Skip to main content

Advertisement

SpringerLink
Log in

Insulin resistance and glycine metabolism in humans

  • Review Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Plasma glycine level is low in patients with obesity or diabetes and the improvement of insulin resistance increases plasma glycine concentration. In prospective studies, hypoglycinemia at baseline predicts the risk of developing type 2 diabetes and higher serum glycine level is associated with decreased risk of incident type 2 diabetes. Consistently, plasma glycine concentration is lower in the lean offspring of parents with type 2 diabetes compared to healthy subjects. Among patients with type 2 diabetes, hypoglycinemia occurs before clinical manifestations of the disease, but the pathophysiological mechanisms underlying glycine deficit and its potential clinical repercussions are unclear. Glycine participates in several metabolic pathways, being required for relevant human physiological processes. Humans synthesize glycine from glyoxylate, glucose (via serine), betaine and likely from threonine and during the endogenous synthesis of L-carnitine. Glycine conjugates bile acids and other acyl moieties producing acyl-glycine derivatives. The glycine cleavage system catalyzes glycine degradation to carbon dioxide and ammonium while tetrahydrofolate is converted into 5,10-methylene-tetrahydrofolate. Glycine is utilized to synthesize serine, sarcosine, purines, creatine, heme group, glutathione, and collagen. Glycine is a major quantitative component of collagen. In addition, the role of glycine maintaining collagen structure is critical, as glycine residues are required to stabilize the triple helix of the collagen molecule. This quality of glycine likely contributes to explain the occurrence of medial arterial calcification and the elevated cardiovascular risk associated with diabetes and chronic kidney disease, as emerging evidence links normal collagen content with the initiation and progression of vascular calcification in humans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Adibi SA (1980) Roles of branched-chain amino acids in metabolic regulation. J Lab Clin Med 95(4):475–484

    CAS  PubMed  Google Scholar 

  • Ahmad MS, Alsaleh M, Kimhofer T, Ahmad S, Jamal W, Wali SO, Nicholson JK, Damanhouri ZA, Holmes E (2017) Metabolic phenotype of obesity in a saudi population. J Proteome Res 16(2):635–644. https://doi.org/10.1021/acs.jproteome.6b00710

    Article  CAS  PubMed  Google Scholar 

  • Anderson DD, Stover PJ (2009) SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis. PLoS ONE 4(6):e5839. https://doi.org/10.1371/journal.pone.0005839

    Article  PubMed  PubMed Central  Google Scholar 

  • Astner I, Schulze JO, van den Heuvel J, Jahn D, Schubert WD, Heinz DW (2005) Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans. EMBO J 24(18):3166–3177. https://doi.org/10.1038/sj.emboj.7600792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Augustin P, Hromic A, Pavkov-Keller T, Gruber K, Macheroux P (2016) Structure and biochemical properties of recombinant human dimethylglycine dehydrogenase and comparison to the disease-related H109R variant. FEBS J 283(19):3587–3603. https://doi.org/10.1111/febs.13828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Azize NA, Ngah WZ, Othman Z, Md Desa N, Chin CB, Md Yunus Z, Mohan A, Hean TS, Syed Zakaria SZ, Lock-Hock N (2014) Mutation analysis of glycine decarboxylase, aminomethyltransferase and glycine cleavage system protein-H genes in 13 unrelated families with glycine encephalopathy. J Hum Genet 59(11):593–597. https://doi.org/10.1038/jhg.2014.69

    Article  PubMed  Google Scholar 

  • Baek JY, Jun DY, Taub D, Kim YH (2003) Characterization of human phosphoserine aminotransferase involved in the phosphorylated pathway of l-serine biosynthesis. Biochem J 373(Pt 1):191–200. https://doi.org/10.1042/bj20030144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bar-joseph I, Pras E, Reznik-Wolf H, Marek-Yagel D, Abu-Horvitz A, Dushnitzky M, Goldstein N, Rienstein S, Dekel M, Pode-Shakked B, Zlotnik J, Benarrosh A, Gillery P, Hofliger N, Auray-Blais C, Garnotel R, Anikster Y (2012) Mutations in the sarcosine dehydrogenase gene in patients with sarcosinemia. Hum Genet 131(11):1805–1810. https://doi.org/10.1007/s00439-012-1207-x

