizu T (2014) Effects of breastfeeding on the risk factors for metabolic syndrome in preterm infants. J Dev Orig Health Dis 5(6):459–464. doi:10.1017/S2040174414000397

    Article  CAS  Google Scholar 

  36. Franco JG, Dias-Rocha CP, Fernandes TP, Albuquerque Maia L, Lisboa PC, Moura EG, Pazos-Moura CC, Trevenzoli IH (2015) Resveratrol treatment rescues hyperleptinemia and improves hypothalamic leptin signaling programmed by maternal high-fat diet in rats. Eur J Nutr. doi:10.1007/s00394-015-0880-7

    Google Scholar 

  37. Conceição EP, Trevenzoli IH, Oliveira E, Franco JG, Carlos AS, Nascimento-Saba CC, Moura EG, Lisboa PC (2011) Higher white adipocyte area and lower leptin production in adult rats overfed during lactation. Horm Metab Res 43(7):513–516. doi:10.1055/s-0031-1275702

    Article  Google Scholar 

  38. Coughlan MT, Yap FY, Tong DC, Andrikopoulos S, Gasser A, Thallas-Bonke V, Webster DE, Miyazaki J, Kay TW, Slattery RM, Kaye DM, Drew BG, Kingwell BA, Fourlanos S, Groop PH, Harrison LC, Knip M, Forbes JM (2011) Advanced glycation end products are direct modulators of beta-cell function. Diabetes 60(10):2523–2532. doi:10.2337/db10-1033

    Article  CAS  Google Scholar 

  39. Zhao Z, Zhao C, Zhang XH, Zheng F, Cai W, Vlassara H, Ma ZA (2009) Advanced glycation end products inhibit glucose-stimulated insulin secretion through nitric oxide-dependent inhibition of cytochrome c oxidase and adenosine triphosphate synthesis. Endocrinology 150(6):2569–2576. doi:10.1210/en.2008-1342

    Article  CAS  Google Scholar 

  40. Zhu Y, Shu T, Lin Y, Wang H, Yang J, Shi Y, Han X (2011) Inhibition of the receptor for advanced glycation endproducts (RAGE) protects pancreatic beta-cells. Biochem Biophys Res Commun 404(1):159–165. doi:10.1016/j.bbrc.2010.11.085

    Article  CAS  Google Scholar 

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Acknowledgments

This work was funded by the Brazilian Foundation: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento Pessoal de Nível Superior (CAPES), Paraná Science Foundation (Fundação Araucária).

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    Authors and Affiliations

    1. Department of Biotechnology, Genetics, and Cellular Biology, State University of Maringá, Maringá, PR, Brazil

      Flávio Andrade Francisco, Sandra da Silva Silveira, Lucas Paulo Jacinto Saavedra, Kelly Valério Prates, Vander Silva Alves, Claudinéia Conationi da Silva Franco, Tatiane Aparecida Ribeiro, Laize Peron Tófolo, Ananda Malta, Elaine Vieira, Kesia Palma-Rigo, Audrei Pavanello, Isabela Peixoto Martins, Veridiana Mota Moreira & Paulo Cezar de Freitas Mathias

    2. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

      Luiz Felipe Barella

    3. Carlos Chagas Filho Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

      Rosiane Aparecida Miranda

    4. Institute of Health Sciences, Federal University of Mato Grosso, Sinop, MT, Brazil

      Júlio Cezar de Oliveira

    5. Department of Physiological Sciences (DCiF) – Biological Science Institute II (ICB-II), Room 220, Federal University of Goiás (UFG) – Campus II, Esperança Avenue s/n, CEP 74690-900, Goiânia, GO, Brazil

      Rodrigo Mello Gomes

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    1. Flávio Andrade Francisco
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    Paulo Cezar de Freitas Mathias and Rodrigo Mello Gomes have contributed equally to this work.

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    Francisco, F.A., Barella, L.F., Silveira, S.d. et al. Methylglyoxal treatment in lactating mothers leads to type 2 diabetes phenotype in male rat offspring at adulthood. Eur J Nutr 57, 477–486 (2018). https://doi.org/10.1007/s00394-016-1330-x

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