    Article  CAS  PubMed  Google Scholar 

  • Beagle B, Yang TL, Hung J, Cogger EA, Moriarty DJ, Caudill MA (2005) The glycine N-methyltransferase (GNMT) 1289 C → T variant influences plasma total homocysteine concentrations in young women after restricting folate intake. J Nutr 135(12):2780–2785

    CAS  PubMed  Google Scholar 

  • Benarrosh A, Garnotel R, Henry A, Arndt C, Gillery P, Motte J, Bakchine S (2013) A young adult with sarcosinemia. No benefit from long duration treatment with memantine. JIMD Rep 9:93–96. https://doi.org/10.1007/8904_2012_185

    Article  CAS  PubMed  Google Scholar 

  • Bishop L, Kanoff R, Charnas L, Krenzel C, Berry SA, Schimmenti LA (2008) Severe methylenetetrahydrofolate reductase (MTHFR) deficiency: a case report of nonclassical homocystinuria. J Child Neurol 23(7):823–828. https://doi.org/10.1177/0883073808315410

    Article  PubMed  Google Scholar 

  • Boden G, Rezvani I, Owen OE (1984) Effects of glucagon on plasma amino acids. J Clin Invest 73(3):785–793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caudill MA, Dellschaft N, Solis C, Hinkis S, Ivanov AA, Nash-Barboza S, Randall KE, Jackson B, Solomita GN, Vermeylen F (2009) Choline intake, plasma riboflavin, and the phosphatidylethanolamine N-methyltransferase G5465A genotype predict plasma homocysteine in folate-deplete Mexican-American men with the methylenetetrahydrofolate reductase 677TT genotype. J Nutr 139(4):727–733. https://doi.org/10.3945/jn.108.100222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cellini B, Bertoldi M, Montioli R, Paiardini A, Borri Voltattorni C (2007) Human wild-type alanine:glyoxylate aminotransferase and its naturally occurring G82E variant: functional properties and physiological implications. Biochem J 408(1):39–50. https://doi.org/10.1042/bj20070637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen YM, Chen LY, Wong FH, Lee CM, Chang TJ, Yang-Feng TL (2000) Genomic structure, expression, and chromosomal localization of the human glycine N-methyltransferase gene. Genomics 66(1):43–47. https://doi.org/10.1006/geno.2000.6188

    Article  CAS  PubMed  Google Scholar 

  • Cho HM, Jun DY, Bae MA, Ahn JD, Kim YH (2000) Nucleotide sequence and differential expression of the human 3-phosphoglycerate dehydrogenase gene. Gene 245(1):193–201

    Article  CAS  PubMed  Google Scholar 

  • Collet JF, Gerin I, Rider MH, Veiga-da-Cunha M, Van Schaftingen E (1997) Human L-3-phosphoserine phosphatase: sequence, expression and evidence for a phosphoenzyme intermediate. FEBS Lett 408(3):281–284

    Article  CAS  PubMed  Google Scholar 

  • Dinescu A, Brown TR, Barelier S, Cundari TR, Anderson ME (2010) The role of the glycine triad in human glutathione synthetase. Biochem Biophys Res Commun 400(4):511–516. https://doi.org/10.1016/j.bbrc.2010.08.081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ding Y, Svingen GF, Pedersen ER, Gregory JF, Ueland PM, Tell GS, Nygard OK (2015) Plasma glycine and risk of acute myocardial infarction in patients with suspected stable angina pectoris. J Am Heart Assoc 5(1):e002621. https://doi.org/10.1161/jaha.115.002621

    Article  PubMed  PubMed Central  Google Scholar 

  • Ding Y, Pedersen ER, Svingen GF, Helgeland O, Gregory JF, Loland KH, Meyer K, Tell GS, Ueland PM, Nygard OK (2016) Methylenetetrahydrofolate dehydrogenase 1 polymorphisms modify the associations of plasma glycine and serine with risk of acute myocardial infarction in patients with stable angina pectoris in WENBIT (Western Norway B Vitamin intervention trial). Circ Cardiovasc Genet 9(6):541–547. https://doi.org/10.1161/circgenetics.116.001483

    Article  CAS  PubMed  Google Scholar 

  • Drabkova P, Sanderova J, Kovarik J, Kandar R (2015) An assay of selected serum amino acids in patients with type 2 diabetes mellitus. Adv Clin Exp Med 24(3):447–451. https://doi.org/10.17219/acem/29223

    Article  PubMed  Google Scholar 

  • Edgar AJ (2002) The human l-threonine 3-dehydrogenase gene is an expressed pseudogene. BMC Genet 3:18

    Article  PubMed  PubMed Central  Google Scholar 

  • Edgar AJ, Polak JM (2000) Molecular cloning of the human and murine 2-amino-3-ketobutyrate coenzyme A ligase cDNAs. Eur J Biochem 267(6):1805–1812

    Article  CAS  PubMed  Google Scholar 

  • Fan J, Ye J, Kamphorst JJ, Shlomi T, Thompson CB, Rabinowitz JD (2014) Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510(7504):298–302. https://doi.org/10.1038/nature13236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Felig P, Marliss E, Cahill GF Jr (1969) Plasma amino acid levels and insulin secretion in obesity. N Engl J Med 281(15):811–816. https://doi.org/10.1056/nejm196910092811503

    Article  CAS  PubMed  Google Scholar 

  • Felig P, Marliss E, Ohman JL, Cahill CF Jr (1970) Plasma amino acid levels in diabetic ketoacidosis. Diabetes 19(10):727–728

    Article  CAS  PubMed  Google Scholar 

  • Feng Q, Kalari K, Fridley BL, Jenkins G, Ji Y, Abo R, Hebbring S, Zhang J, Nye MD, Leeder JS, Weinshilboum RM (2011) Betaine-homocysteine methyltransferase: human liver genotype-phenotype correlation. Mol Genet Metab 102(2):126–133. https://doi.org/10.1016/j.ymgme.2010.10.010

    Article  CAS  PubMed  Google Scholar 

  • Fiehn O, Garvey WT, Newman JW, Lok KH, Hoppel CL, Adams SH (2010) Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and type 2 diabetic obese African-American women. PLoS ONE 5(12):e15234. https://doi.org/10.1371/journal.pone.0015234

    Article  PubMed  PubMed Central  Google Scholar 

  • Field MS, Kamynina E, Watkins D, Rosenblatt DS, Stover PJ (2015) Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis. Proc Natl Acad Sci USA 112(2):400–405. https://doi.org/10.1073/pnas.1414555112

    Article  CAS  PubMed  Google Scholar 

  • Floegel A, Stefan N, Yu Z, Muhlenbruch K, Drogan D, Joost HG, Fritsche A, Haring HU, Hrabe de Angelis M, Peters A, Roden M, Prehn C, Wang-Sattler R, Illig T, Schulze MB, Adamski J, Boeing H, Pischon T (2013) Identification of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomic approach. Diabetes 62(2):639–648. https://doi.org/10.2337/db12-0495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Furujo M, Kinoshita M, Nagao M, Kubo T (2012) Methionine adenosyltransferase I/III deficiency: neurological manifestations and relevance of S-adenosylmethionine. Mol Genet Metab 107(3):253–256. https://doi.org/10.1016/j.ymgme.2012.08.002

    Article  CAS  PubMed  Google Scholar 

  • Gall WE, Beebe K, Lawton KA, Adam KP, Mitchell MW, Nakhle PJ, Ryals JA, Milburn MV, Nannipieri M, Camastra S, Natali A, Ferrannini E, RISC Study Group (2010) alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS ONE 5(5):e10883. https://doi.org/10.1371/journal.pone.0010883

    Article  PubMed  PubMed Central  Google Scholar 

  • Garrow TA, Brenner AA, Whitehead VM, Chen XN, Duncan RG, Korenberg JR, Shane B (1993) Cloning of human cDNAs encoding mitochondrial and cytosolic serine hydroxymethyltransferases and chromosomal localization. J Biol Chem 268(16):11910–11916

    CAS  PubMed  Google Scholar 

  • Glynn EL, Piner LW, Huffman KM, Slentz CA, Elliot-Penry L, AbouAssi H, White PJ, Bain JR, Muehlbauer MJ, Ilkayeva OR, Stevens RD, Porter Starr KN, Bales CW, Volpi E, Brosnan MJ, Trimmer JK, Rolph TP, Newgard CB, Kraus WE (2015) Impact of combined resistance and aerobic exercise training on branched-chain amino acid turnover, glycine metabolism and insulin sensitivity in overweight humans. Diabetologia 58(10):2324–2335. https://doi.org/10.1007/s00125-015-3705-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gregersen N, Kolvraa S, Mortensen PB (1986) Acyl-CoA: glycine N-acyltransferase: in vitro studies on the glycine conjugation of straight- and branched-chained acyl-CoA esters in human liver. Biochem Med Metab Biol 35(2):210–218

    Article  CAS  PubMed  Google Scholar 

  • Hart CE, Race V, Achouri Y, Wiame E, Sharrard M, Olpin SE, Watkinson J, Bonham JR, Jaeken J, Matthijs G, Van Schaftingen E (2007) Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. Am J Hum Genet 80(5):931–937. https://doi.org/10.1086/517888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hausler MG, Jaeken J, Monch E, Ramaekers VT (2001) Phenotypic heterogeneity and adverse effects of serine treatment in 3-phosphoglycerate dehydrogenase deficiency: report on two siblings. Neuropediatrics 32(4):191–195. https://doi.org/10.1055/s-2001-17373

    Article  CAS  PubMed  Google Scholar 

  • Hobert JA, Liu A, Pasquali M (2016) Analysis by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Curr Protoc Hum Genet 91:17.25.1–17.25.12. https://doi.org/10.1002/cphg.19

    Article  Google Scholar 

  • Hol FA, van der Put NM, Geurds MP, Heil SG, Trijbels FJ, Hamel BC, Mariman EC, Blom HJ (1998) Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects. Clin Genet 53(2):119–125

    Article  CAS  PubMed  Google Scholar 

  • Holme E, Kjellman B, Ronge E (1989) Betaine for treatment of homocystinuria caused by methylenetetrahydrofolate reductase deficiency. Arch Dis Child 64(7):1061–1064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Humm A, Fritsche E, Steinbacher S, Huber R (1997) Crystal structure and mechanism of human l-arginine:glycine amidinotransferase: a mitochondrial enzyme involved in creatine biosynthesis. EMBO J 16(12):3373–3385. https://doi.org/10.1093/emboj/16.12.3373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hutcheson JD, Goettsch C, Bertazzo S, Maldonado N, Ruiz JL, Goh W, Yabusaki K, Faits T, Bouten C, Franck G, Quillard T, Libby P, Aikawa M, Weinbaum S, Aikawa E (2016) Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nat Mater 15(3):335–343. https://doi.org/10.1038/nmat4519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Irving BA, Carter RE, Soop M, Weymiller A, Syed H, Karakelides H, Bhagra S, Short KR, Tatpati L, Barazzoni R, Nair KS (2015) Effect of insulin sensitizer therapy on amino acids and their metabolites. Metabolism 64(6):720–728. https://doi.org/10.1016/j.metabol.2015.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Item CB, Stockler-Ipsiroglu S, Stromberger C, Muhl A, Alessandri MG, Bianchi MC, Tosetti M, Fornai F, Cioni G (2001) Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet 69(5):1127–1133. https://doi.org/10.1086/323765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaeken J, Detheux M, Van Maldergem L, Foulon M, Carchon H, Van Schaftingen E (1996) 3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis. Arch Dis Child 74(6):542–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaeken J, Detheux M, Fryns JP, Collet JF, Alliet P, Van Schaftingen E (1997) Phosphoserine phosphatase deficiency in a patient with Williams syndrome. J Med Genet 34(7):594–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson MR, Barnes S, Kwakye JB, Diasio RB (1991) Purification and characterization of bile acid-CoA:amino acid N-acyltransferase from human liver. J Biol Chem 266(16):10227–10233

    CAS  PubMed  Google Scholar 

  • Kim HY, Heo YS, Kim JH, Park MH, Moon J, Kim E, Kwon D, Yoon J, Shin D, Jeong EJ, Park SY, Lee TG, Jeon YH, Ro S, Cho JM, Hwang KY (2002) Molecular basis for the local conformational rearrangement of human phosphoserine phosphatase. J Biol Chem 277(48):46651–46658. https://doi.org/10.1074/jbc.M204866200

    Article  CAS  PubMed  Google Scholar 

  • Knowles L, Morris AA, Walter JH (2016) Treatment with mefolinate (5-methyltetrahydrofolate), but not folic acid or folinic acid, leads to measurable 5-methyltetrahydrofolate in cerebrospinal fluid in methylenetetrahydrofolate reductase deficiency. JIMD Rep 29:103–107. https://doi.org/10.1007/8904_2016_529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lamers Y, Williamson J, Gilbert LR, Stacpoole PW, Gregory JF 3rd (2007) Glycine turnover and decarboxylation rate quantified in healthy men and women using primed, constant infusions of [1,2-(13)C2]glycine and [(2)H3]leucine. J Nutr 137(12):2647–2652

    CAS  PubMed  Google Scholar 

  • Lamers Y, Williamson J, Ralat M, Quinlivan EP, Gilbert LR, Keeling C, Stevens RD, Newgard CB, Ueland PM, Meyer K, Fredriksen A, Stacpoole PW, Gregory JF 3rd (2009) Moderate dietary vitamin B-6 restriction raises plasma glycine and cystathionine concentrations while minimally affecting the rates of glycine turnover and glycine cleavage in healthy men and women. J Nutr 139(3):452–460. https://doi.org/10.3945/jn.108.099184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee TD, Yang H, Whang J, Lu SC (2005) Cloning and characterization of the human glutathione synthetase 5′-flanking region. Biochem J 390(2):521–528. https://doi.org/10.1042/bj20050439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lennerz BS, Vafai SB, Delaney NF, Clish CB, Deik AA, Pierce KA, Ludwig DS, Mootha VK (2015) Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans. Mol Genet Metab 114(1):73–79. https://doi.org/10.1016/j.ymgme.2014.11.010

    Article  CAS  PubMed  Google Scholar 

  • Lim U, Peng K, Shane B, Stover PJ, Litonjua AA, Weiss ST, Gaziano JM, Strawderman RL, Raiszadeh F, Selhub J, Tucker KL, Cassano PA (2005) Polymorphisms in cytoplasmic serine hydroxymethyltransferase and methylenetetrahydrofolate reductase affect the risk of cardiovascular disease in men. J Nutr 135(8):1989–1994

    CAS  PubMed  Google Scholar 

  • Luka Z, Pakhomova S, Luka Y, Newcomer ME, Wagner C (2007) Destabilization of human glycine N-methyltransferase by H176 N mutation. Protein Sci 16(9):1957–1964. https://doi.org/10.1110/ps.072921507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luka Z, Mudd SH, Wagner C (2009) Glycine N-methyltransferase and regulation of S-adenosylmethionine levels. J Biol Chem 284(34):22507–22511. https://doi.org/10.1074/jbc.R109.019273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Magnusson M, Wang TJ, Clish C, Engstrom G, Nilsson P, Gerszten RE, Melander O (2015) Dimethylglycine deficiency and the development of diabetes. Diabetes 64(8):3010–3016. https://doi.org/10.2337/db14-1863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuo M, Terai K, Kameda N, Matsumoto A, Kurokawa Y, Funase Y, Nishikawa K, Sugaya N, Hiruta N, Kishimoto T (2012) Designation of enzyme activity of glycine-N-acyltransferase family genes and depression of glycine-N-acyltransferase in human hepatocellular carcinoma. Biochem Biophys Res Commun 420(4):901–906. https://doi.org/10.1016/j.bbrc.2012.03.099

    Article  CAS  PubMed  Google Scholar 

  • Moolenaar SH, Poggi-Bach J, Engelke UF, Corstiaensen JM, Heerschap A, de Jong JG, Binzak BA, Vockley J, Wevers RA (1999) Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: NMR spectroscopy study. Clin Chem 45(4):459–464

    CAS  PubMed  Google Scholar 

  • Moro-Furlani AM, Turner VS, Hopkinson DA (1980) Genetical and biochemical studies on human phosphoserine phosphatase. Ann Hum Genet 43(4):323–333

    Article  CAS  PubMed  Google Scholar 

  • Njalsson R, Carlsson K, Bhansali V, Luo JL, Nilsson L, Ladenstein R, Anderson M, Larsson A, Norgren S (2004) Human hereditary glutathione synthetase deficiency: kinetic properties of mutant enzymes. Biochem J 381(Pt 2):489–494. https://doi.org/10.1042/bj20040114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Byrne J, Hunt MC, Rai DK, Saeki M, Alexson SE (2003) The human bile acid-CoA:amino acid N-acyltransferase functions in the conjugation of fatty acids to glycine. J Biol Chem 278(36):34237–34244. https://doi.org/10.1074/jbc.M300987200

    Article  PubMed  Google Scholar 

  • Okamura-Ikeda K, Hosaka H, Yoshimura M, Yamashita E, Toma S, Nakagawa A, Fujiwara K, Motokawa Y, Taniguchi H (2005) Crystal structure of human T-protein of glycine cleavage system at 2.0 a resolution and its implication for understanding non-ketotic hyperglycinemia. J Mol Biol 351(5):1146–1159. https://doi.org/10.1016/j.jmb.2005.06.056

    Article  CAS  PubMed  Google Scholar 

  • Oppici E, Fargue S, Reid ES, Mills PB, Clayton PT, Danpure CJ, Cellini B (2015) Pyridoxamine and pyridoxal are more effective than pyridoxine in rescuing folding-defective variants of human alanine:glyoxylate aminotransferase causing primary hyperoxaluria type I. Hum Mol Genet 24(19):5500–5511. https://doi.org/10.1093/hmg/ddv276

    Article  CAS  PubMed  Google Scholar 

  • Owen EE, Robinson RR (1963) Amino acid extraction and ammonia metabolism by the human kidney during the prolonged administration of ammonium chloride. J Clin Invest 42:263–276. https://doi.org/10.1172/JCI104713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palmer ND, Stevens RD, Antinozzi PA, Anderson A, Bergman RN, Wagenknecht LE, Newgard CB, Bowden DW (2015) Metabolomic profile associated with insulin resistance and conversion to diabetes in the Insulin Resistance Atherosclerosis study. J Clin Endocrinol Metab 100(3):E463–E468. https://doi.org/10.1210/jc.2014-2357

    Article  CAS  PubMed  Google Scholar 

  • Patel DK, Ogunbona A, Notarianni LJ, Bennett PN (1990) Depletion of plasma glycine and effect of glycine by mouth on salicylate metabolism during aspirin overdose. Hum Exp Toxicol 9(6):389–395. https://doi.org/10.1177/096032719000900606

    Article  CAS  PubMed  Google Scholar 

  • Pelletier JN, MacKenzie RE (1994) Binding of the 2′,5′-ADP subsite stimulates cyclohydrolase activity of human NADP(+)-dependent methylenetetrahydrofolate dehydrogenase/cyclohydrolase. Biochemistry 33(7):1900–1906

    Article  CAS  PubMed  Google Scholar 

  • Perseghin G, Ghosh S, Gerow K, Shulman GI (1997) Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study. Diabetes 46(6):1001–1009

    Article  CAS  PubMed  Google Scholar 

  • Rebouche CJ, Engel AG (1980) Tissue distribution of carnitine biosynthetic enzymes in man. Biochim Biophys Acta 630(1):22–29

    Article  CAS  PubMed  Google Scholar 

  • Renwick SB, Snell K, Baumann U (1998) The crystal structure of human cytosolic serine hydroxymethyltransferase: a target for cancer chemotherapy. Structure 6(9):1105–1116

    Article  CAS  PubMed  Google Scholar 

  • Rinaldo P, Schmidt-Sommerfeld E, Posca AP, Heales SJ, Woolf DA, Leonard JV (1993) Effect of treatment with glycine and L-carnitine in medium-chain acyl-coenzyme a dehydrogenase deficiency. J Pediatr 122(4):580–584

    Article  CAS  PubMed  Google Scholar 

  • Sekhar RV, McKay SV, Patel SG, Guthikonda AP, Reddy VT, Balasubramanyam A, Jahoor F (2011) Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine. Diabetes Care 34(1):162–167. https://doi.org/10.2337/dc10-1006

    Article  CAS  PubMed  Google Scholar 

  • Shaham O, Wei R, Wang TJ, Ricciardi C, Lewis GD, Vasan RS, Carr SA, Thadhani R, Gerszten RE, Mootha VK (2008) Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity. Mol Syst Biol 4:214. https://doi.org/10.1038/msb.2008.50

    Article  PubMed  PubMed Central  Google Scholar 

  • Shekhonin BV, Domogatsky SP, Muzykantov VR, Idelson GL, Rukosuev VS (1985) Distribution of type I, III, IV and V collagen in normal and atherosclerotic human arterial wall: immunomorphological characteristics. Coll Relat Res 5(4):355–368

    Article  CAS  PubMed  Google Scholar 

  • Shoolingin-Jordan PM, Al-Daihan S, Alexeev D, Baxter RL, Bottomley SS, Kahari ID, Roy I, Sarwar M, Sawyer L, Wang SF (2003) 5-Aminolevulinic acid synthase: mechanism, mutations and medicine. Biochim Biophys Acta 1647(1–2):361–366

    Article  CAS  PubMed  Google Scholar 

  • Simon E, Vogel M, Fingerhut R, Ristoff E, Mayatepek E, Spiekerkotter U (2009) Diagnosis of glutathione synthetase deficiency in newborn screening. J Inherit Metab Dis 32(Suppl 1):S269–S272. https://doi.org/10.1007/s10545-009-1213-x

    Article  PubMed  Google Scholar 

  • Stockler-Ipsiroglu S, van Karnebeek C, Longo N, Korenke GC, Mercimek-Mahmutoglu S, Marquart I, Barshop B, Grolik C, Schlune A, Angle B, Araujo HC, Coskun T, Diogo L, Geraghty M, Haliloglu G, Konstantopoulou V, Leuzzi V, Levtova A, Mackenzie J, Maranda B, Mhanni AA, Mitchell G, Morris A, Newlove T, Renaud D, Scaglia F, Valayannopoulos V, van Spronsen FJ, Verbruggen KT, Yuskiv N, Nyhan W, Schulze A (2014) Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab 111(1):16–25. https://doi.org/10.1016/j.ymgme.2013.10.018

    Article  CAS  PubMed  Google Scholar 

  • Stockler-Ipsiroglu S, Apatean D, Battini R, DeBrosse S, Dessoffy K, Edvardson S, Eichler F, Johnston K, Koeller DM, Nouioua S, Tazir M, Verma A, Dowling MD, Wierenga KJ, Wierenga AM, Zhang V, Wong LJ (2015) Arginine:glycine amidinotransferase (AGAT) deficiency: clinical features and long term outcomes in 16 patients diagnosed worldwide. Mol Genet Metab 116(4):252–259. https://doi.org/10.1016/j.ymgme.2015.10.003

    Article  CAS  PubMed  Google Scholar 

  • Stover PJ, Chen LH, Suh JR, Stover DM, Keyomarsi K, Shane B (1997) Molecular cloning, characterization, and regulation of the human mitochondrial serine hydroxymethyltransferase gene. J Biol Chem 272(3):1842–1848

    Article  CAS  PubMed  Google Scholar 

  • Swanson MA, Coughlin CR Jr, Scharer GH, Szerlong HJ, Bjoraker KJ, Spector EB, Creadon-Swindell G, Mahieu V, Matthijs G, Hennermann JB, Applegarth DA, Toone JR, Tong S, Williams K, Van Hove JL (2015) Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia. Ann Neurol 78(4):606–618. https://doi.org/10.1002/ana.24485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takashina C, Tsujino I, Watanabe T, Sakaue S, Ikeda D, Yamada A, Sato T, Ohira H, Otsuka Y, Oyama-Manabe N, Ito YM, Nishimura M (2016) Associations among the plasma amino acid profile, obesity, and glucose metabolism in Japanese adults with normal glucose tolerance. Nutr Metab (Lond) 13:5. https://doi.org/10.1186/s12986-015-0059-5

    Article  Google Scholar 

  • Thalacker-Mercer AE, Ingram KH, Guo F, Ilkayeva O, Newgard CB, Garvey WT (2014) BMI, RQ, diabetes and sex affect the relationships between amino acids and clamp measures of insulin action in humans. Diabetes 63(2):791–800. https://doi.org/10.2337/db13-0396

    Article  PubMed  PubMed Central  Google Scholar 

  • Uchida M, Sugaya M, Kanamaru T, Hisatomi H (2010) Alternative RNA splicing in expression of the glutathione synthetase gene in human cells. Mol Biol Rep 37(4):2105–2109. https://doi.org/10.1007/s11033-009-9675-3

    Article  CAS  PubMed  Google Scholar 

  • Vanek V, Budesinsky M, Kabeleova P, Sanda M, Kozisek M, Hanclova I, Mladkova J, Brynda J, Rosenberg I, Koutmos M, Garrow TA, Jiracek J (2009) Structure-activity study of new inhibitors of human betaine-homocysteine S-methyltransferase. J Med Chem 52(12):3652–3665. https://doi.org/10.1021/jm8015798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wahren J, Felig P, Cerasi E, Luft R (1972) Splanchnic and peripheral glucose and amino acid metabolism in diabetes mellitus. J Clin Invest 51(7):1870–1878. https://doi.org/10.1172/jci106989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walford GA, Ma Y, Clish C, Florez JC, Wang TJ, Gerszten RE (2016) Metabolite profiles of diabetes incidence and intervention response in the diabetes prevention program. Diabetes 65(5):1424–1433. https://doi.org/10.2337/db15-1063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waluk DP, Schultz N, Hunt MC (2010) Identification of glycine N-acyltransferase-like 2 (GLYATL2) as a transferase that produces N-acyl glycines in humans. Faseb J 24(8):2795–2803. https://doi.org/10.1096/fj.09-148551

    Article  CAS  PubMed  Google Scholar 

  • Waluk DP, Sucharski F, Sipos L, Silberring J, Hunt MC (2012) Reversible lysine acetylation regulates activity of human glycine N-acyltransferase-like 2 (hGLYATL2): implications for production of glycine-conjugated signaling molecules. J Biol Chem 287(20):16158–16167. https://doi.org/10.1074/jbc.M112.347260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Q, Lu K, Du H, Zhang Q, Chen T, Shu Y, Hua Y, Zhu L (2014) Association between cytosolic serine hydroxymethyltransferase (SHMT1) gene polymorphism and cancer risk: a meta-analysis. Biomed Pharmacother 68(6):757–762. https://doi.org/10.1016/j.biopha.2014.08.002

    Article  CAS  PubMed  Google Scholar 

  • Wang-Sattler R, Yu Z, Herder C, Messias AC, Floegel A, He Y, Heim K, Campillos M, Holzapfel C, Thorand B, Grallert H, Xu T, Bader E, Huth C, Mittelstrass K, Doring A, Meisinger C, Gieger C, Prehn C, Roemisch-Margl W, Carstensen M, Xie L, Yamanaka-Okumura H, Xing G, Ceglarek U, Thiery J, Giani G, Lickert H, Lin X, Li Y, Boeing H, Joost HG, de Angelis MH, Rathmann W, Suhre K, Prokisch H, Peters A, Meitinger T, Roden M, Wichmann HE, Pischon T, Adamski J, Illig T (2012) Novel biomarkers for pre-diabetes identified by metabolomics. Mol Syst Biol 8:615. https://doi.org/10.1038/msb.2012.43

    Article  PubMed  PubMed Central  Google Scholar 

  • Xie W, Wood AR, Lyssenko V, Weedon MN, Knowles JW, Alkayyali S, Assimes TL, Quertermous T, Abbasi F, Paananen J, Häring H, Hansen T, Pedersen O, Smith U, Laakso M, Dekker JM, Nolan JJ, Groop L, Ferrannini E, Adam KP, Gall WE, Frayling TM, Walker M, MAGIC Investigators, DIAGRAM Consortium, GENESIS Consortium, and RISC Consortium (2013) Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes. Diabetes 62(6):2141–2150. https://doi.org/10.2337/db12-0876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan-Do R, Duong E, Manning Fox JE, Dai X, Suzuki K, Khan S, Bautista A, Ferdaoussi M, Lyon J, Wu X, Cheley S, MacDonald PE, Braun M (2016) A glycine-insulin autocrine feedback loop enhances insulin secretion from human β-cells and is impaired in type 2 diabetes.”. Diabetes 65(8):2311–2321

    Article  CAS  PubMed  Google Scholar 

  • Zhao H, Shen J, Djukovic D, Daniel-MacDougall C, Gu H, Wu X, Chow WH (2016) Metabolomics-identified metabolites associated with body mass index and prospective weight gain among Mexican American women. Obes Sci Pract 2(3):309–317. https://doi.org/10.1002/osp4.63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhong SL, Zhang J, Hu Q, Chen WX, Ma TF, Zhao JH (2014) C1420T polymorphism of cytosolic serine hydroxymethyltransferase and risk of cancer: a meta-analysis. Asian Pac J Cancer Prev 15(5):2257–2262

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Internal Medicine Department, Hospital General Juan Cardona, c/Pardo Bazán s/n, 15406, Ferrol, Spain

    M. Adeva-Andany, E. Ameneiros-Rodríguez, C. Fernández-Fernández, C. Donapetry-García & A. Domínguez-Montero

  2. National Institutes of Health, National Institute of Arthritis and Metabolic Diseases, Bethesda, USA

    G. Souto-Adeva

Authors
  1. M. Adeva-Andany
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Souto-Adeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Ameneiros-Rodríguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Fernández-Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Donapetry-García
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Domínguez-Montero
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Adeva-Andany.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

There was no financial support for this work.

Additional information

Handling Editor: J. D. Wade.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Adeva-Andany, M., Souto-Adeva, G., Ameneiros-Rodríguez, E. et al. Insulin resistance and glycine metabolism in humans. Amino Acids 50, 11–27 (2018). https://doi.org/10.1007/s00726-017-2508-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-017-2508-0

Keywords

Search

Navigation